Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex
Mutated Genes and Abnormal Protein Expression (141)
Clicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.
|TP53 ||17p13.1 ||P53, BCC7, LFS1, TRP53 || ||-TP53 and Esophageal Cancer || 380|
|EGFR ||7p11.2 ||ERBB, HER1, mENA, ERBB1, PIG61, NISBD2 ||Amplification |
|-EGFR Amplification in Esophageal Cancer || 138|
|PTGS2 ||1q31.1 ||COX2, COX-2, PHS-2, PGG/HS, PGHS-2, hCox-2, GRIPGHS ||Overexpression ||-PTGS2 (COX2) Overexpression in Esophageal Cancer |
-COX2 Polymorphisms and Esophageal Cancer
|ALDH2 ||12q24.12 ||ALDM, ALDHI, ALDH-E2 || ||-ALDH2 and Esophageal Cancer || 89|
|MET ||7q31.2 ||HGFR, AUTS9, RCCP2, c-Met, DFNB97 || ||-C-MET and Esophageal Cancer || 62|
|CDKN1A ||6p21.2 ||P21, CIP1, SDI1, WAF1, CAP20, CDKN1, MDA-6, p21CIP1 || ||-CDKN1A Expression in Esophageal Cancer || 47|
|CD9 ||12p13.31 ||MIC3, MRP-1, BTCC-1, DRAP-27, TSPAN29, TSPAN-29 || ||-CD9 expression in Esophageal Cancer || 44|
|PIK3CA ||3q26.32 ||MCM, CWS5, MCAP, PI3K, CLOVE, MCMTC, PI3K-alpha, p110-alpha ||Prognostic ||-PIK3CA and Esophogeal Cancer || 42|
|ADH1B ||4q23 ||ADH2, HEL-S-117 || ||-ADH1B and Esophageal Cancer || 31|
|ERCC2 ||19q13.32 ||EM9, TTD, XPD, TTD1, COFS2, TFIIH || ||-ERCC2 and Esophageal Cancer || 30|
|PLCE1 ||10q23.33 ||PLCE, PPLC, NPHS3 || ||-PLCE1 and Esophageal Cancer || 29|
|NOTCH1 ||9q34.3 ||hN1, AOS5, TAN1, AOVD1 || ||-NOTCH1 and Esophageal Cancer || 19|
|SOX2 ||3q26.33 ||ANOP3, MCOPS3 || ||-SOX2 and Esoghogeal Cancer || 16|
|FGF4 ||11q13.3 ||HST, KFGF, HST-1, HSTF1, K-FGF, HBGF-4 || ||-FGF4 and Esophageal Cancer || 14|
|CTTN ||11q13.3 ||EMS1 ||Amplification |
|-CTTN and Esophogeal Cancer || 13|
|COL4A5 ||Xq22.3 ||ATS, ASLN, ATS1, CA54 || ||-COL4A5 and Esophageal Cancer || 11|
|RB1 ||13q14.2 ||RB, pRb, OSRC, pp110, p105-Rb, PPP1R130 || ||-RB1 and Esophageal Cancer || 10|
|STMN1 ||1p36.11 ||Lag, SMN, OP18, PP17, PP19, PR22, LAP18, C1orf215 || ||-STMN1 and Esophageal Cancer || 10|
|CDC25B ||20p13 || || ||-CDC25B and Esophageal Cancer || 10|
|SPARC ||5q33.1 ||ON, OI17, BM-40 || ||-SPARC and Esophageal Cancer || 10|
|EP300 ||22q13.2 ||p300, KAT3B, MKHK2, RSTS2 ||Prognostic ||-EP300 and Esophageal Cancer || 9|
|CYP2A6 ||19q13.2 ||CPA6, CYP2A, CYP2A3, P450PB, CYPIIA6, P450C2A || ||-CYP2A6 and Esophageal Cancer || 9|
|COL4A6 ||Xq22.3 ||DFNX6, DELXq22.3, CXDELq22.3 || ||-COL4A6 and Esophageal Cancer || 9|
|CCN1 ||1p22.3 ||GIG1, CYR61, IGFBP10 || ||-CYR61 and Esophageal Cancer || 9|
|FSCN1 ||7p22.1 ||HSN, SNL, p55, FAN1 || ||-FSCN1 and Esophageal Cancer || 9|
|S100A9 ||1q21.3 ||MIF, NIF, P14, CAGB, CFAG, CGLB, L1AG, LIAG, MRP14, 60B8AG, MAC387 || ||-S100A9 and Esophageal Cancer || 8|
|CRP ||1q23.2 ||PTX1 || ||-CRP and Esophageal Cancer || 8|
|NFE2L2 ||2q31 ||NRF2 || ||-NFE2L2 mutations in Esophageal Cancer || 7|
|C2orf40 ||2q12.2 ||ECRG4 || ||-C2orf40 and Esophageal Cancer || 7|
|DEC1 ||9q33.1 ||CTS9 || ||-DEC1 and Esophageal Cancer || 7|
|ADH1C ||4q23 ||ADH3 || ||-ADH1C and Esophageal Cancer || 7|
|CTSB ||8p23.1 ||APPS, CPSB || ||-CTSB and Esophageal Cancer || 6|
|MIRLET7C ||21q21.1 ||LET7C, let-7c, MIRNLET7C, hsa-let-7c || ||-MicroRNA let-7c and Esophageal Cancer || 6|
|S100A8 ||1q21.3 ||P8, MIF, NIF, CAGA, CFAG, CGLA, L1Ag, MRP8, CP-10, MA387, 60B8AG || ||-S100A8 and Esophageal Cancer || 6|
|HOTAIR ||12q13.13 ||HOXAS, HOXC-AS4, HOXC11-AS1, NCRNA00072 || ||-HOTAIR and Esophageal Cancer || 6|
|LOXL2 ||8p21.3 ||LOR, LOR2, WS9-14 || ||-LOXL2 and Esophageal Cancer || 5|
|PTPN1 ||20q13.13 ||PTP1B || ||-PTPN1 and Esophageal Cancer || 5|
|UCHL1 ||4p13 ||NDGOA, PARK5, PGP95, SPG79, PGP9.5, Uch-L1, HEL-117, PGP 9.5, HEL-S-53 || ||-UCHL1 and Esophageal Cancer || 5|
|RHBDF2 ||17q25.1 ||TEC, TOC, TOCG, RHBDL5, RHBDL6, iRhom2 ||Germline ||-RHBDF2 mutations in Tylosis - a familial esophageal cancer syndrome || 5|
|S100A2 ||1q21.3 ||CAN19, S100L || ||-S100A2 and Esophageal Cancer || 5|
|GPX3 ||5q33.1 ||GPx-P, GSHPx-3, GSHPx-P || ||-GPX3 and Esophageal Cancer || 5|
|TNFRSF6B ||20q13.33 ||M68, TR6, DCR3, M68E, DJ583P15.1.1 || ||-TNFRSF6B and Esophageal Cancer || 5|
|RRM2B ||8q22.3 ||P53R2, MTDPS8A, MTDPS8B || ||-RRM2B and Esophageal Cancer || 5|
|MMP7 ||11q22.2 ||MMP-7, MPSL1, PUMP-1 || ||-MMP7 Expression in Esophageal Cancer || 5|
|IGFBP7 ||4q12 ||AGM, PSF, TAF, FSTL2, IBP-7, MAC25, IGFBP-7, RAMSVPS, IGFBP-7v, IGFBPRP1 || ||-IGFBP7 and Esophageal Cancer || 5|
|TMEFF2 ||2q32.3 ||TR, HPP1, TPEF, TR-2, TENB2, CT120.2 || ||-TMEFF2 and Esophageal Cancer || 5|
|SKIL ||3q26 ||SNO, SnoA, SnoI, SnoN || ||-SKIL and Esophageal Cancer || 5|
|SOX17 ||8q11.23 ||VUR3 || ||-SOX17 and Esophageal Cancer || 5|
|XRCC2 ||7q36.1 ||FANCU || ||-XRCC2 and Esophageal Cancer || 5|
|LCN2 ||9q34.11 ||p25, 24p3, MSFI, NGAL || ||-LCN2 and Esophageal Cancer || 5|
