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PLoS One:发现调节前列腺癌发展的miRNA以及治疗药物

来源:生物谷 2012-03-20 22:41

去势抵抗性前列腺癌 (CRPC) 的发生促进了前列腺癌(PCa)病人的高死亡率,这在某种程度上归因于肿瘤干细胞(CSCs)的存在及出现。近期来自美国韦恩州立大学医学院的Fazlul H. Sarkar等人研究表明,解除对Let-7(一种miRNAs)表达的控制会促进PCa的发生和发展,并且这个过程能够被BR-DIM所改变。相关研究发表在3月19日美国《公共科学图书馆·综合(PLoS One)上。

在几种已知的miRNAs中,let-7家族通过调节CSCs在引起PCa的复发以及发展中起到了重要作用。然而,let-7家族促进PCa侵略性的机制还未可知。Zeste homolog 2(EZH2)的增强子是一个公认的let-7家族的目标,在过去被证明其可以控制干细胞功能。在这项研究中,研究人员发现,在人类 PCa组织样品中,尤其是在更高Gleason等级的肿瘤中,失去let-7 家族与EZH2的过表达一致。在PCa 细胞中,通过转染 let-7前体细胞,let-7的过表达会减少EZH2的表达,并抑制克隆及球体形成的能力,这与抑制EZH2 3′UTR荧光素酶的活性后效果一致。研究人员还发现,对PCa细胞使用用BR-DIM (3,3′-二吲哚甲烷)治疗后,会上调let-7并下调EZH2的表达,这与抑制自我更新和克隆能力一致。

此外,在我们正在做的二期临床实验中,BR-DIM的介入治疗先于根治性前列腺切除术。结果表明:使用BR-DIM治疗后, PCa组织样本中let-7 的上调与EZH2的表达下调一致。这些结果表明,失去 let-7会调停EZH2的增强型表达,然后促进PCa的侵略性,而这些都可以通过BR-DIM的治疗来改变。因此,BR-DIM可能有一定的临床药物。(生物谷Deepblue编译)

Loss of Let-7 Up-Regulates EZH2 in Prostate Cancer Consistent with the Acquisition of Cancer Stem Cell Signatures That Are Attenuated by BR-DIM

Dejuan Kong, Elisabeth Heath, Wei Chen, Michael L. Cher, Isaac Powell, Lance Heilbrun, Yiwei Li, Shadan Ali, Seema Sethi, Oudai Hassan, Clara Hwang, Nilesh Gupta, Dhananjay Chitale, Wael A. Sakr, Mani Menon, Fazlul H. Sarkar.

The emergence of castrate-resistant prostate cancer (CRPC) contributes to the high mortality of patients diagnosed with prostate cancer (PCa), which in part could be attributed to the existence and the emergence of cancer stem cells (CSCs). Recent studies have shown that deregulated expression of microRNAs (miRNAs) contributes to the initiation and progression of PCa. Among several known miRNAs, let-7 family appears to play a key role in the recurrence and progression of PCa by regulating CSCs; however, the mechanism by which let-7 family contributes to PCa aggressiveness is unclear. Enhancer of Zeste homolog 2 (EZH2), a putative target of let-7 family, was demonstrated to control stem cell function. In this study, we found loss of let-7 family with corresponding over-expression of EZH2 in human PCa tissue specimens, especially in higher Gleason grade tumors. Overexpression of let-7 by transfection of let-7 precursors decreased EZH2 expression and repressed clonogenic ability and sphere-forming capacity of PCa cells, which was consistent with inhibition of EZH2 3′UTR luciferase activity. We also found that the treatment of PCa cells with BR-DIM (formulated DIM: 3,3′-diindolylmethane by Bio Response, Boulder, CO, abbreviated as BR-DIM) up-regulated let-7 and down-regulated EZH2 expression, consistent with inhibition of self-renewal and clonogenic capacity.Moreover, BR-DIM intervention in our on-going phase II clinical trial in patients prior to radical prostatectomy showed upregulation of let-7 consistent with down-regulation of EZH2 expression in PCa tissue specimens after BR-DIM intervention. These results suggest that the loss of let-7 mediated increased expression of EZH2 contributes to PCa aggressiveness, which could be attenuated by BR-DIM treatment, and thus BR-DIM is likely to have clinical impact..

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