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    Cancer Ler 45 (2020) 191-190 Contents lists available nt ScienceDirect Cancer Letters ELSEVIER journal homepage: vw esevier comlocatleanlet Epstein-Barr virus-associated gastric cancer: A distinct subtype “ot Jing Yang**"'*, Zhifeng Liu’, Bin Zeng", Guangsheng Hu", Runliang Gan”*” Deparment of Gaoronerig, Te Ft Afi atl of Unveety of Souh Chine Henan. 21001, Haan Prove, Che = Caer Rema eH Pove Rey Larry of Taner bir Mtr Paty nero oath Ce an, 42001, Chin < Depart of Other, The at Afi Hep Ory of Sth Chia Hi 42001, nan Pov, her Repwrds wc vis CBV) Noles fetes ‘lnicopatoetea fees Epstein Bar vis (EBV) associated gastric cancer (BVAGO is common malignant unos associated with EBV Infection. The moleeuarclasfcation of gaste carcinoma indicates that EBVaGC Is a dstin®subeype ia tems fof oncogenesis and molecular feats. Vital procein, Basn-HI-A sghtoard wanseips (BART) niRNAS, ee ‘Bam HUA rightward fame | (BARFT) promote oncogenesis fer EBV infection vate neiton of metylain, regulation of host geue expression, and malignant uansfomaton, Together with abnoxnal mutations ane mplifeation ofthe host genome as diving facts, intrartion herween the EBV geaone and host genome fecrlete carcinogenesis. The molecular profile of EAVAGC is tha of EBV dvving DNA hypermetylation, Fequentphospatilinosiol-45. bisphosphate 3Kinase,eaalytie subunit alia (IKSCA) tations, ad che overexpression of Jans kinase 2 (JAK2), programme death igane-1 (PDL), an PDAL2. Clinically, the fe ‘quency ofyiph node metastasis s lowes, andthe prognosis beter for EBVAGC than EBV negative gastic ‘ance (EBVAGC). Pathologialy, EBVAGC I gasuie adenocaclnoma with Iphald soma. This review in ‘exprets how the EBV geome is involved in the oncogenesis of gst canes al desis the mole ae lnicopathologcal features of EBVaGc. 1. Introduction molecular subtypes: EBV-positive, microsatellite instability (MSD, genomic stability (GS), and chromesomal instability (CIN) (1.1). Mo. lecular classification evidence from patients with EBVaGC has indicated {hat EBVaGE Isa distinct subtype In tris of oncogenesis. We reviewed EBY infection, roles ofthe EBV genome in oncogenesis, molecular po: Gastric cancers are responsible for ~780,000 deaths annually, raking them the cird-most prevalent ype of eancer mortality globally (11 Epstein-Barr virus associated gastric eancer (EBVaGC) isa common highlighting the malignancy associated with EBV infection [2]. The EBVaGC comprises about 1.3%-90.996 ofall gastric cancers according Co geographic dis tribution (9-61, with «global average of 8.9% ofall gestric cancers [2] ‘secounting for about 75,000 new diagnoses annuslly (2) ‘Whar drives mutations and the molecular eharacterstes oF GC have. been under investigation. Epstein-Barr virus (EBV)-posiive GC has the {¢pG island methyiator phenotype [7,8]- High-throughput sequencing has shown that EBV-positive gastric caicer has distinct mutation pat terns (9, 10]. Gastric eancers are generally divided into the following file, and clinicopathological features of EBVAG involvement of dhe EBV genome in gastic carcinogenesis, 2. Definition Burke et al. (1990) initially identified EBVAGC as EBV-infected tumor cells using polymerase chain reaction (PCR) analysis of paraffin embedded samples of undifferentiated Iymphoepthelial gastric tateinoms (121. Today, EBV negative GC (EBYNGC) and EBVAGC in Adrevinons: BARFI, Bani ighovata fim T; BARTS, Ban tghovatd anseips; BARFL, Ham fingnent H ightwad open veadng fame 1; BOR BL eo 1epessor; CIN, chtomosona stabil: DLBCL, thse ange el Iyphou; EBER, EBV enced sual RNA; EBERL/2 ISH, EBV encore sual RNA 1/2 Inst hybudzation; EBNAL, EBV nuclear anigens 1; EBV, Epstein-Barr vis; EBVaGC, Epstel-Batrvinus-ssolated gassecancer; EBViGC, Epstein Ban negative ‘asc eancer, GS, enone stability JAK, Janus kinase 2; LMP, latent membrane roel MSI, micosatellite instability; NPC, nasopharyngeal catlnoma; P-LA lopianaed death igsnd 1; PIKICA, phosphatiylinstl 4.5 bisphosphate 3 kinase, cataytle subunit alpha; TOGA, The Canées Geneme Atlas * Conesponing shor Cancer Reseach sie, Hunan Provine Key Laboratory of Tor Cella Mole Pathology, University of South Chin, Hanan, 421001, China mall addres: genruliangsusecd.ca(R. Ga) "These authors conned equally o ee work, ps /do.org/ 10.2016 Jeane. 