|PTTG1 ||5q33.3 ||EAP1, PTTG, HPTTG, TUTR1 || ||-PTTG1 and Esophageal Cancer || 4|
|PRINS ||10p12.1 ||NCRNA00074 || ||-PRINS and Esophageal Cancer || 4|
|TOP2A ||17q21.2 ||TOP2, TP2A || ||-TOP2A Expression in Esophageal Cancer || 4|
|TP53INP1 ||8q22.1 ||SIP, Teap, p53DINP1, TP53DINP1, TP53INP1A, TP53INP1B || ||-TP53INP1 and Esophageal Cancer || 4|
|HOXB7 ||17q21.32 ||HOX2, HOX2C, HHO.C1, Hox-2.3 || ||-HOXB7 and Esophageal Cancer || 4|
|KMT2D ||12q13.12 ||ALR, KMS, MLL2, MLL4, AAD10, KABUK1, TNRC21, CAGL114 || ||-KMT2D and Esophageal Cancer || 4|
|PLA2G4A ||1q31.1 ||GURDP, cPLA2, PLA2G4, cPLA2-alpha || ||-PLA2G4A and Esophageal Cancer || 4|
|HOXA13 ||7p15.2 ||HOX1, HOX1J || ||-HOXA13 and Esophageal Cancer || 4|
|BIRC2 ||11q22.2 ||API1, MIHB, HIAP2, RNF48, cIAP1, Hiap-2, c-IAP1 || ||-BIRC2 and Esophageal Cancer || 4|
|CREBBP ||16p13.3 ||CBP, RSTS, KAT3A, RSTS1 ||GWS ||-CREBBP and Esophageal Cancer || 4|
|MAPK14 ||6p21.31 ||RK, p38, CSBP, EXIP, Mxi2, CSBP1, CSBP2, CSPB1, PRKM14, PRKM15, SAPK2A, p38ALPHA || ||-MAPK14 and Esophageal Cancer || 4|
|KRT7 ||12q13.13 ||K7, CK7, SCL, K2C7 || ||-KRT7 and Esophageal Cancer || 3|
|CKS2 ||9q22.2 ||CKSHS2 || ||-CKS2 and Esophageal Cancer || 3|
|ANO1 ||11q13.3 ||DOG1, TAOS2, ORAOV2, TMEM16A || ||-ANO1 and Esophageal Cancer || 3|
|IL23R ||1p31.3 || || ||-IL23R and Esophageal Cancer || 3|
|MT1G ||16q13 ||MT1, MT1K || ||-MT1G and Esophageal Cancer || 3|
|ELF3 ||1q32.1 ||ERT, ESX, EPR-1, ESE-1 || ||-ELF3 and Esophageal Cancer || 3|
|NQO2 ||6p25.2 ||QR2, DHQV, DIA6, NMOR2 || ||-NQO2 and Esophageal Cancer || 3|
|FGF19 ||11q13.3 || || ||-FGF19 and Esophageal Cancer || 3|
|ODC1 ||2p25 ||ODC || ||-ODC1 and Esogapheal Cancer || 3|
|CLDN3 ||7q11.23 ||RVP1, HRVP1, C7orf1, CPE-R2, CPETR2 || ||-CLDN3 and Esophageal Cancer || 3|
|MAML1 ||5q35.3 ||Mam1, Mam-1 || ||-MAML1 and Esophageal Cancer || 3|
|CTSL ||9q21.33 ||MEP, CATL, CTSL1 || ||-CTSL1 and Esophageal Cancer || 3|
|PERP ||6q24 ||THW, KCP1, PIGPC1, KRTCAP1, dJ496H19.1 || ||-PERP and Esophageal Cancer || 3|
|RACK1 ||5q35.3 ||H12.3, HLC-7, PIG21, GNB2L1, Gnb2-rs1 || ||-GNB2L1 and Esophageal Cancer || 3|
|FAT1 ||4q35.2 ||FAT, ME5, CDHF7, CDHR8, hFat1 || ||-FAT1 mutation in Esophogeal Cancer || 3|
|SOX6 ||11p15.2 ||SOXD, HSSOX6 || ||-SOX6 and Esophageal Cancer || 3|
|DMBT1 ||10q26.13 ||SAG, GP340, SALSA, muclin || ||-DMBT1 supression in Esophageal Cancer? || 3|
|KDM4C ||9p24.1 ||GASC1, JHDM3C, JMJD2C, TDRD14C || ||-KDM4C and Esophageal Cancer || 3|
|PTK7 ||6p21.1-p12.2 ||CCK4, CCK-4 || ||-PTK7 and Esophageal Cancer || 2|
|ZNF750 ||17q25.3 ||ZFP750 ||Deletion ||-ZNF750 mutation in Esophageal Cancer || 2|
|DGCR8 ||22q11.21 ||Gy1, pasha, DGCRK6, C22orf12 || ||-DGCR8 and Esophageal Cancer || 2|
|DRD2 ||11q23.2 ||D2R, D2DR || ||-DRD2 and Esophageal Cancer || 2|
|CD47 ||3q13.1-q13.2 ||IAP, OA3, MER6 || ||-CD47 and Esophageal Cancer || 2|
|GATA5 ||20q13.33 ||CHTD5, GATAS, bB379O24.1 || ||-GATA5 and Esophageal Cancer || 2|
|AKR1C2 ||10p15.1 ||DD, DD2, TDD, BABP, DD-2, DDH2, HBAB, HAKRD, MCDR2, SRXY8, DD/BABP, AKR1C-pseudo || ||-AKR1C2 and Esophageal Cancer || 2|
|REG1A ||2p12 ||P19, PSP, PTP, REG, ICRF, PSPS, PSPS1 || ||-REG1A and Esophageal Cancer || 2|
|ADAMTS9 ||3p14.1 || || ||-ADAMTS9 and Esophageal Cancer || 2|
|ASH1L ||1q22 ||ASH1, KMT2H, MRD52, ASH1L1 || ||-ASH1L and Esophageal Cancer || 2|
|HLA-E ||6p21.3 ||MHC, QA1, EA1.2, EA2.1, HLA-6.2 || ||-HLA-E and Esophageal Cancer || 2|
|AQP3 ||9p13.3 ||GIL, AQP-3 || ||-AQP3 and Esophageal Cancer || 2|
|HHIP ||4q31.21 ||HIP || ||-HHIP and Esophageal Cancer || 2|
|CDH3 ||16q22.1 ||CDHP, HJMD, PCAD || ||-CDH3 and Esophageal Cancer || 2|
|SERPINA1 ||14q32.13 ||PI, A1A, AAT, PI1, A1AT, PRO2275, alpha1AT || ||-SERPINA1 and Esophageal Cancer || 2|
|IRF2 ||4q35.1 ||IRF-2 || ||-IRF2 and Esophageal Cancer || 2|
|KPNA2 ||17q24.2 ||QIP2, RCH1, IPOA1, SRP1alpha, SRP1-alpha || ||-KPNA2 and Esophageal Cancer || 2|
|POLK ||5q13.3 ||DINP, POLQ, DINB1 || ||-POLK and Esophageal Cancer || 2|
|IFITM1 ||11p15.5 ||9-27, CD225, IFI17, LEU13, DSPA2a || ||-IFITM1 and Esophageal Cancer || 2|
|EZR ||6q25.3 ||CVL, CVIL, VIL2, HEL-S-105 || ||-EZR and Esophageal Cancer || 2|
|RAC3 ||17q25.3 || || ||-RAC3 and Esophageal Cancer || 2|
|GPX2 ||14q23.3 ||GPRP, GPx-2, GI-GPx, GPRP-2, GPx-GI, GSHPx-2, GSHPX-GI || ||-GPX2 and Esophageal Cancer || 2|
|PINX1 ||8p23.1 ||LPTL, LPTS || ||-PINX1 and Esophageal Cancer || 2|
|FAT2 ||5q33.1 ||CDHF8, CDHR9, HFAT2, MEGF1 || ||-FAT2 mutation in Esophogeal Cancer || 2|
|PRDX1 ||1p34.1 ||PAG, PAGA, PAGB, PRX1, PRXI, MSP23, NKEFA, TDPX2, NKEF-A || ||-PRDX1 and Esophageal Cancer || 2|
|ITGA6 ||2q31.1 ||CD49f, VLA-6, ITGA6B || ||-ITGA6 and Esophageal Cancer || 2|
