miR-202 Diminishes TGFβ Receptors and Attenuates TGFβ1-Induced EMT in Pancreatic Cancer.
miR-202 Diminishes TGFβ Receptors and Attenuates TGFβ1-Induced EMT in Pancreatic Cancer.
复制标题
DOI：
10.1158/1541-7786.mcr-16-0327
复制
发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Govindarajan R
中科院分区：
文献类型：
--
作者：
Mody HR;Hung SW;Pathak RK;Griffin J;Cruz-Monserrate Z;Govindarajan R
本实验室已有研究证实，碳环腺苷类似物、组蛋白甲基转移酶抑制剂3-去氮杂环素A(DZNep)可抑制转化生长因子β诱导的上皮向间充质转化。此外，DZNep在表观上重新编程miRNAs(MiRs)，通过miR-663/4787介导的RNA干扰调节内源性转化生长因子β1的水平(摩尔癌症研究，2016年9月13日，PII：Molcanres.0083.2016)。虽然DZNep也可减弱外源性转化生长因子β诱导的EMT反应，但其抑制机制尚不清楚。在此，DZNep诱导miR-202-5p针对转化生长因子β受体TGFBR1和TGFBR2进行RNA干扰，从而有助于抑制外源性转化生长因子β诱导的胰腺癌细胞内皮细胞转化。慢病毒过表达miR-202显著降低了转化生长因子β受体的蛋白水平，抑制了转化生长因子β信号转导和细胞表型特征。一贯地，针对miR-202-5p的反义miRs的转染导致TGFBR1和TGFBR2蛋白表达增加，并诱导了这些细胞的EMT特征。在星状胰腺细胞中，miR-202的过表达减缓了生长速度，并减少了间质细胞外膜基质(ECM)的蛋白表达。在免疫缺陷和免疫活性的原位胰腺癌小鼠模型中，miR-202减少了肿瘤负担和转移。综上所述，这些发现证明了丹参在受体水平上抑制转化生长因子β信号的另一种机制，并揭示了miR-202在胰腺癌中的EMT抑制作用。这些发现支持基于小分子(如DZNep类似物)或大分子(如miRs)的表观遗传修饰剂与传统核苷类似物(如吉西他滨、卡培他滨)相结合的可能性，以提高当前胰腺癌治疗的抗转移潜力。
Previous studies in our laboratory identified that 3-deazaneplanocin A (DZNep), a carbocyclic adenosine analog and histone methyl transferase inhibitor, suppresses TGFβ-induced epithelial-to-mesenchymal (EMT) characteristics. In addition, DZNep epigenetically reprograms miRNAs (miRs) to regulate endogenous TGFβ1 levels via miR-663/4787 mediated RNA interference (Mol Cancer Res. 2016 Sep 13. pii: molcanres.0083.2016). While DZNep also attenuates exogenous TGFβ-induced EMT response, the mechanism of this inhibition was unclear. Here, DZNep induced miR-202-5p to target both TGFβ receptors, TGFBR1 and TGFBR2, for RNA interference and thereby contribute to the suppression of exogenous TGFβ-induced EMT in pancreatic cancer cells. Lentiviral overexpression of miR-202 significantly reduced the protein levels of both TGFβ receptors and suppressed TGFβ signaling and EMT phenotypic characteristics of cultured parenchymal pancreatic cancer cells. Consistently, transfection of anti-miRs against miR-202-5p resulted in increased TGFBR1 and TGFBR2 protein expressions and induced EMT characteristics in these cells. In stellate pancreatic cells, miR-202 overexpression slowed growth as well as reduced stromal extracellular membrane matrix (ECM) protein expression. In orthotopic pancreatic cancer mouse models, both immunodeficient and immunocompetent, miR-202 reduced tumor burden and metastasis. Together, these findings demonstrate an alternative mechanism of DZNep in suppressing TGFβ signaling at the receptor level and uncover the EMT suppressing role of miR-202 in pancreatic cancer. These findings support the possibility of combining small molecule- (e.g., DZNep analogs) or large molecule- (e.g., miRs) based epigenetic modifiers with conventional nucleoside analogs (e.g., gemcitabine, capecitabine) to improve the anti-metastatic potential of current pancreatic cancer therapy.