# Mechanisms that promote hepatocellular carcinoma due to chronic ethanol exposure

> **NIH NIH R21** · CATHOLIC UNIVERSITY OF AMERICA · 2023 · $184,329

## Abstract

SUMMARY
Hepatocellular carcinoma (HCC) is the fifth most common cancer world-wide with over 600,000 new cases per
year and a dismal five-year survival rate at less than 9%. Most HCC patients have chronic liver disease resulting
mainly from HCV/HBV infection, chronic alcohol consumption or aflatoxin exposure. Although most patients that
develop HCC have cirrhosis or hepatitis, the mechanisms promoting HCC differ between pathologies such that
not all cases should be treated the same. This proposal is aimed at understanding the mechanisms that promote
HCC due to chronic ethanol exposure, a form of HCC that is on the rise as HCV and HBV infections are being
better prevented and treated. In particular, this proposal is focused on understanding chromosome 8q24
amplification that is observed more frequently in alcohol-induced HCC. Because c-Myc resides on this amplified
region, we propose that at later stages of HCC, chromosome 8q24 is amplified leading to high c-Myc levels. The
high Myc promotes Miz1 transcriptional repression and loss of the epithelial phenotype and acquisition of
mesenchymal cell traits. Concomitantly, the high c-Myc activates Zeb1 expression driving cells through the
epithelial to mesenchymal transition (EMT) further repressing the epithelial phenotype. As cells metastasize and
colonize at secondary sites, epithelial traits are partially reacquired as cells progress through the mesenchymal
to epithelial transition (MET). Our hypothesis is that the temporal expression patterns of c-Myc, Zeb1 and
Miz1 and epithelial vs. mesenchymal traits are unique in patients with alcohol-induced HCC and can
predict prognosis, drug resistance and potential treatment strategies. In Aim 1 we ask two major questions:
1) does 8q24 amplification drive EMT in alcohol-associated HCC? and 2) do metastatic lesions reacquire a more
epithelial phenotype? To answer these questions, we will examine protein expression patterns using
immunohistochemical (IHC) staining of paraffin-embedded human HCC resections (to answer question 1) and
affected lymph nodes and metastatic lesions (to answer question 2). Staining will be correlated to cancer stage,
clinicopathologic variables, alcohol consumption and patient responses to treatment. We will also confirm 8q24
amplification using FISH analysis of c-Myc expression. To directly determine the temporal relationship between
c-Myc, Miz1, Zeb1 and the epithelial vs. mesenchymal phenotypes, we will perform targeted transcriptome
analysis and morphological analysis of human benign and HCC tissue. We will also perform overexpression and
knockdown studies to directly establish the temporal relationship between c-Myc, Miz1, Zeb1 and epithelial vs.
mesenchymal phenotypes in selected cell lines and primary human normal and HCC cells in culture. Finally,
due to the tremendous need to develop new strategies for effective combination therapies to treat HCC, we will
examine drug sensitivity in cells to clinically relevant compounds. We ...

## Key facts

- **NIH application ID:** 10666121
- **Project number:** 1R21AA030353-01A1
- **Recipient organization:** CATHOLIC UNIVERSITY OF AMERICA
- **Principal Investigator:** PAMELA L. TUMA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $184,329
- **Award type:** 1
- **Project period:** 2023-05-05 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10666121

## Citation

> US National Institutes of Health, RePORTER application 10666121, Mechanisms that promote hepatocellular carcinoma due to chronic ethanol exposure (1R21AA030353-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10666121. Licensed CC0.

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