Targeting sphingosine-1-phosphate axis in obesity-promoted hepatocellular carcinoma

Abstract

This proposal will provide evidence that the SphK1/S1P/S1PR1 axis is one of the critical factors that bridge obesity, inflammation, and hepatocellular carcinoma (HCC)[1-5]. Surgical procedures such as liver resection and liver transplantation are the first-line treatments for HCC patients. However, the high incidence of tumor recurrence and metastasis after liver surgery remains a major problem [6, 7]. Therefore, development of novel therapies are need to eliminate tumor recurrence and metastasis after liver surgery. This proposal will pave the way for development of new cancer therapeutics targeting the SphK1/S1P/S1PR1 axis as a promising strategy for effective treatment of HCC. Targeting this axis that leads to NFkb -IL6-STAT3 amplification loop could also disrupt existing pre-metastatic niches and thus may prevent metastasis and recurrence that is a major problem in HCC. The strategies used for this study will be based on an animal model for obesity-promoted hepatocellular carcinoma development and progression using DEN-induced HCC (diethylnitrosamine) combined with diet-induced obesity ("high fat diet") in mice C57Bl/6 wild type and SphK1 knockout. In addition, signaling pathway inhibitors for S1PR1-SphK1-S1P will be used. Various methodologies will be applied to evaluate the physiological, cellular and molecular effects in each condition studied. (AU)