# Tumor-promoting liver injuries and mechanisms

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $502,440

## Abstract

The goal of this project is to decipher how various liver injuries and disorders can
accelerate and exacerbate development of hepatocellular carcinoma (HCC), one leading cause
of cancer-related mortality worldwide. The immediate focus is on elucidating the tumorigenic
liver damages generated ironically by loss of pro-oncogenic molecules in hepatocytes. In recent
experiments, we found that deletion of Shp2/Ptpn11, previously known to be pro-oncogenic,
aggravated HCC development induced by diethylnitrosamine (DEN) or by Pten deficiency and
NASH. Consistently, several other groups reported that targeted removal of oncoproteins, such
as c-Met, Ikkb, and b-catenin, from hepatocytes indeed aggravated HCC induced by DEN or
other oncogenic drivers. However, the underlying mechanisms for the anti-oncogenic effect of
these oncoproteins are unclear. Our hypothesis is that loss of the pro-oncogenic molecules
generates a variety of tumor-promoting factors in the liver microenvironment, resulting in
exacerbated tumorigenesis. Of note, these mouse tumor models closely recapitulate many
aspects of the pathogenic process in liver cancer patients. Therefore, we believe that common
mechanisms or oncogenic liver disorders are shared between the mouse models and human
patients in tumor initiation and progression. On this project, we will pursue a comprehensive
analysis of the molecular and cellular events that drive hepato-carcinogenesis using several
mouse models. We propose the following three Specific Aims: 1) to search and identify
tumorigenic factors in livers deficient for c-Met, Ikkb, Shp2 or b-catenin; 2) to determine the
mutation profiles and HCC initiation in these mutants; and 3) to characterize DEN-induced and
spontaneous tumorigenesis in liver deficient for both Shp2 and Ikkb. Success of this project will
decipher common and distinctive mechanisms that drive liver tumorigenesis, and will facilitate
design of novel and effective therapeutic strategies for liver cancer.

## Key facts

- **NIH application ID:** 10112208
- **Project number:** 5R01CA239629-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Gen-Sheng Feng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $502,440
- **Award type:** 5
- **Project period:** 2020-02-20 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112208

## Citation

> US National Institutes of Health, RePORTER application 10112208, Tumor-promoting liver injuries and mechanisms (5R01CA239629-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10112208. Licensed CC0.

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