|MMP11 ||22q11.23 ||ST3, SL-3, STMY3 || ||-MMP11 and Esophageal Cancer || 2|
|RARRES1 ||3q25.32 ||LXNL, TIG1, PERG-1 || ||-RARRES1 and Esophageal Cancer || 2|
|S100A10 ||1q21.3 ||42C, P11, p10, GP11, ANX2L, CAL1L, CLP11, Ca, ANX2LG || ||-S100A10 and Esophageal Cancer || 2|
|KMT2C ||7q36.1 ||HALR, MLL3 || ||-KMT2C and Esophageal Cancer || 2|
|SPRR2A ||1q21.3 || || ||-SPRR2A and Esophageal Cancer || 1|
|PLCD1 ||3p22.2 ||NDNC3, PLC-III || ||-PLCD1 and Esophageal Cancer || 1|
|FTL ||19q13.33 ||LFTD, NBIA3 || ||-FTL and Esophageal Cancer || 1|
|NEURL1 ||10q24.33 ||neu, NEUR1, NEURL, RNF67, neu-1, bA416N2.1 || ||-NEURL and Esophageal Cancer || 1|
|OMD ||9q22.31 ||OSAD, SLRR2C || ||-OMD and Esophageal Cancer || 1|
|VIPR2 ||7q36.3 ||VPAC2, VPAC2R, VIP-R-2, VPCAP2R, PACAP-R3, DUP7q36.3, PACAP-R-3, C16DUPq36.3 || ||-VIPR2 and Esophageal Cancer || 1|
|PDGFRL ||8p22 ||PDGRL, PRLTS || ||-PDGFRL and Esophageal Cancer || 1|
|COX6C ||8q22.2 || || ||-COX6C and Esophageal Cancer || 1|
|SPRR2C ||1q21.3 || || ||-SPRR2C and Esophageal Cancer || 1|
|COPS6 ||7q22.1 ||CSN6, MOV34-34KD || ||-COPS6 and Esophageal Cancer || 1|
|SELENOP ||5p12 ||SeP, SELP, SEPP, SEPP1 || ||-SEPP1 and Esophageal Cancer || 1|
|FNBP1 ||9q34.11 ||FBP17 || ||-FNBP1 and Esophageal Cancer || 1|
|TPM4 ||19p13.12-p13.11 ||HEL-S-108 || ||-TPM4 and Esophageal Cancer || 1|
|MAFG ||17q25.3 ||hMAF || ||-MAFG and Esophageal Cancer || 1|
|CSTB ||21q22.3 ||PME, ULD, CST6, EPM1, STFB, CPI-B, EPM1A || ||-CSTB and Esophageal Cancer || 1|
|ADAM29 ||4q34.1 ||CT73, svph1 || ||-ADAM29 mutations in Esophageal Cancer || 1|
|TCEAL7 ||Xq22.2 ||WEX5 || ||-TCEAL7 and Esophageal Cancer || 1|
|S100A3 ||1q21.3 ||S100E || ||-S100A3 and Esophageal Cancer || 1|
|GJB2 ||13q12.11 ||HID, KID, PPK, CX26, DFNA3, DFNB1, NSRD1, DFNA3A, DFNB1A || ||-GJB2 and Esophageal Cancer || 1|
|PDE4DIP ||1q21.2 ||MMGL, CMYA2 || ||-PDE4DIP and Esophageal Cancer || 1|
|SPRR1A ||1q21.3 ||SPRK || ||-SPRR1A and Esophageal Cancer || 1|
|RASSF10 ||11p15.3 || || ||-RASSF10 and Esophageal Cancer || 1|
|FEZ1 ||11q24.2 ||UNC-76 || ||-FEZ1 and Esophageal Cancer || 1|
|NEMF ||14q21.3 ||NY-CO-1, SDCCAG1 || ||-NEMF and Esophageal Cancer || 1|
|MIR100 ||11q24.1 ||MIRN100, miR-100 || ||-MIR100 and Esophageal Cancer || 1|
|SEPTIN5 ||22q11.21 ||H5, SEPT5, CDCREL, PNUTL1, CDCREL1, CDCREL-1, HCDCREL-1 || ||-SEPT5 and Esophageal Cancer || 1|
|PRRX1 ||1q24.2 ||PMX1, PRX1, AGOTC, PHOX1, PRX-1 || ||-PRRX1 and Esophageal Cancer || 1|
|SETD1B ||12q24.31 ||KMT2G, Set1B ||GWS ||-SETD1B and Esophageal Cancer || 1|
|MIR1256 ||1p36.12 ||MIRN1256, hsa-mir-1256 || ||-MicroRNA miR-1256 and Esophageal Cancer || 1|
|TNFRSF14 ||1p36.32 ||TR2, ATAR, HVEA, HVEM, CD270, LIGHTR || ||-TNFRSF14 and Esophageal Cancer || |
|SPRR1B ||1q21.3 ||SPRR1, GADD33, SPR-IB, CORNIFIN || ||-SPRR1B and Esophageal Cancer || |
|SPRR2B ||1q21.3 || || ||-SPRR2B and Esophageal Cancer || |
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
Fukuoka E, Yamashita K, Tanaka T, et al.Neoadjuvant Chemotherapy Increases PD-L1 Expression and CD8
Anticancer Res. 2019; 39(8):4539-4548 [PubMed
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BACKGROUND/AIM: The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP).
PATIENTS AND METHODS: Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8
RESULTS: The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8
CONCLUSION: NAC-FP induced PD-L1 expression on ICs and CD8
Background: MiR-216a-5p has been reported to be associated with several tumors, including prostate cancer and melanoma. However, its expression level and potential role in esophageal squamous cell carcinoma (ESCC) remain uncertain.
Results: Here, we found that miR-216a-5p expression was significantly down-regulated in clinical ESCC tissues and cells. Functional assays were performed to evaluate the biological effects of miR-216a-5p on cell proliferation and cell apoptosis by CCK-8 assay and flow cytometry in ESCC cell lines, EC9706 and TE-9. The results showed that miR-216a-5p overexpression repressed cell proliferation and induced cell apoptosis. Through bioinformatics prediction and luciferase reporter assay, we revealed that miR-216a-5p could directly target tectonic family member 1 (TCTN1). Moreover, TCTN1 was obviously suppressed by miR-216a-5p overexpression. In addition, TCTN1 expression was significantly increased and inversely correlated with the levels of miR-216a-5p in ESCC tissues. More importantly, down-regulation of TCTN1 imitated, while restoration of TCTN reversed the effects of miR-216a-5p on cell proliferation and apoptosis. At the molecular level, we further found that TCTN1 overexpression reversed the effects of miR-216a-5p transfection on the expression of PCNA, Bcl-2 and Bad.
