PPIH Expression Correlates with Tumor Aggressiveness and Immune Dysregulation in Hepatocellular Carcinoma

Abstract

Purpose Hepatocellular Carcinoma (HCC) features a complex pathophysiology and unpredictable immunosuppressive microenvironment, which limit the effectiveness of traditional therapies and lead to poor patient outcomes. Understanding the immune characteristics of HCC is essential for elucidating the immune microenvironment and developing more effective treatments. This study investigates the role of Peptidyl-prolyl isomerase H (PPIH) in HCC by analyzing its expression, prognosis, methylation levels, and relationship with immune cell infiltration. Methods We utilized bulk sequencing and clinical data from UCSC Xena and the GTEx database for preprocessing and subsequent differential expression analysis of PPIH in tumor and adjacent normal tissues, evaluating prognostic parameters like overall survival and disease-free interval between low and high PPIH expression groups. Immune infiltration was analyzed via CIBERSORT and ssGSEA, while DNA methylation and somatic mutation analyses were performed using MExpress and “maftools”, respectively, alongside in vitro and in vivo experiments to assess PPIH’s functional roles. Results Our findings indicated that PPIH is significantly upregulated in various cancer types, correlating with poor patient prognosis, increased somatic mutations, and altered gene methylation patterns. High PPIH levels were linked to enhanced T regulatory (Treg) cell infiltration and a decline in Th17 cell populations, impacting vital pathways related to DNA damage repair and tumor proliferation. Furthermore, PPIH knockdown in vitro led to reduced cell viability, proliferation, and invasion while promoting apoptosis. In vivo, PPIH knockdown repressed tumor growth and modified the immune microenvironment by attenuating Th17 cell infiltration and potentially increasing Treg cell accumulation. Conclusion This study emphasizes PPIH’s critical role in HCC progression by facilitating tumor growth and survival while modulating the immune landscape, thereby positioning PPIH as a potential therapeutic target for HCC management.