# IGF2 causes DNA damage in liver cancer

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2024 · —

## Abstract

Liver cancer (hepatocellular carcinoma or HCC) is the 2nd leading cause of death from cancer
worldwide and it is the only cancer for which both the incidence and mortality are rising. Traditionally liver
cancer was associated with cirrhosis due to chronic hepatitis B or C viruses, or alcohol consumption but more
recently obesity or the metabolic syndrome accounts for the highest attributable fraction of HCC (37%) in the
US. Approximately 80-90% of obese adults have nonalcoholic fatty liver disease and the metabolic syndrome,
and a subset will go on to develop inflammation and NASH. Obesity is also a risk factor for HBV and HCV-
related liver cancer and even alcoholic cirrhosis-related liver cancer. Furthermore, obesity reduces the efficacy
of anti-HBV vaccination, and increases HCC in individuals treated for HCV. As obese individuals are at a
higher risk of developing all types of HCC (non-viral, viral and alcoholic), there is a critical need to understand
the changes that occur in the liver during obesity, which can guide both prevention efforts and the development
of novel efficacious treatments for HCC.
 Alternative RNA splicing is generally thought to fine tune gene expression and cellular function in
various tissues and contexts but there is also evidence that changes in RNA splicing may have dramatic
effects on the pathogenesis of disease by switching expression of protein isoforms that may have opposing or
antagonistic effects. In the liver, changes in RNA splicing have been documented during development and the
maturation of hepatocytes as well as in HCC but most studies in early liver disease, NAFLD or NASH, have
focused on total mRNA changes rather than changes in individual mRNA isoforms and alternative splicing. The
idea that these changes may be causative for, rather than the result of, liver disease is supported by
accumulating evidence from genetic manipulation of individual splicing factors in mice that contribute to liver
disease. Lipid and glucose metabolism, fibrosis and inflammation are all processes that may be influenced by
alternative splicing and they all may contribute to disease progression. Functional assessment of isoforms is
essential however, as it is not possible a priori to predict the effect of a splice variant on protein activity. We
propose to study two isoform switching events in the insulin receptor (IR) and Yes associated protein 1 (YAP1),
which we have documented during early NAFLD in mice and humans, that may contribute to NASH and HCC.

## Key facts

- **NIH application ID:** 10806791
- **Project number:** 2I01BX004848-05
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** NICHOLAS J WEBSTER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2020-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806791

## Citation

> US National Institutes of Health, RePORTER application 10806791, IGF2 causes DNA damage in liver cancer (2I01BX004848-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10806791. Licensed CC0.

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