Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Central Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
J Cell Biochem. 2019 Apr;120(4):5118-5127. doi: 10.1002/jcb.27788. Epub 2018 Oct 15.
The biological characteristics of bladder cancer include enhanced invasion and migration, which are the main causes of death in patients. Starvation is a typical feature of the bladder cancer microenvironment and can induce autophagy. Autophagy has an important relationship with the invasion and migration of tumors. However, the role of autophagy in the invasion and migration of bladder cancer cells remains unclear. Hence, the aim of the current study was to clarify this role and underlying mechanism. In this study, we found that starvation enhanced the epithelial-mesenchymal transition (EMT)-mediated invasion and migration of T24 and 5637 cells while inducing autophagy. The inhibition of autophagy with chloroquine (CQ) or 3-methyladenine (3MA) decreased EMT-mediated invasion and migration. In addition, the expression of transforming growth factor 1 (TGF-β1) and phosphorylated Smad3 (p-Smad3) increased after starvation. The inhibition of autophagy with CQ or 3MA also decreased the expression of TGF-β1 and p-Smad3. The inhibitor of TGF-β receptor sb431542 also inhibited the invasion, migration, and EMT of T24 and 5637 cells during starvation. Furthermore, recombinant TGF-β1 induced autophagy and inhibition of the TGF-β/Smad signaling pathway with sb431542 suppressed autophagy. In summary, our results suggested that autophagy promotes the invasion and migration of bladder cancer cells by inducing EMT through the TGF-β1/Smad3 signaling pathway. Moreover, autophagy and TGF-β1 can form a positive feedback loop to synergistically promote invasion and migration. Thus, our findings may provide a theoretical basis for the prevention of invasion and migration in bladder cancer.
膀胱癌的生物学特性包括增强的侵袭和迁移，这是患者死亡的主要原因。饥饿是膀胱癌微环境的典型特征，可诱导自噬。自噬与肿瘤的侵袭和迁移有重要关系。然而，自噬在膀胱癌细胞侵袭和迁移中的作用尚不清楚。因此，本研究旨在阐明这一作用及其潜在机制。在本研究中，我们发现饥饿增强了 T24 和 5637 细胞的上皮-间充质转化（EMT）介导的侵袭和迁移，同时诱导自噬。用氯喹（CQ）或 3-甲基腺嘌呤（3MA）抑制自噬可降低 EMT 介导的侵袭和迁移。此外，饥饿后转化生长因子 1（TGF-β1）和磷酸化 Smad3（p-Smad3）的表达增加。CQ 或 3MA 抑制自噬也降低了 TGF-β1 和 p-Smad3 的表达。TGF-β 受体抑制剂 sb431542 也抑制了 T24 和 5637 细胞在饥饿时的侵袭、迁移和 EMT。此外，重组 TGF-β1 诱导自噬，并用 sb431542 抑制 TGF-β/Smad 信号通路可抑制自噬。综上所述，我们的结果表明，自噬通过 TGF-β1/Smad3 信号通路诱导 EMT 促进膀胱癌细胞的侵袭和迁移。此外，自噬和 TGF-β1 可以形成正反馈回路，协同促进侵袭和迁移。因此，我们的发现可能为预防膀胱癌侵袭和迁移提供理论依据。
