PIAS family gene expression: implications for prognosis, immunomodulation, and chemotherapy response.

Background: Cancer remains one of the leading causes of mortality worldwide, characterized by uncontrolled cell proliferation and metastasis. Protein Inhibitor of Activated STAT (PIAS) family genes, comprising PIAS1, PIAS2, PIAS3, and PIAS4, are emerging as significant players in cancer biology due to their roles in SUMOylation, transcriptional regulation, and modulation of signal transduction pathways. This study provides a comprehensive analysis of PIAS family genes from a pan-cancer viewpoint.

Methodology: Detailed in silico analyses using publicly available databases and in vitro analyses involving cell culture, gene knockdown, colony formation, and wound healing assays.

Results: Expression analysis revealed consistent up-regulation of PIAS1, PIAS2, PIAS3, and PIAS4 genes in tumors compared to normal tissues. Univariate Cox regression analyses indicate that high PIAS gene expression correlates with worse overall survival in specific cancers, particularly kidney renal papillary cell carcinoma (KIRP) and liver hepatocellular carcinoma (LIHC). Kaplan-Meier plots further confirm that higher PIAS gene expression is significantly associated with reduced survival probabilities in these cancers. Genetic alteration analysis showed low mutation frequencies in PIAS genes, suggesting their role in cancer progression is likely due to expression regulation rather than genetic mutations. Correlations with immune subtypes, the tumor microenvironment (TME), and immune stimulatory genes highlight the differential expression of PIAS genes across immune landscapes in KIRP and LIHC. Gene enrichment analysis emphasizes the involvement of PIAS genes in crucial cellular processes, including SUMOylation and ubiquitin-mediated proteolysis. Finally, knockdown experiments in HCC-LM3 cells demonstrate that PIAS2 and PIAS3 promote tumor growth and metastasis, reinforcing their potential as therapeutic targets.

Conclusion: This study revealed the multifaceted roles of PIAS genes in KIRP and LIHC biology and their potential as prognostic biomarkers and therapeutic targets.