Zhang Bin, Ougolkov Andrei, Yamashita Kaname, Takahashi Yutaka, Mai Masayoshi, Minamoto Toshinari
Divisions of Diagnostic Molecular Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.
Clin Cancer Res. 2003 Aug 1;9(8):3073-9.
PURPOSE AND STUDY DESIGN: Recent studies have shown that beta-catenin translocated into the cell nucleus functions like an oncogene. Accumulating evidence suggests that activation of the beta-catenin oncogenic signaling cascade along with its twin, the K-ras cascade, may exert syngeneic or synergistic effects on tumor development and progression. In the study reported here, we analyzed oncogenic beta-catenin activation on the basis of its nuclear accumulation (NA) and compared the results with those of mutational activation of K-ras in 74 patients with colorectal cancer to determine whether the two oncogene-mediated signaling cascades interact.
We found two distinct patterns of beta-catenin activation, i.e., diffuse NA in 20 cases (27%) and selective NA at the tumor invasion front (NAinv) in 19 cases (26%). The presence of the NAinv pattern was significantly correlated with advanced Dukes' stage tumor (P = 0.0005) and the presence of distant metastases (P = 0.0064). K-ras proto-oncogene was mutated in the tumors of 31 cases (42%). Activated beta-catenin or K-ras was detected in most (78%) colorectal cancers analyzed, although a weak inverse correlation was found between the activities of the two oncogenes in the tumors. Importantly, most (7 of 8) patients with tumor showing both K-ras activation and the NAinv pattern of beta-catenin activation were in Dukes' stage C at surgery, and half of them developed distant metastases to the liver and lungs.
The results suggest that although oncogenic activation of beta-catenin and K-ras is independent in the process of clinical cancer development, combined analysis of the two major oncogenes can detect most colorectal cancers and identify a subset of patients with poorer outcomes. Consequently, activation of either or both of these oncogenes may serve as a genetic marker for molecular diagnosis.
目的与研究设计：近期研究表明，转位至细胞核的β-连环蛋白发挥癌基因的作用。越来越多的证据表明，β-连环蛋白致癌信号级联与其孪生的K-ras级联的激活可能对肿瘤的发生发展产生同基因或协同效应。在本研究中，我们基于β-连环蛋白的核内积聚（NA）分析其致癌激活情况，并将结果与74例结直肠癌患者K-ras的突变激活情况进行比较，以确定这两种癌基因介导的信号级联是否相互作用。
我们发现β-连环蛋白激活存在两种不同模式，即20例（27%）表现为弥漫性NA，19例（26%）表现为肿瘤浸润前沿的选择性NA（NAinv）。NAinv模式的存在与进展期杜克分期肿瘤（P = 0.0005）及远处转移的存在（P = 0.0064）显著相关。31例（42%）肿瘤中K-ras原癌基因发生突变。在大多数（78%）分析的结直肠癌中检测到激活的β-连环蛋白或K-ras，尽管在肿瘤中这两种癌基因的活性之间发现了微弱的负相关。重要的是，大多数（8例中的7例）肿瘤同时显示K-ras激活和β-连环蛋白激活的NAinv模式的患者在手术时处于杜克分期C期，其中一半发生了肝和肺的远处转移。
结果表明，虽然β-连环蛋白和K-ras的致癌激活在临床癌症发展过程中是独立的，但对这两种主要癌基因的联合分析可以检测到大多数结直肠癌，并识别出预后较差的患者亚组。因此，这些癌基因中任何一个或两个的激活都可作为分子诊断的遗传标志物。
