Archives of Oral Biology 140 (2022) 105454

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Archives of Oral Biology

journal homepage: www.elsevier.com/locate/archoralbio

Molecular biology exploration and targeted therapy strategy

of Ameloblastoma
Yiwen Lu , Xudong Zhang *, Xiangjun Li
Department of Oral & Maxillofacial Surgery, College and Hospital of Stomatology, Hebei Medical University, The Key Laboratory of Stomatology, Hebei Province, China

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: This article aims to systematically and comprehensively discuss molecular biology-related progress and
Ameloblastoma targeted therapeutic strategies for ameloblastoma, which are expected to be helpful for the diagnosis and
Gene mutation treatment of ameloblastoma.
Molecular biology
Design: A comprehensive review of scientific literature relevant to ameloblastoma, including the latest classifi­
Targeted therapy
Non-coding RNA
cation, global epidemiology, molecular biology advances, and targeted therapy.
Results: Among the 156 articles cited, a total of 20 non-coding RNAs, 13 genes, 27 proteins, and 8 pathways were
involved, which play a variety of roles in ameloblastoma. These roles include participation in the biological
behaviours of ameloblastoma migration, differentiation, and apoptosis; detection of ameloblastoma proliferative
properties; detection of ameloblastoma angiogenesis; and identification of ameloblastoma carcinogenesis.
Conclusions: At present, some progress has been made in molecular biology and targeted therapy for amelo­
blastoma involving BRAF and SMO genes. The related non-coding RNAs, genes, proteins, and pathways involved
in this review provide new ideas and directions for the occurrence and development of ameloblastoma and have
the potential to become new gene therapy targets.

1. Introduction ameloblastoma. The classification merges the solid/polycystic and des­

Ameloblastoma (AM) is the most common odontogenic epithelial
tumour. This often results in an enlarged jaw and facial deformities.
Although it is a benign tumour, it has aggressive local growth and a high
recurrence rate after surgery. It can also become malignant or meta­
stasise to distant sites. Many risk factors contribute to the development
of ameloblastoma, such as chronic inflammation, exposure to various
chemicals, human papillomavirus infections, malnutrition, protein or
mineral deficiencies, poor dental health, and individual genetic poly­
morphisms (Effiom et al., 2018). A categorisation of ameloblastoma in
2017 included conventional ameloblastoma, unicystic ameloblastoma,
extraosseous/peripheral ameloblastoma, and metastasising (malignant)
moplastic types into conventional ameloblastomas. Unicystic amelo­
blastomas include intraluminal, luminal, and mural variants (Wright
and Vered, 2017). In 2022, the World Health Organization updated the
classification of ameloblastoma to include adenoid ameloblastoma,
which is a newly-discovered form. Basic histopathological features of
this novel ameloblastoma include ameloblastoma-like components,
tubular structures, cribriform structures, and helical cell aggregates,
with or without dentin-like structures (Vered & Wright, 2022).
2. Epidemiological and clinical features
An analysis of the global incidence and profiles of patients with

Abbreviations: Akt, protein kinase B; AMFR, autocrine motility factor receptor; APC, adenomatous polyposis coli; ARL4C, ADP-ribosylation factor-like 4c; Bcl-2, B-
cell lymphoma-2; BRAF, B-Raf proto-oncogene, serine/threonine kinase; E-cadherin, epithelial cell cadherin; GLI, glioma-associated oncogene; HIF-1α, hypoxia-
inducible factor-1α; MAPK, the mitogen-activated protein kinase; MDM2, mouse double minute 2 homologue; miRNAs, microRNAs; MMP, matrix metalloproteinase;
PCNA, proliferating cell nuclear antigen; PD-L1, programmed death ligand 1; PTCH, protein patched homologue; PTEN, phosphatase and tensin homologue; RAS, rat
sarcoma; Rb, retinoblastoma gene; RBPJ, Recombination Signal Binding Protein For Immunoglobulin Kappa J Region; RECK, reversion-inducing cysteine-rich protein
with Kazal motifs; SHH, sonic hedgehog; SMO, smoothened, frizzled class receptor; VEGF, vascular endothelial growth factor; WT1, Wilms’ tumour gene 1; XIAP, X-
chromosome-linked inhibitor of apoptosis protein; XRCC1, X-ray repair cross-complementing gene 1.
* Correspondence to: Department of Oral & Maxillofacial Surgery, College and Hospital of Stomatology, Hebei Medical University, 383 East Zhongshan Road,
Shijiazhuang, Hebei Province 050017, China.
E-mail address: zxdcrx@163.com (X. Zhang).

https://doi.org/10.1016/j.archoralbio.2022.105454
Received 31 January 2022; Received in revised form 9 May 2022; Accepted 10 May 2022
Available online 13 May 2022
0003-9969/© 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Y. Lu et al.
ameloblastoma in 2020 suggested that the mixed incidence of amelo­
blastoma was 0.92/1 million persons per year. There were no significant
sex differences in ameloblastomas. The incidence of ameloblastoma
worldwide is mainly distributed around the age of 30 years old. In
Europe and North America, ameloblastomas mostly occur in the elderly
(50–60 years old); in Africa and South America, ameloblastomas mostly
occur in younger individuals (around 30 years old), with the highest
incidence in Asia (30–60 years old) (Hendra et al., 2020). The differ­
ences in the age distribution of the incidence rates may be due to dif­
ferences in socioeconomic levels. In developing countries, the incidence
of ameloblastoma tends to be in younger patients, possibly due to
insufficient access to nutrition and healthcare (Hendra et al., 2020;
Reichart et al., 1995). Ethnicity has not been found to affect the age
distribution of ameloblastomas. Mandibular tumours outnumbered
those of the maxilla and other sites, with 87.2% of ameloblastomas
occurring in the mandible, 8.5% in the maxilla, and less frequently in the
surrounding area and soft tissue (extraosseous) lesions. These sites
include the gingiva, alveolar process, nodular soft tissue, buccal and
mandibular vestibules, posterior molar pad, and edentulous area. Con­
ventional ameloblastomas are the most common type, followed by the
unicystic type. Scholars also found that follicular and plexiform are the
two most common histopathological variants. In Africa, the most com­
mon histopathological variant is mixed, followed by follicular variants.
There have been no reports of this in Australia (Hendra et al., 2020).
3. Molecular biological progress of ameloblastoma
3.1. Related genes in ameloblastoma
3.1.1. Oncogenes
3.1.1.1. BRAF gene and SMO gene. The B-Raf proto-oncogene, serine/
threonine kinase (BRAF) gene, also known as mouse sarcoma virus
carcinogen homologue, is one of the most important human proto-
oncogenes and a considerable transduction factor in the mitogen-
activated protein kinase (MAPK) pathway. It is involved in the regula­
tion of biological events, such as cell proliferation, differentiation, and
apoptosis. Various studies have confirmed that BRAF is the most
frequently mutated gene in ameloblastomas. BRAF V600E had the
highest mutation rate (63%), which was attributed to the substitution of
valine with glutamate (Brown et al., 2014; Kurppa et al., 2014; Sweeney
et al., 2014). The protein encoded by the smoothened (SMO) gene is a
vital information converter in the sonic hedgehog (SHH) signalling
pathway, which activates the SHH signalling pathway (Sweeney et al.,
2014). The SHH signalling pathway in SMO genes is aberrantly
expressed in tooth development, as well as in odontogenic cysts and
tumour epithelial components.
Kurppa et al. found that the BRAF V600E mutation was not directly
related to patient age, sex, tumour tissue type, or tumour recurrence
(Kurppa et al., 2014). Sweeney et al. found BRAF and SMO gene mu­
tations in ameloblastoma, in which SMO mutations mostly occur in the
maxilla, while BRAF mutations occur in the mandible. The mutation
sites of SMO are L412F and T535L. Interestingly, studies have found that
SMO mutations frequently co-occur with rat sarcoma (RAS) and fibro­
blast growth factor receptor 2 (FGFR2) gene mutations in the MAPK
pathway, whereas SMO and BRAF mutations may be mutually exclusive
(Sweeney et al., 2014). In the same year, Brown et al. used statistical
analysis to conjecture that BRAF V600E mutations were more likely to
occur in young adults and that SMO mutations were not obviously
associated with histology. In ameloblastomas, RAS and fibroblast
growth factor receptor 2 gene mutations have been found in 28%
(Brown et al., 2014). Similar results were also seen in the study by
Gültekin et al., who observed that mutations in the BRAF gene occurred
almost exclusively in the mandible, whereas mutations in the SMO gene
occurred mainly in the maxilla. Additionally, mutations in the epidermal
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Archives of Oral Biology 140 (2022) 105454
growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene ho­
mologue (KRAS), and neuroblastoma rat sarcoma viral oncogene ho­
mologue (NRAS) genes are also present in ameloblastomas. Patients
with BRAF mutations were younger (average age of 42 years); never­
theless, patients with SMO were mostly older (mean age, 67 years). The
risk of tumour recurrence is lower with single BRAF mutations than with
multiple mutations (Gültekin et al., 2018). Diniz et al. suggested that the
BRAF V600E mutation is independent of tissue type and location. They
also demonstrated that the SMO mutation may only be a secondary
mutation of BRAF and cannot be a marker for maxillary ameloblastoma,
and no SMO L412F mutation was found (Diniz et al., 2015). Zhang
experimental results also confirmed this point of view, and there was no
statistically significant difference in the incidence of the upper and
lower jaws. Sequencing of 30 ameloblastoma specimens revealed no
mutations in L412F or T535L of SMO. Unlike previous research results,
he found that SMO mutations mostly occur in young adults, and the SMO
gene mutation is unrelated to the patient’s sex, location, histological
type, and tumour recurrence, but is closely related to age, active pro­
liferation, and capsule invasion (Zhang, 2016). To explore the rela­
tionship between BRAF V600E expression and ameloblastoma
aggressiveness, Fregnani et al. used tissue microarray and immunohis­
tochemistry methods. They found that BRAF V600E expression was
visibly correlated with cytokeratin-8, cytokeratin-16, parathyroid
hormone-related protein, and p53 expression, suggesting that it is
associated with more aggressive behavioural parameters in amelo­
blastoma (Fregnani et al., 2017).
The relationship between the clinicopathological features of amelo­
blastoma and the BRAF V600E mutation appears to have been addressed
in do Canto’s study. BRAF V600E gene mutation is most common in the
mandible, especially in patients with tumour volume greater than 4 cm
and located in the posterior mandible, and there is no evident correla­
tion with tumour tissue type, age, sex, imaging manifestations, or
tumour status (do Canto et al., 2019). Comparing the frequency of the
BRAF V600E mutation between unicystic and conventional amelo­
blastoma, Heikinheimo et al. noted a high frequency of activation of the
BRAF V600E mutation in both ameloblastomas in the mandible; in
contrast, the incidence of BRAF V600E mutations in unicystic amelo­
blastomas in the maxilla appears to be lower. Mutations in this gene
were found in all three histologic subtypes of unicystic ameloblastoma at
a frequency similar to that of the classic type. The BRAF V600E mutation
has not been found to be obviously associated with local recurrence of
ameloblastoma (Heikinheimo et al., 2019). A recent study also
confirmed that the positive expression of BRAF V600E was not clearly
associated with tumour recurrence or clinicopathological parameters
(Derakhshan et al., 2020). Interestingly, some researchers have found
that unicystic ameloblastoma is more prone to BRAF mutations.
Notably, this study found that the presence of positive surgical margins
had no significant effect on relapse-free interval, suggesting that radical
surgery is not necessarily required in cases requiring highly traumatic
surgery (Bonacina et al., 2021).
In conclusion, BRAF V600E may serve as a useful diagnostic and
therapeutic biomarker because of its high frequency in ameloblastoma.
Owing to the unclear mutational form of SMO, further research is
needed to demonstrate the specific selection of targeted therapies
(Table 1).
3.1.1.2. Bcl-2 gene. B-cell lymphoma-2 (Bcl-2) is one of the most
important oncogenes in apoptosis. Bcl-2 is an anti-apoptotic protein that
participates in tumour cell proliferation by acting on downstream tar­
gets of the SHH pathway (Bigelow et al., 2004). Bcl-2 inhibits
p53-mediated apoptosis (Chiou et al., 1994). Sindura et al. explored the
expression of the Bcl-2 protein in ameloblastoma. Immunohistochemical
analysis of Bcl-2 oncoprotein monoclonal antibody revealed that the
positive rate of Bcl-2 in ameloblastoma was 85% (17/20) and was
expressed in both periameloblastoma cells and stellate reticulum cells.
Y. Lu et al. Archives of Oral Biology 140 (2022) 105454

