Heliyon (Nov 2024)
Identification of PSMD2 as a promising biomarker for pancreatic cancer patients based on comprehensive bioinformatics and in vitro studies
Abstract
Background: Pancreatic cancer patients have limited treatment options and extremely poor prognosis. Dysregulations of proteasome 26S subunit, non-ATPases (PSMDs) contribute to the development of various cancers, whereas the significance of PSMDs in pancreatic cancer is poorly understood. In the present study, we intended to explore the therapeutic potential of PSMDs in pancreatic cancer. Methods: Based on TCGA database, the expression of PSMDs was analyzed in pancreatic cancer patients. Multivariate Cox regression and Kaplan–Meier survival analyses were conducted to investigate the prognostic value of PSMDs. The correlations between the expression of PSMD2/14 and immune cell infiltration, immune checkpoint genes’ expression, enrichment of signaling pathways, and the sensitivity of chemotherapies were also evaluated. Knockdown and overexpression experiments were performed to explore the biological function of PSMD2/14. Immunoblotting was conducted to detect the downstream signaling pathway of PSMD2. Results: Most of the PSMDs, except for PSMD5 and PSMD6, were significantly upregulated in pancreatic cancer tissues. Patients with higher grade tumor had increased mRNA levels of PSMD1/2/5/7/8/11/12/14. Survival and multivariate Cox regression analyses indicated that PSMD2 and PSMD14 were biomarkers of worse prognosis. High expression of PSMD2 and PSMD14 was positively correlated with the levels immune checkpoint genes but not with the infiltration of specific immune cell types. In vitro knockdown of PSMD2, but not PSMD14, increased the apoptosis, gemcitabine's toxicity and inhibited the growth capacity of MIA cells. Conversely, decreased apoptosis and gemcitabine sensitivity along with accelerated cell proliferation ability were observed in PSMD2-overexpressing PANC-1 cells. Mechanistically, PSMD2 activated the AKT/mTOR signaling pathway, consistent with the findings from KEGG and GSEA analysis. The AKT specific inhibitor MK-2206 exhibited higher cytotoxicity in MIA and PANC-1 cells with high PSMD2 expression. Importantly, MK-2206 largely reversed the oncogenic functions of PSMD2 on the growth and proliferation of PANC-1 cells. Conclusion: In summary, our study provided a comprehensive bioinformatics analysis of PSMDs in pancreatic cancer. We identified that PSMD2 acted as a tumor-promoting protein in pancreatic cancer through the activation of the AKT/mTOR pathway. The overexpression of PSMD2 may be a potential biomarker that predicts the response of pancreatic cancer patients to AKT inhibitor treatments.
