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.
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.
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DOI：
10.1371/journal.pone.0033729
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Sarkar FH
中科院分区：
文献类型：
--
作者：
Kong D;Heath E;Chen W;Cher ML;Powell I;Heilbrun L;Li Y;Ali S;Sethi S;Hassan O;Hwang C;Gupta N;Chitale D;Sakr WA;Menon M;Sarkar FH
去势抵抗性前列腺癌（CRPC）的出现导致了前列腺癌（PCa）患者的高死亡率，这部分归因于癌症干细胞（CSC）的存在和出现。最近的研究表明，microRNAs（miRNAs）的表达失调有助于PCa的发生和发展。在几种已知的miRNAs中，let-7家族通过调控CSC在PCa的复发和进展中发挥关键作用，但let-7家族参与PCa侵袭性的机制尚不清楚。增强子Zeste同源物2（Enhancer of Zeste homolog 2，EZH 2）是let-7家族的一个靶点，被证实控制干细胞功能。在这项研究中，我们发现let-7家族的丢失与相应的EZH 2在人PCa组织标本中的过表达，特别是在较高的Gleason分级肿瘤中。通过转染let-7前体过表达let-7可降低EZH 2的表达，抑制PCa细胞的克隆形成能力和球体形成能力，这与抑制EZH 2 3′UTR荧光素酶活性一致。我们还发现，用BR-DIM（由Bio Response，Boulder，CO配制的DIM：3，3 ′-二吲哚基甲烷，缩写为BR-DIM）处理PCa细胞上调let-7表达并下调EZH 2表达，这与自我更新和克隆形成能力的抑制一致。此外，在我们正在进行的II期临床试验中，在根治性前列腺切除术前对患者进行BR-DIM干预显示，BR-DIM干预后，let-7的上调与PCa组织标本中EZH 2表达的下调一致。这些结果表明，let-7介导的EZH 2表达增加的损失有助于PCa侵袭性，其可以通过BR-DIM治疗减弱，因此BR-DIM可能具有临床影响。
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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影响因子：
3.7
作者：
Kong D;Banerjee S;Ahmad A;Li Y;Wang Z;Sethi S;Sarkar FH
通讯作者：
Sarkar FH
DOI：
10.1016/s1570-0232(02)00923-6
发表时间：
2003-04-25
影响因子：
3
作者：
Anderton, MJ;Jukes, R;Williams, ML
通讯作者：
Williams, ML
影响因子：
5.3
作者：
Herranz, Nicolas;Pasini, Diego;Peiro, Sandra
通讯作者：
Peiro, Sandra
影响因子：
2.7
作者：
Benjamini, Yoav;Krieger, Abba M.;Yekutieli, Daniel
通讯作者：
Yekutieli, Daniel
影响因子：
5.2
作者：
Kong, Dejuan;Li, Yiwei;Wang, Zhiwei;Banerjee, Sanjeev;Ahmad, Aamir;Kim, Hyeong-Reh Choi;Sarkar, Fazlul H.
通讯作者：
Sarkar, Fazlul H.