# Interplay of bile acid and estrogen signaling

> **NIH NIH R01** · UNIVERSITY OF RHODE ISLAND · 2021 · $423,398

## Abstract

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.

## Key facts

- **NIH application ID:** 10071137
- **Project number:** 5R01CA213419-04
- **Recipient organization:** UNIVERSITY OF RHODE ISLAND
- **Principal Investigator:** Ruitang Deng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,398
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071137

## Citation

> US National Institutes of Health, RePORTER application 10071137, Interplay of bile acid and estrogen signaling (5R01CA213419-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071137. Licensed CC0.

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