Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA.
Cancer Res. 2011 Jul 1;71(13):4720-31. doi: 10.1158/0008-5472.CAN-11-0365. Epub 2011 May 9.
The growth and survival of tumor cells in an unfavorable hypoxic environment depend upon their adaptability. Here, we show that both normal and tumor cells expressing the protein kinase Akt2 are more resistant to hypoxia than cells expressing Akt1 or Akt3. This is due to the differential regulation of microRNA (miR) 21, which is upregulated by hypoxia only in Akt2-expressing cells. By upregulating miR-21 upon oxygen deprivation, Akt2 downregulates PTEN and activates all three Akt isoforms. miR-21 also targets PDCD4 and Sprouty 1 (Spry1), and the combined downregulation of these proteins with PTEN is sufficient to confer resistance to hypoxia. Furthermore, the miR-21 induction by Akt2 during hypoxia depends upon the binding of NF-κB, cAMP responsive element-binding protein (CREB), and CBP/p300 to the miR-21 promoter, in addition to the regional acetylation of histone H3K9, all of which are under the control of Akt2. Analysis of the Akt2/miR-21 pathway in hypoxic MMTV-PyMT-induced mouse mammary adenocarcinomas and human ovarian carcinomas confirmed the activity of the pathway in vivo. Taken together, this study identifies a novel Akt2-dependent pathway that is activated by hypoxia and promotes tumor resistance via induction of miR-21.
肿瘤细胞在不利的缺氧环境中的生长和存活依赖于其适应性。在这里，我们表明，表达蛋白激酶 Akt2 的正常和肿瘤细胞比表达 Akt1 或 Akt3 的细胞对缺氧更具抵抗力。这是由于 microRNA (miR) 21 的差异调节所致，miR-21 仅在 Akt2 表达的细胞中被缺氧上调。通过在缺氧剥夺时上调 miR-21，Akt2 下调 PTEN 并激活所有三种 Akt 同工型。miR-21 还靶向 PDCD4 和 Sprouty 1 (Spry1)，并且与 PTEN 一起下调这些蛋白足以赋予对缺氧的抗性。此外，Akt2 在缺氧期间诱导 miR-21 取决于 NF-κB、cAMP 反应元件结合蛋白 (CREB) 和 CBP/p300 与 miR-21 启动子的结合，以及组蛋白 H3K9 的区域乙酰化，所有这些都受 Akt2 的控制。在缺氧 MMTV-PyMT 诱导的小鼠乳腺腺癌和人卵巢癌中对 Akt2/miR-21 通路的分析证实了该通路在体内的活性。总之，这项研究确定了一种新的 Akt2 依赖性通路，该通路被缺氧激活，并通过诱导 miR-21 促进肿瘤耐药性。
