# Sphingosine kinase 2 in sexual dimorphism of hepatocellular carcinoma

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $370,665

## Abstract

PROJECT SUMMARY
 Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide and its
incidence is increasing due to endemic obesity. Sexual dimorphism exists in HCC incidence as women have a
significantly lower risk for developing HCC than men. However, the molecular mechanisms of HCC sexual
dimorphism remain unclear, hindering development of better therapies for this disease. This proposal will
utilize a new model that we developed of diet-induced progression of NASH to HCC that recapitulates key
physiological, metabolic, histologic and transcriptomic changes observed in the human disease to examine
previously unrecognized roles of sphingosine kinase 2 (SphK2), an enzyme that regulates the balance of
bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in sexual dimorphism of
HCC. Similar to humans, we found that on this diet, wild-type male mice, but not females, develop HCC.
Strikingly, SphK2 knockout male mice have reduced tumor incidence, whereas in females, liver cancer
developed only in SphK2 knockout mice. Thus, we propose that SphK2 plays a critical role in sexual
dimorphism of HCC. We will test the central hypothesis that SphK2 protects females from HCC, while
promoting it in males through several mutually non-exclusive mechanisms in distinct hepatic subcellular
organelles. Aim 1 will examine the role of liver SphK2 in key signaling pathways that promote HCC in males
and Aim 2 will define the role of SphK2 in nuclear and mitochondrial mechanisms mediating resistance of
females to HCC. Our proposal utilizes a unique animal model and state-of-the-art techniques to identify novel
SphK2-regulated molecular mechanisms involved in sexual disparity in diet-induced progression of NASH to
HCC, and also has translational implications for the use of SphK2 inhibitors now in clinical trials. This study will
lead to better understanding of sex differences in HCC important for personalized treatment strategies for this
devastating disease.

## Key facts

- **NIH application ID:** 10904697
- **Project number:** 5R01CA266124-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Christopher D Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $370,665
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904697

## Citation

> US National Institutes of Health, RePORTER application 10904697, Sphingosine kinase 2 in sexual dimorphism of hepatocellular carcinoma (5R01CA266124-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10904697. Licensed CC0.

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