lncRNA H19 regulates epithelial-mesenchymal transition and metastasis of bladder cancer by miR-29b-3p as competing endogenous RNA
lncRNA H19 regulates epithelial-mesenchymal transition and metastasis of bladder cancer by miR-29b-3p as competing endogenous RNA
复制标题
lncRNA H19通过miR-29b-3p作为竞争性内源RNA调节膀胱癌的上皮间质转化和转移
DOI：
10.1016/j.bbamcr.2017.08.001
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发表时间：
2017-10-01
影响因子：
5.1
通讯作者：
Chen, Junxia
中科院分区：
文献类型：
--
作者：
Lv, Mengxin;Zhong, Zhenyu;Chen, Junxia
越来越多的证据表明，长链非编码RNA（lncRNA）在肿瘤的发生和转移中起重要作用。EMT（epithelial-to-mesenchymal transition）被认为是包括膀胱癌（BC）在内的多种肿瘤侵袭和转移的关键步骤。最近的研究表明，IncRNA H19通过调节EMT和逆转MET（间充质-上皮转化）参与转移。然而，基本的机制在很大程度上仍然未知。本研究应用基因芯片技术筛选了BC的1 ncRNA和mRNA表达谱。我们发现H19和DNMT 3B在BC组织和细胞中显示出较高的共表达。在功能上，我们证明H19可以增加BC细胞的增殖，侵袭和迁移，调节EMT以及重新排列细胞骨架。此外，H19的异位表达在体内促进肿瘤发生、血管生成和肺转移，而H19的敲低在体内和体外具有相反的作用。从机制上讲，我们证明H19可以直接与miR-29 b-3 p（miR 29 b）结合并抑制靶DNMT 3B的表达。H19和miR-29 b-3 p显示出共定位。更重要的是，上调H19拮抗miR-29 b-3 p介导的BC细胞增殖、迁移和EMT抑制。此外，H19敲低部分逆转了miR-29 b-3 p抑制剂对DNMT 3B的功能，并促进了miR-29 b-3 p诱导的MET。总而言之，我们首次证明H19可能作为miR-29 b-3 p的ceRNA（竞争性内源性RNA）发挥作用，并解除对DNMT 3B的抑制，从而导致BC的EMT和转移。我们的研究结果强调了H19在BC进展中的新机制，并提供了H19/miR-29 b-3 p/DNMT 3B轴作为BC的有希望的治疗靶点。
Accumulating evidences indicate that long noncoding RNAs (lncRNAs) might play important roles in tumorigenesis and metastasis. EMT (epithelial-to-mesenchymal transition) is considered as a critical step in invasion and metastasis of various tumors including bladder cancer (BC). Recent researches have showed that IncRNA H19 is implicated in metastasis through regulating EMT and the reverse MET (mesenchymal-to-epithelial transition). However, underlying mechanisms remain largely unknown. Here, we screened 1ncRNA and mRNA expression profiles of BC with microarray assay. We found that H19 and DNMT3B displayed a higher co-expression in BC tissues and cells. Functionally, we demonstrated that H19 could increase proliferation, invasion and migration, regulate EMT as well as rearrange cytoskeleton of BC cells in vitro. Moreover, ectopic expression of H19 promoted tumorigenesis, angiogenesis and pulmonary metastasis in vivo, whereas knockdown of H19 has a contrary role in vivo and in vitro. Mechanistically, we proved that H19 could directly bind to miR-29b-3p (miR29b) and derepress the expression of target DNMT3B. H19 and miR-29b-3p showed a co-localization. More importantly, up-regulating H19 antagonized miR-29b-3p-mediated proliferation, migration and EMT suppression in BC cells. Furthermore, H19 knockdown partially reversed the function of miR-29b-3p inhibitor on DNMT3B and facilitated miR-29b-3p-induced MET. Taken together, we demonstrated for the first time that H19 might function as ceRNA (competing endogenous RNA) for miR-29b-3p and relieve the suppression for DNMT3B, which led to EMT and metastasis of BC. Our findings highlight a novel mechanism of H19 in progression of BC and provide H19/miR-29b-3p/DNMT3B axis as a promising therapeutic target for BC.