# Intra- and inter-cellular signals that drive hepato-oncogenesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $401,163

## Abstract

Liver cancer, mainly hepatocellular carcinoma (HCC), has become a most deadly
malignant disease worldwide. So far, pharmaceutic inhibition of major oncogenic pathways
has achieved little therapeutic benefit to liver cancer patients. We believe this is due to under-
appreciation of the complexity in mechanisms of hepato-oncogenesis. In recent experiments,
we and others have identified paradoxically anti-oncogenic effects of classical oncogenic
molecules, such as c-Met, EGFR, β-catenin, Ikkβ, Jnk, and Shp2, in the liver. Ablating these
molecules in hepatocytes enhanced HCC induced by chemical carcinogen DEN. To test a
theory that loss of the oncogenic molecules generates an oncogenic microenvironment that
promotes DEN-induced HCC, we have established another mouse HCC model, by
transfection of oncogenic β-catenin (CAT), c-Met (MET) and PIK3CA (PIK), oncoproteins
frequently detected in human HCCs. As expected, MET/CAT-driven HCC was aggravated in
β-catenin-deficient liver, due to tumor-promoting factors induced by β-catenin removal. In
contrast, Shp2 deletion dramatically suppressed HCC driven by MET/CAT or MET/PIK,
despite a similar pro-tumorigenic environment in Shp2-deficient liver. Based on these novel
unanticipated data, we propose a new hypothesis that although removal of Shp2 or β-catenin
generates cell-extrinsic tumorigenic factors in the hepatic environment, the endogenous Shp2
is indispensable for oncogenic signaling in hepatocytes. To test this hypothesis, we propose
three specific aims on this project. Aim 1 is to determine the cell-intrinsic role of Shp2 in
hepato-oncogenic signaling. Aim 2 is to determine the cell-autonomous effect of β-catenin in
liver tumorigenesis. Aim 3 is to search and identify cell-extrinsic factors induced by loss of the
oncoproteins in hepatocytes. The results are expected to be instrumental for design of novel
therapeutic strategies for liver cancer by inhibiting both cell-intrinsic oncogenic signals and
the secondary environmental factors.

## Key facts

- **NIH application ID:** 10772996
- **Project number:** 5R01CA236074-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jin Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $401,163
- **Award type:** 5
- **Project period:** 2020-02-10 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772996

## Citation

> US National Institutes of Health, RePORTER application 10772996, Intra- and inter-cellular signals that drive hepato-oncogenesis (5R01CA236074-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10772996. Licensed CC0.

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