miR-101 Inhibits Cholangiocarcinoma Angiogenesis through Targeting Vascular Endothelial Growth Factor (VEGF)
miR-101 Inhibits Cholangiocarcinoma Angiogenesis through Targeting Vascular Endothelial Growth Factor (VEGF)
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DOI：
10.1016/j.ajpath.2013.01.045
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发表时间：
2013-05-01
影响因子：
6
通讯作者：
Wu, Tong
中科院分区：
文献类型：
--
作者：
Zhang, Jinqiang;Han, Chang;Wu, Tong
最近的证据表明miRNAs在肝脏生物学和疾病中的重要作用，尽管miRNAs在胆管癌中的意义仍有待进一步确定。本研究旨在探讨miR-101在胆管癌发生发展中的生物学功能及其分子机制。采用原位杂交和定量RT-PCR方法检测miR-101在人胆管癌组织和细胞系中的表达。与非癌胆管上皮细胞相比，miR-101在43.5%的人胆管癌标本和本研究中使用的所有三种胆管癌细胞系中的表达降低。miR-101的强制过表达显著抑制了重度联合免疫缺陷小鼠中胆管癌的生长。miR-101过表达的异种移植肿瘤组织显示毛细血管密度降低，血管内皮生长因子（VEGF）和环氧合酶-2（考克斯-2）水平降低。通过计算分析和实验测定，VEGF和考克斯-2 mRNA被鉴定为胆管癌细胞中miR-101的真正靶点。miR-101通过直接靶向VEGF mRNA 3 '非翻译区和通过抑制考克斯-2抑制VEGF基因转录来抑制胆管癌血管生成。这项研究确立了miR-101在胆管癌中的一种新的肿瘤抑制作用，并提示了靶向miR-101和相关信号通路用于未来治疗的可能性。
Recent evidence has suggested an important role of miRNAs in liver biology and diseases, although the implication of miRNAs in cholangiocarcinoma remains to be defined further. This study was designed to examine the biological function and molecular mechanism of miR-101 in cholangiocarcinogenesis and tumor progression. In situ hybridization and quantitative RT-PCR were performed to determine the expression of miR-101 in human cholangiocarcinoma tissues and cell lines. Compared with noncancerous biliary epithelial cells, the expression of miR-101 is decreased in 43.5% of human cholangiocarcinoma specimens and in all three cholangiocarcinoma cell lines used in this study. Forced overexpression of miR-101 significantly inhibited cholangiocarcinoma growth in severe combined immunodeficiency mice. miR-101-overexpressed xenograft tumor tissues showed decreased capillary densities and decreased levels of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). The VEGF and COX-2 mRNAs were identified as the bona fide targets of miR-101 in cholangiocarcinoma cells by both computational analysis and experimental assays. miR-101 inhibits cholangiocarcinoma angiogenesis by direct targeting of VEGF mRNA 3'untranslated region and by repression of VEGF gene transcription through inhibition of COX-2. This study established a novel tumor-suppressor role of miR-101 in cholangiocarcinoma and it suggests the possibility of targeting miR-101 and related signaling pathways for future therapy.