Kornmann M, Maruyama H, Bergmann U, Tangvoranuntakul P, Beger H G, White M F, Korc M
Department of Medicine, University of California, Irvine 92697, USA.
Cancer Res. 1998 Oct 1;58(19):4250-4.
Insulin receptor substrate-2 (IRS-2) is a multisite docking protein implicated in mitogenic signaling after activation of the insulin and insulin-like growth factor (IGF)-I receptors. In the present study, we characterized IRS-2 expression and function in human pancreatic cancer. IRS-2 mRNA and protein were expressed in ASPC-1 and COLO-357 human pancreatic cancer cell lines. Insulin, IGF-I, and IGF-II enhanced the growth of both cell lines, stimulated tyrosine phosphorylation of IRS-2, and increased IRS-2-associated phosphatidylinositol (PI) 3-kinase activity. The mitogenic effects of insulin, IGF-I, and IGF-II were markedly attenuated by the PI 3-kinase inhibitor LY 294002. Northern blot analysis of total RNA extracted from normal and cancerous tissues revealed that IRS-2 mRNA levels were increased in the cancer tissues (P = 0.032). In the normal pancreas, IRS-2 immunoreactivity was present at low levels in some ductal and acinar cells and at moderate levels in a heterogeneous pattern in all of the endocrine islets. In the pancreatic cancers, IRS-2 was abundant in the ductal-like cancer cells. These findings indicate that IRS-2 is overexpressed in human pancreatic cancer and suggest that it may contribute to enhanced mitogenic signaling via the PI 3-kinase pathway, thereby leading to excessive growth stimulation in this malignancy.
胰岛素受体底物-2（IRS-2）是一种多位点对接蛋白，在胰岛素和胰岛素样生长因子（IGF）-I受体激活后的促有丝分裂信号传导中起作用。在本研究中，我们对IRS-2在人胰腺癌中的表达和功能进行了表征。IRS-2 mRNA和蛋白在人胰腺癌ASPC-1和COLO-357细胞系中表达。胰岛素、IGF-I和IGF-II可促进这两种细胞系的生长，刺激IRS-2的酪氨酸磷酸化，并增加与IRS-2相关的磷脂酰肌醇（PI）3激酶活性。PI 3激酶抑制剂LY 294002可显著减弱胰岛素、IGF-I和IGF-II的促有丝分裂作用。对从正常组织和癌组织中提取的总RNA进行Northern印迹分析显示，癌组织中IRS-2 mRNA水平升高（P = 0.032）。在正常胰腺中，IRS-2免疫反应性在一些导管和腺泡细胞中呈低水平存在，在所有内分泌胰岛中呈异质性中等水平存在。在胰腺癌中，IRS-2在导管样癌细胞中丰富。这些发现表明IRS-2在人胰腺癌中过度表达，并提示它可能通过PI 3激酶途径促进促有丝分裂信号增强，从而导致这种恶性肿瘤中过度的生长刺激。
