TFAP2C Knockdown Sensitizes Bladder Cancer Cells to Cisplatin Treatment via Regulation of EGFR and NF-κB.

Abstract

Simple SummaryBladder cancer (BCa) is considered one of the most common neoplasms of the urology system. Cisplatin-based chemotherapy has been the primary treatment for patients with advanced or metastatic BCa. Nevertheless, cisplatin resistance often limits the treatment of bladder cancer. We expect to find approaches to improve the therapeutic efficacy of cisplatin in bladder cancer. In recent years, many studies have shown that transcription factor AP-2 gamma (TFAP2C) acts as a key player in cancer development and and its expression level is closely related to the sensitivity of tumors to cisplatin. Our study investigated whether TFAP2C affects the sensitivity of BCa cells to cisplatin and the possible mechanisms. We found that TFAP2C expression was significantly upregulated in most BCa tissues compared to adjacent normal tissues. The present study confirmed that TFAP2C knockdown enhanced the anti-tumor effects of cisplatin by decreasing cisplatin-induced activation levels of epidermal growth factor receptor (EGFR) and nuclear factor kappaB (NF-κB). Specifically, this study provides a novel approach to improve the efficacy of cisplatin.Cisplatin is the first-line chemotherapy for advanced or metastatic bladder cancer. Nevertheless, approximately half of patients with BCa are insensitive to cisplatin therapy or develop cisplatin resistance during the treatment process. Therefore, it is especially crucial to investigate ways to enhance the sensitivity of tumor cells to cisplatin. Transcription factor AP-2 gamma (TFAP2C) is involved in cancer development and chemotherapy sensitivity. However, its relationship with chemotherapy has not been studied in BCa. In this study, we aimed to investigate the therapeutic potential of TFAP2C in human BCa. Results based on TCGA (The Cancer Genome Atlas), GTEx (The Genotype-Tissue Expression) and GEO (Gene Expression Omnibus) data showed that TFAP2C expression was upregulated in BCa tissues and that its high expression was associated with poor prognosis. Meanwhile, we demonstrated the overexpression of TFAP2C in BCa clinical specimens. Subsequently, in vitro, we knocked down TFAP2C in BCa cells and found that TFAP2C knockdown further increased cell cycle arrest and apoptosis caused by cisplatin. In addition, the inhibitory effect of cisplatin on BCa cell migration and invasion was enhanced by TFAP2C knockdown. Our data indicated that cisplatin increased epidermal growth factor receptor (EGFR) and nuclear factor-kappaB (NF-κB) activation levels, but TFAP2C knockdown suppressed this effect. Finally, in vivo data further validated these findings. Our study showed that TFAP2C knockdown affected the activation levels of EGFR and NF-κB and enhanced the anti-tumor effects of cisplatin in vivo and in vitro. This provides a new direction to improve the efficacy of traditional cisplatin chemotherapy.