Szabolcs Matthias, Keniry Megan, Simpson Laura, Reid Latarsha J, Koujak Susan, Schiff Sarah C, Davidian Giselle, Licata Scott, Gruvberger-Saal Sofia, Murty Vundavalli V V S, Nandula Subhadra, Efstratiadis Argiris, Kushner Jake A, White Morris F, Parsons Ramon
Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Am J Pathol. 2009 Jan;174(1):276-86. doi: 10.2353/ajpath.2009.080086. Epub 2008 Dec 18.
Mutations in the phosphatase and tensin homologue (PTEN)/phosphatidylinositol-3 kinase-alpha (PI3K) signaling pathway are frequently found in human cancer. In addition, Pten(+/-) mice develop tumors in multiple organs because of the activation of the PI3K signaling cascade. Because activation of PI3K signaling leads to feedback inhibition of insulin receptor substrate-2 (IRS2) expression, an upstream activator of PI3K, we therefore anticipated that IRS2 expression would be low in tumors that lack PTEN. Surprisingly, however, an elevation of IRS2 was often detected in tumor samples in which PTEN levels were compromised. To determine the potential contribution of Irs2 to tumor progression, Pten(+/-) mice were crossed with Irs2(+/-) mice. Deletion of Irs2 did not affect the initiation of neoplasia found in Pten(+/-) mice but suppressed cancer cell growth, proliferation, and invasion through the basement membrane. Deletion of Irs2 also attenuated the expression of Myc in prostatic intraepithelial neoplasia in Pten(+/-) mice. In addition, the expression levels of IRS2 and MYC were highly correlated in human prostate cancer, and IRS2 could stimulate MYC expression in cultured cells. Our findings provide evidence that the PI3K-activating adaptor Irs2 contributes to tumor progression in Pten(+/-) mice by stimulating both Myc and DNA synthesis.
磷酸酶与张力蛋白同源物（PTEN）/磷脂酰肌醇-3激酶α（PI3K）信号通路中的突变在人类癌症中经常被发现。此外，Pten(+/-)小鼠由于PI3K信号级联的激活而在多个器官中发生肿瘤。由于PI3K信号的激活导致对PI3K的上游激活剂胰岛素受体底物-2（IRS2）表达的反馈抑制，因此我们预计在缺乏PTEN的肿瘤中IRS2表达会较低。然而，令人惊讶的是，在PTEN水平受损的肿瘤样本中经常检测到IRS2升高。为了确定Irs2对肿瘤进展的潜在贡献，将Pten(+/-)小鼠与Irs2(+/-)小鼠杂交。Irs2的缺失并不影响Pten(+/-)小鼠中肿瘤形成的起始，但抑制了癌细胞通过基底膜的生长、增殖和侵袭。Irs2的缺失还减弱了Pten(+/-)小鼠前列腺上皮内瘤变中Myc的表达。此外，在人类前列腺癌中，IRS2和MYC的表达水平高度相关，并且IRS2可以在培养细胞中刺激MYC表达。我们的研究结果提供了证据，表明PI3K激活衔接蛋白Irs2通过刺激Myc和DNA合成促进Pten(+/-)小鼠的肿瘤进展。
