Adverse clinical outcomes and immunosuppressive microenvironment of RHO-GTPase activation pattern in hepatocellular carcinoma

TL;DR

This study shows that a high Rho GTPase-related gene score in liver cancer is linked to worse survival and a less responsive immune environment, suggesting potential for personalized treatment strategies.

Contribution

The RGPRG score is introduced as a novel gene-based predictor of survival and immunotherapy response in hepatocellular carcinoma.

Findings

High RGPRG score correlates with worse survival and increased immunosuppressive cells in HCC patients.

Low RGPRG score is associated with immune-active tumor microenvironment and better immunotherapy outcomes.

RGPRG score is linked to survival in 27 other cancers and inhibits HCC cell growth when targeting SFN.

Abstract

Emerging evidence suggests that Rho GTPases play a crucial role in tumorigenesis and metastasis, but their involvement in the tumor microenvironment (TME) and prognosis of hepatocellular carcinoma (HCC) is not well understood.

We aim to develop a tumor prognosis prediction system called the Rho GTPases-related gene score (RGPRG score) using Rho GTPase signaling genes and further bioinformatic analyses.

Our work found that HCC patients with a high RGPRG score had significantly worse survival and increased immunosuppressive cell fractions compared to those with a low RGPRG score. Single-cell cohort analysis revealed an immune-active TME in patients with a low RGPRG score, with strengthened communication from T/NK cells to other cells through MIF signaling networks. Targeting these alterations in TME, the patients with high RGPRG score have worse immunotherapeutic outcomes and decreased survival time in the immunotherapy cohort. Moreover, the RGPRG score was found to be correlated with survival in 27 other cancers. In vitro experiments confirmed that knockdown of the key Rho GTPase-signaling biomarker SFN significantly inhibited HCC cell proliferation, invasion, and migration.

This study provides new insight into the TME features and clinical use of Rho GTPase gene pattern at the bulk-seq and single-cell level, which may contribute to guiding personalized treatment and improving clinical outcome in HCC.

The online version contains supplementary material available at 10.1186/s12967-024-04926-0.

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