Conclusions: Our results demonstrate that miR-216a-5p might serve as a tumor suppressor in ESCC cells through negatively regulating TCTN1 expression, indicating the possibility that miR-216a-5p and TCTN1 might be attractive targets for ESCC therapeutic intervention.
Esophageal squamous cell carcinoma (ESCC) is a malignancy that severely threatens human health and carries a high incidence rate and a low 5-year survival rate. MicroRNAs (miRNAs) are commonly accepted as a key regulatory function in human cancer, but the potential regulatory mechanisms of miRNA-mRNA related to ESCC remain poorly understood.The GSE55857, GSE43732, and GSE6188 miRNA microarray datasets and the gene expression microarray datasets GSE70409, GSE29001, and GSE20347 were downloaded from Gene Expression Omnibus databases. The differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were obtained using GEO2R. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). A protein-protein interaction (PPI) network and functional modules were established using the STRING database and were visualized by Cytoscape. Kaplan-Meier analysis was constructed based on The Cancer Genome Atlas (TCGA) database.In total, 26 DEMs and 280 DEGs that consisted of 96 upregulated and 184 downregulated genes were screened out. A functional enrichment analysis showed that the DEGs were mainly enriched in the ECM-receptor interaction and cytochrome P450 metabolic pathways. In addition, MMP9, PCNA, TOP2A, MMP1, AURKA, MCM2, IVL, CYP2E1, SPRR3, FOS, FLG, TGM1, and CYP2C9 were considered to be hub genes owing to high degrees in the PPI network. MiR-183-5p was with the highest connectivity target genes in hub genes. FOS was predicted to be a common target gene of the significant DEMs. Hsa-miR-9-3p, hsa-miR-34c-3p and FOS were related to patient prognosis and higher expression of the transcripts were associated with a poor OS in patients with ESCC.Our study revealed the miRNA-mediated hub genes regulatory network as a model for predicting the molecular mechanism of ESCC. This may provide novel insights for unraveling the pathogenesis of ESCC.
Zhang Y, Chen H, Zhu H, Sun XCBX8 promotes tumorigenesis and confers radioresistance in esophageal squamous cell carcinoma cells through targeting APAF1.
Gene. 2019; 711:143949 [PubMed
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As a transcriptional repressor, Chromobox 8 (CBX8) overexpression is found to be associated with tumorigenesis in several cancers. However, its role in radiotherapy resistance remains poorly characterized. Our study is the first to explore the correlation between CBX8 and radioresistance. We report here that CBX8 is upregulated in Esophageal Squamous Cell Carcinoma (ESCC) tissues and cells and serves as an indicator of poor prognosis for ESCC patients. CBX8 knockdown inhibits cell proliferation, colony formation capability, DNA repair and promotes cell apoptosis. Moreover, the transcriptome sequencing analysis demonstrates that CBX8 downregulates the expression of Apoptotic protease activating factor 1 (APAF1), which is the core protein that mediates mitochondrial apoptotic pathways. APAF1 depletion could abrogate apoptosis induced by CBX8 knockdown in irradiated ESCC cells. Our results provide novel insight into CBX8 as a therapeutic target to improve the radiosensitivity of ESCC.
Yan Q, Chen T, Yang H, et al.The Effect of FERMT1 Regulated by miR-24 on the Growth and Radiation Resistance of Esophageal Cancer.
J Biomed Nanotechnol. 2019; 15(3):621-631 [PubMed
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The present study addresses the role and underlying mechanism of FERMT1 in the development of esophageal cancer (EC). High level of FERMT1 expression was found in human EC tissues and was significantly correlated with poor overall survival. Overexpression of FERMT1 by a lentiviral vector markedly promoted EC cell proliferation and radiation resistance
BACKGROUND: Melanoma-associated antigen-A (MAGE-A) was recognized as high-expressed in many solid tumors including esophageal carcinoma (EC), nevertheless, was reported to be low/not-expressed in normal tissues. Thus, it was considered as an extraordinary appropriate target for treatment especially in immunotherapy. Therefore, it demanded more detail knowledge on the precise function of MAGE-A.
METHODS: In this study, we used the data from the Cancer Genome Atlas dataset (TCGA-ESCA) to analyze the expression and survival for MAGE A3/4/11 (the subtype of MAGE-A) using the online tool of UALCAN. Furthermore, the high-throughput sequencing data of the patients with esophageal squamous-cell carcinoma (ESCC) from TCGA dataset were performed to analyze the correlation test, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of MAGE A3/4/9/11 using LinkeDomics (online tool) and ClueGO (inner software of Cytoscape). Finally, relative gene expressions of MAGE A3/4/9/11 were verified by quantitative real-time PCR (q-PCR) in the patients with EC.
RESULTS: MAGE A3/4/11 was high-expressed in tissues of patients with ESCC, and there was no difference in survival time for patients between the high-expressed with the low/medium-expressed. The Go enrichment analysis showed that the 4 MAGE-A subtypes (MAGE-A3/4/9/11) were enriched in the regulation of the adaptive immune response, translational initiation, interleukin-4 production, response to type I interferon, and skin development, respectively. The KEGG results showed that they were enriched in T cell receptor signaling pathway (MAGE-A3), Th1 and Th2 differentiation, antigen processing and presentation (MAGE-A4), cytokine-cytokine receptor interaction (MAGE-A9), and chemokine signaling pathway (MAGE-A11).
CONCLUSION: MAGE A3/4/9/11 was high-expressed in EC, and were enrolled in the regulation of immune response. They may consider as candidate immune target for EC treatment and provided the messages for further research in the function of MAGE-A.
Rubinstein JC, Nicolson NG, Ahuja NNext-generation Sequencing in the Management of Gastric and Esophageal Cancers.
Surg Clin North Am. 2019; 99(3):511-527 [PubMed
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Next-generation sequencing has enabled genome-wide molecular profiling of gastric and esophageal malignancies at single-nucleotide resolution. The resultant genomic profiles provide information about the specific oncogenic pathways that are the likely driving forces behind tumorigenesis and progression. The abundance of available genomic data has immense potential to redefine management paradigms for these difficult disease processes. The ability to capitalize on the information provided through high-throughput sequencing technologies will define cancer care in the coming decades and could shift the paradigm from current stage-based, organ-specific treatments toward tailored regimens that target the specific culprit pathways driving individual tumors.
Pennathur A, Godfrey TE, Luketich JDThe Molecular Biologic Basis of Esophageal and Gastric Cancers.
Surg Clin North Am. 2019; 99(3):403-418 [PubMed
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Esophageal cancer and gastric cancer are leading causes of cancer-related mortality worldwide. In this article, the authors discuss the molecular biology of esophageal and gastric cancer with a focus on esophageal adenocarcinoma. They review data from The Cancer Genome Atlas project and advances in the molecular stratification and classification of esophageal carcinoma and gastric cancer. They also summarize advances in microRNA, molecular staging, gene expression profiling, tumor microenvironment, and detection of circulating tumor DNA. Finally, the authors summarize some of the implications of understanding the molecular basis of esophageal cancer and future directions in the management of esophageal cancer.
