The Expression Of LAT1in Ovarian Cancer And Its Clinical Significance

Background and ObjectiveAmino acids is the basic elements of proteins that are essential to the metabolism and proliferation of the cells. System L amino acids transporters transport branch, aromatic, neutral amino acid and so on. Four isoforms of system L transporters have been identified:LAT1, LAT2, LAT3and LAT4. Researchers have found that the expression of LAT1was increased in many cancers, such as lung cancer, esophageal cancer and astrocytoma. Japanese researcher reported that LAT1was highly expressed in ovarian cancers, but it is not clear whether the expression of LAT1relate with the clinico-pathological features and the prognosis of ovarian cancer.Ovarian cancer is one of the common gynecological malignancies, which is a great threat to the women. Nowadays, surgery and chemotherapy is the major treatments. Cisplatin-based chemotherapy is often used for advanced ovarian cancers. However, cisplatin toxicity including renal damage, bone marrow suppression and drug tolerance is a major obstacle to its clinical application. Therefore, it is very important to find a new medicine which can enhance the chemical sensitivity of cisplatin.In this study,we examined the expression of LAT1in normal ovarian tissues, benign tumors, borderline ovarian tumors and ovarian cancers by immunohistochemistry analysis. The correlations between LAT1expression and clinico—pathological parameters were analyzed, and the prognostic significances of LAT1in ovarian cancers was evaluated. We also explored the effects of System L amino acid transporter inhibitor2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) alone or in combination with cisplatin on the proliferation of human ovarian cancer SKOV3cells and the possible molecular mechanism.Materials and Methods1. Tumor tissue and normal tissue specimens between December2004and June2009were obtained from the Pathology department of Qilu Hospital.2. Immuno-histochemistry analysis was performed to examine the expression of LAT1. The correlations between LAT1expression and clinico—pathological parameters were analyzed, then found the prognostic significances of LAT1in ovarian cancers.3. human SKOV3cells were treated with different concentrations of BCH alone or combination with cisplatin, the cell viability was assessed by CCK-8assay;4. Western blot analysis was performed to detect the affection of mTOR signal pathway by BCH.5. Statistical methods:the data were analyzed by SPSS13.0. P<0.05was considered to be statistically significant.Results1. The expression of LAT1was significantly up-regulated in ovarian cancers (P<0.001). The expression level of LAT1had significant correlation with the histological grade (P=0.03), FIGO stage (P=0.011), and omentum metastasis (P=0.046) in ovarian cancers. Kaplan-Meier survival analysis showed that LAT1-positive patients had poor prognosis(P<0.001). A multivariate analysis based on the COX proportional hazard model demonstrated that LAT1positive expressions (P=0.001) and residual tumor (P=0.045) were the independent prognostic factors of ovarian cancer.2. BCH alone could significantly inhibit the proliferation of SKOV3cells in time-and dose-dependent manners. Compared with BCH administration alone, the cell viability was decreased significantly when BCH was combined with cisplatin (P<0.01),and the effect was more significant when BCH treatment followed cisplatin administration (P<0.05)3. Western blot analysis showed that BCH could inhibit mTOR signal pathway by decreasing the phosphorylation of mTOR、p70S6K and4E-BP1.Conclusions1. The expression of LAT1was significantly up-regulated in ovarian cancers. The expression level of LAT1had significant correlation with the histological grade, FIGO surgical stage, and omentum metastasis in ovarian cancers. The ovarian cancer patients with positive LAT1expression might have poor prognosis.2. BCH alone and in combination with cisplatin could significantly inhibit the proliferation of human ovarian cancer SKOV3cells, it showed synergistic effects when BCH treatment followed cisplatin administration. The mechanism may be the inhabitation of mTOR pathway.