Bile acids promote diethylnitrosamine-induced hepatocellular carcinoma via increased inflammatory signaling
| Autor: | Hua Li, Udayan Apte, Maura O'Neil, Nairita Roy, Lina Sun, Bharat Bhushan, Genea Edwards, Kevin M. Beggs, Prachi Borude, Sumedha Gunewardena, Michael W. Manley, Chad Walesky |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Physiology Liver and Biliary Tract Physiology/Pathophysiology Apoptosis Gastroenterology Pathogenesis chemistry.chemical_compound Liver Neoplasms Experimental Diethylnitrosamine Cells Cultured Bile acid NF-kappa B Middle Aged Endoplasmic Reticulum Stress Tumor Burden Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Hepatocellular carcinoma Neoplastic Stem Cells Female Inflammation Mediators Mitogen-Activated Protein Kinases Signal Transduction Adult medicine.medical_specialty Carcinoma Hepatocellular medicine.drug_class Cholic Acid Biology Kruppel-Like Factor 4 Young Adult 03 medical and health sciences SOX2 Physiology (medical) Internal medicine medicine Animals Humans Cell Proliferation Hepatology Cholic acid HCCS medicine.disease digestive system diseases Mice Inbred C57BL IκBα 030104 developmental biology chemistry Hepatocytes Cancer research Tumor promotion |
| Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 311:G91-G104 |
| ISSN: | 1522-1547 0193-1857 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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