Fu Zhenqiang, Luo Wenzheng, Wang Jingtao, Peng Tao, Sun Guifang, Shi Jingyu, Li Zhihong, Zhang Boai
Department of Neurology, First Affiliated Hospital of Zhengzhou University, China.
Department of Neurosurgery, First Affiliated Hospital of Zhengzhou University, China.
Biochem Biophys Res Commun. 2017 Oct 21;492(3):480-486. doi: 10.1016/j.bbrc.2017.08.070. Epub 2017 Aug 20.
The long noncoding RNA Malat1 has been reported to be an oncogene that promotes tumor progress and correlates with prognosis in glioma. Growing evidence shows that autophagy plays a very important role in tumorigenesis and tumor cell survival, but whether Malat1 regulates autophagy in glioma is still unclear. In this study, we found that Malat1 expression and autophagy activity were significantly increased in glioma tissues compared with adjacent normal tissues. Additionally, Malat1 level was positively correlated with the expression of LC3-II (autophagy marker) mRNA in vivo. In vitro assays revealed that Malat1 significantly promoted autophagy activation and cell proliferation in glioma cells. More importantly, inhibition of autophagy by 3-MA relieved Malat1-induced cell proliferation. These data demonstrated that Malat1 activates autophagy and increases cell proliferation in glioma. We further investigated the molecular mechanisms whereby Malat1 functioned on glioma cell autophagy and proliferation. We found that Malat1 served as an endogenous sponge to reduce miR-101 expression by directly binding to miR-101. Moreover, Malat1 abolished the suppression effects of miR-101 on glioma cell autophagy and proliferation, which involved in upregulating the expression of miR-101 targets STMN1, RAB5A and ATG4D. Overall, our study elucidated a novel Malat1-miR-101-STMN1/RAB5A/ATG4D regulatory network that Malat1 activates autophagy and promotes cell proliferation by sponging miR-101 and upregulating STMN1, RAB5A and ATG4D expression in glioma cells.
据报道，长链非编码RNA Malat1是一种癌基因，可促进肿瘤进展并与胶质瘤的预后相关。越来越多的证据表明，自噬在肿瘤发生和肿瘤细胞存活中起着非常重要的作用，但Malat1是否调节胶质瘤中的自噬仍不清楚。在本研究中，我们发现与相邻正常组织相比，胶质瘤组织中Malat1表达和自噬活性显著增加。此外，Malat1水平与体内LC3-II（自噬标志物）mRNA的表达呈正相关。体外试验表明，Malat1显著促进胶质瘤细胞中的自噬激活和细胞增殖。更重要的是，3-MA抑制自噬可缓解Malat1诱导的细胞增殖。这些数据表明，Malat1激活自噬并增加胶质瘤中的细胞增殖。我们进一步研究了Malat1作用于胶质瘤细胞自噬和增殖的分子机制。我们发现，Malat1作为内源性海绵，通过直接结合miR-101来降低其表达。此外，Malat1消除了miR-101对胶质瘤细胞自噬和增殖的抑制作用，这涉及上调miR-101靶标STMN1、RAB5A和ATG4D的表达。总体而言，我们的研究阐明了一个新的Malat1-miR-101-STMN1/RAB5A/ATG4D调控网络，即Malat1通过在胶质瘤细胞中海绵化miR-101并上调STMN1、RAB5A和ATG4D的表达来激活自噬并促进细胞增殖。
