MALAT1调控miR-30a-5p/Vimentin影响浸润性膀胱癌侵袭转移的实验研究

Aberrant expression of long noncoding RNA MALAT1 and miR-30a-5p/Vimentin involves in cancer invasion and metastasis, and the underling mechanism is still unclear. MALAT1 regulates target gene expression via recruiting EZH2 to catalyze histone methylation. Preliminary work showed that knocking down MALAT1 inhibits the invasive ability and reverses the miR-30a-5p/Vimentin expression in invasive bladder cancer cells. Thus, we proposed a hypothesis that “MALAT1 regulates miR-30a-5p/Vimentin to promote invasive bladder cancer invasion and metastasis”. In this program, we will first determine the expression level of MALAT1/ miR-30a-5p by qPCR, and evaluate the expression of Vimentin/EZH2 by IHC along with WB, and analyze their correlation with bladder cancer pathological staging. Second, we will study the regulatory mechanism between MALAT1/EZH2 and miR-30a-5p by CHIP-PCR. Third, the in vitro assays and tumor models will be employed to study the effect of inhibiting bladder cancer invasion or metastasis by targeting MALAT1/ miR-30a-5p. Our results will reveal a novel mechanism in bladder cancer metastasis focusing on MALAT1/EZH2/ miR-30a-5p, and provide therapeutic potential target to metastatic bladder cancer.

MALAT1和miR-30a-5p/Vimentin表达紊乱是肿瘤侵袭转移的重要环节但机制不明。MALAT1通过募集EZH2催化组蛋白甲基化调控靶基因转录。前期工作示：敲降MALAT1抑制浸润性膀胱癌细胞侵袭能力且逆转miR-30a-5p/Vimentin异常表达。综上我们提出“MALAT1调控miR-30a-5p/Vimentin影响浸润性膀胱癌侵袭转移”的研究假说。本项目将分析浸润性膀胱癌中MALAT1、EZH2、miR-30a-5p、Vimentin表达与肿瘤转移关系；采用CHIP-PCR实验鉴定MALAT1/EZH2调控miR-30a转录的机制；在细胞水平和动物模型中探究干预MALAT1/miR-30a-5p抑制浸润性膀胱癌侵袭转移的效果与机制。预期研究结果将揭示以MALAT1/EZH2/miR-30a-5p为核心的肿瘤侵袭转移机制，并为治疗膀胱癌筛选具有应用前景的靶标。

异常表达的信号传导与转录激活因子3（STAT3）信号系统与头颈部鳞状细胞癌（HNSCC）的侵袭和转移密切相关。然而，STAT3过度表达和HNSCC转移调控的潜在机制仍不清楚。本次研究中，我们证明上调的TGF-β可能通过激活STAT3促进上皮间充质转化（EMT）。此外，我们还探讨了STAT3对HNSCC的作用，特别关注其转录调控及其与长非编码RNA（lncRNA）转移相关肺腺癌转录本1（malat1）的相互作用。染色质免疫沉淀（ChIP）和荧光素酶报告分析显示STAT3可以结合malat1启动子区域并转录激活malat1表达；然后，malat1与miR-30a相互作用，诱导EMT并促进HNSCC转移。总之，我们的发现证实了异常STAT3激活如何在HNSCC中发挥致癌作用，因此可以为STAT3作为HNSCC治疗靶点提供理论基础。

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