Pavelić K, Hrasćan R, Kapitanović S, Karapandza N, Vranes Z, Belicza M, Kruslin B, Cabrijan T
Department of Molecular Medicine, Ruder Bosković Institute, Zagreb, Croatia.
J Pathol. 1995 Dec;177(4):395-400. doi: 10.1002/path.1711770410.
Proto-oncogenes, growth factors/receptors, and tumour suppressor genes were analysed in malignant metastatic insulinomas. Normal pancreas showed only a moderate immunoreaction for c-myc proto-oncogene and a strong reaction for insulin. Benign insulinomas were slightly or moderately positive for transforming growth factor alpha (TGF alpha), weakly positive for epidermal growth factor receptor (EGF-R), and strongly positive for c-myc and insulin. In malignant insulinomas, besides a strong immunoreaction for c-myc and TGF alpha, activation of c-K-ras and overexpression of p53 protein were found. Insulin reaction was moderate or strong. Three out of six malignant insulinomas displayed a c-K-ras point mutation at codon 12. All mutations were guanine to cytosine transversion, resulting in amino acid substitution, glycine to arginine. Mutations were present in metastatic insulinomas only. Patients with mutated c-K-ras oncogene had overexpression of p53 protein as well as c-myc and TGF alpha overexpression. Our results support the view that malignant progression is a consequence of more than one genetic lesion and suggest that activation of myc, TGF alpha an ras genes plays a role in a multistep process of tumour progression, perhaps serving as an initiating event.
对恶性转移性胰岛素瘤中的原癌基因、生长因子/受体和肿瘤抑制基因进行了分析。正常胰腺对c-myc原癌基因仅表现出中度免疫反应，对胰岛素表现出强反应。良性胰岛素瘤对转化生长因子α（TGFα）呈轻度或中度阳性，对表皮生长因子受体（EGF-R）呈弱阳性，对c-myc和胰岛素呈强阳性。在恶性胰岛素瘤中，除了对c-myc和TGFα有强免疫反应外，还发现了c-K-ras的激活和p53蛋白的过表达。胰岛素反应为中度或强阳性。6例恶性胰岛素瘤中有3例在第12密码子处出现c-K-ras点突变。所有突变均为鸟嘌呤到胞嘧啶的颠换，导致氨基酸取代，甘氨酸变为精氨酸。突变仅存在于转移性胰岛素瘤中。c-K-ras癌基因突变的患者同时存在p53蛋白过表达以及c-myc和TGFα过表达。我们的结果支持这样一种观点，即恶性进展是多种遗传损伤的结果，并表明myc、TGFα和ras基因的激活在肿瘤进展的多步骤过程中起作用，可能作为起始事件。
