Downregulation of MiR-31 stimulates expression of LATS2 via the hippo pathway and promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma.
Downregulation of MiR-31 stimulates expression of LATS2 via the hippo pathway and promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma.
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DOI：
10.1186/s13046-017-0622-1
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发表时间：
2017-11-16
期刊：
影响因子：
--
通讯作者：
Song H
中科院分区：
文献类型：
--
作者：
Gao Y;Yi J;Zhang K;Bai F;Feng B;Wang R;Chu X;Chen L;Song H
mirna的失调通过协调抑制大量靶基因与癌症的发展有关。新出现的证据表明，miR-31在致瘤性中起双重作用。然而，miR-31是否在食管鳞状细胞癌（ESCC）中起致癌基因作用以及潜在的靶分子尚不清楚。研究了MiR-31在ESCC中的作用，并在ESCC的进展中确定了靶分子与EMT的关联。Western blot和qRT-PCR检测蛋白和mRNA水平。我们通过体内和体外功能实验研究了miR-31在ESCC细胞系中调节LATS2表达的作用。荧光素酶报告基因检测证实了LATS2是miR-31的潜在靶标。免疫组化法检测正常组织和ESCC组织中LATS2和TAZ的表达。LATS2是Hippo肿瘤抑制信号通路的一个组成部分。据报道，在食管癌中，LATS2的杂合性经常缺失。我们分析了miR-31和LATS2的相互表达调控，并证明在ESCC中，通过下调miR-31在转录后水平上上调LATS2的表达。此外，miR-31显著抑制了与Hippo通路关键分子LATS2 3′-UTR结合的mRNA的荧光素酶活性。然后，LATS2因此促进TAZ的易位，用免疫组织化学检测。miR-31沉默可显著抑制细胞增殖，诱导细胞凋亡，降低体外迁移/侵袭能力。LATS2通过抑制miR-31抑制ESCC细胞增殖和侵袭，以及体内小鼠异种移植模型。同时，LATS2的核定位限制了TAZ的磷酸化。然后，与低风险患者相比，高复发风险患者的TAZ表达水平明显升高，并且高表达与较差的生存率相关。我们的研究表明，miR-31的过表达通过Hippo通路抑制LATS2的表达并激活上皮-间质转化，从而在ESCC中发挥致癌作用。LATS2和TAZ有可能成为预测ESCC复发风险和预后的新型分子标志物。本文的在线版本（10.1186/s13046-017-0622-1）包含补充内容，授权用户可使用。
Dysregulation of miRNAs is associated with cancer development by coordinately suppressing abundant target genes. Emerging evidence indicates that miR-31 plays a dual role in tumorigenicity. However, whether miR-31 plays as an oncogene in esophageal squamous cell carcinoma (ESCC) and the potential target molecules are still unclear. MiR-31 role in ESCC was investigated and an association of the target molecules with EMT was identified in the progression of ESCC. Western blot assays and qRT-PCR was performed to detect the protein and mRNA levels. We investigated the role of miR-31 in the regulation of LATS2 expression in ESCC cell lines via functional assays both in vivo and in vitro. The luciferase reporter assays was conducted to confirm LATS2 is a potential target of miR-31. Immunohistochemistry was used to measure LATS2 and TAZ expression in normal and ESCC tissue. LATS2 is a component of the Hippo tumor-suppressive signaling pathway. Frequent loss of heterozygosity of LATS2 has been reported in esophageal cancer. We analyzed the reciprocal expression regulation of miR-31 and LATS2 and demonstrated that LATS2 expression was elevated by down-regulation of miR-31 at the post-transcriptional level in ESCC. Moreover, miR-31 significantly suppressed the luciferase activity of mRNA combined with the LATS2 3′-UTR, a key molecule in the Hippo pathway. Then, LATS2 consequently promoted the translocation of TAZ, which was examined using immunohistochemistry. Silencing of miR-31 significantly inhibited the cell proliferation, induced apoptosis and decreased the ability of migration/invasion in vitro. LATS2 impedes ESCC cell proliferation and invasion by suppressing miR-31, as well as mice xenograft model in vivo. Meanwhile, the nuclear localization of LATS2 constrained the phosphorylation of TAZ. Then, the expression level of TAZ was notably heightened with a high risk of recurrence compared to that observed in the low-risk patients, as well as, the higher expression associated with a poor survival. Our study demonstrated that overexpression of miR-31 undertook an oncogenic role in ESCC by repressing expression of LATS2 via the Hippo Pathway and activating epithelial-mesenchymal transition. LATS2 and TAZ could be potential novel molecular markers for predicting the risk of recurrence and prognosis of ESCC. The online version of this article (10.1186/s13046-017-0622-1) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Ke, HN;Pei, J;Tao, WF
通讯作者：
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37.3
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影响因子：
4.3
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通讯作者：
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