Table 1
BRAF and SMO mutations in ameloblastoma.
Gene Author Years Number of samples Source of sample/assay method Result

BRAF Kurppa et al. 2014 24 follicular and plexiform ameloblastoma Oral tumour and normal tissue/RT- A high frequency of BRAF mutations (63%) was first
tumour samples, 8 odontogenic keratocystic PCR described when 15 samples showed BRAF V600E
tumour samples, and 6 normal oral mucosa mutations. The occurrence of BRAF mutation is not
samples directly related to patient age, gender, tumour
tissue type, tumour recurrence, etc.
BRAF Sweeney et al. 2014 28 ameloblastoma tissue samples Oral tumour tissue/RT-qPCR, 39% SMO mutations, mostly in the maxilla. 46% of
and Sanger sequencing BRAF mutations occurred in the mandible.
SMO There were 10 cases of SMO mutation site L412F
and 1 case of T535L site.
BRAF Brown et al. 2014 50 ameloblastoma tissue samples Oral tumour tissue/specific PCR 88% of ameloblastoma patients had BRAF
mutations, of which 62% were BRAF V600E. This
mutation is more likely to occur in young adults.
BRAF Brunner et al. 2015 19 ameloblastoma specimens, 18 Oral tumour tissue/Multiple-nested Ameloblastoma BRAF V600E has an approximately
ameloblastoma fibro-dentinoma, 5 PCR, Sanger sequencing 73% mutation rate. BRAF mutations are also present
ameloblastoma fibroma, 4 ameloblastoma in tumours with an ameloblastoma component,
carcinoma, 12 odontogenic calcifying such as ameloblastoma, suggesting that BRAF
cystoma mutations are not characteristic of ameloblastoma.
BRAF Diniz et al. 2015 17 ameloblastoma and 11 odontogenic Oral tumour tissue/RT- PCR, 87% of ameloblastomas displayed the BRAF V600E
carcinoma samples Sanger sequencing mutation. The SMO L412F mutation was not
detected.
SMO Zhang 2016 30 ameloblastoma samples Oral tumour tissue/Single-strand SMO gene mutation is closely related to the
Conformation Polymorphism, patient’s age, active proliferation, and capsule
Sanger sequencing invasion. SMO mutations tend to occur in young
adults.
BRAF Fregnani et al. 2017 93 conventional ameloblastoma Oral tumour tissue/Construction of BRAF-V600E expression was significantly
tissue microarray, correlated with Cytokeratin-8, Cytokeratin-16,
Immunohistochemistry parathyroid hormone-related protein, p53
expression.
BRAF Gultekin et al. 2018 62 ameloblastoma samples Oral tumour tissue/RT-PCR, Next 92% were mutated, of which 60% were BRAF and
and generation sequencing 14% were SMO. BRAF gene mutation occurs in the
SMO mandible, and SMO gene mutation mainly occurs in
the maxilla.
BRAF Alan et al. 2018 84 ameloblastoma samples Oral tumour tissue/ Anti-BRAF V600E antibody positive accounted for
Immunohistochemistry 78.6%. BRAF expression correlated with
mandibular position and tumour size.
BRAF Heikinheimo 2019 39 unicystic ameloblastoma and 39 Oral tumour tissue/Next generation There were 30 cases of unicystic ameloblastoma
and et al. conventional ameloblastoma samples sequencing BRAF V600E gene mutation and 1 case of unicystic
SMO ameloblastoma SMO L412F gene mutation. BRAF
V600E-mutated ameloblastomas were not
significantly associated with increased local
recurrence rates.
BRAF Derakhshan 2020 50 ameloblastoma samples Oral tumour tissue/ The BRAF V600E gene mutation was present in 92%
et al. Immunohistochemistry of the samples. Recurrence accounted for 26%
BRAF Bonacina et al. 2021 74 ameloblastoma samples Oral tumour tissue/quantitative The BRAF V600E mutation rate was 55.4%. The
PCR, pyrosequencing local recurrence rate of ameloblastoma is 30%.
Neither BRAF mutation nor positive surgical
margins were associated with the relapse-free
interval.

This study provides theoretical support for aggressive clinical manifes­
tations of ameloblastoma (Sindura et al., 2013). However, Mishra et al.
found that Bcl-2 protein is only expressed in the outer layer of amelo­
blastoma cells, but not in the inner layer of astrocytes. The inner layer
expresses pro-apoptotic proteins such as caspase-3 (Mishra et al., 2015).
Thereafter, analysis of the microarray data revealed that Bcl-2 expres­
sion was significantly associated with recurrence in 89 patients with
ameloblastoma. Silencing of Bcl-2 not only promotes the apoptosis of
AM-1 cells in vitro but also inhibits tumour formation in AM-1 cells in
vivo (Kim et al., 2019). Bcl-2 may be a biomarker for predicting ame­
loblastoma recurrence, and a therapeutic target for preventing amelo­
blastoma recurrence.
3.1.1.3. Fos gene. The Fos gene family consists of 4 members: FOS,
FOSB, Fos-related antigen 1, and Fos-related antigen 2. These genes
encode leucine zipper proteins that can dimerise with proteins of the Jun
family to form transcription factor complex activator protein 1 (Sun
et al., 2017). Fos proteins are recognised as regulators of cell prolifer­
ation, differentiation, and transformation. Using gene chip technology
analysis, Heikinheimo et al. found 34 differentially expressed genes in
ameloblastoma, with the highest levels of Fos gene and tumour necrosis
factor receptor 1 overexpressed gene (Heikinheimo et al., 2002). Since
then, some researchers have detected the expression of c-Fos, c-Jun, and
human telomerase reverse transcriptase mRNA in ameloblastoma to
varying degrees by in situ hybridisation. The positive rate of c-Fos
mRNA expression in ameloblastomas was the highest (91.5%). c-Fos
may be involved in the regulation of telomerase activity and play a role
in the proliferation of ameloblastomas (Zhong et al., 2006).
3.1.1.4. BIRC5 gene and XIAP gene. Birc5 is an immune-related gene
that inhibits apoptosis and promotes cell proliferation. It is highly
expressed in most tumours, leading to poor prognosis in patients with
cancer (Xu et al., 2021). Survivin is encoded by this gene and can inhibit
apoptosis induced by caspase overexpression. Survivin, a member of the
inhibitor of apoptosis protein family, is highly expressed in most cancers
and is associated with poorer clinical outcomes. Survivin is a direct
target gene of the Wnt pathway and is upregulated by β-catenin (Chen,
Duan, Zhang, & Zhang, 2016). The X-chromosome-linked inhibitor of
apoptosis protein (XIAP) gene encodes for XIAP. This protein is also a
member of the inhibitor of apoptosis protein family, which also inhibits
caspase enzymes to prevent cell apoptosis (Hsieh et al., 2018). Survivin
was significantly expressed in the inner enamel epithelium of the tooth

