Abstract
Our previous study revealed that Ku80 was overexpressed in lung cancer tissues and hsa-miR-623 regulated the Ku80 expression; however, the detailed function of hsa-miR-623 in lung cancer was unclear. We identified that hsa-miR-623 bound to the 3'-UTR of Ku80 mRNA, thus significantly decreasing Ku80 expression in lung adenocarcinoma cells. Hsa-miR-623 was downregulated in lung adenocarcinoma tissues compared with corresponding non-tumorous tissues, and its expression was inversely correlated with Ku80 upregulation. Downregulation of hsa-miR-623 was associated with poor clinical outcomes of lung adenocarcinoma patients. Hsa-miR-623 suppressed lung adenocarcinoma cell proliferation, clonogenicity, migration and invasion in vitro. Hsa-miR-623 inhibited xenografts growth and metastasis of lung adenocarcinoma in vivo. Ku80 knockdown in lung adenocarcinoma cells suppressed tumor properties in vitro and in vivo similar to hsa-miR-623 overexpression. Further, hsa-miR-623 overexpression decreased matrix metalloproteinase-2 (MMP-2) and MMP-9 expression levels, with decreased ERK/JNK phosphorylation. Inhibition of hsa-miR-623 or overexpression of Ku80 promoted lung adenocarcinoma cell invasion, activated ERK/JNK phosphorylation and increased MMP-2/9 expressions, which could be reversed by ERK kinase inhibitor or JNK kinase inhibitor. In summary, our results showed that hsa-miR-623 was downregulated in lung adenocarcinoma and suppressed the invasion and metastasis targeting Ku80 through ERK/JNK inactivation mediated downregulation of MMP-2/9. These findings reveal that hsa-miR-623 may serve as an important therapeutic target in lung cancer therapy.
Highlights
Lung cancer is the leading type of cancer-related deaths worldwide, likely because it is often diagnosed at advanced stages that are beyond the optimal treatment period.[1]
A significant overexpression of Ku80 was observed in primary human lung adenocarcinoma, which was associated with poor clinical outcomes and resistance to cisplatin-based chemotherapy.[11]
We have studied the effect of hsa-miR-526b on Nonsmall cell lung cancer (NSCLC) cell proliferation in our previous study,[10] we will further investigate the potential role of hsa-miR-623 in lung adenocarcinoma in this paper
Summary
Lung cancer is the leading type of cancer-related deaths worldwide, likely because it is often diagnosed at advanced stages that are beyond the optimal treatment period.[1]. Metastatic potential of tumors depends in large part on the ability of the tumor to invade the extracellular matrix, a process that requires cells to lose intercellular adhesion molecules and to express proteolytic enzymes to facilitate invasion.[14] Despite the fact that the search for detailed molecular mechanisms of NSCLC has been intensive, a number of questions concerning the basic nature of tumor metastasis remain incompletely understood.[14] MicroRNAs (miRNAs) are a class of small noncoding RNAs that are approximately 22 nucleotides in length. Our study had explored the function of hsa-miR-526b in NSCLC,[10] so we chose to investigate the role of hsamiR-623 in this paper
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