title: Cross talk between the TM4SF5/focal adhesion kinase and the interleukin-6/STAT3 pathways promotes immune escape of human liver cancer cells.
abstract: TM4SF5 overexpressed in hepatocellular carcinoma activates focal adhesion kinase (FAK) during tumor cell migration. However, it remains unknown how TM4SF5 in hepatocellular carcinoma cells compromises with immune actions initiated by extracellular cytokines. Normal and cancerous hepatocytes with or without TM4SF5 expression were analyzed for the effects of cytokine signaling activity on TM4SF5/FAK signaling and metastatic potential. We found that interleukin-6 (IL-6) was differentially expressed in hepatocytes depending on cancerous malignancy and TM4SF5 expression. IL-6 treatment activated FAK and STAT3 and enhanced focal adhesion (FA) formation in TM4SF5-null cells, but it decreased TM4SF5-dependent FAK activity and FA formation in SNU761-TM4SF5 cells. STAT3 suppression abolished the IL-6-mediated effects in normal Chang cells, but it did not recover the TM4SF5-dependent FAK activity that was inhibited by IL-6 treatment in cancerous SNU761-TM4SF5 cells. In addition, modulation of FAK activity did not change the IL-6-mediated STAT3 activity in either the Chang or SNU761 cell system. TM4SF5 expression in SNU761 cells caused invasive extracellular matrix degradation negatively depending on IL-6/IL-6 receptor (IL-6R) signaling. Thus, it is likely that hepatic cancer cells adopt TM4SF5-dependent FAK activation and metastatic potential by lowering IL-6 expression and avoiding its immunological action through the IL-6-STAT3 pathway.
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Kang
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seo Hee
authors.initials: SH
authors.lastname: Nam
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Haeng Eun
authors.initials: HE
authors.lastname: Song
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Doohyung
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Republic of Korea Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea jwl@snu.ac.kr.
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D022001:Focal Adhesions / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D019947:Receptors, Interleukin-6 / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology
chemical_list: D015850:Interleukin-6; D008565:Membrane Proteins; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C111029:TM4SF5 protein, human; D051416:Focal Adhesion Protein-Tyrosine Kinases