高糖通过YAP1/TAZ抑制膀胱癌自噬的机制研究

Hyperglycemia is a predictor of poor prognosis in solid cancer including bladder cancer (BC). Autophagy plays an essential role in bladder cancer metastasis. However, most previous studies about the relationship between autophagy and hyperglycemia focused on complications of type 2 diabetes, while the relationship between autophagy and hyperglycemia within tumors was largely unknown. Our prophase research found that hyperglycemia suppresses autophagy in BC cells and as the most important effectors of the Hippo pathway, YAP/TAZ act as a key component in it. In this project, we will investigate the role of the Hippo pathway in hyperglycemia-mediated autophagy in BC. Therefore, we proposed that: ①Hyperglycemia regulates YAP1/TAZ through the Hippo signaling pathway and YAP1/TAZ play an important role in hyperglycemia-mediated autophagy; ②YAP1/TAZ can regulate glucose metabolism by targeting genes such as GLUT1; ③In vivo test and clinical trial, hyperglycemia correlates with autophagy and Hippo pathway and enhances bladder cancer metastasis. This study aimed to clarify the potential relationship between “hyperglycemia-YAP1/TAZ- autophagy” and BC progression. Furthermore, it would provide novel strategies for BC treatment.

在恶性肿瘤患者中高血糖提示更差的预后。细胞自噬在肿瘤的恶性进展中发挥重要作用。既往关于“高糖-自噬”的研究多着眼于2型糖尿病相关并发症，在肿瘤尤其膀胱癌中的报道甚少。我们发现：高血糖与膀胱癌患者的病理分级、TNM分期及预后相关；高糖通过调控YAP1/TAZ抑制膀胱癌自噬水平，促进肿瘤进展；YAP1/TAZ能影响膀胱癌细胞的糖代谢。但尚不清楚“高糖-YAP1/TAZ-自噬”轴的具体分子网络及相关机制，我们拟在前期基础上，以Hippo通路为切入点，探索：①高糖通过Hippo通路调控YAP1/TAZ抑制膀胱癌自噬的相关分子机制；②YAP1/TAZ调控膀胱癌细胞糖代谢的具体基因靶点；③临床及动物水平探索糖代谢异常与Hippo通路及自噬相关基因的关系，进一步证实高糖促进膀胱癌恶性进展。本课题拟阐明“高糖-YAP1/TAZ-自噬”轴的具体分子网络及与恶性进展的关系，为开发膀胱癌诊疗手段提供新依据。

在恶性肿瘤患者中高血糖提示更差的预后。糖代谢异常与恶性肿瘤的自噬、EMT等恶性生物学行为密切相关。既往关于糖代谢异常导致细胞自噬、EMT的变化的研究多着眼于2型糖尿病相关并发症，在肿瘤尤其膀胱癌中的报道甚少。我们的研究围绕肿瘤代谢异常为中心点，关注细胞自噬、EMT两个重要的恶性生物学行为展开，揭示相关作用机制。我们首先采用回顾性分析临床病例资料，对我院近10余年来的膀胱癌患者的病例资料做分析，得出高血糖影响膀胱癌患者的预后，以及与膀胱癌的病理分级、临床TNM分期密切相关。我们又用免疫组化的方法检测了既往膀胱癌病理组织中YAP1、TAZ的表达量，证实了YAP1、TAZ的高表达与较差的病理分级、临床分期密切相关。我们又采用Western Blot、qRT-PCR等实验手段在不同的膀胱癌细胞株上开展分子机制相关研究，证实了YAP1/TAZ调控膀胱癌细胞糖代谢的具体基因靶点，糖代谢异常需要通过Hippo通路调控YAP1/TAZ抑制膀胱癌自噬或者促进膀胱癌细胞EMT，进而影响膀胱癌的恶性进展。同时我们成功构建了裸鼠糖尿病模型，在动物模型上证实了糖代谢异常与Hippo通路对膀胱肿瘤的发生、发展的调控作用。我们的研究最终部分阐明了“高糖-YAP1/TAZ-自噬(EMT)-恶性进展”轴的具体分子网络及与恶性进展的关系，为开发膀胱癌新的诊疗手段提供了理论依据和数据参考。