Prognostic and chemotherapeutic response prediction by proliferation essential gene signature: Investigating POLE2 in bladder cancer progression and cisplatin resistance

Background: Bladder cancer (BLCA) is the most common genitourinary malignancy.Proliferation essential genes (PEGs) are crucial to the survival of cancer cells.This study aimed to build a PEG signature to predict BLCA prognosis and treatment efficacy.Methods: BLCA PEGs and differentially expressed PEGs were identified using DepMap and TCGA-BLCA datasets, respectively.Based on the prognostic analysis of the differentially expressed PEGs, a PEG model was constructed.Subsequently, we analyzed the relationship between the PEG signature and prognosis of BLCA patients as well as their response to chemotherapy.Finally, we performed random forest analysis to target and functional experiments to validate the most significant PEG which is associated with BLCA progression.CCK-8, invasion, migration, and chemosensitivity assays were performed to assess effects of gene knockdown on BLCA cell proliferation, invasion and migration abilities, and cisplatin chemosensitivity.Results: We screened 10 prognostic PEGs from 201 differentially expressed PEGs and used them to construct a PEG signature model.Patients with high PEG signature score (PEGs-high) exhibited worse OS and lower sensitivity to chemotherapy than those with PEGs-low.We also found significant correlations between the PEG score and previously defined BLCA molecular subtypes.This suggests that the PEG score may effectively predict the molecular subtypes which have distinct clinical outcomes.Random forest analysis revealed that POLE2 (DNA polymerase epsilon subunit 2) was the most significant PEG differentiating BLCA tissue and normal tissue.Bioinformatic analysis and an immunohistochemistry staining assay confirmed that POLE2 was significantly up-regulated in tumor tissues and was associated with poor survival in BLCA patients.Moreover, POLE2 knockdown inhibited the ability of cell clone formation, proliferation, invasion, immigration and IC50 of cisplatin. Conclusion:The PEG signature acts as a potential predictor for prognosis and chemotherapy response in BLCA patients.POLE2 is a key PEG and plays a remarkable role in promoting the malignant progression and cisplatin resistance of BLCA.