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Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

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.

SUBMITTER: Wei S

PROVIDER: S-EPMC5059863 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

Wei Shuang S Zhang Zun-Yi ZY Fu Sheng-Ling SL Xie Jun-Gang JG Liu Xian-Sheng XS Xu Yong-Jian YJ Zhao Jian-Ping JP Xiong Wei-Ning WN

Cell death & disease 20160929 9

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 ...[more]

PMID: 27685632

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Project description:BackgroundSphingosine-1-phosphate receptor 1 (S1PR1) is considered to be closely related to a variety of malignant tumors, but the role and mechanism of S1PR1 in lung adenocarcinoma are not fully understood. In this study, we aim to explore the role and downstream signaling pathways of S1PR1 in the malignant biological functions of lung adenocarcinoma (LUAD).MethodsBioinformatics analysis, RT-qPCR, western blot and immunohistochemistry (IHC) were was used to investigate the expression of S1PR1 in LUAD. The prognosis of S1PR1 was also analyzed. CCK-8 assay, colony formation assay, scratch assay, transwell migration and invasion assay, cell adhesion assay were performed to examine the effect of S1PR1 on LUAD. RNA sequencing was employed to analyze the DEGs in LUAD cells overexpressing S1PR1. Enrichment pathway analysis using KEGG, GO, and GSEA was conducted to predict potential signaling pathways and downstream targets. chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay were performed to verify the direct regulation between FOXA1 and the target genes. Then FOXA1 overexpression were performed to functional rescue experiments. miRNA-30c-5p was identified as a microRNA regulating FOXA1 by dual luciferase reporter assay. The downstream signaling pathways of S1PR1 was detected to clarify the specific pathways to regulates miR-30c-5p.ResultsS1PR1 is significantly decreased in LUAD and is positively correlated with the prognosis. Overexpression of S1PR1 inhibits the proliferation, migration, invasion and adhesion function of LUAD cells by suppressing the expression of COL5A1, MMP1, and SERPINE1. FOXA1 is a key transcription factor regulating the expression of MMP1, COL5A1 and SERPINE1. S1PR1 inhibits the expression of FOXA1 through p-STAT1/miR-30c-5p, thereby suppressing the malignant function of LUAD cells.ConclusionsThe expression of S1PR1 is downregulated in LUAD, which is positively correlated with prognosis. S1PR1 regulates the malignant function of LUAD cells by inhibiting the expression of COL5A1, MMP1 and SERPINE1 through the p-STAT1/miR-30c-5p/FOXA1 signaling pathway.

Project description:This study aimed to determine the effect of miR-186-3p and KRT18 interaction on the biological behavior of colon cancer cells. A biotin-microRNA pull-down assay was performed to identify potential miRNAs. qRT-PCR was used to verify the KRT18 and miR-186-3p levels. In addition, Western blotting was used to detect the KRT18 protein levels. The functional connection between KRT18 and miR-186-3p was confirmed using a dual luciferase reporter assay. BrdU incorporation, MTT assay, and flow cytometry were performed to verify the biological function coupled with in vivo assays. A significant decrease in miR-186-3p expression was observed in colon carcinoma tissues and cells. Functionally, overexpression of miR-186-3p displayed an obvious suppressive action on cell proliferation and viability, and a stimulatory action on the apoptotic ability of SW620 and SW480 cells. Conversely, reduced miR-186-3p had a marked stimulatory effect on proliferation and viability, and a suppressive apoptotic effect. Inhibition of tumorigenesis was observed in mice treated with the miR-186-3p agomir. Furthermore, we identified that miR-186-3p regulated KRT18 levels in colon carcinoma, where silenced KRT18 suppressed proliferation and viability and promoted apoptosis. However, the addition of a miR-186-3p inhibitor weakened the effects of si-KRT18. Additionally, the activation of MAPK signaling pathway upon miR-186-3p silencing was antagonized by the combined transfection of si-KRT18 and miR-186-3p inhibitor. miR-186-3p suppresses proliferation and viability, but facilitates apoptosis in colon cancer cells by targeting KRT18 and negatively regulating the MAPK signaling pathway, indicating that the miR-186-3p/KRT18 axis may be a promising therapeutic target for colon carcinoma.Abbreviations: KRT18: keratin 18; NC: negative control; si‑: small interfering RNA; inhibitor: miR-186-3p inhibitor; OD: optical density; PI: propidium iodide; FITC: fluorescein isothiocyanate; 3'UTR: 3'untranslated region; WT: wild-type; MUT: mutant-type; miR: microRNA.

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Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

Publications

Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

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