Molecular mechanisms of

Chemoresistance in Oral Cancer

Molecular Mechanisms of Chemoresistance in Oral Cancer.

Wang C, Liu XQ, Hou JS, Wang JN, Huang HZ.
Chin J Dent Res. 2016 Mar;19(1):25-33. doi: 10.3290/j.cjdr.a35694. Review.
Drug transporters & Chemoresistance
• ABC: ATP binding cassette
• well documented multi-drug transporters
• classified into seven subfamilies designated with A to G, based on
the sequence and structural homology
• ABCB1 (MDR-1 or P-gp): unidirectional ATP-dependent pump to ex-
port drugs from cells, rapidly eliminate paclitaxel and vincristine, ex-
pression increase in recurrent OSCC, enhancement of sensitivity by
silencing
• ABCC1 (MRP1):
• ABCG2 (BCRP or MXR)
Dysfunction of apoptosis
• Bcl-2 family members
Comprised of anti-apoptotic proteins (e.g. Bcl-2 and Bcl-Xl) and pro-
apoptotic proteins (e.g. Bax, Bak and Bad)
• Survivin
• A member of the inhibitor of the apoptosis protein family
• Identified as one of the most important biomarkers in the determina-
tion of chemoresistance
• to promote cell proliferation and survival through directly binding to
caspase
• P53
• ABCC2
DNA damage and repair
• NER (nucleotide excision repair)
• Alteration of the NER-related genes and pathways contributed to
cisplatin-resistant phenotypes in oral cancer cells
• ERCC1 (excision repair cross-complimentary group 1), key compo-
nents of the NER pathway
• XRCC1, XRCC2 DNA repair genes
• XRCC1 was also involved in EMT-mediated chemoresistance
• Snail could directly enhance the expression of XRCC1 at transcription level
• NHEJ (nonhomologous end joining)
• TRIP13
Epithelial mesenchymal transition
• E-cadherin
• The decreased expression of E-cadherin is one of the most important hallmarks of
EMT
• ABC transporters

• Transcriptional factors
• Key regulators to drive EMT procedure by targeting CDH1 promotors, such as
Snai1, Snai2, Twist1, ZEB1 and ZEB2
• Cytokines
• TGFβ, EGF, FGF, IL, SDF-1, could induce EMT via a distinct signal pathway and ac-
tivate EMT-related transcriptional factors
• miR-200b and miR-15b
miRNA deregulation
• Chemosensitive miRNA
• miR-21
• Chemoresistant miRNAs
• miR-214, miR-23a
• Both miR-200b and miR-15b could reverse cisplatin-induced
EMT and enhance chemosensitivity by targeting BMI1.
• miR-181, Let-7d: through the inhibition of Twist or Snail
• miR-21, most famous oncomiRNA, is an independent and poor
prognostic factor and functions as an apoptotic inhibitor
through the silencing of TPM1 and PTEN
Autophagy related chemoresistance
• Evolutionary conserved catabolic process where cells self-di-
gest intracellular organelles to regulate normal turnover
• Cellular housekeeper to eliminate damaged organelles and
protect cells against carcinogenesis
• Pro-survival signal
• Beclin1
• LC3, ATG9a, ATG5
• Atg12-Atg5
ETC
• Metabolic reprogramming
• Tumor microenvironment: Tumor-associated macrophages
and cancer-associated fibroblast
• lncRNA, circRNA, ceRNA
• Genetics and epigenetic alterations