Reduced messenger RNA expression level of p21 CIP1 in human colorectal carcinoma tissues and its association with p53 gene mutation.

p21 Cip1 was first isolated as one of the cyclin-dependent kinase (Cdk) interacting proteins induced by wild-type p53 gene product, and it appears to play an essential regulatory role in the control of cell proliferation as a potent, tight-binding inhibitor of cyclin-Cdk complex that blocks the G1/S transition of the cell cycle. We have now examined the p21 Cip1 mRNA expression levels in 16 surgically excised human colorectal tumor and non-tumor tissues by Northern-blot analysis with reference to the identification of p53 gene mutations. p53 gene mutations were detected in 6 tumor tissues but not in the other 10 tissues by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method and following direct sequencing. The mean p21 Cip1 mRNA expression level in tumor tissues was significantly suppressed compared to that of non-tumor tissues, irrespective of p53 gene mutations. In p53 gene mutation-detected cases, the mean expression level of p21 Cip1 mRNAs of tumor tissues was about 60% of that of cases without p53 gene mutation. Moreover, the relative mRNA expression levels of p21 Cip1 significantly decreased as the pathohistological stages progressed by Dukes' staging system, while in patients with liver metastasis these levels were significantly suppressed compared to those of patients without organ metastasis. These results indicate that reduced expression of p21 Cip1 mRNA is critical for growth activity and malignant potential of human colorectal carcinoma, and that the decrease in p21 Cip1 mRNA level is due to p53 gene mutation as well as other mechanisms during human colorectal carcinogenesis.