MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells.
MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells.
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DOI：
10.1126/scisignal.2000356
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发表时间：
2009-10-13
影响因子：
7.3
通讯作者：
Tsichlis PN
中科院分区：
文献类型：
--
作者：
Iliopoulos D;Polytarchou C;Hatziapostolou M;Kottakis F;Maroulakou IG;Struhl K;Tsichlis PN
虽然已知Akt在人类癌症中发挥作用，但其三种亚型对肿瘤发生的相对贡献仍有待确定。我们在Akt 1 −/−/Akt 2 −/−/Akt 3 −/−细胞系中分别表达了每种亚型。生长因子刺激的细胞的microRNA分析揭示了每种亚型的独特microRNA特征。在差异调节的microRNA中，miR-200家族的丰度在携带Akt 2的细胞中降低。TGFβ处理的MCF 10A细胞中的Akt 1敲低也降低了miR-200的丰度。然而，敲除Akt 2或Akt 1和Akt 2两者则没有。此外，在相同细胞中敲低Akt 1，促进TGFβ诱导的上皮间充质转化（EMT）和干细胞样表型。由于miR-200下调，MMTV-cErbB 2/Akt 1 −/−小鼠中发生的癌症表现出侵袭性增加。最后，在一组原发性和转移性人乳腺癌中Akt 1与Akt 2的比率以及miR-200和编码E-钙粘蛋白的mRNA的丰度与以下假设一致：在许多情况下，乳腺癌转移可能受Akt-miR-200-E-钙粘蛋白轴的控制。我们的结论是EMT的诱导是由microRNA控制的，其丰度取决于Akt 1和Akt 2之间的平衡，而不是整体Akt活性。
Although Akt is known to play a role in human cancer, the relative contribution of its three isoforms to oncogenesis remains to be determined. We expressed each isoform individually in an Akt1−/−/Akt2−/−/Akt3−/− cell line. MicroRNA profiling of growth factor-stimulated cells revealed unique microRNA signatures for each isoform. Among the differentially-regulated microRNAs, abundance of the miR-200 family was decreased in cells bearing Akt2. Akt1 knockdown in TGFβ-treated MCF10A cells also decreased the abundance of miR-200. However, knockdown of Akt2, or of both Akt1 and Akt2, did not. Furthermore, Akt1 knockdown in the same cells, promoted TGFβ-induced epithelialmesenchymal-transition (EMT) and a stem cell-like phenotype. Carcinomas developing in MMTV-cErbB2/Akt1−/− mice showed increased invasiveness because of miR-200 downregulation. Finally, the ratio of Akt1 to Akt2 and the abundance of miR-200 and of the mRNA encoding E-cadherin in a set of primary and metastatic human breast cancers were consistent with the hypothesis that in many cases, breast cancer metastasis may be under the control of the Akt-miR-200-E-cadherin axis. We conclude that induction of EMT is controlled by microRNAs whose abundance depends on the balance between Akt1 and Akt2, rather than the overall Akt activity.
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影响因子：
20.3
作者：
Levy, Dana S.;Kahana, Jason A.;Kumar, Rakesh
通讯作者：
Kumar, Rakesh
影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
DOI：
10.1073/pnas.0308090100
发表时间：
2004-02-03
影响因子：
11.1
作者：
Seton-Rogers, SE;Lu, Y;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
64.5
作者：
Padmanabhan S;Mukhopadhyay A;Narasimhan SD;Tesz G;Czech MP;Tissenbaum HA
通讯作者：
Tissenbaum HA