1.3.1 P27

1.3.1 P27

P27 is a novel cyclin-dependent kinase inhibitor (CDKI) gene discovered by Polyak et al. in 1994. The gene is located at the 12p12–12p13.1 junction and consists of two coding exons (Exon 1 is approximately 474 bp, Exon 2 is approximately 120 bp), one non-coding exon, and one intron (approximately 600 bp), forming an open reading frame of 594 bp. It encodes a polypeptide of 198 amino acids and is a thermally stable protein with a molecular weight of 27 kDa.

P27 has various biological functions, including regulating the cell cycle, promoting cell differentiation, mediating intercellular adhesion, and inducing apoptosis. An important factor in tumor initiation and progression is the loss of control over cell cycle regulation. P27 is a tumor suppressor gene that acts as a cyclin-dependent kinase inhibitor (CDK), participating in the negative regulation of the cell cycle by broadly inhibiting CDK activity, thereby halting the cell cycle at the G1 phase and preventing entry into the S phase, ultimately stopping cell proliferation. P27 also plays an important role in cell differentiation and development; Nguyen et al. [4] found that P27 can independently promote neuronal differentiation and migration. There is also evidence suggesting that increased sensitivity to induced differentiation in HT29 colon cancer cell lines is associated with increased P27 expression. P27 expression increases when intercellular contact is inhibited; it is now widely believed that regulation of intercellular adhesion can be achieved by altering cell shape or changing the cell's ability to receive extracellular signals, thereby regulating P27 expression. P27 serves as a regulatory point for the G1/S transition, and there is a close correlation between changes in its activity and cell apoptosis.

Zhang et al. [42] constructed an esophageal cancer model in nude mice and found that apoptosis of esophageal cancer cells was closely related to high expression of P27 (achieved through adenovirus vector construction), which led to a significant decrease in survivin levels. Wei Jianbao et al. [43] investigated the relationship between P27 protein expression and cell apoptosis in hepatocellular carcinoma, revealing that P27 protein was positively expressed in 32 out of 86 liver cancer tissue samples, with a positive rate of 37.2%. The apoptosis index in the positive group was 6.72%, while in the negative group it was 2.83%, showing a significant difference between the two groups. Therefore, P27 protein expression in hepatocellular carcinoma is closely related to cell apoptosis, and its anti-cancer mechanism may involve promoting cell apoptosis. Research has shown that P27 is significantly correlated with the occurrence, development, malignancy, metastasis, and prognosis of hepatocellular carcinoma. Immunohistochemical analysis of P27 expression levels in 100 samples of hepatocellular carcinoma tissue and adjacent liver tissue revealed positive expression rates of 83.3%, 84.2%, and 59.7% in normal liver tissue, adjacent hepatitis tissue, and adjacent cirrhotic tissue, respectively. The expression rates of P27 in adjacent dysplastic hepatocytes and hepatocellular carcinoma were 55.9% and 38.0%, respectively; in trabecular hepatocellular carcinoma, the positive expression rate was 63.2%; and in well-differentiated hepatocellular carcinoma and non-metastatic groups, the positive expression rates were 81.8% and 67.6%, respectively. These results indicate that P27 expression increases progressively from normal liver tissue to adjacent liver tissue and then to hepatocellular carcinoma tissue, suggesting that P27 plays an important role in inhibiting the proliferation, growth, and metastasis of hepatocellular carcinoma cells [44]. Wang Ke et al. [45] used immunohistochemistry to detect P27 protein expression in 33 cases of hepatocellular carcinoma tissue and performed image analysis on positive staining particles. The results showed that the average absorbance value of P27 was significantly higher in well-differentiated, non-vascular-infiltrated, and less than 3 cm diameter hepatocellular carcinoma tissues than in moderately or poorly differentiated, vascular-infiltrated, and greater than 3 cm diameter tissues. Furthermore, the invasiveness and malignancy of hepatocellular carcinoma were correlated with decreased P27 protein expression.

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