title: Bile acids promote diethylnitrosamine-induced hepatocellular carcinoma via increased inflammatory signaling.
abstract: Hepatocellular carcinoma (HCC) is the most common hepatic malignancy and the third leading cause of cancer related deaths. Previous studies have implicated bile acids in pathogenesis of HCC, but the mechanisms are not known. We investigated the mechanisms of HCC tumor promotion by bile acids the diethylnitrosamine (DEN)-initiation-cholic acid (CA)-induced tumor promotion protocol in mice. The data show that 0.2% CA treatment resulted in threefold increase in number and size of DEN-induced liver tumors. All tumors observed in DEN-treated mice were well-differentiated HCCs. The HCCs observed in DEN-treated CA-fed mice exhibited extensive CD3-, CD20-, and CD45-positive inflammatory cell aggregates. Microarray-based global gene expression studies combined with Ingenuity Pathway Analysis revealed significant activation of NF-κB and Nanog in the DEN-treated 0.2% CA-fed livers. Further studies showed significantly higher TNF-α and IL-1β mRNA, a marked increase in total and phosphorylated-p65 and phosphorylated IκBα (degradation form) in livers of DEN-treated 0.2% CA-fed mice. Treatment of primary mouse hepatocytes with various bile acids showed significant induction of stemness genes including Nanog, KLF4, Sox2, and Oct4. Quantification of total and 20 specific bile acids in liver, and serum revealed a tumor-associated bile acid signature. Finally, quantification of total serum bile acids in normal, cirrhotic, and HCC human samples revealed increased bile acids in serum of cirrhotic and HCC patients. Taken together, these data indicate that bile acids are mechanistically involved pathogenesis of HCC and may promote HCC formation via activation of inflammatory signaling.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; Department of Hepatic Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Lina
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Kevin
authors.initials: K
authors.lastname: Beggs
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Prachi
authors.initials: P
authors.lastname: Borude
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Genea
authors.initials: G
authors.lastname: Edwards
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Bharat
authors.initials: B
authors.lastname: Bhushan
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Chad
authors.initials: C
authors.lastname: Walesky
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Nairita
authors.initials: N
authors.lastname: Roy
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Michael W
authors.initials: MW
authors.lastname: Manley
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas; Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Sumedha
authors.initials: S
authors.lastname: Gunewardena
authors.affiliation: Department of Pathology, University of Kansas Medical Center, Kansas City, Kansas; and.
authors.forename: Maura
authors.initials: M
authors.lastname: O'Neil
authors.affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; uapte@kumc.edu.
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019826:Cholic Acid / Q000097:blood / Q000633:toxicity*; D004052:Diethylnitrosamine; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D055815:Young Adult
chemical_list: D018836:Inflammation Mediators; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D016328:NF-kappa B; D004052:Diethylnitrosamine; D020928:Mitogen-Activated Protein Kinases; D019826:Cholic Acid
keywords: NF-κB; Nanog; cholic acid; proliferation