Activation of Src kinase in primary colorectal carcinoma - An indicator of poor clinical prognosis
Activation of Src kinase in primary colorectal carcinoma - An indicator of poor clinical prognosis
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DOI：
10.1002/cncr.10221
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发表时间：
2002-01-15
期刊：
影响因子：
6.2
通讯作者：
Gallick, GE
中科院分区：
文献类型：
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作者：
Allgayer, H;Boyd, DD;Gallick, GE
背景。与正常粘膜相比，大多数结肠和直肠腺癌中非受体蛋白酪氨酸激酶 Src 的比活性增加。然而，这种差异的预后意义尚不清楚。本研究的目的是确定 Src 活性是否是结肠癌患者临床预后不良的标志。由于Src激活导致尿激酶/纤溶酶原激活剂受体(u-PAR)的表达，因此Src和u-PAR的表达与患者的存活率相关。方法。通过免疫复合物激酶测定，对 45 名结直肠癌患者的肿瘤和邻近正常结肠粘膜的 Src 活性进行了筛选。通过酶联免疫吸附测定法测定u-PAR的表达。在分类和回归树（CART）分析后比较原发肿瘤与正常粘膜的活性比率，以确定特异性Src活性升高的预后意义，u-PAR的表达与Src活性相关。 结果。通过 CART 分析，肿瘤中的 Src 活性比正常粘膜升高两倍以上，这一点非常显着。 Src 活性增加与 Dukes 分期、pT 和 pN 分级以及 u-PAR 水平增加显着相关 (P < 0.001)。 Kaplan Meier 分析显示，所有患者 (P = 0.0004) 和 Dukes A-C 期患者 (P = 0.0037) 的 Src 活性升高与总生存期缩短之间存在显着相关性。在接受根治性切除的患者中，发现与无病生存率降低存在显着相关性（P < 0.0001）。多变量分析显示，Src 活性升高是独立于 M 分类的预后参数（P = 0.0125，相对风险 3.34，95% 置信区间 1.31-9.76）。结论。 Src活性是人类结肠癌各个阶段临床预后不良的独立指标。这些数据表明Src特异性抑制剂可能在抑制肿瘤进展和转移方面具有治疗作用，并且Src活性的测量可能有助于选择早期患者进行辅助治疗。 (C) 2002 年美国癌症协会。
BACKGROUND. The specific activity of the non-receptor protein tyrosine kinase, Src, is increased in the majority of colon and rectal adenocarcinomas compared to normal mucosa. However, the prognostic significance of this difference is unknown. The objective of the current study was to determine if Src activity is a marker for poor clinical prognosis in colon carcinoma patients. As Src activation leads to expression of urokinase/plasminogen activator receptor (u-PAR), expression of Src and u-PAR were correlated with patient survival.METHODS. Tumors and adjacent normal colonic mucosae from 45 patients with colorectal carcinoma were screened for Src activity by the immune complex kinase assay. Expression of u-PAR was determined by enzyme linked immunoabsorbent assay. The primary tumor-to-normal mucosa ratios of activity, were compared following classification and regression tree (CART) analysis to determine the prognostic significance of elevated specific Src activity, Expression of u-PAR was correlated with Src activity.RESULTS. By CART analysis, Src activity in tumors elevated more than twofold over normal mucosa was significant. Increased Src activity significantly correlated with Dukes stage, pT and pN classification, and increased u-PAR levels (P < 0.001). Kaplan Meier analysis showed a significant association between elevated Src activity and shorter overall survival of all patients (P = 0.0004) and of Dukes Stage A-C patients (P = 0.0037). In patients who underwent curative resection, a significant correlation with a decreased disease-free survival rate was found (P < 0.0001). Multivariate analysis revealed that elevated Src activity was a prognostic parameter independent of M classification (P = 0.0125, relative risk 3.34, 95% confidence interval 1.31-9.76).CONCLUSIONS. Src activity is all independent indicator of poor clinical prognosis in all stages of human colon carcinoma. These data suggest that Src-specific inhibitors may have a therapeutic role in inhibiting tumor progression and metastasis, and that measurement of Src activity may aid in selection of early stage patients for adjuvant therapy. (C) 2002 American Cancer Society.