Indoleamine 2, 3-dioxygenase 1 (IDO1) is a primary enzyme that generates immunosuppressive metabolites. It plays a major role in tumor immunology and is a potential immune-based therapeutic target. We have reported that IDO1 protein expression was associated with an unfavorable clinical outcome in esophageal cancer. Recently, it has been reported that IDO1 expression is regulated by methylation of the IDO1 promoter. Thus, the aim of this study was to examine the relationship between IDO1 expression, IDO1 promoter methylation, and clinicopathological features in esophageal cancer. We first confirmed changes in IDO1 expression levels in vitro by treating cells with 5-azacytidine. We then evaluated the relationship between IDO1 expression levels, IDO1 promoter methylation (bisulfite pyrosequencing), and clinicopathological features using 40 frozen samples and 242 formalin-fixed, paraffin-embedded samples resected from esophageal cancer patients. We treated cell lines with 5-azacytidine, and the resulting hypomethylation induced significantly higher IDO1 expression (P < .001). In frozen samples, IDO1 expression levels correlated inversely with IDO1 promoter methylation levels (R = -0.47, P = .0019). Furthermore, patients in the IDO1 promoter hypomethylation group (n = 67) had a poor prognosis compared with those in the IDO1 promoter hypermethylation group (n = 175) (overall survival, P = .011). Our results showed that IDO1 promoter hypomethylation regulated IDO1 expression and was associated with a poor prognosis in esophageal cancer patients.
Intratumoral heterogeneity, particularly the potential cancer stemness of single cancer cells, has not yet been fully elucidated in human esophageal cancer. Single‑cell transcriptome sequencing of two types of esophageal adenocarcinoma (EAC) and two types of esophageal squamous cell carcinoma (ESCC) tissues was performed, and the intratumoral cancer stemness of the types of esophageal cancer were characterized at the single‑cell level in the present study. By comparing the transcriptomic profiles of single cancer cells with high and low stemness in individual patients, it was revealed that the overexpression of cell cycle‑associated genes in EAC cells was highly correlated with stemness, whereas overexpression of genes involved in the signaling pathways of DNA replication and DNA damage repair was significantly correlated with stemness in ESCC. High expression of these stemness‑associated genes was correlated with poor prognosis of patients. Additionally, poly [ADP‑ribose] polymerase(PARP)4 was identified as a novel cancer stemness‑associated gene in ESCC and its association with survival was validated in a cohort of 121 patients with ESCC. These findings have profound potential implications for the use of cell cycle inhibitors in EAC and PARP inhibitors in ESCC, which may provide novel mechanistic insights into the plasticity of esophageal cancer.
Wang T, Feng Y, Zhao Z, et al.IL1RN Polymorphisms Are Associated with a Decreased Risk of Esophageal Cancer Susceptibility in a Chinese Population.
Chemotherapy. 2019; 64(1):28-35 [PubMed
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BACKGROUND: Recent evidence suggested that IL1RN (interleukin-1 receptor antagonist) polymorphisms increased the susceptibility to cancers. The present study aimed to evaluate whether IL1RN was related to esophageal cancer susceptibility in a Northwest Han Chinese population.
METHODS: The case-control study was conducted on 384 esophageal cancer patients and 499 healthy controls. We successfully genotyped four SNPs distributed in IL1RN. The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to observe the expression of IL1RN in esophageal cancer tissues and normal tissues. RegulomeDB and HaploReg v4.1 were used to calculate possible functional effects of the polymorphisms. We also used genetic models to detect any potential association between IL1RN variants and esophageal cancer risk.
RESULTS: In our study, rs3181052 was associated with a reduced risk of esophageal cancer in the codominant (odds ratio [OR] = 0.70, 95% confidence interval [CI] 0.52-0.93, p = 0.040), the dominant (OR = 0.75, 95% CI 0.57-0.99, p = 0.041), and the overdominant (OR = 0.71, 95% CI 0.54-0.93, p = 0.012) model. The rs452204 was associated with a 0.76-fold (OR = 0.76, 95% CI 0.58-0.99; p = 0.043) decreased esophageal cancer risk under the overdominant model without adjustment. We also found that rs3181052 had a negative effect on esophageal cancer under the overdominant model (OR = 0.72, 95% CI 0.53-0.97, p = 0.033) adjusted for age and gender. In stratified analyses by age >55 years, rs3181052 reduced the risk of esophageal cancer in the dominant and overdominant models. In addition, rs315919 had a remarkable influence on esophageal cancer risk in females, while the association was not significant between rs3181052 and esophageal cancer risk in males.
CONCLUSIONS: Our study provided the first evidence that IL1RN rs3181052, rs452204, and rs315919 are correlated with a decreased risk of esophageal cancer in a Northwest Han Chinese population. These findings may be useful for the development of early prognostics for esophageal cancer. However, further larger studies on different ethnic populations are warranted to verify these findings.
Ma J, Li TF, Han XW, Yuan HFDownregulated MEG3 contributes to tumour progression and poor prognosis in oesophagal squamous cell carcinoma by interacting with miR-4261, downregulating DKK2 and activating the Wnt/β-catenin signalling.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1513-1523 [PubMed
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Long noncoding RNA (lncRNA) MEG3 has been widely reported to be decreased in a growing list of primary human tumours and play a key role in tumour suppression. However, there are few reports about MEG3 expression and function in oesophagal squamous cell carcinoma (ESCC). Here, we found that MEG3 expression was significantly downregulated in tumour tissues, and its low expression was associated with large tumour size, lymph node metastasis and advanced clinical stage in ESCC patients. Univariate and multivariate analyses revealed low expression of MEG3 as an independent predictor for disease-free survival and overall survival. Cell experiments showed that MEG3 inhibited ESCC cell proliferation, migration and invasion. Subsequently, miR-4261 was identified and confirmed to be the target of MEG3, and MEG3 functions, at least in part, by targeting miR-4261. Additionally, Dickkopf-2 (DKK2), a Wnt/β-catenin signalling inhibitor, was identified to be a target of miR-4261. MEG3 interacted with miR-4261, derepressed DKK2 and blocked the Wnt/β-catenin signalling, thereby inhibiting tumourigenesis and progression in ESCC. In vivo experiments also confirmed this conclusion. Our study for the first time elaborated the critical role of MEG3-miR-4261-DKK2-Wnt/β-catenin signalling axis in ESCC, and MEG3 could represent a novel diagnostic and prognostic biomarker and therapeutic target in ESCC.
Anti-PUF60 autoantibodies are reportedly detected in the sera of patients with dermatomyositis and Sjögren's syndrome; however, little is known regarding its existence in the sera of cancer patients. FIR, a splicing variant of the PUF60 gene, is a transcriptional repressor of c-myc. In colorectal cancer, there is an overexpression of the dominant negative form of FIR, in which exon 2 is lacking (FIRΔexon2). Previously, large-scale SEREX (serological identification of antigens by recombinant cDNA expression cloning) screenings have identified anti-FIR autoantibodies in the sera of cancer patients. In the present study, we revealed the presence and significance of anti-FIR (FIR/FIRΔexon2) Abs in the sera of patients with esophageal squamous cell carcinoma (ESCC). Our results were validated by an amplified luminescence proximity homogeneous assay using sera of patients with various cancer types. We revealed that anti-FIRΔexon2 Ab had higher sensitivity than anti-FIR Ab. Receiver operating characteristic (ROC) analysis was applied for evaluating the use of anti-FIRΔexon2 Ab as candidate markers such as anti-p53 Ab and carcinoembryonic antigen, and the highest area under the ROC curve was observed in the combination of anti-FIRΔexon2 Ab and anti-p53 Ab. In summary, our results suggest the use of anti-FIRΔexon2 Ab in combination with the anti-p53 Ab as a predictive marker for ESCC. The area under the ROC curve was further increased in the advanced stage of ESCC. The value of anti-FIRΔexon2 autoantibody as novel clinical indicator against ESCC and as a companion diagnostic tool is discussed.
Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort (n = 508). Furthermore, knockdown of BRCA1/2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment.
Li H, Yang F, Chai L, et al.CCAAT/Enhancer Binding Protein β-Mediated MMP3 Upregulation Promotes Esophageal Squamous Cell Cancer Invasion
Genet Test Mol Biomarkers. 2019; 23(5):304-309 [PubMed
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Miyamoto K, Minegaki T, Tanahashi M, et al.Synergistic Effects of Olaparib and DNA-damaging Agents in Oesophageal Squamous Cell Carcinoma Cell Lines.
Anticancer Res. 2019; 39(4):1813-1820 [PubMed
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BACKGROUND/AIM: Chemotherapy is an important first-line treatment for oesophageal squamous cell carcinoma (ESCC). However, there are few secondary options. Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, enhances the cytotoxicity of various anticancer drugs and has been used to treat advanced ovarian and breast cancers. This study examined the effect of olaparib on the cytotoxicity of anticancer drugs in ESCC cell lines.
MATERIALS AND METHODS: ESCC KYSE70 and KYSE140 cells were grown in Dulbecco's modified Eagle's medium and treated with 5-fluorouracil (5-FU), cisplatin, docetaxel, doxorubicin, SN-38, or temozolomide without or with olaparib.
RESULTS: Olaparib enhanced the cytotoxicity of all tested anticancer drugs and increased the effects of cisplatin, doxorubicin, SN-38, and temozolomide synergistically. These anticancer drugs caused the accumulation of phospho-histone H2AX Ser139 (γH2AX), a biomarker of DNA damage, and olaparib increased this accumulation.
CONCLUSION: PARP inhibitors may potentiate the anticancer activity of DNA-damaging agents in ESCC patients synergistically.
BACKGROUND At present, there is no effective targeted therapy for esophageal squamous cell carcinoma (ESCC), and it is urgent to find new targets for the treatment of ESCC. TRAF4 has been regarded as a cause of carcinogenesis due to overexpression in many cancer types and participation in multiple signaling pathways. However, there are few studies on TRAF4 in ESCC worldwide. Its expression in ESCC and whether it affects the prognosis of patients still remain unclear. MATERIAL AND METHODS We detected the expressions of TRAF4, ki-67, and p53 in 100 cases of ESCC and 80 cases of adjacent normal esophageal squamous epithelium tissues by immunohistochemical technique. We further explored the relationship between TRAF4 and ESCC and its prognosis through statistical analysis. RESULTS TRAF4 was highly expressed in ESCC tissues and was mainly expressed in the cytoplasm. Overexpression of TRAF4 in ESCC was also associated with high expression of ki-67 and p53 (P<0.05). We also found that patients with high expression of TRAF4 had significantly lower OS than in patients with low TRAF4 expression (P<0.05). Overexpression of TRAF4 was an independent risk factor affecting the prognosis of patients (P<0.05). CONCLUSIONS We found that TRAF4 was highly expressed in ESCC tissues and was mainly expressed in the cytoplasm of cancer cells. Overexpression of TRAF4 was an independent risk factor affecting the overall prognosis of patients. The results indicated that TRAF4 may become a new target for the treatment of ESCC in the future.
The reported risk susceptibility between
Xie W, Huang P, Wu B, et al.Clinical significance of LOXL4 expression and features of LOXL4-associated protein-protein interaction network in esophageal squamous cell carcinoma.
Amino Acids. 2019; 51(5):813-828 [PubMed
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Lysyl oxidase-like 4 (LOXL4), a member of the LOX family proteins, catalyzes oxidative deamination of lysine residues in collagen and elastin, which are responsible for maintaining extracellular matrix homeostasis. In this study, the mRNA expression of LOXL4 in seven esophageal squamous cell carcinoma (ESCC) cell lines and 15 ESCC pairs of clinical samples were examined. Furthermore, LOXL4 protein levels in the ESCC cell lines were determined using western blotting. With the use of immunofluorescence, LOXL4 was observed to be localized primarily in the cytoplasm, but was also present in the nucleus. In addition, the results indicated that the upregulated expression of LOXL4 was associated with poor survival in patients with ESCC even following curative resection (P = 0.010). Similar Kaplan-Meier estimator curves for proteins that interact with LOXL4, SUV39H1 (P = 0.014) and COL2A1 (P = 0.011), were plotted. The analyses based on the protein-protein interaction network depicted the expression of LOXL4 and its associated proteins as well as their functions, suggesting that LOXL4 and its associated proteins may serve a significant role in the development and progression of ESCC. In conclusion, the results of the present study suggest that LOXL4 is a potential biomarker for patients with ESCC, as well as SUV39H1 and COL2A1, and high expression levels of these genes are associated with poor prognosis in patients with ESCC.
The dysregulation of Fbxo4-cyclin D1 axis occurs at high frequency in esophageal squamous cell carcinoma (ESCC), where it promotes ESCC development and progression. However, defining a therapeutic vulnerability that results from this dysregulation has remained elusive. Here we demonstrate that Rb and mTORC1 contribute to Gln-addiction upon the dysregulation of the Fbxo4-cyclin D1 axis, which leads to the reprogramming of cellular metabolism. This reprogramming is characterized by reduced energy production and increased sensitivity of ESCC cells to combined treatment with CB-839 (glutaminase 1 inhibitor) plus metformin/phenformin. Of additional importance, this combined treatment has potent efficacy in ESCC cells with acquired resistance to CDK4/6 inhibitors in vitro and in xenograft tumors. Our findings reveal a molecular basis for cancer therapy through targeting glutaminolysis and mitochondrial respiration in ESCC with dysregulated Fbxo4-cyclin D1 axis as well as cancers resistant to CDK4/6 inhibitors.
BACKGROUNDS: Since Mesenchymal epithelial transition (MET) amplification has been regarded as a potential treatment target, the knowledge of its prevalence and prognostic importance is crucial. However, its clinical pathologic characteristics are not well known in esophageal squamous cell carcinoma (ESCC).
METHODS: We investigated MET gene status with fluorescence in situ hybridization (FISH) assay in 495 ESCC cases using tissue microarrays. Prognostic significance as well as correlations with various clinicopathological parameters was evaluated.
RESULTS: Among 495 patients, 28 (5.7%) cases were MET FISH positive, including 5 cases (1%) with true gene amplification. There were no statistically significant associations between MET FISH-positivity and clinicopathologic characteristics. A significantly poorer prognosis was observed in 28 patients with MET FISH-positivity (disease free survival/DFS, P < 0.001 and overall survival/OS, P = 0.001). Multivariate analysis revealed MET FISH-positivity was an independent prognostic factor for DFS (hazard ratio/HR, 1.953; 95% confidence interval/CI, 1.271-2.999; P = 0.002) and OS (HR, 1.926; 95% CI, 1.243-2.983; P = 0.003). MET FISH-positivity was associated with DFS (P = 0.022 and 0.020) and OS (P = 0.046 and 0.024) both in stage I-II ESCC and in stage III-IVa ESCC. No statistical significance (DFS, P = 0.492 and OS, P = 0.344) was detected between stage I-II ESCC with MET FISH-positivity and stage III-IVa ESCC with FISH-negativity.
CONCLUSIONS: Increased MET gene copy number is an independent prognostic factor in ESCC, and ESCC might have potentially been up-staged by increased MET gene copy number. The results indicate that increased MET gene copy number is a very promising parameter, in clinical therapy and follow-up plans.
