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长链非编码 RNA MALAT1 通过 Ezh2 促进肾透明细胞癌的侵袭转移并与 miR-205 相互作用。

Long Noncoding RNA MALAT1 Promotes Aggressive Renal Cell Carcinoma through Ezh2 and Interacts with miR-205.

机构信息

Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California.

Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.

出版信息

Cancer Res. 2015 Apr 1;75(7):1322-31. doi: 10.1158/0008-5472.CAN-14-2931. Epub 2015 Jan 19.

DOI:10.1158/0008-5472.CAN-14-2931
PMID:25600645
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5884967/
Abstract

Recently, long noncoding RNAs (lncRNA) have emerged as new gene regulators and prognostic markers in several cancers, including renal cell carcinoma (RCC). In this study, we investigated the contributions of the lncRNA MALAT1 in RCC with a specific focus on its transcriptional regulation and its interactions with Ezh2 and miR-205. We found that MALAT1 expression was higher in human RCC tissues, where it was associated with reduced patient survival. MALAT1 silencing decreased RCC cell proliferation and invasion and increased apoptosis. Mechanistic investigations showed that MALAT1 was transcriptionally activated by c-Fos and that it interacted with Ezh2. After MALAT1 silencing, E-cadherin expression was increased, whereas β-catenin expression was decreased through Ezh2. Reciprocal interaction between MALAT1 and miR-205 was also observed. Lastly, MALAT1 bound Ezh2 and oncogenesis facilitated by MALAT1 was inhibited by Ezh2 depletion, thereby blocking epithelial-mesenchymal transition via E-cadherin recovery and β-catenin downregulation. Overall, our findings illuminate how overexpression of MALAT1 confers an oncogenic function in RCC that may offer a novel theranostic marker in this disease.

摘要

最近，长链非编码 RNA（lncRNA）作为几种癌症（包括肾细胞癌[RCC]）中的新基因调控因子和预后标志物而出现。在这项研究中，我们研究了 lncRNA MALAT1 在 RCC 中的作用，特别关注其转录调控及其与 Ezh2 和 miR-205 的相互作用。我们发现，MALAT1 在人 RCC 组织中的表达更高，与患者生存时间缩短相关。MALAT1 沉默降低了 RCC 细胞的增殖和侵袭能力，增加了细胞凋亡。机制研究表明，c-Fos 转录激活了 MALAT1，MALAT1 与 Ezh2 相互作用。MALAT1 沉默后，E-cadherin 表达增加，而 Ezh2 下调导致 β-catenin 表达减少。还观察到 MALAT1 与 miR-205 之间的相互作用。最后，MALAT1 与 Ezh2 结合，通过 Ezh2 耗竭抑制 MALAT1 促进的致癌作用，从而通过 E-cadherin 恢复和 β-catenin 下调阻断上皮间质转化。总之，我们的研究结果阐明了 MALAT1 在 RCC 中过表达如何赋予致癌功能，这可能为该疾病提供一种新的治疗诊断标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/bebcfe28d0dd/nihms657695f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/ddb064561e3e/nihms657695f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/99b126e7cddb/nihms657695f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/533df7f108ee/nihms657695f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/8f2b6c4d11a8/nihms657695f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/c31864812548/nihms657695f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/bebcfe28d0dd/nihms657695f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/ddb064561e3e/nihms657695f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/99b126e7cddb/nihms657695f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/533df7f108ee/nihms657695f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/8f2b6c4d11a8/nihms657695f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/c31864812548/nihms657695f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90b8/5884967/bebcfe28d0dd/nihms657695f6.jpg

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