Interplay of bile acid and estrogen signaling

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Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related deaths. At present, there are limited options in treating HCC patients. There are urgent needs to develop effective therapies for HCC. Both farnesoid x receptor (FXR) and estrogen receptor  (ER) signaling are linked to HCC. A large body of evidence support a view that FXR and ER signaling provide protection against HCC development. FXR knockout (FXR-KO) mice spontaneously developed HCC as they aged while ER-KO mice exhibited increased susceptibility to chemical-induced HCC. Consistent with their protective roles in HCC, FXR and ER signaling were dysregulated or defective in large percentages (60-80%) of HCC patients with decreased or total lack of FXR or ER expression with concurrent switches to its variants or different isoforms. In our preliminary studies with FXR-KO, ER-KO and double FXR and ER knockout (FXR/ER-DKO) mice, we discovered that FXR and ER signaling crosstalked each other through coordinately regulating a novel oncogene ubiquitin specific peptidase 2 (USP2) in the development of HCC. The overall objective of this proposal is to understand the interplay of FXR and ER signaling in HCC development and the underlying mechanisms. The central hypothesis, built on our extensive preliminary results, is that FXR and ER signaling have both tumor-protective and promoting activities dependent on the status of the other signaling through their regulation of USP2 in a reciprocal antagonistic manner. Specific Aim 1 is to delineate the interplay of FXR and ER signaling in HCC development. Specific Aim 2 is to determine the oncogenic roles of USP2 as a downstream target of FXR and ER signaling in the development of HCC. Specific Aim 3 is to investigate the mechanistic insights into the intriguing crosstalk between FXR and ER signaling in regulating USP2. The study represents a pioneering effort to delineate the complex and interactive nature of FXR and ER signaling in HCC development. The experiments proposed are built on our extensive, robust and novel preliminary findings as well as our long-standing experience in studying FXR and ER signaling and their interaction in liver diseases including cholestasis and HCC. With newly generated FXR/ER-DKO mice, our laboratory is thus uniquely poised to investigate the interplay of FXR and ER signaling in HCC development. Implementation of these innovative concepts and findings is expected to greatly enable the advancement of developing novel therapies for HCC.