3
Y. Lu et al.
germ. Follicular, plexiform, and metastatic ameloblastomas are pre­
dominantly expressed in the tumour cells adjacent to the basement
membrane. Most tumour cells of basal cells, desmoplastic amelo­
blastoma, and ameloblastic carcinoma were positive for survivin. XIAP
is expressed in most epithelial cells of the tooth germ and benign and
malignant ameloblastoma, and the expression level of XIAP mRNA is
significantly higher in follicular than in plexiform ameloblastoma
(Kumamoto & Ooya, 2004). The nuclear immune expression of survivin
promotes cell proliferation, while cytoplasmic immune expression is
related to the regulation mechanism of apoptosis. One study established
that in the cytoplasm, positive expression of survivin in conventional
ameloblastoma was significantly higher than that in unicystic amelo­
blastoma, suggesting the invasive behaviour of ameloblastoma. Nuclear
survivin immunoexpression was only expressed in the plexiform variant
of conventional ameloblastoma, indicating that nuclear survivin
immunoexpression may be related to tumour type and cell proliferation
(González-González et al., 2015).
3.1.2. Tumour suppressor genes
3.1.2.1. RECK gene. As a tumour suppressor gene, a reversion-inducing
cysteine-rich protein with Kazal motifs (RECK) gene negatively regu­
lates matrix metalloproteinase (MMP) through the RECK protein,
inhibiting the role of MMP in degrading the extracellular matrix and
tumour angiogenesis (Dong et al., 2010). Kumamoto utilised immuno­
histochemical methods to detect the expression of RECK in the tooth
germ and in benign and malignant ameloblastoma tumours. The results
showed that the expression of RECK in ameloblastoma was lower than
that in the tooth germ, follicular variant was apparently lower than
plexiform variant, and acanthomatous variant was distinctly lower than
other types (Kumamoto & Ooya, 2006a). Immunohistochemistry and
reverse transcription-polymerase chain reaction (RT-PCR) were used to
detect the expression of RECK and MMP-2 in keratocystic odontogenic
tumours, ameloblastomas, and ameloblastic carcinomas. Some re­
searchers found that the expression of RECK protein was overtly reduced
in ameloblastoma, the expression of recurrence was notably lower in
that of primary tumours, and there was no distinct difference between
the different histological types. The expression of the RECK protein was
negatively correlated with the expression of MMP-2 protein, suggesting
that RECK may play an important role in the invasion, recurrence, and
malignant transformation of ameloblastoma by regulating MMP-2
(Zhang et al., 2009). To explore the effect of RECK overexpression on
the invasive ability of ameloblastoma cells, Liang et al. constructed
human telomerase reverse transcriptase (+)-ameloblastoma-immortal­
ised cell lines that stably express RECK. Overexpression of RECK
noticeably inhibited the invasion of human telomerase reverse tran­
scriptase (+)-ameloblastoma cells and decreased the activities of MMP-2
and MMP-9 but did not affect cell proliferation (Liang et al., 2014).
Recently, some researchers have employed polymerase chain
reaction-single-strand conformation polymorphism and DNA sequence
analysis to detect the polymorphism of the RECK gene in ameloblastoma
tumour specimens and detected RECK and MMP-9 proteins by western
blotting. They found that the rs16932912(g/a) nucleotide poly­
morphisms in the RECK gene were closely related to the proliferative
activity, capsular invasion, and clinical recurrence of ameloblastoma
(Zhang et al., 2017).
3.1.2.2. PTEN gene. The phosphatase and tensin homologue (PTEN)
gene, located on chromosome 10q23.3, consists of 9 exons and encodes a
protein composed of 403 amino acids with phosphatase activity (Ali
et al., 2014). Nodit et al. found that the frequency of PTEN allele dele­
tion was not only associated with benign or malignant ameloblastoma,
recurrence, and aggressive behaviour, but also with age, sex, histologi­
cal subtype, and prognosis (Nodit et al., 2004). Using immunohisto­
chemical methods, Kumamoto et al. found that high expression of
4
Archives of Oral Biology 140 (2022) 105454
protein kinase B (Akt) and phosphoinositide 3-kinases and low expres­
sion of PTEN in ameloblastoma tumour tissue may be involved in the
tumourigenesis of odontogenic epithelial cells by activating the Akt
signalling pathway (Kumamoto & Ooya, 2007). Using the same
approach, Scheper et al. found the involvement of the PTE­
N/AKT/mammalian target of rapamycin (mTOR) signalling pathway in
ameloblastoma (Scheper et al., 2008). However, the pathogenesis of this
pathway in ameloblastoma remains to be further explored. A study on
the expression of protein patched homologue (PTCH) in Nigerian ame­
loblastoma patients showed that PTCH is moderately and strongly
expressed in ameloblasts and the stellate reticulum, providing theoret­
ical support for the use of anti-PTCH chemotherapy drugs in Nigerian
ameloblastoma patients (Udeabor et al., 2015). Another study explored
the genetic alterations of exon 5 of PTEN in patients with Indian ame­
loblastoma and noticed a 25% frequency of somatic mutations in the 5th
exon of PTEN. This gene may play a role in ameloblastoma pathogenesis
(Narayan et al., 2019). Later, the same study observed that PTEN
expression was decreased in epithelial tissues of 17 of 20 amelo­
blastomas, and the expression of PTEN in the tooth germ and amelo­
blastoma was statistically different. They hypothesised that PTEN may
be involved in the pathogenesis of ameloblastoma through reduced
expression of the Akt pathway (Narayan et al., 2020). Recently, research
has been conducted on the methylation status of PTEN promoters in
ameloblastomas. Using methylation-specific polymerase chain reaction
genomics, immunohistochemistry, and RT-PCR, PTEN promoter
methylation was found to be present in many ameloblastomas. How­
ever, this phenomenon was not broadly correlated with the loss of PTEN
expression. In addition, genetic or epigenetic mechanisms other than
methylation of the PTEN promoter may contribute to the inactivation of
PTEN in ameloblastoma cells (Lapthanasupkul et al., 2020).
3.1.2.3. APC gene. The adenomatous polyposis coli (APC) gene is
located at 5q21 and is a tumour suppressor gene. APC regulates cell
proliferation and differentiation by inhibiting Wnt/β-catenin pathway.
Mutations in the APC gene alter the APC protein encoded, resulting in an
inactive APC protein. However, this inactive APC protein exhibited a
negative dominant effect when it bound to the wild type APC gene
product. It blocks the physiological functions of wild type APCs,
resulting in changes in intracellular signals, and ultimately abnormal
cell adhesion, growth, differentiation, proliferation, apoptosis, and
carcinogenesis (Cheadle et al., 2002). As a negative regulator of β-cat­
enin, the main function of APC is to interact with β-catenin and
epithelial cell cadherin (E-cadherin) to affect cell adhesion and inter­
cellular signalling (Ilyas & Tomlinson, 1997). Kumamoto employed
β-catenin and APC immunohistochemical methods for immunohisto­
chemical detection of tooth germ and benign and malignant amelo­
blastoma tissue samples. The results showed that there was no β-catenin
expression in the tooth germ, APC was markedly expressed in the
epithelial cells adjacent to the basement membrane in tooth germ and
ameloblastoma, and the expression was notably lower in benign and
malignant ameloblastoma. Follicular and plexiform variant amelo­
blastomas have high nuclear β-catenin and low APC expression. It has
been speculated that the Wnt signalling pathway may play a role in
ameloblastoma development and cell differentiation through dysregu­
lation of cell proliferation (Kumamoto & Ooya, 2005). Tanahashi et al.
explored the abnormal expression of Wnt signalling molecule in ame­
loblastoma and found that APC gene mutation was not associated with
nuclear aggregation of β-catenin, and no APC missense mutation was
found in any cases (Tanahashi et al., 2008). However, Siriwardena’s
findings contradict this notion. Nuclear accumulation of β-catenin was
present in all ameloblastoma cases and in 75% of odontogenic cyst cases,
and mutations in the APC gene were present in 50% of ameloblastoma
cases and in 25% of odontogenic cyst cases. These results suggest that
abnormal β-catenin expression and APC missense mutations may be
involved in the pathogenesis of odontogenic tumours (Siriwardena et al.,
Y. Lu et al.
2009). Recently, APC gene mutations in ameloblastomas have been
analysed, and a gene mutation was found in ameloblastoma. The mu­
tation sites were 1543 (T→C), 4564 (G→A), 5353 (T→G), 5550 (T→A),
and 5969 (G→A). The mutation rate was 15%, suggesting that APC gene
mutation deserves attention in monitoring the degree of tumour ma­
lignancy, and that this gene may become a marker of malignant trans­
formation of ameloblastoma (Li et al., 2016).
3.1.2.4. p53 gene. The p53 gene is a tumour suppressor gene with the
highest correlation with human tumours found to date. Inactivation of
this gene plays a strong role in tumour formation. Its wild type induces
apoptosis in cancer cells, thereby preventing carcinogenesis, whereas
the mutant type of p53 can increase carcinogenesis. The protein encoded
by this gene is a transcription factor that controls cell cycle initiation
(Chi et al., 2015). P53 protein is mainly distributed in the nucleoplasm
of cells and can specifically bind to DNA. Its activity is regulated by
post-translational modifications, such as phosphorylation, acetylation,
methylation, and ubiquitination, and it participates in cellular gene
repair (Yu et al., 2018). Mouse double minute 2 (MDM2) is a key
negative regulator of p53, which is highly expressed in tumours and
plays an important role in their occurrence and development (Oliner,
Saiki, & Caenepeel, 2016). Using immunohistochemistry and direct
DNA sequencing techniques, Kumamoto et al. analysed the expression of
p53, MDM2, and p14 proteins in ameloblastomas and tooth germs. P53,
MDM2, and p14 are highly expressed in benign and malignant amelo­
blastomas. Changes in the p53-MDM2-p14 cascade may be involved in
the occurrence and malignant transformation of ameloblastomas
(Kumamoto et al., 2004). Subsequently, to verify the relationship be­
tween the p53 codon 72 polymorphism and ameloblastoma, 78 cases of
ameloblastoma and 94 normal individuals were genotyped for p53
codon 72. The Arg allele at codon 72 of the p53 gene has been speculated
to increase susceptibility to ameloblastoma, and this increased risk may
not be influenced by patient sex or tumour clinical characteristics.
Furthermore, individuals carrying the Arg allele have a markedly higher
risk of developing ameloblastoma than those who are homozygous
(Kitkumthorn et al., 2010). Through the immunohistochemical pattern
of p53 and MDM2 in odontogenic keratin cysts and ameloblastoma
variants, Singh et al. observed that the immunoexpression of p53 and
MDM2 was highest in odontogenic keratin cysts, followed by classic
ameloblastomas, and lowest in the unicystic type. The results show that
there is a positive correlation between these two molecules, which has
an impact on the aetiology and development of tumours and provides
new ideas for the development of novel tumour therapeutic drugs (Singh
et al., 2020).
3.1.2.5. Rb gene. The retinoblastoma gene (Rb) is a tumour suppressor
gene. This gene is mutated in many different cancers; however, its role in
retinoblastoma was first reported. The protein product of this gene is a
transcription factor that controls the expression of genes that drive cell
division (Wiman, 1993). As early as 2004, some scholars found that the
activity or release of telomerase may be related to the low expression of
Rb and suggested that the regulatory pathway of Rb/E2F transcription
factor 1 may be related to the proliferation and differentiation of ame­
loblastoma cells (Zhong et al., 2004). Subsequently, Kumamoto et al.
detected Rb protein expression in the tooth germ and benign and ma­
lignant ameloblastoma. The study found that the expression of Rb in
benign and malignant ameloblastoma was higher than that in the tooth
germ, and the expression in the plexiform variant was markedly higher
than that in the follicular variant. Rb appears to play a role in regulating
the cell cycle, proliferation, and differentiation of ameloblastomas
(Kumamoto & Ooya, 2006b).
3.1.2.6. WT1 gene. Wilms’ tumour gene 1 (WT1) is a tumour suppressor
gene. A previous study found that WT1 showed different expression
levels in 35 of 37 cases of classic ameloblastoma. Ameloblasts are more
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immunoreactive than stromal and stellate reticulum cells. Neither his­
tological type nor subtype was significantly associated with the intensity
of WT1 expression in ameloblastomas. At present, the role of WT1 in the
biological behaviour of ameloblastoma has not been well studied, but it
provides a new direction for exploring the pathogenesis of amelo­
blastoma and has obvious prognostic and treatment-oriented effects
(Khalele & Al-Shiaty, 2016).
3.1.3. DNA repair genes
The X-ray repair cross-complementing gene 1 (XRCC1) is an impor­
tant DNA repair gene. The XRCC1 protein produced interacts with DNA
polymerase and participates in the process of base excision repair
(Zhang et al., 2012). XRCC1 single nucleotide polymorphisms affect
DNA repair ability and correlate with the efficacy of chemotherapy
drugs, such as cisplatin or carboplatin (Sun et al., 2009). Since the ge­
netic susceptibility of single nucleotide polymorphisms may predict
ameloblastoma in high-risk patients, Yanatatsaneejit et al. performed
restriction fragment length polymorphism analysis of XRCC1 in amelo­
blastoma samples and blood from healthy controls. Polymorphisms at
codons 194 and 399 were significantly increased in patients with ame­
loblastoma (Yanatatsaneejit et al., 2013). Santos et al. performed a
quantitative immunohistochemical evaluation of 30 solid amelo­
