THRAP3 as a key oncogenic driver in Hepatocellular carcinoma

Abstract

Cancer remains a leading cause of mortality worldwide, with hepatocellular carcinoma (HCC) representing the most prevalent form of primary liver cancer. Despite advances in therapeutic strategies, the prognosis for HCC patients remains poor due to late diagnosis, limited treatment efficacy, and chemoresistance. One of the key contributors to chemoresistance is the hyperactivation of the DNA damage response (DDR), which enables cancer cells to repair chemotherapy-induced DNA damage and evade apoptosis. Recent studies have highlighted the involvement of RNA-processing factors in the regulation of DDR pathways. Among them, Thyroid Hormone Receptor Associated Protein 3 (THRAP3) is an RNA-binding protein (RBP) known to be involved in RNA processing, including splicing and nuclear export. Analysis of a publicly available HCC dataset revealed that THRAP3 was significantly increased in tumor tissues compared to adjacent non-tumor tissues, and high THRAP3 expression was correlated with poor patient survival rate. Indeed, we confirmed this upregulation in our liver cancer human patient samples. To investigate the functional role of THRAP3 in HCC progression, we generated THRAP3 knockdown hepatocellular carcinoma cell lines and established a DEN-induced liver- specific THRAP3 knock out liver cancer mice model. Functional assays demonstrated that THRAP3 depletion markedly suppressed HCC cell proliferation. Consistent with the in vitro results, xenograft demonstrated similar tumor-suppressive effects. We also confirmed that cancer cell migration and invasion were reduced when THRAP3 was deficient, suggesting a critical role of THRAP3 in maintaining malignant phenotypes. Consistently, in vivo experiments using the DEN-induced liver cancer mice model confirmed that Thrap3 knock out significantly reduced tumor growth. Mechanistically, THRAP3 silencing attenuated activation of the ATM- dependent DNA damage repair pathway, leading to increased DNA damage accumulation in liver cancer. Collectively, these findings identify THRAP3 as a key molecular regulator of DNA damage response and tumor aggressiveness in HCC. Our results provide evidence that targeting THRAP3 could represent a promising therapeutic strategy to overcome chemoresistance and limit HCC progression.