Pan-cancer and experimental analyses reveal TTC39B as a suppressor of cell proliferation in clear cell renal cell carcinoma

Abstract

Tetratricopeptide repeat domain protein 39B (TTC39B) is a lipid metabolism–related gene recently implicated in cholesterol regulation. However, its clinical and biological relevance in human cancers remains undefined. Based on multi-omics data from the Cancer Genome Atlas (TCGA) pan-cancer dataset representing 33 cancer types and other complementary resources, bioinformatics methods were employed to evaluate the relationships between TTC39B expression and clinical characteristics, patient survival, immune invasion, tumor microenvironment features, and immune checkpoint gene expression. Cellular function experiments were used to verify the proliferative regulatory role of TTC39B in clear cell renal cell carcinoma. TTC39B exhibited tumor type–specific dysregulation across cancers, with heterogeneous expression patterns observed at both transcriptomic and proteomic levels. Clinically, TTC39B expression was significantly associated with sex, tumor stage, grade, and metastatic status in multiple cancer types. Survival analyses demonstrated that had different prognostic risk associations in different cancer types, such as being associated with unfavorable outcomes in glioma, brain lower-grade glioma, and acute myeloid leukemia, while showing protective effects in clear cell renal cell carcinoma, colorectal cancer, and metastatic melanoma. Importantly, immune infiltration analyses consistently revealed correlations between TTC39B expression and multiple components of the tumor microenvironment, including stromal activation, immune cell infiltration, and immune checkpoint gene expression across diverse malignancies. In addition, genomic analyses indicated associations with copy number variation, tumor mutational burden, microsatellite instability, and tumor stemness indices, suggesting a role of TTC39B in regulating genomic stability and tumor evolution. Functional validation in renal clear cell carcinoma confirmed that TTC39B suppresses tumor cell proliferation in vitro. This comprehensive pan-cancer analysis demonstrates a dual prognostic and immunological association of TTC39B across various cancer backgrounds. Given its association with lipid metabolism and immune regulation, TTC39B represents a promising candidate for future mechanistic studies and therapeutic exploration across diverse cancer types.