blastomas. A positive correlation between the expression of apur­
inic/apyrimidinic endonuclease-1 and the nuclear expression of XRCC-1
was observed, suggesting that the base and nucleotide excision repair
pathways may play a role in ameloblastoma (Santos et al., 2020).
3.1.4. P63 gene
P63 is a member of the p53 gene family, which plays an important
role in the development, differentiation, and morphogenesis of various
epithelial tissues, is of great significance for the development of the
ectoderm during embryogenesis (Guo et al., 2012). P63 can act as an
oncogene or a tumour suppressor gene in different contexts. The TA
isoform of p63 usually suppresses tumours by inhibiting cell prolifera­
tion, survival, and metastasis, whereas the DeltaN isoform can initiate
tumourigenesis by promoting cell proliferation and survival (Chen et al.,
2018). P63 appears to function as an oncogene in ameloblastoma. Some
researchers have found that P63 is highly expressed in a variety of
odontogenic tumours, including ameloblastoma (Varsha et al., 2014).
Subsequently, the biological relationship between p63 and amelo­
blastoma has received increasing attention. Using immunohistochem­
istry and a cross-sectional retrospective study, Jaafari-Ashkavandi et al.
found that the expression level of p63 in conventional ameloblastoma
was higher than that in the unicystic type. P63-positive cells were pre­
sent in the basal and suprabasal layers, and p63 expression was higher in
more aggressive ameloblastoid lesions, suggesting that the frequency
and intensity of p63 expression are related to the aggressiveness of
odontogenic lesions (Jaafari-Ashkavandi et al., 2015). To evaluate the
role of p63 in odontogenic epithelial cell differentiation and tumouri­
genesis, Gupta et al. used immunohistochemical methods to detect
higher expression of p63 in ameloblastoma tissue specimens. P63 over­
expression is a marker of cell proliferation and may be a prognostic
indicator of the aggressiveness of odontogenic lesions (Gupta et al.,
2019). Alsaegh et al. also found that the expression of ΔNp63 was
related to the proliferation of odontogenic epithelial cells in dentigerous
cysts, odontogenic keratocysts, and ameloblastomas; however, there
were marked differences in the expression of p63 among the three. This
indicates that the roles and pathways of ΔNp63 in odontogenic tumours
differ from those in odontogenic cysts (Alsaegh et al., 2020). Interest­
ingly, using the PV-9000 immunohistochemical method to detect the
anti-apoptotic protein p63, Zhang et al. found that the expression of p63
in the follicular type of ameloblastoma was lower than that in the
plexiform type. Low expression of p63 is closely related to tumour
capsule invasion and recurrence (Zhang et al., 2017). The biological
behaviour of p63 in ameloblastomas requires further investigation.
Y. Lu et al.
3.2. Associated protein markers in ameloblastoma
3.2.1. Cell proliferation-related markers
3.2.1.1. Ki-67 and PCNA. Ki-67 is an antigen of proliferating cells, its
function is closely related to mitosis and is indispensable in cell prolif­
eration. Ki-67 antigen is a protein involved in cell division and prolif­
eration in the nucleus (Zhang et al., 2018). It is expressed in the S, G1,
G2, and M phases of the cell cycle, and is absent in the G0 phase. It is
often used as a reliable marker of tumour cell proliferation (Qian et al.,
2014). The faster the tumour grows, the poorer the tissue differentiation
ability and the more sensitive it is to Ki-67. Proliferating cell nuclear
antigen (PCNA) is a protein with a molecular weight of 36 kD, which is
synthesised in the nucleus and exists in the nucleus. There was no
obvious expression of PCNA in cells in the G0-G1 phase; however, in the
late G1 phase, its expression increases significantly, reached a peak in
the S phase, and decreased significantly in the G2-M phase. The change
in its amount is consistent with DNA synthesis, and its expression in cells
can be exploited as an indicator to evaluate the state of cell proliferation
(Barton & Levine,2008). An experimental study found that, compared
with PCNA, Ki-67 is a more specific marker of ameloblast tumour cell
proliferation (Bologna-Molina et al., 2013). Interestingly, mini­
chromosome maintenance complex component 5, which is also
expressed in the nucleus, was found to be more sensitive than Ki-67 in
ameloblastoma (Apellániz et al., 2018). This discovery remains to be
confirmed in further studies.
3.2.2. Tumour deterioration related markers
3.2.2.1. Calcein. Calcein, a 29 kDa calcium-binding protein of the EF-
hand family, is expressed in various normal and tumour tissues. Using
immunohistochemistry, Anandani et al. found positive calcein expres­
sion in 16 ameloblastoma samples. However, only one case of kerato­
cystic odontogenic tumour was positive, and positive expression was
limited to the stellate reticulum epithelium. Calcein appears to serve as a
marker for differentiating between these two tumour types (Anandani
et al., 2014). Since then, some researchers have performed calcein im­
munoassays on odontogenic cysts, apical cysts, odontogenic keratocysts,
and ameloblastomas. All ameloblastomas were positive, whereas in
other tumours and cysts calcein was not detected (Rudraraju et al.,
2019). Similar results were also shown in a recent study by Varshney
et al. (2020). Calcein may be used as a specific immunohistochemical
marker for the identification of ameloblastomas. At present, the bio­
logical function of calcein is unknown; it may be related to the occur­
rence, development, and invasion of ameloblastoma, but the specific
mechanism needs to be further explored.
3.2.2.2. HIF-1α. Hypoxia-inducible factor-1α (HIF-1α) is a protein that
promotes cell survival under hypoxic conditions. This protein is
involved in the invasion of malignant tumours via co-expression with
various proteins, such as glucose transporter 1 (Seleit et al., 2017). The
expression of HIF-1α in ameloblastoma, calcified cystic odontogenic
tumour, and dental follicle tissue was detected by immunohistochem­
istry. The results indicated that the highest expression was observed in
ameloblastoma, suggesting that this protein may be involved in the
aggressiveness of ameloblastoma (da Costa et al., 2016). Later, the same
scholar discovered that HIF-1α was overexpressed in the solid epithelial
and cystic forming areas of ameloblastoma, suggesting that there may be
a correlation between hypoxia, apoptosis, and cytogenesis (da Costa
et al., 2018). Yoshimoto et al. detected significantly higher expression of
HIF-1α and zinc finger E-box-binding homeobox 1 in ameloblastic car­
cinoma than in ameloblastoma. Under hypoxic conditions, HIF-1α and
zinc finger E-box-binding homeobox 1 may achieve
epithelial-mesenchymal transition through transforming growth
factor-beta, thereby giving rise to tumour malignancy (Yoshimoto et al.,
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2019). When studying the relationship between HIF-1α and
hypoxia-induced apoptosis in ameloblastoma, Valladares et al. found
that HIF-1α and glucose transporter 1 were highly expressed and posi­
tively correlated. This conclusion confirms the results of previous studies
(Valladares et al., 2021). Hypoxia may be associated with anti-apoptotic
effects in ameloblastomas.
3.2.2.3. SRY-box transcription factor 2 and Octamer-binding transcription
factor 4. SRY-box transcription factor 2 is a member of the Sox region Y-
related HMG (high mobility group) protein family, which is responsible
for maintaining the self-renewal and pluripotency of embryonic stem
cells. necessary conditions. Its regulation of expression is highly sensi­
tive, and weak changes can trigger embryonic stem cells to differentiate
into various cell types. The interaction between SRY-box transcription
factor 2 and octamer-binding transcription factor 4 plays a role in the
embryonic stem, often as a stem cell marker (Rizzino & Wuebben,
2016). Compared with benign ameloblastoma, the expression of
SRY-box transcription factor 2 and octamer-binding transcription factor
4 was statistically different in ameloblastic carcinoma; therefore,
SRY-box transcription factor 2 may be a potential marker for amelo­
blastic carcinoma (Khan et al., 2018; Lei et al., 2014). In future studies,
the overexpression of octamer-binding transcription factor 4 and
SRY-box transcription factor 2 and the invasive behaviour of tumours
could be taken as the next direction.
3.2.2.4. CXC chemokine receptor 4/Stromal cell derived factor-1. CXC
chemokine receptor 4 is the chemokine receptor most commonly
expressed in cancer cells. Because it is expressed in cancers of many
different origins, it is an attractive target for cancer diagnosis and
therapy. Stromal cell derived factor-1 is a ligand for CXC chemokine
receptor 4, and their interaction triggers a variety of signalling path­
ways. Tumour cell proliferation and growth can be significantly
inhibited by blocking CXC chemokine receptor 4/stromal cell derived
factor-1 signalling (Toyozawa et al., 2012). CXC chemokine receptor 4
and stromal cell derived factor-1 were positively expressed in amelo­
blastoma osteoclasts. This suggests that CXC chemokine receptor
4/stromal cell derived factor-1 may be involved in the invasive growth
of ameloblastoma (Liu, Tian, et al., 2021).
3.2.2.5. AMFR and Collagen IV. Autocrine motility is a protein secreted
by tumour cells that stimulates tumour motility. Autocrine motility
factor receptor (AMFR) is a 78 kD glycoprotein. Type IV collagen,
together with laminin, is a major component of the basement mem­
brane, and is involved in cell adhesion, migration, differentiation, and
growth (Grewal & Sethi, 2014). As the main structural component of the
basement membrane, type IV collagen exists in six distinct genetic
forms, α1(IV)–α6(IV), which constitute the scaffold of the basement
membrane. In the tooth germ, the basement membrane of the inner
enamel epithelium expresses α1(IV), α2(IV), and α4(IV), while the outer
enamel epithelium expresses the α1(IV), α2(IV), α5(IV), and α6(IV)
chains. Besides, there is a strong positive expression of the α1(IV), α2
(IV), α5(IV), and α6(IV) chains around the tumour epithelium in the
ameloblastoma basement membrane. α4(IV) is weakly expressed in
primitive tumour cell nests or invaded latent sites (Nakano et al., 2002).
Furthermore, in specimens of ameloblastoma, the α1(IV) and α2(IV)
chains are highly expressed in the basement membrane adjacent to
blood vessels (Nagatsuka et al., 2002). Degradation of type IV Collagen
is closely related to the invasive behaviour of tumours, and AMFR has
been detected in unicystic ameloblastoma, classic ameloblastoma,
odontogenic keratocystoma, and ameloblastic carcinoma. The results
showed that type IV collagen had the highest expression in classical
ameloblastomas and the lowest expression in odontogenic keratocystic
tumours. Low expression of type IV collagen is associated with disease
progression. AMFR has the highest expression in ameloblastic carci­
noma and the lowest expression in classic ameloblastomas.
Y. Lu et al.
AMFR-positive expression has been found to correlate with tumour
invasive potential (Grewal & Sethi, 2014).
3.2.3. Tumour angiogenesis related markers
3.2.3.1. VEGF. Vascular endothelial growth factor (VEGF), also known
as the vascular permeability factor, is a highly specific vascular endo­
thelial cell growth factor. It promotes vascular permeability, extracel­
lular matrix degeneration, vascular endothelial cell migration,
proliferation, and angiogenesis (Xu et al., 2019). Both benign and ma­
lignant ameloblastomas express VEGF, suggesting that the upregulation
of VEGF may be associated with tumour-like changes and the malignant
transformation of ameloblastoma (Kumamoto et al., 2002). Gupta et al.
examined the immunohistochemical expression of VEGF in 15 cases of
ameloblastoma and found that, in all cases, it was strongly expressed by
stellate cells in the follicular centre and suprabasal layer (Gupta et al.,
2016). Additionally, abnormal activation of the Wnt/β-catenin signal­
ling pathway may lead to increased VEGF expression in ameloblastomas
(Dutra et al., 2017). Recently, it was found that the interaction between
HIF-1α, MMP-2, VEGF, and vascular endothelial growth factor receptor
2 proteins is related to hypoxia-induced angiogenesis under hypoxic
conditions, which may contribute to increased tumour growth and
invasiveness (de Mendonça et al., 2020).
3.2.3.2. Cyclooxygenase-2. Cyclooxygenase-2 has angiogenic potential
in a variety of human tumours and is an important mediator of the in­
flammatory response, affecting cell proliferation, apoptosis, angiogen­
esis, and metastasis (Escobar et al., 2021). Alsaegh et al. detected
cyclooxygenase-2 expression in ameloblastoma epithelial cells using
immunohistochemistry, which may be associated with ameloblastoma
cell proliferation (Alsaegh et al., 2017). To explore the relationship
between cyclooxygenase-2 and the aggressiveness of ameloblastomas,
28 of 63 primary ameloblastomas were found to be cytoplasmic positive
for cyclooxygenase-2 by immunohistochemistry, mainly located in the
surrounding columnar cells. Statistically, cyclooxygenase-2 is signifi­
cantly associated with recurrence, BRAF V600E, and 5-year disease-free
survival expression (Montezuma et al., 2018).
3.2.4. Markers associated with cell surface and intracellular changes
3.2.4.1. MMP. Epithelial-mesenchymal transition (EMT) refers to the
transformation of epithelial cells into mesenchymal cells in the extra­
cellular matrix under specific physiological or pathological conditions
(Hao et al., 2018). MMPs are a class of calcium-and zinc-dependent
proteolytic enzymes that can degrade almost all protein components in
the extracellular matrix and regulate many intracellular factors. These
properties allow MMPs to promote the separation of epithelial cells from
surrounding tissue and participate in epithelial-mesenchymal transition
(Radisky & Radisky, 2010).
