TRNP1 regulates tumorigenesis and enhances immunotherapy response via c-Kit/STAT3 signaling in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, with a poor prognosis and high mortality rates. Therapeutic resistance, high recurrence, and limited treatment options contribute to its aggressive nature. The TMF1-regulated nuclear protein 1 (TRNP1) is a highly conserved nuclear protein, recently implicated in tumorigenesis. TRNP1 is upregulated in HCC, but its role in tumorigenesis and immunotherapy resistance remains underexplored. This study investigates the mechanistic roles of TRNP1 in HCC progression through the c-Kit/signal transducers and activators of transcription 3 (STAT3) signaling pathway and its impact on immunotherapy efficacy, particularly in the context of programmed cell death protein 1 (PD-1) blockade.

The expression of TRNP1 was analyzed using bioinformatics tools and confirmed through HCC patient tissue samples. Knockdown and overexpression models of TRNP1 were established in HCC cell lines to investigate its effects on cellular behaviors, including proliferation, migration, invasion, and apoptosis. Transcriptomics explored downstream pathways, identifying the c-Kit/STAT3 signaling axis. In vivo experiments assessed the efficacy of combining TRNP1 knockdown with anti-PD-1 therapy in reducing tumor volume.

TRNP1 was significantly upregulated in HCC tissues compared to adjacent non-cancerous tissues. High TRNP1 expression correlated with reduced overall survival (OS) and disease-free survival (DFS). TRNP1 knockdown inhibited tumor cell proliferation, colony formation, migration, and invasion while promoting apoptosis. In contrast, TRNP1 overexpression enhanced these malignant phenotypes. Mechanistically, TRNP1 promoted HCC progression by activating the c-Kit/STAT3 signaling pathway. Notably, TRNP1 knockdown, combined with PD-1 blockade, further reduced tumor volume, enhancing the efficacy of immunotherapy.

This study establishes TRNP1 as a tumor-promoting factor in HCC, driving cancer progression via the c-Kit/STAT3 pathway. Moreover, TRNP1 knockdown sensitizes tumors to PD-1 blockade, suggesting a novel therapeutic strategy for improving immunotherapy outcomes in HCC patients. TRNP1 could serve as a potential biomarker and therapeutic target in HCC treatment.