2020.02.01 Received 23 June 2020; Reclted in teised fom 28 August 2020; Accepted 21 September 2020 Available online 23 Seprember 2020 (0304'3835/© 2020 The Authors. Published by bevy BY. This is an open access article under the OC BYNGND_ license histopathological specimens are usually distinguished sing BY encoded small RNA 1/2 in situ hybridizations (EBERI/2 18H) [19]. ‘Moreover, a ew method of droplet digital PCR diagnosing (@4PCR) can. detect EBVAGC in tissue samples by calulating the copy numbers of EBV-DNA [14] 8. EBV infection and oncogenesis Double-stranded DNA EV isolated from « Burkite lymphoma cell, line was the frst virus tobe asocinted with human malignancy in 1964 (05). Today, EBV is a confirmed pathogen associated with a broad spectrum of multiple human malignancies inetuding Burkitt, Hodgkin ‘and NK/T-cell lymphomas, nasopharyngeal carcinoma (NPC), leo ‘myosarcoma, and gastric carcinoma [16,17]. A prospective study of 2, 7760 patients with GC including 140 with EBV-positive GC validated by BER ISH found that plasma EBV-DNA load was a good marker of reottence and chemosensitivity [18]. The plasmin EBV-DNA load in patients with EBVAGC decreases after gastrectomy and chemotherapy, ‘and increases during disease progression [18]. These findings suggested the etiological involvement of EBV in gastric oncogenesis 1. EBV infection BBY (also known as human herpesvirus 4) infects over 9036 of the ‘adult population, mostly with lifelong asympeomate state [191 Rates of infection due to free EBV in saliva entering gastric epithelial ces a ‘extremely low [20]. However, precisely how EBV infects epithelial cells has remained vmelear, Direet celLto-cell contact mtediated by B I ‘phocytes isthe predominant way of EBV entry into epithelial ells (21). Infection with EBV starts in the oropharynx where it targets oral mucosal ‘epithelium aud oropharyngeal B cells daring primary infection (161. The ‘oropharyngeal nuicose Is heavily infiltrated wid lymphocytes, and cell-free virus in saliva binds firstly to the cell membrane of B Iynpho: ‘ytes, then to oropharyngeal epithelial cells [16]. The efficiency of EBV infection Is 800-fold higher in epithelial cells co-cultured with EBV-positive B cells than in cell-free infection (21. After persistent infection of oral epithelial eels, BBV selectively be: ‘comes Tnteney that is a cartier sta, but not Iytie [16]. The vie ‘genome replicates simultaneously with that of the host cell in latency, in latency 0 latency | Normal EBV infected People ‘Burkitt lymphoma Fig. 1. Thespecsum of EBV latency gene expression. Epstln Baur virus latency sls as ener er 495 (2020) 191-199 the absence of autonomous replication. The EBV genome does not integrate into the host genome and is maintained as plasmids ealled episomes. Notably, EBER-ISH is positive inall infected gastric carcinoma cells and adjacent dysplastic epithelium, but, negative in surrounding ‘normal epithelial cells and Iymphocytes, indicating that EBV infection occurs before transformation [22]. The uniform terminal fragment of [BBY nuclear antigens 1 (EBNA1) expressed by GCs suggests that EBVaGC results from the monoclonal proliferation of EBV infected cells [25] Depending on the physiological and pathologial stats ofthe host, EBV expresses latency 0,1, Il, and II genes. 1 shows that these Ix teney types differ among diverse EBV associated malignancies 8.2. BBV latene genes in EBVaGC Epstein-Barr virus is a direct transforming pathogen through its regulation of host gene expression and cell eyele pathways [26]. The roles of EBV in oncogenesis involve dhe expression of is own genes and regulation of the host genonie, Viral gene expression by EBVaGC is loser to latency I and limited to EBV-encoded small RNA (EBER), EBNAL, and BamiHLA rightward transcripts (BARTS) ineliding micro RNA from BARTS [27]. However, recent findings suggest that the viral latent profile of EBVAGC corresponds co latency Tor Uf in the Tater, latent membrane protein (LMP)-1, 2, and 28, BamHE-A rightward transeripts 1(BARFI) are also expressed [25]. Fig. 1 shows this inter mediate state of EBVAGC between latency Land Il. The abundance of EBER is proportional to that of EBV DNA genomes, and thus isthe gold standard for detecting EBVaGC [26]. Datasets of RNA sequences have been re-analyzed to quantify EBV gene expression in a