Expression Of Thymidylate Synthase In Non-small Cell Lung Cancer And Its Relasionship With Ki-67 Protein Expression

BackgroundPrimary bronchogenic carcinoma(Lung cancer)is originated from tunica mucosa bronchiorum or glandular organ ,which is often regionality lymph node or hemato- genous metastasis. The advancement speed of condition is closely associated with cell biologic characteristics. Lung cancer is divided into non-small cell lung cancer and small cell lung cancer according to histopathology ,the former accounts for the major. As one of the maximal mobility malignant tumors, lung cancer is developing by the speed of 0.5% every year. Although new diagnose and treatment techniques have been developed, the expected 5-year survival rate for advanced stage patients is not encou- raging .Lung cancer is currently the leading cause of cancer death in developed countries and in big cities in china, which is severly threatening people,s life. Resently,some researchers believe that the carcinogenesis and development of lung cancer is a complicated course which is related to polygene regulation,cell proliferation and apoptosis.Currently ,the concrete mechanism of lung cancer is not clear.Thymidylate synthase (TS) catalyzes the anessential step in DNA synthesis: methylation of deoxyuridine-5′- monophos- phate (dUMP) to deoxythymidine -5′-monophosphate (dTMP), which is an important substrate for DNA synthesis. TS may be involved in the carcinoge- nesis and development of many kinds of tumors.The expression of TS in normal tissue is much lower ,while it is obviously increased in tumour tissue. As a kind of important antitumor drug, 5-Fluorouracil (5-FU) inhibits DNA synthesis by forming a stable covalent ternary complex consisting of fluorodeoxyuridine-5′-monophosphate (FdUMP), 5,10-methylenetetrahydrofolate (m-THF) and TS.So,TS is believed to be a important target emzyme in treating magnificant tumor.. The effectiveness of these drugs is well proven, and has been proved to correlate with the expression of TS in gastrointestinal malignancy .On the other hand, the significance of TS expression for 5-FU based chemotherapy has not been well investigated in non-small cell lung cancer (NSCLC), because 5-FU and its derivatives have not been thought to be effective against NSCLC in general.Currently,a few researches about TS are concentrated not in lung cancer.but in gastroenterics in our country.Necleic proliferation related antigen(Ki-67)is currently generally acknowledged to be a kind of nuclear proliferation maker gene.The expression activity of Ki-67 is closely associated with many kinds of proliferation activity of tumor cell. There is still some differences about the associativity between the clinical significance and expression of TS and Ki-67 in NSCLC through a few researches at abroad, but those researches were rare at home. High expression of TS is thought to be associated with poor prognosis in some kinds of cancers. However, this association has not been clarfied for non-small cell lung carcinoma. In the current study, the authors investigated the clinicopathologic significance of TS,Ki-67 protein level and the correlation with cellular proliferation in patients with lung cancer.The researchers wished to provide more imformations and theory evidences for adjunctive therapy with NSCLC about TS depressor.Objective1. To observe the expression of TS and Ki-67 in NSCLC cancer tissue,2. To investigate the relationship between the expression of TS,Ki-67 and clinical characteristic,3. To investigate the associativity between the expression level of TS and Ki-67 in NSCLC tumour tissue.MethodsAuthors examined the protein expression of TS and Ki-67 in cancer tissues of surgically removed from 51 cases NSCLC using the method of immunohistochemistry(IHC). TS expression was evaluated on the staining intensity in the cytoplasm using a visual grading system in which the intensity of the staining was categorized as high,low,and negative group according to their positive percentage. The evaluation of Ki-67 expression was based on the proportion of positively stained cells, in which the nuclei were stained dark brown, among a total of 1000 cells that were counted. The Ki-67 labeling index was evaluated based on the percentage of the cancer cells. Medical statistic software were employed to analyze the expression of Ts and Ki-67 and clinipathological factors.Results1. In NSCLC,the relationship between the expression of TS and clinipathological factors The total positive rate of TS was 68.6%(35/51), and the positive rate of squa- mous cell carcinoma,adenocarcinoma,adenosquamous carcinoma is 66.7%(14/21),69.6%(16/23),71.4%(5/7)respectively. There was closely relationship between TS and cellular differentiation (P〈0.05); otherwise, there was no relationship between TS and TNM stage, lymph node metastasis ,histological subtype,age and sex (P>0.05).2. In NSCLC, the relationship between the expression of Ki-67 and clinipatholo- gical factors The total positive rate of TS was 72.5%(37/51), and the positive rate of squamous cell carcinoma,adenocarcinoma,adenosquamous carcinoma is 71.4%(15/21),73.9%(17/23),71.4%(5/7)respectively. A obvious correlation was observed between the expression levels of Ki-67 and stage of disease, lymph node metastasis, tu- mor differentiation ( P<0.05);there was no relationship between Ki-67 and histological subtype,age and sex(P>0.05).3. In NSCLC,the correlation between the expression of TS and Ki-67 There was obvious positive correlation between the expression of TS and Ki-67 (Spearman,s test r=0.84 p<0.001).The Ki-67 LI is significantly increased in TS high,moderate and negative group,there were statistics difference in every group (two simples t text P<0.05).Conclusions1. The expression of TS is closely associated with NSCLC cell proliferation and differentiation.2. The expression of Ki-67 is closely associated with NSCLC cell proliferation,differentiation,stage of diseaseand lymph node metastasis.3 .A obvious correlation was observed between the expression levels of Ki-67 and stage of disease, lymph node metastasis, tumor differentiation4. There was obvious positive correlation between the expression of TS and Ki-67.5. TS and Ki-67 may be valuable indexes to predict cell differentiation and proliferation grade in patients with NSCLC.