HBSS诱导的自噬增强TGF-β/Smad介导的膀胱癌细胞上皮间质转化和侵袭转移的机制研究

The biological characteristics of bladder cancer is easy to invasion and metastasis, which is the main reason for death of patients. Research has shown that invasion and metastasis of bladder cancer is closely related to epithelial-mesenchymal transition (EMT). TGF-β mediates EMT course mainly through the canonical Smad pathway. Autophagy, a cellular self-protective mechanism, has an important relationship with the occurrence and development of tumors. However, it has been not yet clear that the role of TGF-β/Smad signaling in regulation of autophagy, EMT, invasion and metastasis in bladder cancer. Our earlier study indicates hunger environment promoting TGF-β expression enhances EMT-mediated invasion and metastasis and induces autophagy in bladder cancer. Inhibition of autophagy impaires TGF-β mediated EMT to cause decreased invasion and metastasis in vitro. It has been currently unkown about the specific mechanism of invasion and metastasis as well as the effect of TGF-β on regulating EMT in bladder cancer under tumor microenvironment. Therefore, we hypothesize that induced autophagy enhancing TGF-β mediated EMT signalling pathway is closely associated with increased invasion and metastasis of bladder cancer in tumor microenvironment. This project aims to explore the correlation and potential mechanism between autophagy and EMT mediated invasion and metastasis through studying in vitro and in vivo, and provide theoretical basis for seeking novel therapeutic target of bladder cancer.

膀胱癌具有易侵袭转移的特点，这是膀胱癌患者死亡的主要原因。研究表明：膀胱癌的侵袭转移与上皮间质转化（EMT）密切相关。TGF-β主要通过经典Smad通路调控EMT。自噬是一种细胞自我保护机制，与肿瘤的发生发展密切相关。但是TGF-β/Smad信号在膀胱癌自噬、EMT及细胞侵袭转移中的具体调控机制，迄今尚不清楚。我们的前期研究发现，饥饿环境可以增强TGF-β的表达，诱导EMT介导的膀胱癌侵袭转移能力，同时促进自噬活化。抑制自噬削弱TGF-β调控的EMT，导致膀胱癌侵袭转移能力下降。目前对于肿瘤微环境中膀胱癌侵袭转移的具体机制以及TGF如何影响EMT的机制仍不明确。因此设想：肿瘤微环境中膀胱癌侵袭转移与诱导性自噬增强TGF-β介导的EMT信号通路密切相关。本项目拟通过体内外实验研究饥饿环境下，探索膀胱癌自噬与EMT介导的侵袭转移的关系及潜在机制，为寻找膀胱癌新的治疗靶点提供理论依据

膀胱癌具有易侵袭转移的特点，这是膀胱癌患者死亡的主要原因。本研究前期数据表明：膀胱癌的侵袭转移与上皮间质转化（EMT）密切相关。本项目进一步探索了TGF-β/Smad信号在膀胱癌自噬、EMT及细胞侵袭转移中的具体调控机制。我们研究发现，饥饿环境可以增强TGF-β的表达，诱导EMT介导的膀胱癌侵袭转移能力，同时促进自噬活化。抑制自噬削弱TGF-β调控的EMT，导致膀胱癌侵袭转移能力下降。项目研究成果证明肿瘤微环境中膀胱癌侵袭转移与诱导性自噬增强TGF-β介导的EMT信号通路密切相关。本项目通过体内外实验研究饥饿环境下，探索了膀胱癌自噬与EMT介导的侵袭转移的关系及具体机制，为膀胱癌新的治疗靶点选择提供理论依据。团队在此基础上同时探索饥饿诱导膀胱癌细胞自噬水平增强与膀胱癌细胞恶性进展的调控关系，关注到糖代谢重编程在其中起到的关键作用并深入讨论LDHA作为糖酵解关键酶受TME调控的具体机制及所产生效应，以及潜在的临床意义；还利用公共数据库资源以及本中心收集临床样本，对EMT相关的膀胱癌患者预后影响因素进行探索，筛选了具有潜力的预测标志物并进行了一系列验证，为临床早期诊断和预测膀胱癌患者预后提供新的可靠依据。