Benzil D L, Finkelstein S D, Epstein M H, Finch P W
Department of Clinical Neurosciences, Brown University, Providence, Rhode Island.
Cancer Res. 1992 May 15;52(10):2951-6.
Protein kinase C (PKC) is a family of isoenzymes which play an important role in regulating cell proliferation and differentiation. Constitutive activation of PKC, either by phorbol esters or overexpression of specific isoenzymes, leads to growth abnormalities in vitro and tumor promotion in vivo. Since stimulation of PKC in cultured astrocytes results in biochemical and morphological alterations associated with the transformed phenotype, we wanted to determine whether abnormal expression of specific isoenzymes of PKC was important in development of human astrocytomas in vivo. We have detected a specific pattern of alpha-PKC expression in human astrocytomas which is noteworthy because the highest transcript levels were detected in well-differentiated (Grade 1) tumors, with intermediate expression in anaplastic (Grade 2) astrocytomas and low or nondetectable levels in glioblastomas (Grade 3 astrocytomas) and normal controls. In comparison, the beta-PKC transcript was not detected in any of the tumors, while the gamma-PKC transcript was present in only one Grade 2 tumor. Immunohistochemistry, using a monoclonal antibody to alpha-PKC, revealed diffuse, positive cytoplasmic signals in most cells of the Grade 1 tumors. Grade 2 tumors exhibited heterogeneity of alpha-PKC expression, although a significant percentage of cells showed positivity. In contrast, only a small number of differentiated cells within Grade 3 tumors were positive for alpha-PKC expression, with the more malignant, dedifferentiated cells uniformly negative. Throughout all tumor grades, the staining pattern of alpha-PKC closely paralleled that of glial fibrillary acidic protein. Taken in conjunction with the established role of PKC in tumor promotion, these results suggest that the alpha-PKC isoenzyme plays a specific role in facilitating clonal expansion of transformed astrocytes in low-grade astrocytomas. Analysis of alpha-PKC may therefore serve as a direct biological marker of malignancy which may serve to enhance the current histopathological grading system.
蛋白激酶C（PKC）是一类同工酶家族，在调节细胞增殖和分化中发挥重要作用。通过佛波酯或特定同工酶的过表达对PKC进行组成型激活，会导致体外生长异常和体内肿瘤促进。由于在培养的星形胶质细胞中刺激PKC会导致与转化表型相关的生化和形态学改变，我们想确定PKC特定同工酶的异常表达在人类星形细胞瘤的体内发展中是否重要。我们在人类星形细胞瘤中检测到了α-PKC表达的特定模式，这值得注意，因为在分化良好（1级）的肿瘤中检测到最高的转录水平，在间变性（2级）星形细胞瘤中表达中等，而在胶质母细胞瘤（3级星形细胞瘤）和正常对照中表达低或未检测到。相比之下，在任何肿瘤中均未检测到β-PKC转录本，而γ-PKC转录本仅在一个2级肿瘤中存在。使用抗α-PKC单克隆抗体进行免疫组织化学分析，显示1级肿瘤的大多数细胞中存在弥漫性的阳性细胞质信号。2级肿瘤表现出α-PKC表达的异质性，尽管有相当比例的细胞呈阳性。相反，3级肿瘤中只有少数分化细胞α-PKC表达呈阳性，而恶性程度更高、去分化的细胞均为阴性。在所有肿瘤分级中，α-PKC的染色模式与胶质纤维酸性蛋白的染色模式密切平行。结合PKC在肿瘤促进中的既定作用，这些结果表明α-PKC同工酶在促进低级别星形细胞瘤中转化星形胶质细胞的克隆扩增中起特定作用。因此，对α-PKC的分析可能作为恶性肿瘤的直接生物学标志物，可用于加强当前的组织病理学分级系统。
