Identification of oncogenic microRNA-17-92/ZBTB4/specificity protein axis in breast cancer.
Identification of oncogenic microRNA-17-92/ZBTB4/specificity protein axis in breast cancer.
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DOI：
10.1038/onc.2011.296
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发表时间：
2012-02-23
期刊：
影响因子：
8
通讯作者：
Safe, S.
中科院分区：
文献类型：
--
作者：
Kim, K.;Chadalapaka, G.;Lee, S-O;Yamada, D.;Sastre-Garau, X.;Defossez, P-A;Park, Y-Y;Lee, J-S;Safe, S.
人POK家族成员是具有POZ结构域和锌指的转录因子，其主要充当转录抑制因子。该家族的几个成员参与肿瘤发生，这促使我们评估单个POK家族成员的表达水平是否与癌症的临床结果相关。我们已经观察到ZBTB 4在乳腺癌患者中下调，并且其表达与无复发生存率显著相关。对来自NCI-60细胞系的mRNA和microRNA（miR）表达数据的进一步整合分析揭示了ZBTB 4与源自miR-17-92簇及其旁系同源物的致癌miR之间的负相关性。使用MDA-MB-231和MCF-7人乳腺癌细胞的实验结果证实，源自这些簇的miRNA（包含miR-17- 5 p、miR-20 a、miR-106 a、miR-106 b和miR-93）负调控ZBTB 4表达。ZBTB 4的过表达或通过使用阿替洛尔恢复ZBTB 4抑制乳腺癌细胞的生长和侵袭，并且这种作用部分是由于ZBTB 4依赖性抑制特异性蛋白1（Sp1）、Sp3和Sp 4基因，以及随后的几种Sp-dependent癌基因的下调，部分是通过ZBTB 4和Sp转录因子之间对富含GC的启动子序列的竞争。这些结果证实ZBTB 4作为一种新的肿瘤抑制基因对乳腺癌生存具有预后意义，致癌miR-17-92/ZBTB 4/Sp轴可能是一个潜在的治疗靶点。
The human POK family members are transcription factors with a POZ domain and zinc fingers that act primarily as transcriptional repressors. Several members of this family are involved in oncogenesis and this prompted us to assess whether expression levels of individual POK family members are associated with clinical outcomes in cancer. We have observed that ZBTB4 is downregulated in breast cancer patients, and that its expression is significantly correlated with relapse-free survival. Further integrative analysis of mRNA and microRNA (miR) expression data from the NCI-60 cell lines revealed an inverse correlation between ZBTB4 and oncogenic miRs derived from the miR-17-92 cluster and its paralogues. The experimental results using MDA-MB-231 and MCF-7 human breast cancer cells confirm that miRNAs derived from these clusters, containing miR-17-5p, miR-20a, miR-106a, miR-106b and miR-93, negatively regulate ZBTB4 expression. Overexpression of ZBTB4 or restoration of ZBTB4 by using an antagomir inhibit growth and invasion of breast cancer cells, and this effect is due, in part, to ZBTB4-dependent repression of the specificity protein 1 (Sp1), Sp3, and Sp4 genes, and subsequent downregulation of several Sp-dependent oncogenes, in part, through competition between ZBTB4 and Sp transcription factors for GC-rich promoter sequences. These results confirm that ZBTB4 functions as a novel tumor suppressor gene with prognostic significance for breast cancer survival, and the oncogenic miR-17-92/ZBTB4/Sp axis may be a potential therapeutic target.
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影响因子：
11.2
作者：
Lee SO;Abdelrahim M;Yoon K;Chintharlapalli S;Papineni S;Kim K;Wang H;Safe S
通讯作者：
Safe S
影响因子：
5.7
作者：
Liu H;D'Andrade P;Fulmer-Smentek S;Lorenzi P;Kohn KW;Weinstein JN;Pommier Y;Reinhold WC
通讯作者：
Reinhold WC
影响因子：
11.2
作者：
Chadalapaka G;Jutooru I;Chintharlapalli S;Papineni S;Smith R 3rd;Li X;Safe S
通讯作者：
Safe S
影响因子：
5.7
作者：
Blower, Paul E.;Verducci, Joseph S.;Sadee, Wolfgang
通讯作者：
Sadee, Wolfgang
影响因子：
4.8
作者：
Koh, Dong-In;Choi, Won-Il;Hur, Man-Wook
通讯作者：
Hur, Man-Wook