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HGF/MET axis drives hepatocellular carcinoma progression and determines sensitivity to MET-targeted therapy

Xie, Qian, Su, Yanli, Dykema, Karl, Johnson, Jennifer, Koeman, Julie, Giorgi, Valeria, Essenburg, Curt, Kang, Liang, Iwaya, Keiichi, Seki, Shuhji, Khoo, Sok, Zhang, Boheng, Buonaguro, Franco, Marincola, Francesco, Furge, Kyle, VandeWoude, George and Shinomiya, Nariyoshi (2013) HGF/MET axis drives hepatocellular carcinoma progression and determines sensitivity to MET-targeted therapy. Genes Cancer.

Abstract

Overexpression of hepatocyte growth factor (HGF), which activates the MET pathway, is common in hepatocellular carcinoma (HCC), but the mechanism of how it regulates the pathogenesis of hepatitis B virus (HBV)-caused HCC is unknown. Using genetically engineered mouse models, we found that overexpression of HGF (C3HHGF mice) and of hepatitis B virus surface antigen (C3HHBsAg mice) each induced spontaneous HCC, but that HGF overexpression accelerated HBsAg production and gave the fastest HCC progression. HCC tumors from C3HHGF mice showed gene expression patterns highly similar to those from HBV-positive HCC patients who had poor prognosis, strongly suggesting that HGF has a leading role in the molecular basis of HBV-induced HCC. Overexpression of HGF was also found in hepatitis C-positive HCC patients. Those tumors have up-regulated HGF and VEGF signaling pathways, as found in C3HHGF mice, indicating that HGF plays a similar role in HCV-induced HCC. Therapeutically, both C3HHGF and human HCC xenograft models with HGF overexpression or MET amplification were sensitive to MET inhibitors, providing a rationale for applying MET-targeted therapy to patients who have HGF-driven HCC.

Item Type: Article
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/9113

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