University of Ulsan College of Medicine Seoul, Seoul-t'ukpyolsi, Republic of Korea
Abstract: Several molecular programs involved in maintaining stem cell properties have been identified as novel molecular signals implicated in oncogenic dedifferentiation, metastasis of cancer, and major contributors to chemoresistance following cancer treatment. Furthermore, the heterogeneity observed in malignant tumors aligns with the diverse differentiation potentials of stem cells. Bladder cancer, a prevalent and deadly malignancy ranking as the sixth most common malignant tumor in men worldwide, recognizes the stemness feature as a poor prognostic factor for cancer malignancy, alongside various clinical and pathological factors. This study aimed to identify the mechanisms underlying the stemness features of muscle-invasive bladder cancer (MIBC), an aggressive form of the disease with limited therapeutic options. We previously reported that phosphorylation of Transcription factor CP2-like protein 1 (TFCP2L1) at Thr177 by cyclin-dependent kinase 1 (CDK1) is a central mechanism in embryonic stem cells (ESCs) pluripotency as well as adult bladder carcinogenesis. Here, we found that Zinc Finger Protein 143 (ZNF143) transcription factor physically interacted with TFCP2L1 and OCT-4 for maintaining naïve pluripotency in murine ESCs. In T24 human bladder cancer cells, the expression level of ZNF143 correlated with cell proliferation capacity. The positive effect of ZNF143 was observed also in tumor sphere formation and limiting dilution colony formation assays, supporting a crucial role of ZNF143 in the stemness features of bladder cancer cells. Additionally, increased ZNF143 expression enhanced glutathione (GSH) dynamics, which is a potential predictive and therapeutic trait for neoadjuvant chemotherapy response in bladder cancer. Indeed, ectopic expression of ZNF143 induced resistance to cisplatin as evidenced by the cell viability and apoptosis assays, demonstrating the significant role of ZNF143 in the response to cisplatin-based chemotherapy in bladder cancer cells. Collectively, our findings suggest that ZNF143 plays a critical role in promoting the stemness properties and chemo-resistance of bladder cancer cells. This study could provide a foundation for developing targeted therapies against ZNF143, potentially improving treatment outcomes for patients with MIBCs.
Funding Source: This research was supported by the National Research Foundation of Korea (NRF-2021R1A2C2005790), the Ministry of Education (RS-2024-00449162), and Asan Institute for Life Sciences, Asan Medical Center (2025IP0083), Seoul, Korea.
