MicroRNA-150 directly targets MUC4 and suppresses growth and malignant behavior of pancreatic cancer cells
MicroRNA-150 directly targets MUC4 and suppresses growth and malignant behavior of pancreatic cancer cells
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DOI：
10.1093/carcin/bgr223
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发表时间：
2011-12-01
期刊：
影响因子：
4.7
通讯作者：
Singh, Ajay P.
中科院分区：
文献类型：
--
作者：
Srivastava, Sanjeev K.;Bhardwaj, Arun;Singh, Ajay P.
胰腺癌（PC）由于诊断晚、缺乏有效的治疗手段，是所有癌症中预后最差的一种。因此，识别新的基因靶点，这是差异表达的PC和功能参与恶性表型，是至关重要的，以实现早期诊断和有效的治疗策略的发展。我们以前已经表明，MUC 4，一种异常过表达的跨膜粘蛋白，促进PC细胞的生长，侵袭和转移，从而强调了其作为临床靶点的潜力。在这里，我们报告了一种新的microRNA（miRNA）介导的机制，潜在的MUC 4在PC中的异常表达。我们证明MUC 4的3'非翻译区含有高度保守的miRNA-150（miR-150）结合基序，并且其与miR-150的直接相互作用下调内源性MUC 4蛋白水平。我们还发现，miR-150介导的MUC 4下调与人表皮生长因子受体2及其磷酸化形式的伴随减少有关，导致下游信号的激活减少。此外，我们的研究结果表明，miR-150过表达抑制PC细胞的生长，克隆形成，迁移和侵袭，并增强细胞间粘附。最后，我们的数据揭示了miR-150在恶性胰腺组织中的表达下调，这与MUC 4蛋白水平呈负相关。总之，这些发现确立了miR-150作为PC中MUC 4的新调节剂和肿瘤抑制miRNA。
Pancreatic cancer (PC) has the worst prognosis among all cancers due to its late diagnosis and lack of effective therapies. Therefore, identification of novel gene targets, which are differentially expressed in PC and functionally involved in malignant phenotypes, is critical to achieve early diagnosis and development of effective therapeutic strategies. We have shown previously that MUC4, an aberrantly overexpressed transmembrane mucin, promotes growth, invasion and metastasis of PC cells, thus underscoring its potential as a clinical target. Here, we report a novel microRNA (miRNA)-mediated mechanism underlying aberrant expression of MUC4 in PC. We demonstrate that the 3' untranslated region of MUC4 contains a highly conserved miRNA-150 (miR-150) binding motif and its direct interaction with miR-150 downregulates endogenous MUC4 protein levels. We also show that miR-150-mediated MUC4 downregulation is associated with a concomitant decrease in human epidermal growth factor receptor 2 and its phosphorylated form, leading to reduced activation of downstream signaling. Furthermore, our findings demonstrate that miR-150 overexpression inhibits growth, clonogenicity, migration and invasion and enhances intercellular adhesion in PC cells. Finally, our data reveal a downregulated expression of miR-150 in malignant pancreatic tissues, which is inversely associated with MUC4 protein levels. Altogether, these findings establish miR-150 as a novel regulator of MUC4 and a tumor suppressor miRNA in PC.