cohort of gastric fatcinomas in TCGA [28]. That study classified most EBV postive samples as latency I, and a minority a latency I. Most ofthe EBV reads were BARTS (25]. Latent membrane protein 24, and 10 a lesser extent, EMI were expressed [28]. This variety might have been due to sample size and veehnology. Tosiay, investigators agree thatthe latent gene expression of EBVAGC. {slimited to EBER, EBNAI, and BARTS with nost having no or low LMP find LMP 28 expression, aid LMP2A is expressed in about 40% of pa Lents with EBVAGC (26-28), Pig. 2 shows the levels of relevant latency gene expression by EBV in GC, which are diseused separately in the following sections. latency Il latency Ill Hodgkin lymphoma Infectious mononucleosis Nasopharyngeal carcinoma Lymphoblastod cell line TINK lymphoma PTLDIDLECL and scot ding to profiles of latent gee expesion [24,251 ‘Latency genes of Epstein Barr virus associated gastie eancer (EBVaGC) ince EBER, EBER2, EBNAL, BART mlRNAS, and BARFL, most of which lak or expess low levels of latent membrane proteins (LAW) 1 and LMP 28. LMP2A i expressed about 40% of patients with EBVaGC [26.2]. DLBCL, ifise large B ell Iynptiona; PTLD, post-ansplant Iyphoprolifeatve disease Fig. 2, Profiles of EBV viral gene transcription expression in Epeten-Bar vine associated ganic carcinoma. Red shows EBV latent gene tanseripion fexpresed i EBVAGC. Graybar shows clave expiession level of cone ‘sponding genes. This gute was dss based on the orginal data [20-25 (For Interpretetion of the references to colour inthis gute legend, the reader ie teferted tothe Web version of sare) 21, BER ‘The non-coding small RNA EBERI and EBER2 coniprise 167 and 173 nucleotides, respectively that are transcribed by EBV using RNA poly erase I. Although they are abundant in latent EBVaGC, their roles in [gastric enteinogenesis remain snknovin (20). Transfecting ERER into the EBV.negative GC cell line NU-GC-3 induces the expression of insulin-like growth factor 1 (IGF-1), which serves as an autocrine growth faetor to promote cel proliferation in gastric careinoma cells. This effect ‘ean be blocked by ant-1GF 1 antibodies [30]. Besides, EBER can upre {late the expression of 1L6 and downstream STATS to downregulate the cell eyele inhibitors, p2, and p27, which are associated with che toresstaice in vitro [1]. Moreover, EBER promotes the migration phenotype in vito by aetivating pro-metastatic PEAK and pPAKI, ad lowaregulating ant metastatie RhoGD1 and KAL [31] 92.2, EBNAL EBNAL isthe only protein encoding gene involved in ll latent types, ‘of EBV associated malignancies. Although Important for the replication ‘and stabilizing of EBV episomes, the expression oF EBNAL in EBVAGC keeps very low levels, somtetinies even absent [28]. By competing with 53 for ubiquitin-specie protease 7, which degrades p53 protein to lose its funetion by ubiquitination, EBNAL can promote EBV anediated host cell growth and transformation in viero [52]. In addition, EBNAL ‘expressed in 1/2 cells enbiancestuinorigenieity in immnocempetent allograft Balbe mice according to xenograft tests [32]. Furthermore EBNAI contributes tothe epigenetic deregulation of gestrokines (GKN) 1 and 2, which are specifi tumor suppressor genes in GC [3]. EBNAL lrectly combines with the divergent promoter ofthe GKN] and 2 genes ‘sch thet both GKN are transcriptionally repressed by DNA methylation In vitro, However, considering the low level of EBNA-1 expression in EBVaGC, its significance in oncogenesis and as @ therapeutic target re ‘quires more supportive high-throughput sequencing daa, 22:3. LMP 1 ‘The latent membrane proteins (LMP) 1, 2, and 2B, are Toeated inthe host cell membrane. The LMP! gene encodes a viral protein that is ‘expressed in Hodgkin Iymmpliomss, nssopharyngealcarclnoms, ad GC Investigators agree that LMPI is expressed at low levels in EBVaGC [5457]. One systematic review found thet LMP1 was expressed in only 10% of patients with EBVAGC. This might be explained by methylation ‘of the LMP! promote, Li etal, determined the methylation profiles of promotets of LMP1, LMP2A, and LMP2B in 41 EBVaGC samples and 5 EBV-positive cell lines by methylation specific PCR and bisulfite sequencing. They concluded tha all LMP promoters were methylated to different degrees and that LMPI expression could be recovered using & demethylation agent [50]. From a mainstream perspective, LMP pro mores oncogenesis by activating survival and growth pachuays in Hodgkin lymphomasand NPC [38]. However, LMPI enlanees apoptosis In gastric eareinoma cells, unlike the growth enhancement in NPC cells ener er 495 (2020) 191-199 [9], Primary gastric epithelial cells infected with recombinant EBV shovted a disordered cell cycling phenotype with restrited expression of set of viral latent genes which was similar to EBV positive gastric eateinom biopsy specimens without EBNA2 and LMP [10]. These findings indicated thac LMP is probably nota key oncogenic protein in EBVAGC. 