LncRNA MALAT1 promotes gastric cancer progression via inhibiting autophagic flux and inducing fibroblast activation.
LncRNA MALAT1 promotes gastric cancer progression via inhibiting autophagic flux and inducing fibroblast activation.
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LncRNA MALAT1通过抑制自噬流和诱导成纤维细胞激活促进胃癌进展
DOI：
10.1038/s41419-021-03645-4
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发表时间：
2021-04-06
影响因子：
9
通讯作者：
Li C
中科院分区：
文献类型：
--
作者：
Wang Z;Wang X;Zhang T;Su L;Liu B;Zhu Z;Li C
自噬缺陷导致炎症反应失调，在胃癌的发生发展中起重要作用。各种研究表明，长链非编码RNA可以作为自噬的新调节因子。此前，据报道，长非编码RNA MALAT 1在GC细胞中上调，并可积极调节各种癌症中的自噬。在此，我们首次发现MALAT 1可以通过阻断自噬流促进GC细胞分泌白细胞介素-6（IL-6）。此外，由MALAT 1诱导的IL-6可以激活正常成纤维细胞向癌症相关成纤维细胞的转化。肿瘤微环境中GC细胞和癌症相关成纤维细胞之间的相互作用可能促进癌症进展。从机制上讲，MALAT 1过表达通过与RNA结合蛋白ELAVL 1竞争性相互作用激活AKT/mTOR通路以损害自噬通量，从而使GC细胞中的PTEN mRNA不稳定。自噬抑制的结果是，SQSTM 1积累促进NF-κB易位以提高IL-6表达。总体而言，这些结果表明，GC细胞和成纤维细胞之间的细胞间相互作用是由促进GC进展的MALAT 1增加引起的自噬抑制介导的，为GC提供了新的预防和治疗策略。
Autophagy defection contributes to inflammation dysregulation, which plays an important role in gastric cancer (GC) progression. Various studies have demonstrated that long noncoding RNA could function as novel regulators of autophagy. Previously, long noncoding RNA MALAT1 was reported upregulated in GC cells and could positively regulate autophagy in various cancers. Here, we for the first time found that MALAT1 could promote interleukin-6 (IL-6) secretion in GC cells by blocking autophagic flux. Moreover, IL-6 induced by MALAT1 could activate normal to cancer-associated fibroblast conversion. The interaction between GC cells and cancer-associated fibroblasts in the tumour microenvironment could facilitate cancer progression. Mechanistically, MALAT1 overexpression destabilized the PTEN mRNA in GC cells by competitively interacting with the RNA-binding protein ELAVL1 to activate the AKT/mTOR pathway for impairing autophagic flux. As a consequence of autophagy inhibition, SQSTM1 accumulation promotes NF-κB translocation to elevate IL-6 expression. Overall, these results demonstrated that intercellular interaction between GC cells and fibroblasts was mediated by autophagy inhibition caused by increased MALAT1 that promotes GC progression, providing novel prevention and therapeutic strategies for GC.
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