MicroRNA-375 and MicroRNA-221: Potential Noncoding RNAs Associated with Antiproliferative Activity of Benzyl Isothiocyanate in Pancreatic Cancer.
MicroRNA-375 and MicroRNA-221: Potential Noncoding RNAs Associated with Antiproliferative Activity of Benzyl Isothiocyanate in Pancreatic Cancer.
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DOI：
10.1177/1947601911409212
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发表时间：
2011-02-01
期刊：
影响因子：
--
通讯作者：
Haldar, Subrata
中科院分区：
文献类型：
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作者：
Basu, Aruna;Alder, Hansjuerg;Haldar, Subrata
MicroRNAs(MiRNAs)的非调控存在或缺失可能在导致肿瘤转化的分子途径中发挥重要作用。目前，人们还认为干扰miRNA功能的方法应该有助于为人类癌症开发新的治疗机会。在这项研究中，我们提供了抗癌药物异硫氰酸苄酯(BITC)能够调节已知在胰腺癌患者中异常表达的miR-221和miR-375等miRNAs水平的证据。有趣的是，在培养的胰腺癌细胞中，miR-375的异位表达或miR-221的强制沉默降低了细胞的活力，并使BITC的抗增殖作用变得敏感。我们还发现，与Kras(G12D)诱导的胰腺上皮内瘤变(Panin)相比，假定的肿瘤抑制基因miR-375在非病理小鼠胰腺中的表达更丰富。相反，在有Panin病变的小鼠胰腺中，致癌miR-221的表达显著增加。虽然miR-375已被证明在胰腺癌患者中异常表达，但还没有一项全面的研究来研究这种miRNA在胰腺癌细胞中靶向的分子通路。进一步的基因表达芯片分析显示，胰腺癌的潜在生物标志物Igfbp5和CAV-1在miR-375转染细胞中显著下调。相应地，在有癌前病变的小鼠胰腺中，Igfbp5和CAV-1的表达明显升高，其中miR-375的表达减弱。综上所述，我们的研究结果提示，抗癌剂BITC可能靶向miR-221和miR-375的表达，将高增殖的胰腺癌细胞切换到低增殖状态。
The deregulated presence or absence of microRNAs (miRNAs) might play an important role in molecular pathways leading to neoplastic transformation. At present, it is also thought that the approaches to interfere miRNA functions should be helpful for developing novel therapeutic opportunities for human cancer. In this study, we provide evidence that the anticancer agent benzyl isothiocyanate (BITC) has the ability to modulate the level of miRNAs such as miR-221 and miR-375, known to be abnormally expressed in pancreatic cancer patients. Interestingly, ectopic expression of miR-375 or the enforced silencing of miR-221 in cultured pancreatic cancer cells attenuates cell viability and sensitizes antiproliferative action of BITC. We also show that the expression of putative tumor suppressor miR-375 is more abundant in nonpathological mice pancreata than those with Kras(G12D)-driven pancreatic intraepithelial neoplasia (PanIN). To the contrary, the expression of oncogenic miR-221 is significantly elevated in the mouse pancreas with PanIN lesions. Although miR-375 has been shown to be aberrantly expressed in pancreatic cancer patients, there has not been a comprehensive study to investigate the molecular pathways targeted by this miRNA in pancreatic cancer cells. Further analysis by gene expression microarray revealed that IGFBP5 and CAV-1, potential biomarkers of pancreatic cancer, were significantly downregulated in cells transfected with miR-375. Correlatively, elevated expression of IGFBP5 and CAV-1 was evident in the mouse pancreas with preneoplastic lesions in which the expression of miR-375 wanes. Taken together, our findings suggest that anticancer agent BITC might target the expression of miR-221 and miR-375 to switch hyperproliferative pancreatic cancer cells to a hypoproliferative state.