# Targeting oncogenes for hepatocellular carcinoma

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $402,127

## Abstract

Summary
Hepatocellular carcinoma (HCC), the fifth most common cancer and the second most common cause of
cancer-related deaths worldwide, has no effective treatment for advanced disease. The present proposal
focuses on two interacting proteins, AEG-1 and SND1, which function as bona fide oncogenes for HCC. AEG-1
and SND1 cooperate to increase RNA-induced silencing complex (RISC) activity where AEG-1 functions as a
scaffold protein and SND1 functions as a nuclease. However, there is a gap of knowledge in our understanding
of the mechanism(s) driving AEG-1 and SND1 cooperative oncogenic functions. In primary hepatocytes, AEG-
1 is predominantly localized in the nucleus, while in HCC cells AEG-1 is primarily localized in the endoplasmic
reticulum (ER) membrane. Preliminary results indicate ER-anchoring is required for AEG-1 oncogenic function.
ER-anchored AEG-1 binds specifically to secretory and membrane protein-encoding mRNAs to facilitate their
translation. Analysis of SND1 RNA-interactome also identifies membrane protein-encoding mRNAs. Co-
localization studies show that both AEG-1 and SND1 are located on ER membrane in HCC cells. Both AEG-1
and SND1 activate NF-κB. ER-anchored AEG-1 functions as a platform for upstream signaling molecules of
NF-κB pathway and thus plays an essential role in NF-κB activation. The mechanism by which SND1 activates
NF-κB is not known. We hypothesize that in transformed hepatocytes, AEG-1 translocates from the nucleus
and anchors into the ER membrane where it recruits SND1 and both cooperate to promote HCC by modulating
post-transcriptional regulation of mRNAs in RISC, translational regulation of membrane proteins and activation
of NF-κB, AEG-1 and SND1 require each other for optimum functioning and might not exert oncogenic activity
alone, and combinatorial inhibition of AEG-1 and SND1 might be an effective therapeutic strategy for HCC.
Experiments are designed to interrogate these hypotheses using novel mouse models and targeted
nanoplexes delivering siRNA for AEG-1 and SND1. This proposal will contribute to our long-term objectives of
identifying key players regulating HCC pathogenesis and translating this knowledge into development of novel
and effective targeted therapies. The immediate objective of the proposal is in-depth understanding of the
molecular mechanisms by which AEG-1 and SND1 promote HCC and evaluate a combinatorial strategy of
inhibiting AEG-1 and SND1 in a mouse model as a potential therapeutic. Thus the proposal has both
mechanistic and therapeutic significance and innovation. Successful completion of the proposed studies will
establish new targets for developing therapeutics and provide pre-clinical evidence for a targeted protocol.

## Key facts

- **NIH application ID:** 9904586
- **Project number:** 5R01CA230561-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Devanand Sarkar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,127
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904586

## Citation

> US National Institutes of Health, RePORTER application 9904586, Targeting oncogenes for hepatocellular carcinoma (5R01CA230561-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904586. Licensed CC0.

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