Assert R, Kötter R, Bisping G, Scheppach W, Stahlnecker E, Müller K M, Dusel G, Schatz H, Pfeiffer A
Department of Internal Medicine, Berufsgenossenschaftliche Kliniken Bergmannsheil, University of Bochum, Germany.
Int J Cancer. 1999 Jan 5;80(1):47-53. doi: 10.1002/(sici)1097-0215(19990105)80:1<47::aid-ijc10>3.0.co;2-j.
The protein-kinase-C (PKC) family of iso-enzymes regulates mitogenic signal transduction in colorectal-cell lines. Its function in human colonic mucosal proliferation is controversial. Our study investigated the role of PKC with regard to proliferation and changes of PKC iso-enzyme expression in colonic biopsies compared with small adenomas. In short-term tissue-culture experiments of colonic mucosal biopsies, we found reduced S-phase labeling in the 2 apical compartments of longitudinally sectioned crypts when PKC was activated by 200 nM of the phorbol ester TPA (n = 8). Thus, PKC inhibited growth of differentiated colonocytes which may influence cell homeostasis in colonic crypts. Furthermore, we have determined the expression of PKC alpha, -beta1, -beta2, -delta and -epsilon in colonic adenomas smaller than 1 cm in diameter of 18 patients and found a significant increase of PKC alpha in the cytosolic fraction and decreased membrane levels of PKC beta2 in adenomas compared to normal, neighboring mucosa while protein levels of PKC beta1, -delta and -epsilon were not altered. Moreover PKC delta but not PKC alpha mRNA expression was significantly lowered in adenoma tissue in 7 patients, as determined by ribonuclease-protection analysis. Changes in the regulation patterns of PKC isoforms suggest a decreased activation state of PKC even in small adenomas. This is compatible with an anti-proliferative function of PKC serving to protect mucosa from expanding mutated cells.
蛋白激酶 C（PKC）同工酶家族调节结肠癌细胞系中的促有丝分裂信号转导。其在人类结肠黏膜增殖中的作用存在争议。我们的研究调查了 PKC 在结肠活检组织增殖方面的作用以及与小腺瘤相比 PKC 同工酶表达的变化。在结肠黏膜活检组织的短期组织培养实验中，当用 200 nM 的佛波酯 TPA 激活 PKC 时（n = 8），我们发现纵向切片隐窝的 2 个顶端区域的 S 期标记减少。因此，PKC 抑制分化结肠细胞的生长，这可能影响结肠隐窝中的细胞稳态。此外，我们测定了 18 例直径小于 1 cm 的结肠腺瘤中 PKCα、-β1、-β2、-δ 和 -ε 的表达，发现与正常相邻黏膜相比，腺瘤中胞质部分的 PKCα 显著增加，PKCβ2 的膜水平降低，而 PKCβ1、-δ 和 -ε 的蛋白水平未改变。此外，通过核糖核酸酶保护分析确定，7 例患者的腺瘤组织中 PKCδ 而非 PKCα 的 mRNA 表达显著降低。PKC 同工型调节模式的变化表明即使在小腺瘤中 PKC 的激活状态也降低。这与 PKC 的抗增殖功能一致，有助于保护黏膜免受突变细胞的扩张。