Under normal conditions, MMPs work with tissue inhibitors of
metalloproteinases (TIMPs) to regulate the extracellular matrix turnover
and maintain cell stability (Aggarwal et al., 2015). Siqueira et al.
explored the expression of MMPs, TIMPs, and growth factors in amelo­
blastoma using immunohistochemistry. Ameloblastoma cells showed
enhanced expression of MMP-1, MMP-2, and epidermal growth factor
receptor, and there was a positive correlation between epidermal
growth factor and TIMP-1, transforming growth factor-alpha, and
TIMP-2. Growth factor-generated signals are transduced through the
extracellular signal-regulated kinase (ERK) pathway. Ameloblastoma
stroma contains a phosphorylated (activated) form of ERK. These results
suggest that the interaction of MMPs, TIMPs, and growth factors may
bring about the biological behaviour of ameloblastoma, and it is spec­
ulated that the signals generated by this molecular network may be
transmitted through the ERK 1/2 pathway (Siqueira et al., 2010). Sub­
sequently, some researchers found that MMP-2, TIMP-2, and MMP-14
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were expressed in all ameloblastoma tissues by RT-PCR. The mRNA
levels of TIMP-2 and MMP-14 in recurrent and conventional amelo­
blastoma tissues were significantly higher than those in primary and
unicystic types. The high expression of MMP-2, TIMP-2, and MMP-14
mRNA may be involved in the local invasion process of amelo­
blastomas (Zhang et al., 2010). Inhibitors of MMP-2 activity can inhibit
the local invasive ability of ameloblastoma by reducing MMP-2 activity,
which also proves that MMP-2 activity is related to the invasive
behaviour of ameloblastoma (Zhang et al., 2009). MMP can be used as a
marker to differentiate between benign and malignant ameloblastomas.
A study found that, compared with ameloblastoma, the expression of
MMP-2 in parenchymal cells of ameloblastic carcinoma and MMP-9 in
stromal cells was significantly higher. However, there was no difference
in the expression of MMP-2 in stromal cells and MMP-9 in parenchymal
cells (Yoon et al., 2011). MMP-2 and MMP-9 are proteolytic enzymes of
the Wnt/β-catenin signalling pathway. Elevated hydrostatic pressure
can upregulate MMP-2 and MMP-9 expression by activating the
Wnt/β-catenin pathway and promoting the migration and invasion of
ameloblastoma cells (Yang et al., 2018). MMP-9 is not only derived from
ameloblastoma cells but also secreted by osteoclasts, which can degrade
the extracellular matrix of bone, and may also be associated with ame­
loblastoma bone invasion (Kibe et al., 2013). Kelppe et al. also found
that osteoclasts lining bone margins express MMP-9. In addition, MMP-8
and MMP-9 expression was detected in the extracellular domain of
polymorphonuclear neutrophils, which are involved in extracellular
remodelling through a mild inflammatory response. However, both
these molecules are expressed in ameloblasts. MMP-7 is expressed in
some apoptotic cells (Kelppe et al., 2021). The mutant allele of
rs3918242S in MMP-9 was found to be overexpressed in patients with
ameloblastoma by polymerase chain reaction restriction fragment
length polymorphism analysis and sequencing in the blood of patients
with ameloblastoma. There was a significant difference in the frequency
of MMP2 rs2438659, suggesting that this polymorphism may enhance
the aggressiveness of ameloblastoma (Aloka et al., 2019).
3.2.4.2. E-cadherin and β-catenin. Epithelial cell cadherin (E-cadherin)
is a transmembrane glycoprotein with a molecular weight of 120 kDa
that belongs to the family of calcium-dependent adhesion molecules in
epithelial cells (McVeigh et al., 2014). This protein can enhance the
adhesion between tumours, thereby inhibiting tumour cell invasion and
metastasis. E-cadherin showed strong positive expression in the cell
edge region in the tissue epithelium, while the expression of E-cadherin
was low or even absent in most tumour tissues compared to normal
tissues. E-cadherin expression in cancer cells is inversely proportional to
the degree of tumour differentiation. The down-regulation of E-cadherin
expression in tumour cells may lead to the destruction of epithelial cells,
thereby offering tumour cells the ability to migrate and resulting in
tumour cell invasion and metastasis (Hao et al., 2018). β-catenin is a
multifunctional protein that interacts with E-cadherin at cell junctions
and is involved in the formation of adhesive bands. Free β-catenin can
enter the nucleus and regulate gene expression, and its abnormal
expression or activation can result in tumour formation (Qian et al.,
2016). These two proteins are both involved in the
epithelial-mesenchymal transition process. When studying the expres­
sion of E-cadherin and β-catenin in ameloblastoma compared with
normal tissue, some researchers found that there was no significant
difference in the expression of these molecules between normal tissue
and ameloblastoma by the immunohistochemical method. These results
indicate that these molecules have little correlation with tumour
aggressiveness (Alves Pereira et al., 2010). Nevertheless, some re­
searchers put forward a different point of view and found that the
expression of E-cadherin on the surface of peripheral columnar epithe­
lial cells and cuboidal epithelial cells of ameloblastoma was reduced or
absent. In contrast, the expression of β-catenin was reduced on the
epithelial cell membrane, and ectopic expression was observed in the
Y. Lu et al.
cytoplasm and/or nucleus. This indicates that these two molecules are
involved in the occurrence of invasive behaviour (Hao et al., 2018).
Kelppe et al. detected that the expression of E-cadherin in the maxillary
tissue of ameloblastoma was weaker than that in the mandible, and
β-catenin was expressed in the cell membrane of ameloblastoma. The
weaker expression of E-cadherin in the maxilla than in the mandibular
ameloblastoma may be related to the early recurrence of maxillary
ameloblastoma (Kelppe et al., 2021).
3.2.4.3. Toll-like receptor 2. Toll-like receptor 2 is a single trans­
membrane cell surface and toll-like receptor. As a membrane protein
receptor, toll-like receptor 2 is expressed on the surface of specific cells,
recognises foreign substances and transmits signals to cells of the im­
mune system (Shrestha et al., 2021). The insulin-like growth factor re­
ceptor is a protein receptor located on human cell membranes.
Insulin-like growth factor 2 functions in combination with insulin-like
growth factor receptor. Insulin-like growth factor 2 is an imprinted
gene that is expressed only in the paternal alleles. The gene encoding
this protein promotes the growth and division of cells in various tissues.
It is highly active during foetal development, but its activity decreases
significantly after birth (Brouwer-Visser & Huang, 2015; Nordin et al.,
2014). Using cDNA microarray analysis and gene set enrichment anal­
ysis, Kondo et al. found that KRAS signalling is highly activated in
ameloblastomas compared to normal oral tissue. Insulin-like growth
factor 2, a member of the KRAS-responsive gene family, was found to
promote the proliferation of the BRAF-mutated ameloblastoma cell line
AMU-AM1. The RAS-RAF-MAPK pathway promotes ameloblastoma cell
growth by mediating insulin-like growth factor 2 stimulation.
KRAS-responsive gene sets were easily inactivated, and caspase activity
increased after toll-like receptor 2 knockout, suggesting that toll-like
receptor 2 signalling may mediate survival signalling in amelo­
blastoma cells. Toll-like receptor 2 knockout readily inactivated in­
flammatory response-related genes, suggesting that toll-like receptor 2
mediates inflammatory signalling in ameloblastoma cells. In addition,
the study also found that toll-like receptor 2 agonists can activate the
NF-κB signalling pathway in AMU-AM1 cells. However, whether toll-like
receptor 2 is associated with BRAF V600E mutation remains unclear
(Kondo et al., 2020).
3.2.4.4. ARL4C. ADP-ribosylation factor -like 4c (ARL4C) is a member
of the ADP-ribosylation factor subfamily involved in intracellular vesicle
trafficking and signal transduction. One study ascertained through gene
set enrichment analysis (GSEA) that ARL4C expression was positively
correlated with the epithelial-mesenchymal transition gene set. The re­
searchers also speculated that ARL4C stimulated cell invasion and pro­
gression by promoting epithelial-mesenchymal transition and motility
(Hu et al., 2018). Furthermore, overexpression of ARL4C may be asso­
ciated with changes in the EGF/RAS-MAPK and Wnt/β-catenin signal­
ling pathways. One study found that ARL4C was barely detected in
non-tumour areas but was strongly expressed in ameloblastomas.
ARL4C elevation in ameloblastoma cells is dependent on the
RAF1-MEK/ERK pathway. Tumour cells deficient in this factor show
decreased proliferation and migration. The RAF1-MEK/ERK-ARL4C axis
may cooperate with the BRAF V600E-MEK/ERK pathway to promote the
occurrence and development of ameloblastomas (Fujii et al., 2022).
In addition, several proteins may be associated with ameloblastoma.
Peripheral ameloblastoma and intraoral basal cell carcinoma can be
differentiated using epithelial-glycoprotein-adhesion-molecule mouse
monoclonal antibody. Peripheral ameloblastomas do not react to
epithelial-glycoprotein-adhesion-molecules mouse monoclonal anti­
body, whereas intraoral basal cell carcinomas stain positively for this
antibody. (Upadhyaya et al., 2018). The proteins that may be involved
in the epithelial-mesenchymal transition of ameloblastoma are fibro­
nectin 1, versican (proteoglycan), type I collagen α1 chain, syndecan-2,
mitogen-activated protein kinase 3, and Src family tyrosine kinase Fyn
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(Zhang et al., 2022). These proteins are all involved in cell adhesion,
proliferation, migration, and angiogenesis, thereby playing important
roles in the construction and maintenance of tissue morphology. Addi­
tionally, their abnormal expression may be closely related to the
occurrence and development of ameloblastoma.
3.3. Expression of non-coding RNA in ameloblastoma
Noncoding RNAs (ncRNAs) are RNAs that do not code for proteins;
however, this does not mean that these RNAs do not contain information
or function. Emerging evidence suggests that ncRNAs play a critical role
in tumourigenesis and prognosis (Mattick & Makunin, 2006). Data on
the expression of ncRNAs in ameloblastoma are available. Small
nucleolar RNAs (snoRNAs) are a class of 60–170 bp in length. snoRNAs
are small non-coding RNAs present in the nucleolus of eukaryotic cells
and are mainly responsible for post-transcriptional modification and
maturation of RNAs (Liang et al., 2019). Long non-coding RNAs
(lncRNAs) are transcripts longer than 200 nucleotides that are not
translated into proteins, and there are a large number of lncRNAs in
cells. Although these lncRNAs do not encode any proteins, their
expression has important biological roles in different tissues and
developmental stages (González-Moro & Santin, 2021; Wang et al.,
2018). LncRNAs can be involved in epigenetic, transcriptional, and
post-transcriptional regulation; for example, they can be involved in X
chromosome silencing, genomic imprinting, chromatin modification,
transcriptional activation, and intranuclear trafficking (Wang et al.,
2018). In 2017, Davanian et al. first reported the difference in lncRNA
expression between ameloblastoma and normal tissues, and at the same
time, they explained the relationship between lncRNA expression and
ameloblastoma tumour size. LncRNAs and snoRNAs LINC340,
SNORD116-25, SNORA11, SNORA21, SNORA47, and SNORA65 are
distinct ncRNA signatures in ameloblastomas. The presence of these
ncRNAs was not associated with BRAF V600E, and SMO-L412F muta­
tions, tissue type, or tumour location but was positively associated with
tumour size. These results provide new diagnostic and therapeutic di­
rections for ameloblastomas (Davanian et al., 2017). By constructing a
network of competing endogenous RNAs mediated by lncRNAs, some
researchers have found that lncRNAs may play a role in the pathogenesis
of human diseases by regulating the expression of microRNAs (miRNAs)
(Wang et al., 2019). Diniz et al. found that KIAA0125 lncRNA was
upregulated in ameloblastomas using high-density genome-wide
microarray analysis. They predicted that this lncRNA interacts with 41
miRNA families. Four miRNAs in these families, including miR-135a-5p,
miR-204-5p, and miR-205-5p, were overexpressed in ameloblastomas,
whereas miR-150-5p was underexpressed. In the future,
KIAA0125-lncRNA may be used as a therapeutic target for amelo­
blastoma in extensive and recurrent cases (Diniz et al., 2019). Using
microarray technology, Sun et al. evaluated the function of an overex­
pressed lncRNA in ameloblastoma samples and found that
ENST00000512916 silencing inhibited ameloblastoma cell proliferation
and migration and decreased cyclin dependent kinase 2/4/6 levels. In
established ameloblastoma cell lines, lncRNA upregulation enhances
homeobox C13 expression and stimulates cell cycle progression (Sun
et al., 2020). In addition, through network analysis of lncRNA-mRNA
co-expression in patients with ameloblastoma, some researchers found
that the outer membrane protein involucrin was the most connected
core gene and was negatively correlated with the co-expressed lncRNA
MAGI2-AS3 (MAGI2 Antisense RNA 3) (You et al., 2020).
miRNAs are common ncRNAs containing 19–25 bp. Studies have
found that miRNAs are ubiquitous in various eukaryotic cells, play a
vital role in regulating cell differentiation, migration, apoptosis, and
maintenance of cell homoeostasis, and can participate in different stages
of tumour pathology (Liu, 2021a; Sun, 2021). Circular RNAs (circRNAs)
are ncRNAs with closed-loop structures linked end-to-end. CircRNAs are
ubiquitous in eukaryotic transcriptomes, because they cannot be
degraded by ribonucleases. CircRNAs are involved in various signalling
Y. Lu et al. Archives of Oral Biology 140 (2022) 105454