Singh V, Singh AP, Sharma I, et al.Epigenetic deregulations of Wnt/β-catenin and transforming growth factor beta-Smad pathways in esophageal cancer: Outcome of DNA methylation.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):192-203 [PubMed
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Background: Promoter methylation of tumor suppressor genes (TSGs) is a well-reported portent in carcinogenesis; hence, it is worthy to investigate this in high-risk Northeast population of India. The study was designed to investigate methylation status of 94 TSGs in esophageal squamous cell carcinoma (ESCC). Further, the effect of OPCML promoter methylation on gene expression was analyzed by immunohistochemistry. Moreover, in silico protein-protein interactions were examined among 8 TSGs identified in the present study and 23 epigenetically regulated genes reported previously by our group in ESCC.
Materials and Methods: Methylation profiling was carried out by polymerase chain reaction array and OPCML protein expression was examined by tissue microarray-based immunohistochemistry.
Results: OPCML, NEUROG1, TERT, and WT1 genes were found hypermethylated and SCGB3A1, CDH1, THBS1, and VEGFA were hypomethylated in Grade 2 tumor. No significant change in OPCML expression was observed among control, Grade 1, and Grade 2 tumor. Conclusively, hypermethylation of the studied OPCML promoter in Grade 2 tumor produced no effect on expression. Unexpectedly, OPCML expression was downregulated in Grade 3 tumor in comparison to other groups signifying that downregulation of OPCML expression may lead to higher grade of tumor formation at the time of diagnosis of ESCC in patients. Significant interactions at protein level were found as VEGFA:PTK2, CTNNB1:CDH1, CTNNB1:VEGFA, CTNNB1:NEUROG1, CTNND2:CDH1, and CTNNB1:TERT. These interactions are pertinent to Wnt/β-catenin and TGF-β-Smad pathways.
Conclusions: Deranged OPCML expression may lead to high-grade ESCC as well as epigenetically regulated genes, that is, CDH1, CTNNB1, CTNND2, THBS1, PTK2, WT1, OPCML, TGFB1, and SMAD4 may alter the Wnt/β-catenin and TGF-β-Smad pathways in ESCC. Further study of these genes could be useful to understand the molecular pathology of ESCC with respect to epithelial-mesenchymal transition (EMT) mediated by Wnt/β-catenin and TGF-β signaling pathways.
Wanchai V, Jin J, Bircan E, et al.Genome-wide tracts of homozygosity and exome analyses reveal repetitive elements with Barrets esophagus/esophageal adenocarcinoma risk.
BMC Bioinformatics. 2019; 20(Suppl 2):98 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Barrett's esophagus (BE) is most commonly seen as the condition in which the normal squamous epithelium lining of the esophagus is replaced by goblet cells. Many studies show that BE is a predisposing factor for the development of esophageal adenocarcinoma (EAC), a particularly lethal cancer. The use of single nucleotide polymorphisms (SNPs) to map BE/EAC genes has previously provided insufficient genetic information to fully characterize the heterogeneous nature of the disease. We therefore hypothesize that rigorous interrogation of other types of genomic changes, e.g. tracts of homozygosity (TOH), repetitive elements, and insertion/deletions, may provide a comprehensive understanding of the development of BE/EAC.
RESULTS: First, we used a case-control framework to identify TOHs by using SNPs and tested for association with BE/EAC. Second, we used a case only approach on a validation series of eight samples subjected to exome sequencing to identify repeat elements and insertion/deletions. Third, insertion/deletions and repeat elements identified in the exomes were then mapped onto genes in the significant TOH regions. Overall, 24 TOH regions were significantly differentially represented among cases, as compared to controls (adjusted-P = 0.002-0.039). Interestingly, four BE/EAC-associated genes within the TOH regions consistently showed insertions and deletions that overlapped across eight exomes. Predictive functional analysis identified NOTCH, WNT, and G-protein inflammation pathways that affect BE and EAC.
CONCLUSIONS: The integration of common TOHs (cTOHs) with repetitive elements, insertions, and deletions within exomes can help functionally prioritize factors contributing to low to moderate penetrance predisposition to BE/EAC.
Glucose transporter 1 (GLUT1) expression is a prognostic marker for esophageal squamous cell carcinoma (ESCC). Recent work on GLUT1 and development of specific inhibitors supports the feasibility of GLUT1 inhibition as a treatment for various cancers. The anti-proliferative effects of GLUT1-specific small interfering RNA (siRNA) and a GLUT1 inhibitor were evaluated in ESCC cell lines. Expression of pro-proliferative and anti-proliferative signaling and effector molecules was examined by western blotting and quantitative RT-PCR. GLUT1 expression in pretreatment clinical biopsy samples was measured by immunohistochemistry and correlated with various clinicopathological parameters and response to chemotherapy. The reduction in standardized uptake value (SUV) of
Ma W, Zhang CQ, Dang CX, et al.Upregulated long-non-coding RNA DLEU2 exon 9 expression was an independent indicator of unfavorable overall survival in patients with esophageal adenocarcinoma.
Biomed Pharmacother. 2019; 113:108655 [PubMed
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In this study, we aimed to explore the expression profiles of some known functional lncRNAs in esophageal adenocarcinoma (EAD) and to screening the potential prognostic makers, using data from The Cancer Genome Atlas (TCGA)-esophageal carcinoma (ESCA). Results showed that DLEU2 is a high potential OS related marker among 73 functional lncRNAs. DLEU2 and its intronic miR-15a and miR-16-1 expression were significantly upregulated in EAD compared with adjacent normal tissues. However, miR-15a and miR-16-1 expression were only weakly correlated with DLEU2 expression. Univariate and multivariate analysis confirmed that DLEU2 expression, but not miR-15a or miR-16-1 expression is an independent prognostic marker in terms of OS (HR:1.688, 95%CI: 1.085-2.627, p = 0.020) in EAD patients. The exon 9 of DLEU2 is very strongly co-expressed with DLEU2 (Pearson's r = 0.96) and showed better predictive value than total DLEU2 expression in predicting the OS of EAD patients. Multivariate analysis confirmed its independent prognostic value (HR:1.970, 95%CI: 1.266-3.067, p = 0.003), after adjustment of histologic grade, pathological stages and the presence of residual tumor. By checking the methylation status of DLEU2 gene, we excluded the possibility of the influence of two CpG sites near the DLEU2 exon 9 locus on its expression. In addition, although copy number alterations (CNAs) were observed DLEU2 gene, heterozygous loss (-1), low-level copy gain (+1) and high-level amplification (+2) had no significant association with DLEU2 transcription. Based on these findings, we infer that DLEU2 exon 9 expression might serve as a valuable biomarker of unfavorable OS in EAD patients.
Homeobox genes are known to be classic examples of the intimate relationship between embryogenesis and tumorigenesis, which are a family of transcriptional factors involved in determining cell identity during early development, and also dysregulated in many malignancies. Previously, HOXB7, HOXC6 and HOXC8 were found abnormally upregulated in esophageal squamous cell carcinoma (ESCC) tissues compared with normal mucosa and seen as poor prognostic predictors for ESCC patients, and were shown to promote cell proliferation and anti-apoptosis in ESCC cells. These three HOX members have a high level of functional redundancy, making it difficult to target a single HOX gene. The aim of the present study was to explore whether ESCC cells are sensitive to HXR9 disrupting the interaction between multiple HOX proteins and their cofactor PBX, which is required for HOX functions. ESCC cell lines (KYSE70, KYSE150, KYSE450) were treated with HXR9 or CXR9, and coimmunoprecipitation and immunofluorescent colocalization were carried out to observe HOX/PBX dimer formation. To further investigate whether HXR9 disrupts the HOX pro-oncogenic function, CCK-8 assay and colony formation assay were carried out. Apoptosis was assessed by flow cytometry, and tumor growth in vivo was investigated in a xenograft model. RNA-seq was used to study the transcriptome of HXR9-treated cells. Results showed that HXR9 blocked HOX/PBX interaction, leading to subsequent transcription alteration of their potential target genes, which are involved in JAK-signal transducer and activator of transcription (STAT) activation and apoptosis inducement. Meanwhile, HXR9 showed an antitumor phenotype, such as inhibiting cell proliferation, inducing cell apoptosis and significantly retarding tumor growth. Therefore, it is suggested that targeting HOX/PBX may be a novel effective treatment for ESCC.
