Long noncoding RNA MALAT1 sponging miR-26a-5p to modulate Smad1 contributes to colorectal cancer progression by regulating autophagy
Long noncoding RNA MALAT1 sponging miR-26a-5p to modulate Smad1 contributes to colorectal cancer progression by regulating autophagy
复制标题
长非编码 RNA MALAT1 海绵 miR-26a-5p 调节 Smad1 通过调节自噬促进结直肠癌进展
DOI：
10.1093/carcin/bgab069
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发表时间：
2021
期刊：
影响因子：
4.7
通讯作者：
Lu Wang
中科院分区：
文献类型：
--
作者：
Jiamin Zhou;Miao Wang;Anrong Mao;Yiming Zhao;Longrong Wang;Ye Xu;Hao Jia;Lu Wang
抽象。越来越多的证据表明，骨形态发生蛋白（BMP）-Smad在大肠癌的发生、发展过程中具有调节自噬的功能。然而，控制这一过程的监管机制仍不清楚。在这里，我们发现Smad 1，BMP 2-Smad信号的关键效应子，通过上调自噬相关基因5（ATG 5）的表达诱导自噬，并且Smad 1与近端启动子结合以诱导其表达。此外，BMP 2诱导CRC中的自噬。Smad 1的过表达促进了结直肠癌细胞的成瘤和迁移，而ATG 5的敲低能够部分挽救Smad 1对结直肠癌细胞增殖和迁移的促进作用。从机制上讲，转移相关肺腺癌转录物1（MALAT 1）可能通过与miR-26 a-5 p竞争性结合而作为竞争性内源性RNA，从而调节下游靶点Smad 1的去抑制。此外，临床分析结果显示，Smad 1与MALAT 1呈正相关，与miR-26 a-5 p呈负相关。总之，我们的研究结果表明，Smad 1可能作为一个癌基因在CRC通过自噬。
Abstract. Accumulating evidences have suggested that bone morphogenetic protein (BMP)-Smad have a functional role in regulating autophagy in the development of human colorectal cancer (CRC). However, the regulatory mechanisms controlling this process remain unclear. Here, we showed that Smad1, the key effector of BMP2-Smad signaling, induces autophagy by upregulating autophagy-related gene 5 (ATG5) expression, and Smad1 binds to the proximal promoter to induce its expression. Moreover, BMP2 induces autophagy in CRC. Overexpression of Smad1 promotes tumorigenesis and migration of CRC cells, and knockdown of ATG5 is able to rescue the Smad1-induced promotion of CRC proliferation and migration partially. Mechanistically, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) may act as a competing endogenous RNA by binding with miR-26a-5p competitively and thus modulating the de-repression of downstream target Smad1. Furthermore, clinical analysis results show that Smad1 is positively correlated with MALAT1 and negatively correlated with miR-26a-5p in CRC samples. In conclusion, our results demonstrated that Smad1 may serve as an oncogene in CRC through autophagy.