The Expression And Relationship Of Smad4, P21 And UPA In Lung Carcinoma

Background and ObjectiveLung cancer is one of malignant rumors with the highest morbidity and mortality in the world. Although a varrity of antitumoral measures including surgery, irradiation and chemotherapy are taken, the 5-years survival rate of lung cancer is still below 15%, mainly due to the carcinogebesis of lung cancer is progression with many steps and phases and its mechanism is rather complex. Modern molecular biology studies have shown that the occurrence and development of malignant tumors are asscociated with abnormal cell signal transduction, which is one of the important mechanisms of cancer formation, so, the relationship between cell signal transduction and cancer become a new foucs in molecular biological researches. Therefore, it is important to demonstrate the pathogenesis of tumor by studing the relations among abnormal signal transduction, tumor formation and progression, which will benefit to diagnosticate and develop novel therapies and has important practical significance and broad prospects.Smad4 gene known as DPC4 (deleted in pancreatic carcinoma locus 4) gene is a tumor suppressor gene. Its product Smad4 protein takes part in intracellular signal transduction of the transforming growth factor bete(TGF-β)superfamilies. Smad4 plays a key role in TGF-βtransduction pathway. Almost all of the biological effects are the result of the interaction of Smad4. Its low expression or absent expression has been found in a variety of tumor and are closely related with cancer. It can possibly become a new target for cancer therapy. The product of p21 gene is a cyclin-dependent kinase inhibitor protein. Recent studies have shown that p21 involved in cell differentiation, aging and cell proliferation, inhibition of apoptosis and other biological functions. p21 may be involved in the regulation of cell proliferation and apoptosis functions in TGFβsignaling system. uPA (urokinase-type plasminogen activator) is a major proteolytic enzymes, and its function is to convert the plasminogen to the active proteinase, plasmin. The main function of uPA include tissue remodeling and cell migration. Since it is involved in extracellular matrix degradation, uPA may play a key role in the invasion and metastasis of carcinoma. Several studies have suggested that uPA may be an useful prognostic inhibitors.There are few regarding reports of Smad4 protein expression in lung cancer and it has not generally accepted conclusion about the correlation between its expression and clinical pathology. In order to investigate the possible mechanism of lung cancer, The immunohistochemical method was used to examine the expression of Smad4,p21 and uPA in 60 patients with non-small cell lung cancer(NSCLC).Materials and Methods60 surgically resected non-small cell lung carcinoma tissues were collected. Among them male 44, female 16; aged 35-77 years, with an average age of 60; 39 cases were quamous cancer, 21 cases were adenocarcinoma; well-differentiated 17, moderate 20,poorly-fifferentiated 23;there were 20 cases in stage I, 13 cases in stage II, 14 cases in stage III and 13 cases in stage IV; and there were 35 patients with lymph node metastasis. All the patients had no chemotherapy and immunotherapy. All the tissues were fixed in 10% neutral formalin and embedden in paraffin. The expression of Smad4, p21 and uPA were detected by the S-P immunohistochemistry technique in lung carcinoma and normal lung tissue, and the relationship of these results was analyzed. The data were analyzed by statistical software SPSS 11.0. x~2 test and spearman rank correlation were used to analyze the difference between different groups.α=0.05 was considered as the level of tests.Result1. The positive expression rate of smad4 was 65.0% in lung carcinoma, and that was 90.0% in normal lung tissue, and there was significant difference between two groups (P<0.05). The expression of smad4 had no correlated relationship with the sex, age and tissue type between the lung carcinoma tissue and the normal lung tissue(P> 0.05).The positive rates of smad4 expression were 94.1%, 70.0% and 39.1% respectively in the high, moderate and poor differentiation group, and there was significant difference in the three groups(P<0.05). The positive rate of smad4 expression was 78.8 % in clinical stage group I + II, and that was 48.1 % in clinical stage group III+IV, and there was a significant difference between two groups (P<0.05). There was significant difference of the positive expression rate of smad4 between the lymphnode metastasis positive group (51.4%) and the lymphnode metastasis negative group (84.0%)(P <0.05).2. The positive expression rate of p21 was 68.3% in lung carcinoma, and that was 6.7% in normal lung tissue, and there was significant difference between two groups (P<0.05). The expression of p21 had no correlated relationship with the sex, age, tissue type, stage of disease and the lymphnode metastasis between the lung carcinoma tissue and the normal lung tissue(P>0.05).3. The positive expression rate of uPA was 78.3% in lung carcinoma, and that was 0.00% in normal lung tissue, and there was significant difference between two groups(P<0.05). The expression of uPA had no correlated relationship with the sex, age and tissue type between the lung carcinoma tissue and the normal lung tissue(P>0.05).The positive rates of uPA expression were 52.9% 80.0% 95.7% respectively in the high, moderate and poor differentiation group, and there was significant difference in the three groups(P<0.05). The positive rate of uPA expression was 66.7% in clinical stage group I + II, and that was 92.6% in clinical stage group III+IV, and there was a significant difference between two groups (P<0.05 ). There was significant difference of the positive expression rate of uPA between the lymphnode metastasis positive group (100.0 %) and the lymphnode metastasis negative group (48.0%)(P < 0.05).4. In non-small cell lung cancer tissue Smad4 protein expression was positively correlated with the expression of p21 protein and was negatively correlated with the expression of uPA protein.Conclusions1. The low expression of Smad4 and the over expression of p21, uPA were closely correlated with the occurrence,invasion and metastasis of lung carcinoma.2. Smad4 was positive significantly correlated with p21 and negative correlation with uPA. Which suggest Smad4 and uP may be the targent gene of p21 gene. Smad4 may regulate the invasion and metastasisand apoptosis by upregulating the expression p21 and downregulating the expression of uPA.3. Smad4, p21 and uPA regulated commonly the development and the biological behavior of the lung cancer, which hinted that detecting the expression of them in lung cancer has a certain sense for the diagnosis and prognosis of lung cancer.