BACKGROUND: An altered Wnt-signaling activation has been reported during Barrett's esophagus progression, but with rarely detected mutations in APC and β-catenin (CTNNB1) genes.
METHODS: In this study, a robust in-depth expression pattern analysis of frizzled receptors, co-receptors, the Wnt-ligands Wnt3a and Wnt5a, the Wnt-signaling downstream targets Axin2, and CyclinD1, as well as the activation of the intracellular signaling kinases Akt and GSK3β was performed in an in vitro cell culture model of Barrett's esophagus. Representing the Barrett's sequence, we used normal esophageal squamous epithelium (EPC-1, EPC-2), metaplasia (CP-A) and dysplasia (CP-B) to esophageal adenocarcinoma (EAC) cell lines (OE33, OE19) and primary specimens of squamous epithelium, metaplasia and EAC.
RESULTS: A loss of Wnt3a expression was observed beginning from the metaplastic cell line CP-A towards dysplasia (CP-B) and EAC (OE33 and OE19), confirmed by a lower staining index of WNT3A in Barrett's metaplasia and EAC, than in squamous epithelium specimens. Frizzled 1-10 expression analysis revealed a distinct expression pattern, showing the highest expression for Fzd2, Fzd3, Fzd4, Fzd5, Fzd7, and the co-receptor LRP5/6 in EAC cells, while Fzd3 and Fzd7 were rarely expressed in primary specimens from squamous epithelium.
CONCLUSION: Despite the absence of an in-depth characterization of Wnt-signaling-associated receptors in Barrett's esophagus, by showing variations of the Fzd- and co-receptor profiles, we provide evidence to have a significant role during Barrett's progression and the underlying pathological mechanisms.
Turato C, Scarpa M, Kotsafti A, et al.Squamous cell carcinoma antigen 1 is associated to poor prognosis in esophageal cancer through immune surveillance impairment and reduced chemosensitivity.
Cancer Sci. 2019; 110(5):1552-1563 [PubMed
] Free Access to Full Article Related Publications
Squamous cell carcinoma antigen-1 (SCCA1) overexpression is associated with poor prognosis and chemoresistance in several tumor types, however, the underlying mechanisms remain elusive. Here, we report SCCA1 in relation to the immune and peritumoral adipose tissue microenvironment in early and advanced esophageal adenocarcinoma (EAC). In our series of patients with EAC, free SCCA1 serum levels were associated with significantly worse overall survival, and SCCA1-IgM serum levels showed a trend to a worse overall survival. Serum SCCA1 and intratumoral SCCA1 were inversely correlated with immune activation markers. In agreement with these findings, SCCA1 induced the expression of the immune checkpoint molecule programmed death ligand-1 on monocytes and a direct correlation of these 2 molecules was observed in sequential tumor sections. Furthermore, SCCA1 mRNA expression within the tumor was inversely correlated with stem cell marker expression both within the tumor and in the peritumoral adipose tissue. In vitro, in EAC cell lines treated with different chemotherapeutic drugs, cell viability was significantly modified by SCCA1 presence, as cells overexpressing SCCA1 were significantly more resistant to cell death. In conclusion, poor prognosis in EAC overexpressing SCCA1 is due to reduced tumor chemosensitivity as well as intratumoral immunity impairment, likely induced by this molecule.
Liu L, Zhang S, Liu X, Liu JAberrant promoter 2 methylation‑mediated downregulation of protein tyrosine phosphatase, non‑receptor type 6, is associated with progression of esophageal squamous cell carcinoma.
Mol Med Rep. 2019; 19(4):3273-3282 [PubMed
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The human protein tyrosine phosphatase, non‑receptor type 6 (PTPN6) gene is located on chromosome 12p13 and encodes an Mr 68,000 non‑receptor type protein‑tyrosine phosphatase. The PTPN6 gene has been considered as a candidate tumor suppressor in hematological and solid malignancies, and promoter methylation may be an epigenetic modification silencing its expression. However, the detailed role of PTPN6 and its promoter methylation status in the pathogenesis of esophageal squamous cell carcinoma (ESCC) has not been fully elucidated. The aim of the present study was to investigate PTPN6 expression in ESCC tissues and esophageal cancer cell lines, detect the effect of CpG hypermethylation on the activity of PTPN6, and additionally elucidate the role and prognostic significance of PTPN6 in ESCC tumorigenesis and progression. The expression of PTPN6 was identified to be significantly downregulated in esophageal cancer cell lines and ESCC tissues. Marked upregulation of PTPN6 was detected in 5‑aza‑2'‑deoxycytidine‑treated esophageal cancer cells, and frequent hypermethylation of the CpG sites within the P2 promoter (P2) was detected in ESCC tissues and esophageal cancer cell lines. The expression and methylation status of PTPN6 was associated with tumor node metastasis stage, pathological differentiation and lymph node metastasis in patients with ESCC. Aberrant hypermethylation of the P2 exhibited marked tumor specificity and was identified to be associated with the expression level of PTPN6. Downregulation and hypermethylation of PTPN6 were identified to be associated with poor ESCC patient survival. Furthermore, upregulation of PTPN6 inhibited the proliferation and invasion of esophageal cancer cells in vitro. The results of the present study suggest that PTPN6 may serve as a tumor suppressor in ESCC, and it may serve as a potential target for antitumor therapy.
Qiao G, Dai C, He Y, et al.Effects of miR‑106b‑3p on cell proliferation and epithelial‑mesenchymal transition, and targeting of ZNRF3 in esophageal squamous cell carcinoma.
Int J Mol Med. 2019; 43(4):1817-1829 [PubMed
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Previous studies have demonstrated that the dysregulation of microRNAs (miRs) is frequently associated with cancer progression. Deregulation of miR‑106b‑3p has been observed in various types of human cancer. However, the biological function of miR‑106b‑3p in esophageal squamous cell carcinoma (ESCC) remains unclear. Thus, the aim of this study was to investigate the role of miR‑106b‑3p in ESCC. In the current study, the results indicated that miR‑106b‑3p was upregulated in ESCC cell lines and tissues. An increase in miR‑106b‑3p using miR mimics significantly promoted the proliferation of ESCC cells in vitro. Furthermore, the results demonstrated that miR‑106b‑3p overexpression promoted migration, invasion and epithelial‑mesenchymal transition (EMT) of ESCC cells. In addition, zinc and ring finger 3 (ZNRF3) was identified as a target of miR‑106b‑3p in ESCC cells, and the ZNRF3 expression level was inversely associated with miR‑106b‑3p. It was also demonstrated that miR‑106b‑3p has a role in EMT by regulating Wnt/β‑catenin signaling pathway in ESCC. In conclusion, these data suggested that miR‑106b‑3p promotes cell proliferation and invasion, partially by downregulating ZNRF3 and inducing EMT via Wnt/β‑catenin signaling in ESCC cells. Thus, miR‑106b‑3p and ZNRF3 may be novel molecular targets for the future treatment of ESCC.