Expression And Clinical Significance Of PTEN, P27～(kip1) And PCNA In Non-Hodgkin's Lymphoma

Phosphatase and tensinhomology deleted on chromosome ten(PTEN), the first candidate tumor-suppressor gene found on dual-specificity phosphatase activity, shares homology with the protein tyrosine phosphatase family, as well as with the cytoskeletal protein tensin. PTEN can suppress tumor cell growth by antagonizing protein tyrosine kinases and can regulate tumor cell invasion and metastasis through interactions at focal adhesions. Up to now, inactivation of PTEN gene were found in a variety of malignant tumors including breast carcinomas, thyrophyma, lung tumor, mephroma, liver tumor and so on. Recently, many researchers focus on its mechanism investigation, and it is generally believed that there were several putative mechanisms relating to tumor suppression as follows: inhibiting cell invasion and metastasis by dephosphorating focal adhesion kinase (FAK); inhibiting cell growth and increasing cell apoptosis by dephosphorating PIP3; restraining cell differentiation by inhibiting MAPK signal path way. The clinical application of PTEN is to help predict prognosis and to be used in tumor genetic treatment. In human cells, transition from the G1 into the S phase is governed by cyclin-dependent kinases (CDKs), which are activated by binding of positive effectors, the cyclins and inhibited by CDK inhibitors. CDK inhibits fall into two families, INK and CIP/KIP, on the basis of sequence homology. p27kip1,as a member of CIP/KIP, exerts its effects on the regulation of G1/S phase transition by cooperating with proteins of the INK family such as cyclin D-CDK4,cyclin E-CDK2 and cyclin A-CDK2. Besides the key role in cell regulation, additional functions of p27kip1 including apoptosis, regulating cell differentiation, and regulating drug resistance have been recently reported. Although the p27kip1 gene showed very rare genomic alterations in human cancers downregulation of the p27kip1 protein has been shown to be involved in carcinogenesis and associated with the prognosis of a variety of human malignancies, including breast, colon, prostate, liver, gastric, pancreatic, lung, and ovarian cancers. Prolife rating cell nuclear antigen (PCNA), as a widely expressed nuclear protein in S period of cell cycle, is an acid nuclear protein of 36KD, which is produced and expressed only in multiple cells. It is rarely found in stationary cells and begins to increase late in G1 period. It's number arrives at peak in S period and begins to decrease in G2 and M periods. Positive expression of PCNA indicates that the cell is in multiple state, so as to reflect effectively capability of cell multiplication. Now, it has became an effective index in investigating multiple capability of tumor cell. Non-Hodgkin's lymphoma (NHL), as one of malignant tumors, is a serious threat to human being health. It's classification, prognosis, and clinical diagnosis is very difficult. To evaluate action and mechanism of NHL tumor genes in the course of generation and evolution of NHL, the expression of PETN, p27kip1 and PCNA were measured with immunohistochemical technique in 50 cases of NHL. It provided useful indexes for diagnosis, therapy and prognosis of NHL. Results:1) The positive expression rate of PTEN was significantly lower in the cytochylema (56.00%) than that of reactive lymphoid hyperplasia (91.67%). The result was in agreement with the reports that the positive expression rate in malignancy such as glioma, prostate tumor, breast carcinomas, thyrophyma, endometrioma, melanomas et al. was lower than corresponding normal tissue. Decrease of PTEN expression can make differentiation and apoptosis of normal cells disorder, and so as to result in patho tumor genesis. The same is true with NHL. The positive expression rates of PTEN were 85.00%, 50.00% and 21.43% in the indolent lymphoma, moderately aggressive lymphoma, highly aggressive lymphoma respectively, and the expression in lower grade NHL was significantly higher than in high grade NHL (P<0.05), which farther manifest that expression of PTEN protein is closely related to malignant grade in NHL. 2) The expression of p27kip1 was significant correlated with degree of tissue malignancy, the positive expression were 91.67%, 85.00%, 43.75% and 21.43% in reactive lymphoid hyperplasia, indolent lymphoma, moderately aggressive lymphoma and highly agrressive lymphoma. According to the above results, it is evident that the expression of p27kip1 in NHL is much lower than in reactive lymphoid hyperplasia, and its decreasing is accompanied with grade increasing of NHL. The lower expression of p27kip1 has relationship with generation and differentiation degree. The expression of p27kip1 will decrease as soon as receive the stimulation from malignancy proliferation. 3) Of the 50 cases of NHL tissues, expression of PCNA in different degreeswas discovered in all cases and 40.00% of them were strongly positive while the expressions were all weakly positive in reactive lymphoid hyperplasia. Comparing with the above cases, tumor tissues assume overexpressions significantly (P<0.05). The positive degree of PCNA increases with the malignant degree of NHL. It indicates that the occurrence of tumor was closely related to hyperplasia of cells. The expression level of PCNA can indicate the malignant degree and growing status of NHL cells, and provide values on estimating the hyperplastic activity of lymphoma and predicting prognosis. 4) Of the 50 cases of NHL, 26 cases showed positive expressions with PTEN and p27kip1 simultaneously, accounting for 52.00%; 22 cases showed negative expressions with PTEN and p27kip1 simultaneously, accounting for 44.00%. Moreover, there is a significant correlation between PTEN expression and p27kip1 expression (P<0.05). It indicates that in the course of development of NHL, the deficiency and reduction of PTEN expression can induce the decreasing of p27kip1 expression, so that the antitumor effect of p27kip1 was hindered. Comparing the positive expression of p27kip1 with PCNA, we discovered that p27kip1 expression was inversely related to PCNA expression (P<0.05). Perhaps in the development of tumor, increasing of PCNA can activate some mechanisms, such as to decompose p27kip1, which leads to the pathogenesis and progression of tumors. So, it can be accepted that negative expression of p27kip1 and high expression of PCNA are the sign of high malignancy of tumor. Combination test of p27kip1 and PCNA is better than single item test. PTEN is negatively related to PCNA significantly. It indicates...