Sinicrope F A, Roddey G, Lemoine M, Ruan S, Stephens L C, Frazier M L, Shen Y, Zhang W
Department of Gastrointestinal Medical Oncology & Digestive Diseases, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Clin Cancer Res. 1998 May;4(5):1251-61.
p21 (p21WAF1/Cip1), a cyclin-dependent kinase inhibitor, induces G1 arrest and can inhibit the activity of the proliferating cell nuclear antigen (PCNA). We analyzed p21 expression during colorectal tumorigenesis, its association with its transcriptional regulator p53, and its relationship to rates of cell proliferation and apoptosis. p21 and p53 protein expression were examined in sporadic tumors and hereditary nonpolyposis colorectal cancers (HNPCCs) by immunohistochemistry (IHC) and immunoblotting. Apoptosis was examined using a DNA nick end-labeling assay, and cell proliferation was examined by PCNA staining. In normal colorectal epithelia, nuclear p21 staining was uniformly detected in crypt cells of the superficial compartment (upper one-third) that stained negatively for PCNA. p21 and PCNA expression were, therefore, mutually exclusive. In sporadic cases, a decrease in the frequency of p21 expression accompanied adenoma development and progression to carcinoma. Specifically, p21 was detected in 12 of 16 (75%) adenomas and 10 of 32 (31%) carcinomas. In contrast to sporadic cases, HNPCCs with known mutations in DNA mismatch repair genes expressed p21 in 12 of 15 (80%) carcinomas. An inverse relationship between p21 and p53 was observed wherein mutant p53 proteins were detected in 4 of 15 (27%) HNPCCs versus 22 of 32 (69%) sporadic carcinomas. Although p21+ carcinoma cells were generally negative for p53, IHC revealed that some carcinoma cells expressed both p21 and p53 proteins. Furthermore, p53-mutated SW480 colon carcinoma cells were found to coexpress p21 and p53, suggesting that p21 can also be activated by a p53-independent mechanism. No association was found between p21 or PCNA and apoptotic labeling indices in adenomas or carcinomas. In conclusion, a decrease in p21 expression accompanies neoplastic progression in sporadic cases but not in HNPCCs. This finding appears related to p53 status in that the frequency of p53 expression was significantly reduced in HNPCCs compared to sporadic cases, suggesting a difference in their molecular pathways of tumorigenesis.
p21（p21WAF1/Cip1）是一种细胞周期蛋白依赖性激酶抑制剂，可诱导G1期阻滞并能抑制增殖细胞核抗原（PCNA）的活性。我们分析了结直肠癌发生过程中p21的表达情况、其与转录调节因子p53的关联以及其与细胞增殖率和凋亡的关系。通过免疫组织化学（IHC）和免疫印迹法检测散发性肿瘤和遗传性非息肉病性结直肠癌（HNPCC）中p21和p53蛋白的表达。使用DNA缺口末端标记法检测凋亡情况，通过PCNA染色检测细胞增殖情况。在正常结直肠上皮中，在PCNA染色呈阴性的浅表区（上三分之一）隐窝细胞中均检测到核p21染色。因此，p21和PCNA的表达相互排斥。在散发性病例中，随着腺瘤的发展和进展为癌，p21表达频率降低。具体而言，在16例腺瘤中有12例（75%）检测到p21，在32例癌中有10例（31%）检测到p21。与散发性病例相反，在已知DNA错配修复基因存在突变的HNPCC中，15例癌中有12例（80%）表达p21。观察到p21与p53之间呈负相关，其中15例HNPCC中有4例（27%）检测到突变型p53蛋白，而32例散发性癌中有22例（69%）检测到。尽管p21阳性癌细胞通常p53呈阴性，但免疫组织化学显示一些癌细胞同时表达p21和p53蛋白。此外，发现p53突变的SW480结肠癌细胞同时表达p21和p53，这表明p21也可通过p53非依赖性机制被激活。在腺瘤或癌中未发现p21或PCNA与凋亡标记指数之间存在关联。总之，在散发性病例中，p21表达降低伴随肿瘤进展，但在HNPCC中并非如此。这一发现似乎与p53状态有关，因为与散发性病例相比，HNPCC中p53表达频率显著降低，提示它们在肿瘤发生分子途径上存在差异。
