# Signaling pathways during hepatocarcinogenesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $368,669

## Abstract

ABSTRACT
Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. Signaling pathways
which promote HCC pathogenesis remain poorly defined. Activation of PI3K/AKT/mTOR signaling cascade has
been demonstrated in multiple tumor types, including HCC. mTOR regulates cell growth and metabolism via the
formation of two multiprotein complexes: mTORC1 and mTORC2. While mTORC1 has been extensively studied
in HCC, the functional contribution of mTORC2 during hepatocarcinogenesis is not well understood. mTORC2
functions by modulating AGC kinases, especially AKT kinases. AKT functions to regulate multiple pathways,
including FOXOs and TSC1/2 tumor suppressor genes. Our previous studies have shown that coexpression of
activated forms of AKT and Ras could cooperate to rapidly induce liver tumor development in mice. Recently,
we discovered that concomitant activation of Ras and loss of Tsc2 induced HCC formation in mice over long
latency. The results suggest additional signaling function downstream of AKT in HCC pathogenesis. FOXO1 is
a major downstream target of AKT, and its expression is strongly downregulated in human HCC samples.
However, whether loss of FOXO1 is able to promote HCC development, and how it interacts with TSC/mTORC1
to transduce signal downstream of mTORC2/AKT during HCC pathogenesis remains to be determined. Based
on these preliminary data, we hypothesize that TSC/mTORC1 and FOXO1 cascades have distinct roles in
mediating mTORC2/AKT signaling in HCC pathogenesis. To test these hypotheses, we propose the following
three aims. In Aim 1, we will investigate the genetic crosstalk between FOXO1 and TSC tumor suppressors in
HCC. In Aim 2, we will define the functional roles of Tsc/mTORC1 and FoxO1 signaling cascades downstream
of mTORC2/Akt1 in c-Myc driven HCC. And in Aim 3, we plan to elucidate the signaling pathways downstream
of mTORC2/Akt during c-Met/β-catenin HCC pathogenesis. In summary, in this application, we will apply
innovative mouse genetic approaches in combination with in vitro experiments as well as human HCC sample
studies to delineate mTORC2/AKT, TSC/mTORC1 and FOXO1 signaling cascades during hepatic
carcinogenesis. The results will not only provide novel mechanistic insight into how deregulated signaling
pathways contribute to oncogene driven HCC development, but also will help pave the way for precision medicine
for HCC treatment.

## Key facts

- **NIH application ID:** 9906655
- **Project number:** 1R01CA239251-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Xin Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,669
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906655

## Citation

> US National Institutes of Health, RePORTER application 9906655, Signaling pathways during hepatocarcinogenesis (1R01CA239251-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9906655. Licensed CC0.

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