Davidson B, Agulansky L, Goldberg I, Friedman E, Ramon J, Barshack I, Kopolovic J
Department of Pathology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Pathol Res Pract. 1998;194(6):399-404. doi: 10.1016/S0344-0338(98)80030-7.
The ras protooncogene plays a key role in the signal transduction cascade of activated growth factors, and is known to be activated or overexpressed in multiple tumor types, including prostate cancer. rasGTPase activating protein (rasGAP), a major downregulator of ras activity, has been shown to be underexpressed in human trophoblastic tumors, and presumably acts as a tumor suppressor gene product in these neoplasms. To assess the role that rasGAP plays in the development of prostate cancer, we performed immunohistochemical analyses with anti rasGAP antibodies of 125 human prostate tumors from Israel. Staining results were correlated with Gleason grade. In the majority of tumors (99/125-79%) there was either no staining or the tumor and surrounding benign glands had a similar pattern of staining. In up to 16% of the tumors, cytoplasmic, tumor-specific loss of expression was noted, presumably indicative of the role of rasGAP as a tumor suppressor gene. Unexpectedly, in up to 21% of the tumors, nuclear staining was demonstrated, and in about 20% of these, there was an accompanying loss of expression in the non neoplastic cytoplasm. Neither cytoplasmic nor nuclear staining correlated with Gleason grade. These findings of nuclear staining by anti-rasGAP are intriguing, since it is the first time that nuclear translocation of rasGAP is demonstrated, which might indicate that in this subset of tumors, rasGAP acts as a direct acting oncogene. The data indicate that rasGAP may play a dual regulatory role in prostate proliferation and that nuclear expression of it may be associated with malignant transformation of these cells.
原癌基因ras在活化生长因子的信号转导级联反应中起关键作用，已知在包括前列腺癌在内的多种肿瘤类型中被激活或过度表达。rasGTP酶激活蛋白（rasGAP）是ras活性的主要下调因子，已证实在人类滋养层肿瘤中表达不足，推测在这些肿瘤中作为肿瘤抑制基因产物发挥作用。为了评估rasGAP在前列腺癌发生发展中的作用，我们用抗rasGAP抗体对来自以色列的125例人类前列腺肿瘤进行了免疫组化分析。染色结果与Gleason分级相关。在大多数肿瘤（99/125 - 79%）中，要么没有染色，要么肿瘤和周围良性腺体具有相似的染色模式。在高达16%的肿瘤中，观察到细胞质中肿瘤特异性的表达缺失，推测这表明rasGAP作为肿瘤抑制基因的作用。出乎意料的是，在高达21%的肿瘤中出现了核染色，其中约20%在非肿瘤性细胞质中伴有表达缺失。细胞质和核染色均与Gleason分级无关。抗rasGAP核染色的这些发现很有趣，因为这是首次证明rasGAP的核转位，这可能表明在这一肿瘤亚群中，rasGAP作为直接作用的癌基因发挥作用。数据表明rasGAP可能在前列腺增殖中起双重调节作用，其核表达可能与这些细胞的恶性转化有关。
