去勢(shì)抵抗性前列腺癌 (CRPC) 的發(fā)生促進(jìn)了前列腺癌(PCa)病人的高死亡率，這在某種程度上歸因于腫瘤干細(xì)胞(CSCs)的存在及出現(xiàn),。近期來(lái)自美國(guó)韋恩州立大學(xué)醫(yī)學(xué)院的Fazlul H. Sarkar等人研究表明,，解除對(duì)Let-7（一種miRNAs）表達(dá)的控制會(huì)促進(jìn)PCa的發(fā)生和發(fā)展,，并且這個(gè)過(guò)程能夠被BR-DIM所改變。相關(guān)研究發(fā)表在3月19日美國(guó)《公共科學(xué)圖書館·綜合（PLoS One）上,。
在幾種已知的miRNAs中,，let-7家族通過(guò)調(diào)節(jié)CSCs在引起PCa的復(fù)發(fā)以及發(fā)展中起到了重要作用。然而,，let-7家族促進(jìn)PCa侵略性的機(jī)制還未可知,。Zeste homolog 2(EZH2)的增強(qiáng)子是一個(gè)公認(rèn)的let-7家族的目標(biāo)，在過(guò)去被證明其可以控制干細(xì)胞功能,。在這項(xiàng)研究中,，研究人員發(fā)現(xiàn)，在人類 PCa組織樣品中,，尤其是在更高Gleason等級(jí)的腫瘤中,，失去let-7 家族與EZH2的過(guò)表達(dá)一致。在PCa 細(xì)胞中,，通過(guò)轉(zhuǎn)染 let-7前體細(xì)胞,，let-7的過(guò)表達(dá)會(huì)減少EZH2的表達(dá)，并抑制克隆及球體形成的能力,，這與抑制EZH2 3′UTR熒光素酶的活性后效果一致,。研究人員還發(fā)現(xiàn),，對(duì)PCa細(xì)胞使用用BR-DIM (3,3′-二吲哚甲烷)治療后，會(huì)上調(diào)let-7并下調(diào)EZH2的表達(dá),，這與抑制自我更新和克隆能力一致,。
此外，在我們正在做的二期臨床實(shí)驗(yàn)中,，BR-DIM的介入治療先于根治性前列腺切除術(shù),。結(jié)果表明：使用BR-DIM治療后， PCa組織樣本中l(wèi)et-7 的上調(diào)與EZH2的表達(dá)下調(diào)一致,。這些結(jié)果表明,，失去 let-7會(huì)調(diào)停EZH2的增強(qiáng)型表達(dá)，然后促進(jìn)PCa的侵略性,，而這些都可以通過(guò)BR-DIM的治療來(lái)改變,。因此，BR-DIM可能有一定的臨床藥物,。（生物谷Deepblue編譯）
doi: 10.1371/journal.pone.0033729
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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..
