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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Gastroenterology 2016 ; 150 (3): 707-19 Nephropedia Template TP
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TLR4 Signaling via NANOG Cooperates With STAT3 to Activate Twist1 and Promote Formation of Tumor-initiating Stem-like Cells in Livers of Mice #MMPMID26582088
Kumar DBU; Chen CL; Liu JC; Feldman DE; Sher LS; French S; DiNorcia J; French SW; Naini BV; Junrungsee S; Agopian VG; Zarrinpar A; Machida K
Gastroenterology 2016[Mar]; 150 (3): 707-19 PMID26582088show ga
BACKGROUND & AIMS: Obesity and alcohol consumption contribute to steatohepatitis, which increases risk for hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCCs). Mice Hepatocytes that express HCV-NS5A in liver upregulate expression of Toll-like receptor-4 (TLR4), and develop liver tumors containing tumor-initiating stem-like cells (TICs) that express NANOG. We investigated whether the TLR4 signals to NANOG to promote development of TICs and tumorigenesis in mice placed on Western diet high in cholesterol and saturated fat (HCFD). METHODS: We expressed HCV-NS5A from a transgene (NS5A Tg) in Tlr4?/? (C57Bl6/10ScN), and wild type control mice. Mice were fed a HCFD for 12 months. TICs were identified and isolated based on being CD133+, CD49f+, and CD45-. We obtained 142 paraffin-embedded sections of different stage HCCs and adjacent non-tumor areas from the same patients, and performed gene expression, immunofluorescence, and immunohistochemical analyses. RESULTS: A higher proportion of NS5A Tg mice developed liver tumors (39%) than mice that did not express HCV NS5A following the HCFD (6%); only 9% of Tlr4?/? NS5A Tg mice fed HCFD developed liver tumors. Livers from NS5A Tg mice fed the HCFD had increased levels of TLR4, NANOG, pSTAT3, and TWIST1 proteins, and increases in Tlr4, Nanog, Stat3, and Twist1 mRNAs. In TICs from NS5A Tg mice. NANOG and pSTAT3 directly interacts to activate expression of Twist1. Levels of TLR4, NANOG, pSTAT3, and TWIST were increased in HCC compared with non-tumor tissues from patients. CONCLUSIONS: HCFD and HCV-NS5A together stimulated TLR4-NANOG and the OB-R-pSTAT3 signaling pathways resulting in liver tumorigenesis through an exaggerated mesenchymal phenotype with prominent Twist1-expressing TICs.