The Role And Mechanism Of Contactin-1 In Acquired Multidrug Resistance In Lung Adenocarcinoma

Background:Lung cancer is a malignant tumor with high mortality worldwide. It mainly consists of non-small cell lung cancer(NSCLC) and small cell lung cancer(SCLC). Statistics show that NSCLC accounts for 85% of lung cancer and adenocarcinoma is the main type of NSCLC. Although operation is the optimal treatment for lung cancer, many patients lost the best operation time since they are in the late stage of cancer. Therefore chemotherapy is an alternative treatment for lung cancer. The efficiency of combined chemotherapy in SCLC is 57%~80% while 14%~40% in NSCLC. It has been well established that tumor multidrug resistance(MDR) is the primary reason for treatment failure. Despite the accumulating researchs about mechanisms of MDR, the accurate mechanisms underlying MDR remain unknown due to the different response of cancer cells to various drugs and the different MDR mechanisms between SCLC and NSCLC.Contactin-1(CNTN-1), a neural cell adhesion molecule anchored by glycosyl phosphatidylinositol, was discovered to participate in the growth of nervous system previously. Recently some reports have verified that CNTN-1 also plays a role in the invasion and metastasis of certain tumours. Moreover, in our previous studies, CNTN-1 was found to be upregulated by cisplatin in A549/DDP, a MDR cell line induced by cisplatin of lung adenocarcinoma of NSCLC. However the mechanism of the role of CNTN-1 in MDR of lung adenocarcinoma is still unclear. In order to investigate the role of CNTN-1 in MDR of lung adenocarcinoma, in the present study, the cell sensitivety to cisplatin, cell proliferation, cell apoptosis, cell invasion and cell metastasis were evaluated between A549/DDP cells and its progenitor A549 cells both before and after silencing the CNTN-1 expression. Additionally, the CNTN-1 expression was explored in 143 tissue samples from NSCLC patients to analyze the relationship between CNTN-1 expression and clinical characteristics of NSCLC patients.Results:1. CNTN-1 expression was significantly upregulated in A549/DDP cells compared with that of A549 cells.2. A549/DDP cells were more resistant to cisplatin compared with A549 cells. After silencing the CNTN-1 expression, both A549-LV3-CNTN-1 cells and A549/DDP-LV3-CNTN-1 cells became more sensitive to cisplatin while the sensitivity of A549/DDP-LV3-CNTN-1 cells to cisplatin did not reach the level of A549-LV3-CNTN-1 cells.3. No significant difference in cell proliferation was found between A549 cells and A549/DDP cells both before and after silencing the CNTN-1 expression.4. Silencing the CNTN-1 expression apparently promoted apoptosis in A549 cells and A549/DDP cells, however, the apoptosis in A549/DDP-LV3-CNTN-1 cells did not reach the level of A549-LV3-CNTN-1 cells.5. The ability of metastasis and invasion in A549 DDP cells was stronger compared with that in A549 cells. After silencing the CNTN-1 expression, the ability of metastasis and invasion in both A549 and A549/DDP cells were evidently decreased.6. The positive expression of CNTN-1 was found to be associated with lymphatic invasion of both preoperatively and postoperatively combined with adjuvant cisplatin- or carboplatin-based treatment in patients with lung adenocarcinoma. However, the different CNTN-1 expressions were only associated with lymphatic invasion at postoperatively combined with adjuvant cisplatin- or carboplatin-based treatment in patients with lung adenocarcinoma.7. CNTN-1 expression was correlated with smoking and preoperative lymphatic invasion in patients with lung squamous cell carcinoma.Conclusion:1. CNTN-1 has a role in cisplatin-induced MDR in NSCLC;2. CNTN-1 is not only a potential biomarker for predicting lymph node metastasis in patients with lung adenocarcinoma, but also a novel prognostic marker of chemotherapeutic efficacy in patients received with cisplatin or carboplatin-based treatment.