pathways and regulate downstream molecules, which are crucial for the
occurrence and development of tumours and other pathological pro­
cesses and can be used as potential biomarkers and therapeutic targets
for tumour diagnosis (Liu, 2021a). Using real-time quantitative poly­
merase chain reaction (RT-qPCR), bioinformatics analysis, western
blotting, and other methods, Guan et al. found that highly expressed
neural cell adhesion molecule 1 in ameloblastoma can inhibit the
migration of ameloblastoma cells and is regulated by miR-141-3p,
indicating that neural cell adhesion molecule 1 is a therapeutic target
for ameloblastoma (Guan et al., 2020). Liu et al. verified that
hsa_circ_0089153/hsa-miR-608 is sponged, and hsa-miR-608 can
downregulate the epidermal growth factor receptor and p53, which may
further regulate cell proliferation, differentiation, apoptosis, and cell
cycle processes through the MAPK signalling pathway (Liu, Qiao, et al.,
2021). Liu noticed that the expression of programmed death ligand 1
(PD-L1) and hsa-miR-224-3p was negatively correlated when exploring

Table 2
ncRNA expression in ameloblastoma.
NcRNA Author Years Number of samples Source of sample/assay method Result

LINC340, SNORD116-25, Davania 2017 95 ameloblastoma patients Ameloblastoma tumour samples and These ncRNAs were significantly expressed
SNORA11, SNORA21, et al. and 50 normal controls. normal tissue with oral origin and non- in ameloblastoma. NcRNA expression has a
SNORA47 and SNORA65 oral origin/microarray data analysis, RT- distinct pattern in ameloblastoma
qPCR.
KIAA0125 Diniz 2019 13 samples (5 conventional Ameloblastoma, adenomatoid miR-135a-5p, miR-204-5p and miR-205-5p
et al. ameloblastomas, 4 odontogenic tumour and dental follicles/ were up-regulated, and miR-150-5p was
adenomatoid odontogenic microarray data analysis, qPCR. down-regulated. The higher KIAA0125
tumour, and 4 dental follicles). expression levels in ameloblastoma may be
resulted from copy-number gain of
KIAA0125 gene region.
ENST00000512916 Sun et al. 2020 26 pairs of ameloblastoma Oral mucosa/microarray analysis, RT- ENST00000512916 enhances cell
tumour tissues and their qPCR. proliferation, migration, and cell cycle
paired normal tissues and 16 transition. Overexpression of
dental follicles. ENST0000512916 promotes AM-1 cell cycle
progression, which could be reversed by
knockout of HOXC13.
MAGI2-AS3 You et al. 2020 8 ameloblastoma tissue Ameloblastoma tumour samples and SOX2-AS1 was most significantly up-
samples and 8 normal tissue normal tissue with oral origin/microarray regulated in ameloblastoma. MAGI2-AS3 was
samples. data analysis. down-regulated, and the two were negatively
correlated.
miR-141-3p Guan et 2020 25 ameloblastoma tissues and Ameloblastoma tumour samples and Neural cell adhesion molecule 1, which is
al 15 normal tissues. normal tissue with oral origin/RT-qPCR, highly expressed in ameloblastoma, can
microarray data analysis, Western blot, inhibit the migration of ameloblastoma cells
Immunohistochemistry. and is regulated by miR-141-3p, suggesting
that neural cell adhesion molecule 1 serves as
a therapeutic target for ameloblastoma.
miR-424 Ding 2020 30 ameloblastoma tissues and Ameloblastoma tumour samples and The expression level of miR-424 in
et al. 6 normal oral mucosa tissues. normal tissue with oral origin/RT-qPCR, ameloblastoma tissues was significantly
EdU immunofluorescence assay, CCK-8 down-regulated compared with normal oral
assay, scratch assay. mucosa tissues, and it could significantly
reduce the proliferation ability and cell
activity of AM-1 cells and inhibit the
migration ability of cells.
miR-9-3p Sun 2021 15 pairs of ameloblastoma Ameloblastoma tumour samples and miR-9-3p was lowly expressed in
tumour samples and oral- normal tissue with oral origin/microarray ameloblastoma tissues, and RBPJ was highly
derived normal tissue. data analysis, RT-qPCR, Western blot, expressed in ameloblastoma tissues. The
Immunohistochemistry. expression of miR-9-3p and RBPJ was
strongly negatively correlated, and the
expression of RBPJ was closely related to
ameloblastoma invasion.
CASC15 He et al. 2021 8 pairs of ameloblastoma and Ameloblastoma tumour samples and CASC15 is highly expressed in
their normal paratumour normal tissue with oral origin/Next ameloblastoma and may be involved in
tissue. generation sequencing, RT-qPCR. regulating biological behaviours such as cell
proliferation, migration, and cell cycle.
miR-608 Liu, Qiao 2021 16 pairs of conventional Ameloblastoma tumour samples and The expressions of hsa_cic_0089153,
et al. ameloblastoma and adjacent adjacent non-tumour tissue with oral hsa_cic_0001955, hsa_cic_0000517 and
non-tumour tissue. origin /microarray data analysis, RT- hsa_cic_0080425 were upregulated. The
qPCR. function of Hsa_circ_0089153/hsa-miR-608/
EGFRp53 interaction pathway was mainly
enriched in MAPK and related signalling
pathways regulating ameloblastoma
program.
miR-224-3p Liu 2021b 6 pairs of ameloblastoma and Ameloblastoma tumour samples and The expression of PD-L1 in ameloblastoma
corresponding adjacent tissue. corresponding adjacent tissue/ tissue was significantly increased, and the
microarray data analysis, RT-qPCR, expression of hsa-miR-224-3p was
Western blot, Immunohistochemistry. significantly decreased, which can be used as
relevant molecular markers for the diagnosis
of ameloblastoma.
miR-1296 Liu 2021a 16 pairs of ameloblastoma and Ameloblastoma tumour samples and After silencing hsa_circ_0000517, the
adjacent normal epithelial normal tissue with oral origin expression of hsa-miR-1296 was significantly
tissue. /microarray data analysis, RT-qPCR, increased, the expression of catenin delta 1
Immunohistochemistry. was significantly decreased, and the
ameloblastoma invasion and migration
abilities were significantly enhanced.