92.4, LM2A Latent memibrane protein 24 (LMP2A) is expressed in 40% of pa Lents with EBVAGC in contrast to the low levels of LMPI and 28 expression (26,27). The eageinogenie effects of LMP2A in EBVAGC are controversial, The LMP2A induced upregulation of survivin that results resistance to serum free indced apoptosis in the EBV-MKN-1 cell line, ean be blocked using an NF xB inhibitor, indicating that LMP2A ean resist apoptosis nd progress in srvivin [1]. Latent membrane protein 2A represses the expression of aquaporin (AQP) 3, which played crucial roles in cancer progression and metastasis in vitro [42]. In mechanistic emis, LMP2A induces the phosphorylation of ERK, which aetivates DNMTSa transcription and downregulates AQP3 through methylating (CpG islands in the AQPS promoter of the host genome [12] Lentivitus-mediated RNAI knockdown of LMP2A iahibits the growth and colony formation ofthe EBV-positive GC cell line GT38 and arrests the cell eyele atthe GO/G1 phase [45]. However, Seo era established & gastric adenocarcinoma cell Iine (AGS) expressing detectable LMP2A protein using a retroviral vector [4]. Colony-forming assays in soft agar shovved tha the proliferation of clones of thi ell ine was not eahanced compared with control AGS cells, Such divergence requires more ‘comprehensive investigation in vivo and indieted that LMP2A targeted therapy might wot apply coal patients with EBVAGC. 925. BARTS ‘The major miRNA clusters, BamHI rightward transcripts (BARTS) nd Brak fragment H tightwaed open reading frame 1 (BHRED [15], Which comprises 25 EBV miRNA precursors ané 44 EBV mature miRNA Im EBV are documented in the miRBase (htp://w8w-mirbaseor3/)-The BARI cluster, consisting of2 miRNA precursors and 40 mature miRNA from the BamHIA region, are expressed in all EBV infected hosts [40, 47). The BHRET cluster, ineuding 3 miRNA precursors and 4 mature miRNA, axe expressed in Ite infected hosts and latency Ht hosts [46] ‘The BARTS are mult-spliced rightward, 130,000-161,000 nt tran scripts of Bal A fragments of the EBV getiome. Several of these transeripts with predicted open reading ames, such a8 BARFO, RPMS, and 73, probably encode proteins, but these have not been confirmed fn EBVaGC samples [8]. Evidence of BARTs expression in EBVAGC consists of BARFL and 40 aiatire BART miRNAs that have been val dated in EBVaGC tissue samples by quantitative RT-PCR, but evidence of the BHREI cluster is nonexistent [47,09} 3.2.5.1. BART miRNAS. High levels of BART MIRNAS expression and absent BHRFI clusters have been confirmed in EBVAGC cell Lines and patients [47,48,50]-Shinozakt etl. profiled the expression of 44 known EBV muRINA in human sss and EBVAGC cell Knes, and analyzed their target genes in silico [1]. Their bioinformatics analysis uncovered various potential target genes, ineluding those involved in oncogenesis, ‘mor suppression, adhesion associated pathways, and apoptosis, sel 1s the Bcl2 family. They validated the antiapoptotic role of EBV-miR-BART#-5p via the downregulation of Bid expression in EBV-positive cll lines [47]. Epstein-Barr viral mi BARTS-3p (BARTS) fan promote the oncogenesis of GC by directly targeting the rumor suppressor gene TPS3, mutations of which are rare in EBVaGC tissues [SI] Mechanistcally, BARTS direcely targets the ¥-UTR of TP53, downregulates TP5S expression and consequently decreases CDKNIA, BAX, and FAS expression, which leads to apoptosis existance after ehhemotherapeutie drug and fonizing radiation in viro (511. Not only do EBV miRNAs interfere with host genome expression but chey also inhibit / Gastric epithelial cell Fs ener er 495 (2020) 191-199 Regulate host mRNA expression Evading immune destruction 23, Roles of EBV and ost