LOSS OF P21(WAF1 CIP1) PROTEIN EXPRESSION ACCOMPANIES PROGRESSION OF SPORADIC COLORECTAL NEOPLASMS BUT NOT HEREDITARY NONPOLYPOSIS COLORECTAL CANCERS/

p21 (p21(WAF1/Cip1)), a cyclin-dependent kinase inhibitor, induces G(1 ) arrest and can inhibit the activity of the proliferating cell nuclea r antigen (PCNA), We analyzed p21 expression during colorectal tumorig enesis, its association with its transcriptional regulator p53, and it s relationship to rates of cell proliferation and apoptosis. p21 and p 53 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-label ing assay, and cell proliferation was examined by PCNA staining. In no rmal 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 carc inoma, Specifically, p21 was detected in 12 of 16 (75%) adenomas and 1 0 of 32 (31%) carcinomas. In contrast to sporadic cases, HNPCCs with k nown mutations in DNA mismatch repair genes expressed p21 in 12 of 15 (30%) carcinomas. An inverse relationship between p21 and p53 was obse rved wherein mutant p53 proteins were detected in 4 of 15 (27%) HNPCCs versus 22 of 32 (69%) sporadic carcinomas. Although p21+ carcinoma ce lls were generally negative for p53, IHC revealed that some carcinoma cells expressed both p21 and p53 proteins. Furthermore, p53-mutated SW 480 colon carcinoma cells were found to coexpress p21 and p53, suggest ing that p21 can also be activated by a p53-independent mechanism, No association was found between p21 or PCNA and apoptotic labeling indic es in adenomas or carcinomas. In conclusion, a decrease in p21 express ion accompanies neoplastic progression in sporadic cases but not in HN PCCs, This finding appears related to p53 status in that the frequency of p53 expression was significantly reduced in HNPCCs compared to spo radic cases, suggesting a difference in their molecular pathways of tu morigenesis.