9
Y. Lu et al. Archives of Oral Biology 140 (2022) 105454

the targeted regulation of PD-L1 expression in ameloblastoma by targeted therapies targeting the BRAF V600E mutation have been
hsa-miR-224-3p. Hsa-miR-224-3p could be exploited as a molecular approved by the U.S. Food and Drug Administration (FDA) (Roskoski,
marker for the diagnosis of ameloblastoma to target and regulate PD-L1, 2018;Weaver et al., 2020).
thereby affecting the invasive growth of ameloblastoma (Liu, 2021b). Fernandes et al. used vemurafenib in patients with BRAF V600E-
Combined with gene chip technology, Sun observed that miR-9-3p could mutated recurrent ameloblastomas. After 11 months, examination
regulate the Notch signalling pathway by targeting the recombination revealed that the tumour had shrunk, and the patient had no serious
signal binding protein for immunoglobulin kappa J region (RBPJ). In adverse reactions (Fernandes et al., 2018). Broudic-Guibert et al. used
ameloblastoma tissues, the expression of miR-9-3p was strongly nega­ vemurafenib to treat patients with metastatic ameloblastoma with lung
tively correlated with RBPJ expression. Overexpression of miR-9-3p or metastases mutated at this site. After 26 months, the patient’s symptoms
inhibition of RBPJ expression could significantly inhibit the prolifera­ improved and the tumour and metastases continued to shrink (Brou­
tion, migration, and invasion of ameloblastoma cells but had no effect on dic-Guibert et al., 2019). Patients with recurrent ameloblastoma and this
apoptosis (Sun, 2021). Liu discovered that the mutation were treated with dabrafenib. After 16 weeks, the tumour had
hsa_circ_0000517/hsa-miR-1296/catenin delta 1 axis also has regula­ shrunk (> 90%) and Tan et al. removed the remaining tumour (Tan
tory effects on the invasion and migration of ameloblastoma (Liu, et al., 2016). In addition, some researchers have used the
2021a). He et al. found that cancer susceptibility 15 (CASC15) may above-mentioned drugs for combined drug therapy and have achieved
regulate the recurrence and invasion mechanisms of ameloblastoma considerable achievements. Molecularly targeted therapy for metastatic
through the Hedgehog signalling pathway. Cancer susceptibility 15 is ameloblastoma using dabrafenib and trametinib was reported by Kaye
highly expressed in ameloblastomas and may regulate cell proliferation, et al. and Brunet et al. After a few weeks, the tumours in both groups of
migration, and the cell cycle (He et al., 2021). Moreover, miR-424 was patients achieved ideal treatment results (Brunet et al., 2019; Kaye et al.,
found to reduce the biological activity of ameloblastoma, possibly by 2014). Combination therapy not only delayed drug resistance but also
acting as a tumour suppressor gene in tumours (Ding et al., 2020). More resulted in fewer adverse effects than BRAF inhibitor therapy alone
research is needed to explore the biological relationship between (Robert et al., 2015). Based on the available literature, BRAF mutation
ncRNAs and ameloblastoma, which also provides a new direction for inhibitors appear to be effective in the treatment of patients with ame­
molecular targeted therapy (Table 2). The role of these ncRNAs in loblastoma. These drugs should be used with caution during treatment.
ameloblastoma is presented in Table 3. However, single agent binimetinib has not shown satisfactory effi­
cacy against cancers with NRAS mutations. A patient with a malignant
4. Molecular targeted therapy for ameloblastoma ameloblastoma carrying a codon 61NAS mutation had lung metastases
up to 6 cm in length. He was treated with binimetinib for 26 months
4.1. MAPK pathway targeted therapy before discontinuation of the regimen owing to the development of
grade 2 myalgia. MEK inhibitors have many side effects including rash,
Fibroblast growth factor receptor 2 and epidermal growth factor diarrhoea, retinal abnormalities, reduced ejection fraction, increased
receptor activate the MAPK pathway cascade by activating the down­ creatinine phosphokinase levels, and high blood pressure. Severe side
stream RAS, RAF, MEK, and extracellular signal-regulated kinases. It effects can even lead to death, and the incidence of these side effects is
then induces biological behaviours, such as proliferation, migration, surprisingly high (Cleary et al., 2021). At present, it is necessary to
invasion, and differentiation of some epithelial cells (Brown et al., 2014; explore new MEK inhibitors to reduce the occurrence of adverse
Kurppa et al., 2014; Sweeney et al., 2014). Drugs used for molecular reactions.
targeted therapy of ameloblastoma can inhibit the function of mutant Moreover, lenvatinib appears to be effective in patients with FGFR2-
BRAF and MEK (Cleary et al., 2021; Yuan, Dong, Yap, & Hu, 2020). mutated ameloblastoma. A 62-year-old male patient with the FGFR2
BRAF mutations can be inhibited by vemurafenib, dabrafenib, and Y375C mutation was diagnosed with ameloblastoma. After six months of
encorafenib. Trametinib, cobmetinib, and binimetinib inhibit MEK lenvatinib treatment, the size of the patient’s tumour shrank signifi­
mutations. Erdafitinib, pemigatinib, and lenvatinib inhibit the mutated cantly. However, the patient suffered adverse reactions including hy­
fibroblast growth factor receptor 2 gene. The first six molecularly pertension, hypothyroidism, diarrhoea, and weight loss, although these
side effects were relatively mild. There are few studies on the targeted
therapy of fibroblast growth factor receptor 2 mutations in amelo­
Table 3 blastoma and the mechanism of drug sensitivity is not fully understood.
ncRNA expression in ameloblastoma. Therefore, more research is required to elucidate the role of this factor in
NcRNA In vivo In vitro About the role in drug response (Weaver et al., 2020).
experiments experiments ameloblastoma Also, there are some novel targeted therapy drugs in clinical trials
LINC340, SNORD116-25, NO YES Unclear that warrant attention. Inhibitors of RAF, including PLX8394, BGB283,
SNORA11, SNORA21, TAK-580, and CCT3833, can overcome the resistance caused by BRAF
SNORA47 and SNORA65 mutations. Besides, RO5126766, a dual inhibitor of RAF and MEK, has
KIAA0125 NO YES Unclear the advantage of preventing MEK release from RAF (Yuan et al., 2020).
ENST00000512916 YES YES Carcinogenic
effect
MAGI2-AS3 NO NO Unclear 4.2. SHH pathway targeted therapy
miR-141-3p NO YES Tumour
suppressor effect SHH is one of the three ligands of the Hedgehog signalling pathway
miR-424 NO YES Tumour
suppressor effect
and is regulated by PTCH and SMO on the target cell membrane. Under
miR-9-3p NO YES Tumour normal conditions, due to the lack of SHH ligands, PTCH inhibits the
suppressor effect activity of SMO, causing glioma-associated oncogene (GLI) to lose its
CASC15 NO YES Carcinogenic transcriptional activity via a variety of kinases. This signalling pathway
effect
is inhibited. However, when the SHH ligand binds to PTCH, it releases
miR-608 NO YES Tumour
suppressor effect SMO to block the function of the PTCH protein, thereby activating the
miR-224-3p NO YES Tumour activities of GLI1, GLI2, and GLI3 signalling pathways were activated
suppressor effect (Sauk, Nikitakis, & Scheper, 2010). DeVilliers et al. were the first to
miR-1296 NO YES Carcinogenic analyse the gene expression profiles of ameloblastoma using microarray
effect
significance analysis and data clustering. High expression of PTCH and

