Mardilovich Katerina, Shaw Leslie M
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusett 01605, USA.
Cancer Res. 2009 Dec 1;69(23):8894-901. doi: 10.1158/0008-5472.CAN-09-1152. Epub 2009 Nov 17.
Insulin receptor substrate-2 (IRS-2) belongs to the IRS family of adaptor proteins that function as signaling intermediates for growth factor, cytokine, and integrin receptors, many of which have been implicated in cancer. Although the IRS proteins share significant homology, distinct functions have been attributed to each family member in both normal and tumor cells. In cancer, IRS-2 is positively associated with aggressive tumor behavior. In the current study, we show that IRS-2 expression, but not IRS-1 expression, is positively regulated by hypoxia, which selects for tumor cells with increased metastatic potential. We identify IRS-2 as a novel hypoxia-responsive gene and establish that IRS-2 gene transcription increases in a hypoxia-inducible factor-dependent manner in hypoxic environments. IRS-2 is active to mediate insulin-like growth factor I-dependent signals in hypoxia, and enhanced activation of Akt in hypoxia is dependent on IRS-2 expression. Functionally, the elevated expression of IRS-2 facilitates breast carcinoma cell survival and invasion in hypoxia. Collectively, our results reveal a novel mechanism by which IRS-2 contributes to the aggressive behavior of hypoxic tumor cells.
胰岛素受体底物-2（IRS-2）属于衔接蛋白的IRS家族，该家族作为生长因子、细胞因子和整合素受体的信号转导中间体发挥作用，其中许多受体与癌症有关。尽管IRS蛋白具有显著的同源性，但在正常细胞和肿瘤细胞中，每个家族成员都具有不同的功能。在癌症中，IRS-2与侵袭性肿瘤行为呈正相关。在本研究中，我们发现缺氧对IRS-2的表达具有正向调节作用，而对IRS-1的表达无此作用，缺氧会选择具有更高转移潜能的肿瘤细胞。我们将IRS-2鉴定为一种新的缺氧反应基因，并证实IRS-2基因转录在缺氧环境中以缺氧诱导因子依赖的方式增加。IRS-2在缺氧条件下能够介导胰岛素样生长因子I依赖的信号，缺氧时Akt的激活增强依赖于IRS-2的表达。在功能上，IRS-2表达的升高促进了乳腺癌细胞在缺氧条件下的存活和侵袭。总的来说，我们的研究结果揭示了一种新的机制，通过该机制IRS-2促进了缺氧肿瘤细胞的侵袭行为。
