| Summary: | 博士 === 國立臺灣大學 === 臨床醫學研究所 === 103 === Lung cancer is the leading cause of cancer deaths worldwide. Non-small-cell lung cancer (NSCLC) accounts for 85% of all cases of lung cancer. Although there has been progress in the diagnosis and treatment of lung cancer, NSCLC caries a 5-year survival rate of only 17%. Despite the fact that early stage disease may be cured with surgery, only 15%-20% of lung cancer patients were operable at presentation, and about half of them had long-term survival. The remaining almost always died of metastatic disease. Identifying early stage NSCLC with metastatic potential and providing individualized treatment strategies will have a higher probability of truly curing the disease. By using Serial Analysis of Gene Expression (SAGE) database from Cancer Genome Anatomy Project (CGAP), we identified heprain cofactor II (HCII), also named, serine protease inhibitor D1 (SERPIN D1), which is overexpressed in NSCLC. Here, we investigate the clinical significance of HCII and provide molecular evidence to support that HCII could enhance cancer metastasis in NSCLC. HCII expression was higher in NSCLC cell lines with high metastatic ability. We found that high HCII expression in tumor tissue is associated with increased cancer recurrence (P = 0.011) and shorter overall survival times (P=0.005) in 75 clinically operable NSCLC patients. Multivariate Cox proportional hazards regression analysis showed that high HCII expression in tumor tissue, male gender and pathological stage III&IV were associated with reduced overall survival of patients with NSCLC. High pre-treatment plasma concentration of HCII is associated with reduced overall survival in 57 consecutive NSCLC patients. We overexpressed and knockdown HCII expressions in lung cancer cell lines and confirmed that HCII can promote cell motility, invasion ability and filopodium dynamics in NSCLC cells in vitro and increased metastatic colonization in an in vivo mouse model. Exogenous treatment of HCII promoted cancer cell migration, and this promigratory effect of HCII was independent of thrombin. We further showed that HCII could upregulate cancer cell migration through activation of PI3K, which acts upstream of Rac1 and Cdc42, and this effect could be blocked by heparin. We also demonstrated that the promigratory and invasion ability of HCII on lung cancer cells were abolished by mutagenesis at heparin binding site (K185M) of HCII. We suggest that HCII is a novel metastasis enhancer and may be used as a predictor for heparin treatment in NSCLC. We propose that HCII expression levels in tumor tissues or plasma samples could be regarded as a predictive factor for heparin treatment in NSCLC patients.
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