miR-34a通过靶向抑制CD44表达、抑制前列腺癌干细胞生长及肿瘤转移

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发布日期：2011-10-09 17:50 文章来源：欧易生物
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关键词： 丁香园 生物专题 miR-34a 肿瘤干细胞 　 点击次数：

肿瘤干细胞是当前肿瘤研究的热点，针对肿瘤干细胞的抗转移治疗方兴未艾；而microRNA在肿瘤发生发展过程中发挥重要作用，通过调节特定microRNA进行肿瘤治疗显示出良好的应用前景。Liu C等（The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44 Nature Medicine  2011，17,211-215）报道了关于microRNA 34家族成员miR-34a的研究。研究发现miR-34a靶向抑制前列腺癌干细胞biomarker CD44的表达。在前列腺癌，特别是p53突变的前列腺癌中，miR-34a表达下调，导致CD44高表达。抑制miR-34a抑制前列腺癌干细胞生长和肿瘤转移。该研究提示：发展基于miR-34a的新的治疗方法在前列腺癌治疗中具有很好的应用前景。

The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44

Abstract    Cancer stem cells（CSCs）,or tumor-initiating cells, are involved in tumor progression and metastasis1.MicroRNAs (miRNAs) regulate both normal stem cells and CSCs2-5, and dysregulation of miRNAs has been implicated in tumorignesis6. CSCs in many tumor - including cancers of breast7,pancreas8, head and neck9, colon10,11, small intestine12，liver13,stomach14,bladder15,and ovary16 -have been identified using the the adhesion  molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic17 and tumor-initiating and metastatic18,19 capacities are enriched in the  CD44+ cell population, but whether miRNAs regulate CD44+ prostate cancer  cells and prostate cancer metastasis remains unclear.Here we show, through expression analysis, that  miR-34a, a p53 target20-24,was underexpressed  in CD44+ prostate cancer cells purified from xenograft  and primary tumors. Enforced expression of miR-34a in buck or purified CD44+ prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis.In contract, expression of miRNA  antagomirs in CD44- prostate cancer cells promoted tumor development and metastasis.Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice.We  identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR34a overexpression in inhibiting prostate cancer regeration and metastasis.Our study shows that miR-34a is a key negative regulator of CD44+ prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs

原文链接地址：http://www.nature.com/nm/journal/v17/n2/abs/nm.2284.html

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