genomes inthe oncogenesis of GC. The EBV entes gassc epithelial cells mainly via cello el contact with EBV infected B lym plocytes. The EBV genomic as an epsom, itransribed to nce EBERS, EBNAL, LMP, LMP2A, BART nis, and BARFI, a sone are trate into proteins afer a persent latent infection. Abnormal hos genetic mutations and anplifations are oncogenic driving factors Some vial proteins, sch as EBNAL and LMP2A, promote oncogenes bythe CpC island metlaion of promotes of host runor suppressor gents, some of which Induce malignant vansfonning eptesented by BBARFI.tnteracions between EBV and host genones accelerate eatinogeness which shoud highlight the eguatoy role of BART miRNAS targeting the 91UTR of host miRNA transcription. Immune sytem evasion by PDI and PD-L2 amplification shields eatcinogenic wansformation. Al of these aco uimately tae the fate of oncogenesis the expression ofsele-viral antigens, suc as LMPI and LMP2A, thereby interfering with antigen presentation and immune eell activation that ‘enables host cells to escape immune recognition [52]. Given that BART IMiRNAS constitute 15% of toxal miRNA in EBVAGG cell ines [50], details of the regulatory mechanisms of BART miRNAs reqnice further investigation for targeted therapy. 12.5.2, BARFI, The BARFT open reading frame is 40-Kb fragment of BamH-A rightward transcription of the EBV genome. BARFI encoding @ 31-33 kDa protein is expressed in the cytoplasm and the cell membrane (60), from whit itis mainly stereted (54,55), dhen it activates che cell cycle as a growth factor [56]. Unlike the EBV tumor-associated latency iene, BARFI is regarded as an early Iytc gene, as it induces the lytic cycle in Burkit lymphoma cll lines, Dut is expressed during latency in EBVAGC [5]. High levels of BAREI tennscripts are expressed in EBVAGC Ussue samples and cell ine [58]. Although evidence in vivo is insu cient, BARFI functions avira transforming gene in EBVAGC cell Lines (57-59), since it could immortalize a primary monkey kidney epithelia cell Tine (55] and mouse fibroblast lines [60]. BARFT ean eause GC cells to resist apoptosis indsiced by chemotherapy, by indirectly increasing Bel-2, and decreasing Bax in BGC823 (59). BARFL upregulates the NFxB/cyelin DI pathway to promote the proliferation of gastric cart nom cells, an reduces the cell eyele inhibitor p21 in vitro (61. Torrini cecal, generated a BARFLspecifc monoclonal antibody with antitumor potenti that rediced tunior ntasses aad improved the long-term sr vival of SCID mice engrafted with NPC ane Iymphoma cell lines [62 ‘This was explained as mediating complement dependent and antibody dependent cell-mediated eytotoxicty against BARFT postive ‘mor cell in vitro 2]. These findings indiate thar BARF1 could serve ‘8 a therapeutic target in EBVAGC, However, BARFI protein expression in EBVAGC tissues, and wheter EBV-specfie oncogenes lead 10 gastric ‘areinogenesis both require further investigation. ‘abl 1 ists the EBV latent genes related to GC oncogenesis. Based on. analyses of whole genome sequence data of EBVaGC in the TCGA, EBVaGChasa specific expression profile of arent genes combined with & subset of tie genes of which nether reflec typical lytic or abortive lytic Infection, suggesting # unique role ofthe BBV genome in oncogenesis in EBVaGC [05] 4. Molecular features ‘The genetic ane epigenetic tumorigenic profiles of EBVAGC are quite different from that of conventional gastric adenocarcinoma. Global array analyses and high-throughput sequencing studies are underway t0 lasify GCs at the molecular level, ‘Marsusaka etal. (2011) classified GCs imo subgroups based on EBV (fom, EBV(/high, and EBV igh promoter methylation sta {641, Lei et a. (2013) identified proliferative, metabolic, and mesen- ‘chymal gastric molecular subtypes with different responses to PIS kinase inhibitors and -Auorouracl (6), The Cancer Genome Atlas Network (TCGA; 2014) used six genomic and molecular platforms to ‘comprehensively characterize 295 tuiors and categorized GC tumor types as being EBV-positive, oF having mlcrosaelie instability (MSD, _genomie stability (6S) or chromosomal instability (CIN) [11]. However, the clinical application of TCGA molecular classification is limited. The Asian Gancer Research Group (ACRG; 2015) Identified the following

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