Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 cooperates with enhancer of zeste homolog 2 to promote hepatocellular carcinoma development by modulating the microRNA-22/Snail family transcriptional repressor 1 axis
Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 cooperates with enhancer of zeste homolog 2 to promote hepatocellular carcinoma development by modulating the microRNA-22/Snail family transcriptional repressor 1 axis
复制标题
长非编码RNA转移相关肺腺癌转录物1与zeste同源物2的增强子合作，通过调节microRNA-22/Snail家族转录抑制子1轴促进肝细胞癌的发展
DOI：
10.1111/cas.14372
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发表时间：
2020-04-30
期刊：
影响因子：
5.7
通讯作者：
Li, Hang
中科院分区：
文献类型：
--
作者：
Chen, Shaofei;Wang, Guobin;Li, Hang
转移相关肺腺癌转录本1（MALAT1）是一种致癌的长链非编码RNA，已发现其在许多肿瘤中促进致癌和转移。然而，MALAT1在肝细胞癌（HCC）的进展和转移中的潜在作用仍不清楚。在这项研究中，在HCC标本和细胞系中检测到MALAT1水平异常升高。我们发现，MALAT1的敲低在体内和体外均引起增殖、迁移和侵袭的阻滞。机制研究表明，Snail家族转录抑制因子1（SNAI1）是microRNA（miR）-22的直接靶标，并且MALAT1通过充当miR-22的竞争性内源RNA来调节SNAI1表达。抑制miR-22恢复了被MALAT1敲低抑制的SNAI1表达。此外，MALAT1促进了miR-22和E-cadherin的启动子区域的zeste同源物2（EZH2）增强子的富集，这被MALAT1敲低所抑制。MALAT1与EZH2协同作用，通过抑制miR-22和E-cadherin的表达，正调控SNAI1的表达，在上皮细胞向间充质细胞转化中发挥重要作用。总之，我们的研究结果揭示了MALAT1促进HCC进展的机制，并为HCC治疗提供了潜在的靶点。
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic long noncoding RNA that has been found to promote carcinogenesis and metastasis in many tumors. However, the underlying role of MALAT1 in the progression and metastasis of hepatocellular carcinoma (HCC) remains unclear. In this study, aberrantly elevated levels of MALAT1 were detected in both HCC specimens and cell lines. We found that knockdown of MALAT1 caused retardation in proliferation, migration, and invasion both in vivo and in vitro. Mechanistic investigations showed that Snail family transcriptional repressor 1 (SNAI1) is a direct target of microRNA (miR)-22 and that MALAT1 modulates SNAI1 expression by acting as a competing endogenous RNA for miR-22. Inhibition of miR-22 restored SNAI1 expression suppressed by MALAT1 knockdown. Furthermore, MALAT1 facilitated the enrichment of enhancer of zeste homolog 2 (EZH2) at the promoter region of miR-22 and E-cadherin, which was repressed by MALAT1 knockdown. Cooperating with EZH2, MALAT1 positively regulated SNAI1 by repressing miR-22 and inhibiting E-cadherin expression, playing a vital role in epithelial to mesenchymal transition. In conclusion, our results reveal a mechanism by which MALAT1 promotes HCC progression and provides a potential target for HCC therapy.