Abstract
Despite great efforts to improve survival rates, the prognosis of lung cancer patients is still very poor, mainly due to high invasiveness. We developed brain metastatic PC14PE6/LvBr4 cells through intracardiac injection of lung adenocarcinoma PC14PE6 cells. Western blot and RT-qPCR analyses revealed that PC14PE6/LvBr4 cells had mesenchymal characteristics and higher invasiveness than PC14PE6 cells. We found that cyclin D1 was upregulated, miR-95-3p was inversely downregulated, and pri-miR-95 and its host gene, ABLIM2, were consistently decreased in PC14PE6/LvBr4 cells. MiR-95-3p suppressed cyclin D1 expression through direct binding to the 3' UTR of cyclin D1 mRNA and suppressed invasiveness, proliferation, and clonogenicity of PC14PE6/LvBr4 cells. Ectopic cyclin D1 reversed miR-95-3p-mediated inhibition of invasiveness and clonogenicity, demonstrating cyclin D1 downregulation is involved in function of miR-95-3p. Using bioluminescence imaging, we found that miR-95-3p suppressed orthotopic tumorigenicity and brain metastasis in vivo and increased overall survival and brain metastasis-free survival. Consistent with in vitro metastatic cells, the levels of miR-95-3p, pri-miR-95, and ABLIM2 mRNA were decreased in brain metastatic tissues compared with lung cancer tissues and higher cyclin D1 expression was involved in poor prognosis. Taken together, our results demonstrate that miR-95-3p is a potential therapeutic target for brain metastasis of lung adenocarcinoma cells.
Highlights
Metastasis is a common feature of malignancy and a leading cause of cancer-related death
We found that PE14PE6/LvBr4 cells showed morphological features of the epithelialmesenchymal transition (EMT) such as elongated and fibroblast-like morphology (Figure 1A)
The median overall survival (OS) duration in mice injected with PC14PE6/LvBr4 cells was significantly shorter than that in mice injected with PC14PE6 cells, likely because of the larger sizes and greater numbers of brain metastases formed by the PC14PE6/LvBr4 cells
Summary
Metastasis is a common feature of malignancy and a leading cause of cancer-related death. Among the many types of cancer, lung cancer is the most common worldwide with the highest mortality rate (less than 20% 5-year survival rate), resulting from high frequency of metastasis [1, 2]. Non-small cell lung cancers (NSCLCs), which account for approximately 85% of all lung cancers, are highly aggressive and disseminate to various www.impactjournals.com/oncotarget organs, including the brain. About 40% of patients with lung cancer develop brain metastases during their disease lifetime [3]. Despite progress in treating brain metastases including neurosurgery, radiotherapy, and chemotherapy, the 5-year survival rate of NSCLC remains 15% across all stages of the disease. Alteration of gene expression and cellular signaling involved in brain metastases remain poorly understood
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