子宫内膜癌组织中胰岛素受体底物1的表达与活化及其临床意义

Expression and activation of insulin receptor substrate-I in endometrial carcinoma

目的研究子宫内膜癌组织中胰岛素受体底物1（IRS-1）mRNA、蛋白的表达水平及酪氨酸磷酸化程度，并探讨其临床意义。方法选择63例子宫内膜癌（内膜癌组）、21例子宫内膜不典型增生（不典型增生组）及22例正常子宫内膜（正常内膜组）患者进入本研究。收集其临床病理资料，酶联免疫法检测空腹血清胰岛素C肽水平，RT-PCR技术和蛋白印迹法分别检测子宫内膜组织中IRS-1 mRNA及蛋白的相对表达量，免疫共沉淀法检测IRS-1酪氨酸磷酸化程度。结果内膜癌组患者血清C肽水平为（3．2±1．1）μg／L，高于正常内膜组[（2．5±0．7）μg／L]，两组比较，差异有统计学意义（P=0．007）。内膜癌、不典型增生及正常内膜组IRS-1 mRNA、蛋白的相对表达量比较，差异均无统计学意义（F=0．695、0．003，P=0．502、0．997）。内膜癌组IRS-1酪氨酸磷酸化程度[（62±36）％]高于不典型增生及正常内膜组[分别为（53±34）％、（35±33）％]，分别比较，差异均有统计学意义（P=0．048、0．002）；不典型增生组与正常内膜组比较，差异也有统计学意义（P=0．045）。子宫内膜样腺癌患者IRS-1酪氨酸磷酸化程度[（69±33）％]高于非内膜样癌[（34±31）％]，两者比较，差异有统计学意义（t=2．300，P=0．025）。高手术病理分期、细胞分化不良、深肌层浸润及盆腔淋巴结转移者IRS-1酪氨酸磷酸化程度增高（P均〈0．05）。子宫内膜组织中IRS-1酪氨酸磷酸化程度与空腹血清C肽水平呈正相关关系（r=0．491，P=0．001）。结论子宫内膜癌组织中IRS-1的表达无明显变化，但存在IRS-1酪氨酸磷酸化程度增加，并与手术病理分期高、细胞分化不良、深肌层浸润及盆腔淋巴结转移等不良的临床病理特征相关。

Objective To investigate the mRNA, protein expression and tyrosine phosphorylation of insulin receptor sttbstrate-1 （IRS-1） in endometrial carcinoma. Methods Sixty-three endometrial carcinoma （EC） patients, 21 endometrial atypical hyperplasia （AHE） patients and 22 normal control （ NE ） entered this study. Their clinical information were collected. Fasting serum C-peptide concentration was measured. Expression of IRS-1 in endometrium was examined by RT-PCR and western blot. Immunoprecipitation was used to measure the tyrosine phosphorylation of IRS-1. Results C-peptide concentration in EC group was higher than that in NE group [ （ 3.2 ± 1.1 ） vs （2. 5 ± 0. 7 ） μg/L, P = 0. 007]. There were no significant differences in IRS-1 mRNA and protein expression among the three groups. Tyrosine phosphorylation of IRS-1 in EC group [ （62 ± 36） % ] was higher than that in AHE and NE groups [（53 ±34）% and （35 ±33）%; P =0.048, 0.002]. IRS-1 activation in AHE group was also higher than normal control （ P = 0. 045 ）. IRS-1 activation in endometrioid carcinoma [ （ 69 ± 33 ） % ] was higher than that in other histological types [ （ 34 ± 31 ）% ; t = 2. 300, P = 0. 025 ] . IRS-1 tyrosine phosphorylation was significantly higher in patients with advanced stage, high grade, deep myometrial invasion and pelvic lymph node metastasis. IRS-1 activation in endometrium was positively correlated with fasting serum C-peptide concentration （ r = 0. 491, P = 0. 001 ）. Conclusions There is excessive activation of IRS-1 in endometrial carcinoma and atypical hyperplasia. Activation of IRS-1 in endometrial carcinoma is related with poor clinical-pathologic features and may be a prognostic predictor for this tumor. Over-activation of IRS-1 may be an intermediate event linking the hyperinsulinemia and endometrial carcinoma.