New role of PTGES3 uncovered in liver cancer growth and immune evasion
image: Schematic illustration showing the novel mechanism by which PTGES3 nuclear transcriptional regulation promotes hepatocellular carcinoma proliferation and immunosuppression.
Credit: WANG Nianfei
A research team led by Prof. WANG Hongzhi at the Hefei Institutes of Physical Science, Chinese Academy of Sciences, has found a novel role of prostaglandin E synthase 3 (PTGES3) in liver cancer, revealing how it drives both tumor growth and immune suppression.
The study was recently published in Molecular Biomedicine.
Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with limited treatment outcomes. Understanding the key regulators of tumor progression and immune suppression is important for improving therapy.
In this study, PTGES3, a cytoplasmic co-chaperone of HSP90, was identified as a nuclear transcriptional regulator. It was significantly overexpressed in HCC and was associated with poor patient outcomes.
PTGES3 promoted the growth and spread of HCC cells through the PI3K/AKT/mTOR pathway. In a diethylnitrosamine (DEN)-induced mouse model, reducing Ptges3 in liver cells significantly suppressed tumor growth. Single-cell RNA sequencing further showed that lower Ptges3 levels reshaped the tumor immune environment, with fewer M2 macrophages.
PTGES3 activated SP1 by binding to its promoter, leading to increased TGF-β production. This promoted tumor growth and enhanced immune suppression. Blocking TGF-β signaling reversed these effects, suggesting that PTGES3 acted independently of its classical chaperone role.
The findings identify the PTGES3/SP1/TGF-β axis as a potential therapeutic target, offering new strategies for combining targeted therapy with immunotherapy in liver cancer.