title: Inflammation Promotes Expression of Stemness-Related Properties in HBV-Related Hepatocellular Carcinoma.
abstract: The expression of cancer stemness is believed to reduce the efficacy of current therapies against hepatocellular carcinoma (HCC). Understanding of the stemness-regulating signaling pathways incurred by a specific etiology can facilitate the development of novel targets for individualized therapy against HCC. Niche environments, such as virus-induced inflammation, may play a crucial role. However, the mechanisms linking inflammation and stemness expression in HCC remain unclear. Here we demonstrated the distinct role of inflammatory mediators in expressions of stemness-related properties involving the pluripotent octamer-binding transcription factor 4 (OCT4) in cell migration and drug resistance of hepatitis B virus-related HCC (HBV-HCC). We observed positive immunorecognition for macrophage chemoattractant protein 1 (MCP-1)/CD68 and OCT4/NANOG in HBV-HCC tissues. The inflammation-conditioned medium (inflamed-CM) generated by lipopolysaccharide-stimulated U937 human leukemia cells significantly increased the mRNA and protein levels of OCT4/NANOG preferentially in HBV-active (HBV+HBsAg+) HCC cells. The inflamed-CM also increased the side population (SP) cell percentage, green fluorescent protein (GFP)-positive cell population, and luciferase activity of OCT4 promoter-GFP/luciferase in HBV-active HCC cells. Furthermore, the inflamed-CM upregulated the expressions of insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) and activated IGF-IR/Akt signaling in HBV-HCC. The IGF-IR phosphorylation inhibitor picropodophyllin (PPP) suppressed inflamed-CM-induced OCT4 and NANOG levels in HBV+HBsAg+ Hep3B cells. Forced expression of OCT4 significantly increased the secondary sphere formation and cell migration, and reduced susceptibility of HBV-HCC cells to cisplatin, bleomycin, and doxorubicin. Taking together, our results show that niche inflammatory mediators play critical roles in inducing the expression of stemness-related properties involving IGF-IR activation, and the upregulation of OCT4 contributes to cancer migration and drug resistance of HBV-HCC cells. Findings in this paper would provide potential targets for a therapeutic strategy targeting on inflammatory environment for HBV-HCC.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Te-Sheng
authors.initials: TS
authors.lastname: Chang
authors.affiliation: Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chi-Long
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|TMU Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Wu
authors.affiliation: School of Medical Laboratory Sciences and Biotechnology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jun-Jen
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|TMU Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yung Che
authors.initials: YC
authors.lastname: Kuo
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Kam-Fai
authors.initials: KF
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Sin-Yi
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Sey-En
authors.initials: SE
authors.lastname: Lin
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Shui-Yi
authors.initials: SY
authors.lastname: Tung
authors.affiliation: Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Liang-Mou
authors.initials: LM
authors.lastname: Kuo
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Ying-Huang
authors.initials: YH
authors.lastname: Tsai
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|TMU Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.|Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan.|Ph.D. Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yen-Hua
authors.initials: YH
authors.lastname: Huang
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000821:virology; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000150:complications*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000473:pathology* / Q000821:virology; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D018398:Homeodomain Proteins; D007334:Insulin-Like Growth Factor I; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D011034:Podophyllotoxin; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; C111835:CCL2 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C486780:NANOG protein, human; C494173:POU5F1 protein, human; C415032:picropodophyllin