Zhang Dongdong, Liu Yu, Wu Qiuwan, Zheng Yahong, Kaweme Natasha Mupeta, Zhang Zhiming, Cai Mingquan, Dong Youhong
Department of Oncology, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei 441000, China.
Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, School of clinical Medicine, Fujian Medical University, Xiamen 361003, Fujian Province, P.R. China.
J Cancer. 2021 Mar 15;12(10):2952-2959. doi: 10.7150/jca.53356. eCollection 2021.
Chemotherapy is the main therapy for gastric cancer (GC) both before and after surgery, but the emergence of multidrug resistance (MDR) often leads to disease progression and recurrence. P-glycoprotein, encoded by , is a well-known multidrug efflux transporter involved in drug resistance development. Pygo2 overexpression has been identified in several cancers. Previous studies have shown that abnormal expression of Pygo2 is related to tumorigenesis, chemoresistance, and tumor progression. In this study, to evaluate the underlying relationship between Pygo2 and MDR1 in GC, we constructed GC drug-resistant cell lines, SGC7901/cis-platinum (DDP), and collected tissue from GC patients' pre-and post-chemotherapy. We found that Pygo2 was overexpressed in GC, especially in GC drug-resistant cell lines and GC patients who underwent neoadjuvant DDP-based chemotherapy. Pygo2 overexpression may precede MDR1 and correlates with MDR1 in GC patients. Furthermore, knock-down of Pygo2 induced downregulation of MDR1 and restored SGC7901/DDP's sensitivity to DDP. Further mechanistic analysis demonstrated that Pygo2 could modulate MDR1 transcription by binding to the MDR1 promoter region and promoting MDR1 activation. The overall findings reveal that Pygo2 may be a promising biomarker for monitoring drug resistance in GC by regulating MDR1.
化疗是胃癌（GC）手术前后的主要治疗方法，但多药耐药（MDR）的出现常导致疾病进展和复发。由 编码的P-糖蛋白是一种众所周知的参与耐药性发展的多药外排转运蛋白。Pygo2在多种癌症中均有过表达。先前的研究表明，Pygo2的异常表达与肿瘤发生、化疗耐药及肿瘤进展有关。在本研究中，为评估GC中Pygo2与MDR1之间的潜在关系，我们构建了GC耐药细胞系SGC7901/顺铂（DDP），并收集了GC患者化疗前后的组织。我们发现Pygo2在GC中过表达，尤其是在GC耐药细胞系以及接受以DDP为基础的新辅助化疗的GC患者中。Pygo2过表达可能先于MDR1出现，且在GC患者中与MDR1相关。此外，敲低Pygo2可诱导MDR1下调，并恢复SGC7901/DDP对DDP的敏感性。进一步的机制分析表明，Pygo2可通过与MDR1启动子区域结合并促进MDR1激活来调节MDR1转录。总体研究结果表明，Pygo2可能是通过调节MDR1来监测GC耐药性的一个有前景的生物标志物。
