Wang Decai, Zhang Pu, Liu Zijian, Xing' Yifei, Xiao Yajun
Department of Urology Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Cancers (Basel). 2022 Aug 3;14(15):3782. doi: 10.3390/cancers14153782.
Bladder cancer is one of the most prevalent kinds of cancer worldwide, and resistance to gemcitabine is a major problem for patients. The pathogenesis of bladder cancer and mechanism of resistance to chemotherapy remain to be explored. Through bioinformatics analysis, we first found that NXPH4 was independently related to the prognosis of patients with bladder cancer. Through wound healing assays, transwell invasion assays, and plate clone formation assays, we found that NXPH4 promoted the proliferation, migration, and invasion of bladder cancer cells. The induced gemcitabine resistance cell line also showed a higher expression of NXPH4. A glycolytic activity assay demonstrated that the expression of NXPH4 was positively related to glycolysis. A higher level of reactive oxygen species caused by enhanced levels of NXPH4 was found in gemcitabine-resistant cell lines. NDUFA4L2, glycolysis, and reactive oxygen species were shown to be essential for NXPH4-regulated functions through rescue assays in cell lines. The roles of NXPH4-regulated glycolysis, gemcitabine resistance, and NDUFA4L2 were validated in vivo as well. Our results imply that NXPH4 contributes to the proliferation, migration, and invasion of bladder cancer by maintaining the stability of NDUFA4L2 and consequently activating reactive oxygen species and glycolysis.
膀胱癌是全球最常见的癌症类型之一，对吉西他滨耐药是患者面临的一个主要问题。膀胱癌的发病机制及化疗耐药机制仍有待探索。通过生物信息学分析，我们首先发现NXPH4与膀胱癌患者的预后独立相关。通过伤口愈合实验、Transwell侵袭实验和平板克隆形成实验，我们发现NXPH4促进了膀胱癌细胞的增殖、迁移和侵袭。诱导产生的吉西他滨耐药细胞系中NXPH4的表达也更高。糖酵解活性实验表明，NXPH4的表达与糖酵解呈正相关。在吉西他滨耐药细胞系中发现，NXPH4水平升高导致活性氧水平升高。通过细胞系中的拯救实验表明，NDUFA4L2、糖酵解和活性氧对于NXPH4调节的功能至关重要。NXPH4调节糖酵解、吉西他滨耐药及NDUFA4L2的作用在体内也得到了验证。我们的结果表明，NXPH4通过维持NDUFA4L2的稳定性，进而激活活性氧和糖酵解，促进膀胱癌的增殖、迁移和侵袭。
