Epigenetic alterations in cholangiocarcinoma-sustained IL-6/STAT3 signaling in cholangio- carcinoma due to SOCS3 epigenetic silencing.
Cholangiocarcinoma (CCA) is a highly lethal malignant tumor arising from the biliary tract epithelium, characterized by its typically late clinical presentation and lack of effective therapeutic modalities. Chronic inflammatory conditions, including primary sclerosing cholangitis, liver fluke infestation and hepatolithiasis, are listed in the risk factors, but for most cases of CCA the cause is unknown. Recent advances in molecular pathogenesis have highlighted the importance of epigenetic alterations including promoter hypermethylation and histone deacetylation in addition to genetic changes in the process of cholangiocarcinogenesis. This review provides a comprehensive overview of the genes hypermethylated in CCA to date and their putative roles in cholangiocarcinogenesis. Among genes hypermethylated, we found the CpG island hypermethylation in suppressor of cytokine signaling 3 (SOCS3) gene promoter in CCA. Interleukin-6 (IL-6)-mediated signal transducers and activators of transcription 3 (STAT3) activation are aberrantly sustained in CCA cells, resulting in resistance to apoptosis. SOCS3 controls the IL-6/STAT3 signaling pathway by a classic feedback loop. Indeed, SOCS3 epigenetic silencing is responsible for sustained IL-6/STAT3 signaling in CCA. These findings provide new perspectives for epigenetic therapy to restore SOCS3 in this cancer.
Isomoto
Hajime
H
Department of Endoscopy, Nagasaki University Hospital of Medicine and Dentistry, Nagasaki, Japan. hajimei2002@yahoo.co.jp
D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D016147:Genes, Tumor Suppressor; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics
C508600:IL6 protein, human; D015850:Interleukin-6; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins