Li Qing, Yang Tao, Li Dongsheng, Ding Feng, Bai Guang, Wang Wei, Sun Hongzhi
a College of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China; Department of Internal Medicine, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, People's Republic of China.
b Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, People's Republic of China.
Biochem Cell Biol. 2018 Oct;96(5):572-579. doi: 10.1139/bcb-2017-0162. Epub 2018 Feb 1.
Aquaporin-5 (AQP5), a water channel protein, has been reported to possess oncogenic potential in multiple types of malignancies, including colorectal cancer (CRC). However, its effect on the chemosensitivity of CRC cells remains elusive. Hence, this study investigated the effect of AQP5 silencing in CRC cells on 5-fluorouracil (5-FU) sensitivity and attempted to elucidate the underlying mechanisms. A short hairpin RNA construct targeting AQP5 was transfected into HCT116 or HT29 cells to generate stable AQP5-silenced cell lines. The effects of AQP5 knockdown on cell viability, apoptosis, tumor growth, and 5-FU chemoresistance were evaluated. Relative protein levels of Wnt-β-catenin pathway effectors were also measured. The results showed that silencing of AQP5 increased the chemosensitivity of CRC cells to 5-FU, facilitated 5-FU-mediated apoptosis, suppressed tumor growth, and reduced 5-FU chemoresistance in vivo. Furthermore, the effect of AQP5 on 5-FU chemosensitivity was mediated by the Wnt-β-catenin pathway. Silencing of AQP5 inhibited Wnt-β-catenin signaling, whereas overexpression of the degradation-resistant mutant of β-catenin (S33Y) reversed apoptosis induced by AQP5 silencing. Taken together, these results suggest that AQP5 silencing enhances the sensitivity of CRC cells to 5-FU, and the underlying mechanism is related to inhibition of the Wnt-β-catenin pathway. AQP5 could be a useful therapeutic target for CRC treatment.
水通道蛋白5（AQP5）是一种水通道蛋白，据报道在包括结直肠癌（CRC）在内的多种恶性肿瘤中具有致癌潜力。然而，其对CRC细胞化学敏感性的影响仍不清楚。因此，本研究调查了CRC细胞中AQP5沉默对5-氟尿嘧啶（5-FU）敏感性的影响，并试图阐明其潜在机制。将靶向AQP5的短发夹RNA构建体转染到HCT116或HT29细胞中，以生成稳定的AQP5沉默细胞系。评估了AQP5敲低对细胞活力、凋亡、肿瘤生长和5-FU化疗耐药性的影响。还测量了Wnt-β-连环蛋白通路效应器的相对蛋白水平。结果表明，AQP5沉默增加了CRC细胞对5-FU的化学敏感性，促进了5-FU介导的凋亡，抑制了肿瘤生长，并降低了体内5-FU化疗耐药性。此外，AQP5对5-FU化学敏感性的影响是由Wnt-β-连环蛋白通路介导的。AQP5沉默抑制了Wnt-β-连环蛋白信号传导，而β-连环蛋白（S33Y）降解抗性突变体的过表达逆转了AQP5沉默诱导的凋亡。综上所述，这些结果表明，AQP5沉默增强了CRC细胞对5-FU的敏感性，其潜在机制与抑制Wnt-β-连环蛋白通路有关。AQP5可能是CRC治疗的一个有用的治疗靶点。
