MiR-15a and MiR-16 control Bmi-1 expression in ovarian cancer.
MiR-15a and MiR-16 control Bmi-1 expression in ovarian cancer.
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DOI：
10.1158/0008-5472.can-09-2552
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发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Mukherjee P
中科院分区：
文献类型：
--
作者：
Bhattacharya R;Nicoloso M;Arvizo R;Wang E;Cortez A;Rossi S;Calin GA;Mukherjee P
Bmi-1的致癌性激活在包括卵巢癌在内的多种上皮性恶性肿瘤中被发现，但Bmi-1过度表达的具体机制尚未确定。因此，意识到Bmi-1在癌症中的巨大病理学意义，我们想研究microRNA畸变是否在卵巢癌中Bmi-1的调节中发挥作用。在这份报告中，我们确定了两个microRNA，miR-15 a和miR-16，在卵巢细胞系和原代卵巢组织中表达不足。我们证明这些miRNAs直接靶向Bmi-1 3' UTR，并与卵巢癌患者和细胞系中的Bmi-1蛋白水平显著相关。此外，Bmi-1蛋白水平响应于miR-15 a或miR-16表达而下调，并导致卵巢癌细胞增殖和克隆生长的显著降低。这些发现表明，通过恢复卵巢癌和其他涉及Bmi-1上调的癌症中的miR-15 a和miR-16表达来开发治疗策略。
Oncogenic activation of Bmi-1 is found in a wide variety of epithelial malignancies including ovarian cancer, yet a specific mechanism for over expression of Bmi-1 has not been determined. Thus realizing the immense pathological significance of Bmi-1 in cancer, we wanted to investigate if microRNA aberrations played a role in the regulation of Bmi-1 in ovarian cancer. In this report we identify two microRNAs, miR-15a and miR-16 that are under expressed in ovarian cell lines and in primary ovarian tissues. We demonstrate that these miRNAs directly target the Bmi-1 3’ UTR and significantly correlate with Bmi-1 protein levels in ovarian cancer patients and cell lines. Furthermore, Bmi-1 protein levels are down regulated in response to miR-15a or miR-16 expression and lead to significant reduction in ovarian cancer cell proliferation and clonal growth. These findings suggest the development of therapeutic strategies by restoring miR-15a and miR-16 expression in ovarian cancer and in other cancers that involve up regulation of Bmi-1.