Since 1984, mitomycin C (MMC) has been applied in the treatment of non-small-cell lung cancer (NSCLC). MMC-based chemotherapeutic regimens are still under consideration owing to the efficacy and low cost as compared with other second-line regimens in patients with advanced NSCLC. Hence, it is important to investigate whether MMC induces potential negative effects in NSCLC. Here, we found that the malignant lung cancer cells, CL1-2 and CL1-5, were more resistant to MMC than were the parental CL1-0 cells and pre-malignant CL1-1 cells. CL1-2 and CL1-5 cells consistently showed lower sub-G1 fractions post MMC treatment. DNA repair-related proteins were not induced more in CL1-5 than in CL1-0 cells, but the levels of endogenous and MMC-induced phosphorylated Akt (p-Akt) were higher in CL1-5 cells. Administering a p-Akt inhibitor reduced the MMC resistance, demonstrating that p-Akt is important in the MMC resistance of CL1-5 cells. Furthermore, we revealed that cell migration was enhanced by MMC but lowered by a p-Akt inhibitor in CL1-5 cells. This study suggests that in CL1-5 cells, the activity of p-Akt, rather than DNA repair mechanisms, may underlie the resistance to MMC and enhance the cells' migration abilities after MMC treatment.
Purpose: PC4 is a novel marker for diagnosis and treatment of advanced human cancers metastasis. This study aimed to verify that high expression of PC4 is associated with lymphatic metastasis and predicts poor prognosis in lung adenocarcinoma probably via CCR7/VEGF-C/VEGFR-3 cascade.Methods: PC4 protein expressions in 96 lung adenocarcinoma cases, CCR7/VEGF-C/VEGFR-3 protein expressions in 23 lung adenocarcinoma cases, and PC4 clinical outcome in 83 lung adenocarcinoma cases and TCGA as validation were evaluated, respectively. Small interfering RNA was used to explore the relationship of PC4 and the VEGF-C/VEGF-D/VEGFR-3 axis in A549 cells. The correlations between PC4 and CCR7, CCR7 and VEGF-C/VEGFR-3 were analyzed in A549 cells and adenocarcinoma tissues, respectively.Results: The results shown PC4 protein highly expressed in tumor tissue compared with normal lung tissue. High expressions of PC4 were remarkably associated with advanced tumor stage (P=0.032), lymphatic metastasis (P=0.004) and poor clinical outcomes (the cohort: HR: 2.135, 95% CI: 1.279-3.562; TCGA: HR: 2.983, 95% CI: 1.249-7.127) in lung adenocarcinoma. CCR7 expressions were remarkably decreased after PC4 RNAi in A549 cells, and significantly correlated with the expressions of VEGF-C and VEGFR-3 in adenocarcinoma tissues.Conclusion: CCR7/VEGF-C/VEGFR-3 expressions in lung adenocarcinoma were closely associated with lymphatic metastasis. Overexpression of PC4 is a predictor of lymphatic metastasis and poor prognosis in lung adenocarcinoma. PC4 plays important oncogenic roles probably via activation of CCR7/VEGF-C/VEGFR-3, which warrants further study.
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