外泌体lncRNA-UCA1调控缺氧条件下膀胱癌侵袭转移作用机制的研究

Bladder cancer is the most common malignancy in the urinary system. Invasion and metastasis are characteristic features of bladder cancer. Long noncoding RNA -urothelial carcinoma associated 1 (lncRNA-UCA1) has been reported to be involved in invasion and metastasis of bladder cancer, but the underlying mechanisms are still unclear. Our previous studies demonstrated that hypoxia upregulated UCA1 expression in bladder cancer cells. Recently, we have found that the ectopic overexpression of UCA1 promotes bladder cancer cell migration and invasion by inducing epithelial-to-mesenchymal transition (EMT) and matrix metalloproteinase (MMP) expression. Notably, we have observed that UCA1 is indeed present within the exosomes derived from bladder cancer cells and serums of bladder cancer patients and UCA1 is significantly increased in exosomes secreted from hypoxic bladder cancer cells. Therefore, we hypothesize that hypoxia may induce exosomal UCA1 to regulate the behaviors of bladder cancer cells and stromal cells by EMT and MMP. Exosomal UCA1 also contributes to the establishment of a pre-metastatic niche by remodeling stromal cells and promoting extracellular matrix degradation. In this project, we will employ exosomal UCA1 induced by hypoxia to investigate the invasion and metastasis of bladder cancer and the expression changes of some tumor metastasis related molecules, and then analyze the correlation between exosomal UCA1 and bladder cancer metastasis in serum samples. In sum, our study will elucidate the mechanisms of exosomal UCA1 regulating the invasion and metastasis of bladder cancer under hypoxia and explore the clinical value of exosomal UCA1 acting as a biomarker for the diagnosis and surveillance of bladder cancer.

膀胱癌是泌尿系统高发恶性肿瘤，极易侵袭转移。长非编码RNA-UCA1是调节膀胱癌侵袭转移关键分子，但其作用机制尚未阐明。我们曾报道缺氧能显著上调UCA1；还发现外源过表达UCA1可促进膀胱癌细胞基质金属蛋白酶（MMP）表达、上皮间质转化（EMT）及侵袭迁移，而且膀胱癌细胞及患者血清外泌体中均有UCA1表达，缺氧可显著上调膀胱癌细胞外泌体UCA1表达。由此推测膀胱癌原发灶缺氧诱导的外泌体UCA1可通过EMT和MMP调节膀胱癌细胞及微环境基质细胞的表型，促进肿瘤侵袭转移；亦可经血循环调节远端转移部位基质细胞表型及MMP的表达，参与肿瘤转移前微环境形成。本项目拟利用缺氧诱导外泌体UCA1进行细胞及动物实验观察膀胱癌侵袭转移及相关分子变化，分析临床血清样本外泌体UCA1与膀胱癌转移的相关性，以阐明外泌体UCA1调控缺氧条件下膀胱癌侵袭转移的作用机制，探讨其作为膀胱癌诊断及监测标志物的临床价值。

膀胱癌是泌尿系统高发恶性肿瘤，极易侵袭转移。长非编码RNA-UCA1(lncRNA-UCA1)是调节膀胱癌侵袭转移关键分子，但其作用机制尚未阐明。本项目在正常及缺氧培养条件下分离获得膀胱癌细胞来源的外泌体，并对外泌体及其转运的lncRNA-UCA1进行鉴定。利用细胞及动物实验观察膀胱癌细胞来源外泌体及其转运的lncRNA-UCA1对膀胱癌细胞表型及相关分子的影响。利用临床样本分离鉴定膀胱癌血清来源的外泌体并分析血清来源外泌体lncRNA-UCA1与膀胱癌的相关性。本项目研究发现缺氧培养条件下膀胱癌细胞分泌的外泌体能够显著促进膀胱癌细胞增殖迁移与侵袭，并且缺氧增强外泌体转运lncRNA-UCA1。体外及体内实验证实缺氧诱导的外泌体lncRNA-UCA1可通过调控上皮间质转化过程促进肿瘤生长及进展。临床膀胱癌患者血清样本中外泌体lncRNA-UCA1表达水平高于健康对照组。综上所述，本研究阐明了外泌体lncRNA-UCA1调控缺氧条件下膀胱癌侵袭转移的作用机制，为膀胱癌诊断提供了一个潜在的标志物。本项目资助下现已发表SCI收录论文3篇，中国科技核心期刊论文1篇。本项目总投入经费17.5000万元，现已支出经费10.8510万元，剩余经费6.6490万元将用于本项目已产生但未结算以及后续研究支出。