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

Abstract

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.

Disulfidptosis-related prognostic signature correlates with immunotherapy response in colorectal cancer

“…Huang et al 42 found that ASB6 attenuates ER stress to increase the stem cell characteristics of oral squamous cell carcinoma cells and enhance their metastatic ability. The transcription factor TFAP2C is involved in tumour development and chemotherapy sensitivity 43 and has potential as a biomarker of treatment resistance in colorectal cancer 44 . The transcriptional modulator Jun dimerization protein 2 (JDP2) is closely related to tumour differentiation and apoptosis and participates in the regulation of CD8+ T cell immune function 45 .…”

microRNA-660 Enhances Cisplatin Sensitivity via Decreasing SATB2 Expression in Lung Adenocarcinoma

“…Cisplatin promotes tumor cell apoptosis by forming an adduct with the DNA of tumor cells, thereby achieving its anti-tumor effect [ 32 ]. Many studies have confirmed that the decrease in cell cycle arrest is the key factor in tumor cisplatin resistance [ 33 , 34 , 35 ]. We found that the overexpression of miR - 660 decreased the cell proliferation capacity and increased the cell apoptosis rate and cell cycle arrest in cisplatin-treated A549/CDDP and CALU-3 cells.…”

Comparison of 3 and 4 cycles of neoadjuvant gemcitabine and cisplatin for muscle-invasive bladder cancer: a systematic review and meta-analysis

“…The sensitivity of tumors to cisplatin is the most critical factor determining the therapeutic effect for cancer patients; cisplatin sensitivity is far more important than the final cumulative dose and dose intensity of cisplatin [ 48 , 49 ]. Some patients are insensitive to cisplatin [ 50 , 51 ], and even higher doses of GC combination chemotherapy cannot completely eliminate drug-resistant micrometastases. To eradicate these micrometastases, the combination of GC with other antitumor drugs can be considered to improve the efficacy of neoadjuvant chemotherapy.…”