Table1_The long non-coding RNA MALAT1 regulates intestine host-microbe interactions and polyposis.XLSX

The long non-coding RNA (lncRNA) Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) maintains the integrity of the intestinal epithelial barrier and regulates local inflammation. However, its influences on intestinal microbial communities and tissue susceptibility to cancer development remain unexplored. Here, we report that MALAT1 regulates host anti-microbial response gene expression and the composition of mucosal-associated microbial communities in a region-specific manner. In the APC mutant mouse model of intestine tumorigenesis, knocking out MALAT1 results in higher polyp counts in the small intestine and colon. Interestingly, intestine polyps that developed in the absence of MALAT1 were smaller in size. These findings highlight the unexpected bivalent role of MALAT1 in restricting and promoting cancer progression at different disease stages. Among the 30 MALAT1-targets shared by both the small intestine and colon, ZNF638 and SENP8 levels are predictive of colon adenoma patient overall survival and disease-free survival. Genomic assays further revealed that MALAT1 modulates intestinal target expression and splicing through both direct and indirect mechanisms. This study expands the role of lncRNAs in regulating intestine homeostasis, microbial communities, and cancer pathogenesis.

长链非编码RNA（long non-coding RNA，lncRNA）转移相关肺腺癌转录本1（Metastasis-associated lung adenocarcinoma transcript 1，MALAT1）可维持肠上皮屏障完整性并调控局部炎症反应。然而，其对肠道微生物群落及组织癌症发生易感性的影响尚未被探明。本研究发现，MALAT1以区域特异性方式调控宿主抗菌应答基因的表达及黏膜相关微生物群落的构成。在肠道肿瘤发生的APC突变小鼠模型中，敲除MALAT1会导致小肠与结肠的息肉数量增多。值得注意的是，缺失MALAT1时形成的肠道息肉体积更小。上述发现揭示了MALAT1在不同疾病阶段分别限制和促进癌症进展的意外双功能。在小肠和结肠共有的30个MALAT1靶基因中，ZNF638与SENP8的表达水平可预测结肠腺瘤患者的总生存期与无病生存期。基因组学实验进一步证实，MALAT1通过直接与间接两种机制调控肠道靶基因的表达与剪接。本研究拓展了长链非编码RNA在调控肠道稳态、微生物群落及癌症发病机制中的作用。