Zhang T, Nanney L B, Luongo C, Lamps L, Heppner K J, DuBois R N, Beauchamp R D
Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Cancer Res. 1997 Jan 1;57(1):169-75.
We postulated that increased expression of the cell cycle regulators cyclin D1 and cyclin-dependent kinase (Cdk) 4 may be involved in the development of intestinal adenomas associated with familial adenomatous polyposis (FAP). In the present study of multiple intestinal neoplasia (Min) mice and human FAP patients, the expression and distribution of cyclin D1, Cdk4, and cell proliferative activity (5-bromo-2'-deoxyuridine incorporation) in normal and adenomatous intestinal epithelium were investigated. Immunohistochemical analysis of Min mouse intestine revealed that cyclin D1 immunoreactivity in the intestinal epithelium was restricted to the adenomatous areas, with a significantly higher percentage of positively staining nuclei in high-grade dysplasia versus low-grade dysplasia (54.8 +/- 18.4% versus 34.6 +/- 16.9%, P = 0.016). Morphologically normal areas of intestinal epithelia were uniformly negative for cyclin D1 immunoreactivity. Cdk4 nuclear immunoreactivity was restricted to the crypt areas in morphologically normal small intestine and colon. Conversely, Cdk4 immunoreactivity was uniformly abundant in adenomatous areas regardless of the degree of dysplasia. Increased expression of cyclin D1 and Cdk4 in adenomas was accompanied by a significantly increased 5-bromo-2'-deoxyuridine incorporation rate in the same areas. Immunoblot analysis of lysates from surgical specimens revealed increased levels of cyclin D1 and Cdk4 in the majority of intestinal adenomas from human FAP patients in comparison to the adjacent grossly normal colonic mucosa. Our results indicate that overexpression of cyclin D1 and Cdk4 occurs in intestinal adenomas and is associated with increased cell proliferative activity in premalignant neoplastic cells. Increased cyclin D1 immunoreactivity is associated with more severe dysplasia. These data suggest that abnormal up-regulation of these important G1 cell cycle proteins is a relatively early event in intestinal carcinogenesis and that these changes may contribute to malignant progression within those lesions.
我们推测细胞周期调节因子细胞周期蛋白D1（cyclin D1）和细胞周期蛋白依赖性激酶（Cdk）4表达的增加可能与家族性腺瘤性息肉病（FAP）相关的肠道腺瘤的发生有关。在目前对多发性肠道肿瘤（Min）小鼠和人类FAP患者的研究中，我们调查了正常和腺瘤性肠上皮中细胞周期蛋白D1、Cdk4的表达和分布以及细胞增殖活性（5-溴-2'-脱氧尿苷掺入）情况。对Min小鼠肠道进行免疫组织化学分析发现，肠上皮中的细胞周期蛋白D1免疫反应性仅限于腺瘤区域，高级别发育异常区域中阳性染色细胞核的百分比显著高于低级别发育异常区域（54.8±18.4%对34.6±16.9%，P = 0.016）。肠上皮形态学正常区域的细胞周期蛋白D1免疫反应性均为阴性。Cdk4核免疫反应性仅限于形态学正常的小肠和结肠的隐窝区域。相反，无论发育异常程度如何，腺瘤区域的Cdk4免疫反应性均普遍丰富。腺瘤中细胞周期蛋白D1和Cdk4表达的增加伴随着同一区域5-溴-2'-脱氧尿苷掺入率的显著增加。对手术标本裂解物进行免疫印迹分析发现，与相邻大体正常的结肠黏膜相比，大多数人类FAP患者肠道腺瘤中的细胞周期蛋白D1和Cdk4水平升高。我们的结果表明，细胞周期蛋白D1和Cdk4在肠道腺瘤中过度表达，并与癌前肿瘤细胞中细胞增殖活性增加有关。细胞周期蛋白D1免疫反应性增加与更严重的发育异常相关。这些数据表明，这些重要的G1期细胞周期蛋白的异常上调是肠道癌变过程中相对较早的事件，并且这些变化可能有助于这些病变内的恶性进展。