10
Y. Lu et al.
SMO was found in the SHH pathway, indicating that this pathway may
play an important role in the occurrence of ameloblastoma (DeVilliers
et al., 2011). Currently, the U.S. Food and Drug Administration has
approved three drugs that target the SHH pathway: vismodegib, soni­
degib, and arsenic trioxide. Vismodegib and sonidegib are SMO in­
hibitors whereas arsenic trioxide is a GLI inhibitor (Nguyen & Cho,
2022). Interestingly, vismodegib was ineffective against SMO mutants in
ameloblastoma, but arsenic trioxide and KAAD-cyclopamine showed
efficacy against SMO mutants (Sweeney et al., 2014). Notably,
KAAD-cyclopamine inhibits osteoblast formation by inhibiting pur­
morphamine (Stanton & Peng, 2010). This is detrimental for bone
healing and functional recovery. SMO mutation-targeted therapy drugs,
vismodegib and sonidegib, also face the problems of tumour resistance
(Yauch et al., 2009) and adverse reactions. Adverse effects of vismode­
gib include muscle cramps, geriatric/intellectual disability, hair loss,
dysgeusia, weight loss, and death in severe cases (Lacouture et al., 2016;
Sekulic et al., 2012). Adverse effects of sonidegib include dysgeusia,
alopecia, weight loss, fatigue, myalgia, and abnormal liver function
(Frank-Kamenetsky et al., 2002; Minami et al., 2016;).
Clinical trials have demonstrated that several new SMO inhibitors
are capable of treating vismodegib-resistant tumours. Inhibitors
included taladegib, saridegib, mrt-92, ZINC12368305, ABT-199, LEQ-
506, and 0025A. Saridegib is a cyclic dopamine derivative with good
tolerability and mild side effects. Additionally, ZINC12368305 has a
higher binding affinity for SMO-WT than vismodegib. In contrast to
vismodegib, taladegib can overcome resistance caused by the SMO-
D473H mutation and ABT-199 can overcome resistance caused by the
SMO-W539L mutation. 0025A binds to multiple sites on the SMO pro­
tein and the binding affinity to SMO-D473H is higher than that of vis­
modegib. Besides, MRT-92 and LEQ-506 can overcome resistance
produced by the SMO-D473H mutation, and the drug performance is
better than sonidegib. (Nguyen & Cho, 2022).
The use of SHH inhibitors in patients with ameloblastoma has not yet
Fig. 1. Schematic diagram of the relationship between therapy and signalling pathways.
11
Archives of Oral Biology 140 (2022) 105454
been reported. SMO is a potential therapeutic target, and more clinical
studies on ameloblastoma are needed to overcome drug resistance to
targeted drugs and reduce adverse drug reactions. As a common gene
mutation in ameloblastoma,SMO inhibitors may be useful in the clinical
treatment of ameloblastoma as adjuvant therapy, thereby reducing
clinical recurrence and metastasis rates (Fig. 1).
5. Conclusion
This article reviews the latest classification, epidemiological distri­
bution, molecular biology progress, and current status of targeted
therapies for ameloblastoma. Ameloblastoma is a locally aggressive,
benign, and odontogenic tumour. The World Health Organization has
reclassified the types of ameloblastomas based on the impact of the
tumour on treatment and recent advances in molecular genetics.
Describing the incidence and clinical features of ameloblastoma at
various ages and in different regions of the world could provide a
reference for clinical diagnosis and prediction.
At present, most radical methods for ameloblastoma use extensive
local excision of the jaw; however, postoperative facial deformity has a
great impact on the physiological function and psychology of patients,
especially in younger patients. Therefore, conservative treatments, such
as tumour enucleation, are often used, but the postoperative recurrence
rate is high. Repeated tumour recurrence may also give rise to malignant
transformation and distant metastasis, which cause great suffering to
patients. By describing the progress related to molecular biology, this
study highlights a new direction for molecular-targeted therapy.
Molecularly targeted therapy for ameloblastoma could be used as a new
adjuvant therapy. However, drug resistance and adverse reactions
caused by targeted therapy with BRAF and SMO inhibitors need to be
urgently solved in the future. There is no evidence to compare the effects
of single -and double-agent inhibitors on the molecular targeting of
BRAF-mutated genes in the treatment of ameloblastoma. The use of SMO
Y. Lu et al.
and SHH inhibitors in patients with ameloblastoma has not been re­
ported. Molecularly targeted therapy exploration for ameloblastoma
still has a long way to go, and more clinical trials are required.
Tumour-associated gene polymorphisms are associated with odon­
togenic disease risk, and the observed associations need to be validated
in different populations to identify the genetic susceptibility loci for
these diseases. At present, the relationship between p53 expression and
gene polymorphisms has rarely been studied (Ghafouri-Fard,
Atarbashi-Moghadam, & Taheri, 2021). The various subtypes of p63 in
ameloblastoma and their correlation with Ki-67 positive cells are worth
exploring (Jaafari-Ashkavandi et al., 2015). Alterations in exon 5 of
PTEN may play a role in ameloblastom pathogenesis. Further validation
of these findings with large patient cohorts and supportive functional
studies is warranted (Narayan et al., 2019). Under certain conditions,
HIF-1α-mediated positive regulation of glucose transporter 1 under
hypoxia appears to confer apoptosis resistance. The effect of this locking
on apoptosis can be observed by inhibiting the expression of HIF-1α
through mechanism analysis (Valladares et al., 2021). Larger sample
sizes and more genotyped single nucleotide polymorphisms are needed
to determine the importance of the role of MMP-2 and MMP-9 gene
alterations in the biological behaviour of ameloblastoma (Aloka et al.,
2019). MMP-9 in osteoclasts may cause bone degradation around
ameloblastoma, and this independently occurring process requires
further investigation. Also of interest is the role of β-catenin immu­
noexpression in metastatic ameloblastoma and ameloblastic carcinoma
(Kelppe et al., 2021). The specific mechanism of CXC chemokine re­
ceptor 4/stromal cell derived factor-1-mediated ameloblastoma inva­
sion and recurrence still needs to be explored (Liu et al., 2021). It is
worth exploring whether PD-L1-related immunosuppressive drugs can
be used in the treatment of ameloblastoma or can improve the prognosis
of patients (Liu, 2021b). RBPJ may become an important indicator for
judging the aggressive growth of ameloblastoma, but its related mech­
anism is not yet clear (Sun, 2021). The RAF1–MEK/ERK–ARL4C and
BRAF V600E–MEK/ERK pathways may independently regulate AM-1
cell proliferation. Synergistic activation of these two pathways may be
the aetiology of ameloblastoma cell proliferation. Neither the expression
of ARL4C in ameloblastoma nor its effect on ameloblastoma develop­
ment is clear (Fujii et al., 2022). Whether toll-like receptor 2 is associ­
ated with BRAF V600E mutation remains unclear (Kondo et al., 2020).
Furthermore, few studies have assessed lncRNA signalling in amelo­
blastoma samples. LncRNAs require functional validation in animal
models (Wang et al., 2019). It is believed that in the future, with more
in-depth studies of molecular biology in ameloblastoma, more bio­
markers and therapeutic targets of ameloblastoma could be discovered
to accurately diagnose and treat ameloblastoma.
Funding
This study was supported by Natural Science Foundation of Hebei
Province, PR China [Grant no. H2021206165].
Author contributions
Lu Yiwen designed, drafted the thesis and wrote the manuscript.
Zhang Xudong and Li Xiangjun supervised all procedures. All three au­
thors revised the manuscript and approved the final version.
CRediT authorship contribution statement
Yiwen Lu: Conceptualization, Methodology, Data curation, Writing
– original draft, Writing – review & editing, Visualization. Xudong
Zhang: Conceptualization, Writing – review & editing, Supervision,
Visualization, Project administration. Xiangjun Li: Conceptualization,
Writing – review & editing, Supervision,
12
Archives of Oral Biology 140 (2022) 105454
Conflict of interest statement
None.
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