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MiR-454 is down-regulated in osteosarcomas and suppresses cell proliferation and invasion by directly targeting c-Met.

ABSTRACT: OBJECTIVES:Osteosarcoma is the most common primary bone malignancy of children and young adults. Increasing evidence has shown that microRNAs (miRNAs) are associated with cancer development, but, little is known concerning the role of miR-454 in osteosarcoma. MATERIALS AND METHODS:qRT-PCR was performed to detect expression of miR-454 in osteosarcoma cell lines and tissues. To understand its role in osteosarcoma, we reintroduced expression of miR-454 in the MG-63 cell line by transfection with miR-454 mimics or inhibitors. CCK-8 assay and an invasion assay were used to detect the functional role of miR-454. Luciferase assay and western blot analysis were performed to detect the target gene of miR-454. RESULTS:miR-454 was found to be down-regulated in osteosarcoma tissues and cell lines. Its over-expression inhibited tumour growth and invasion and its down-regulation promoted cell proliferation and invasion. Subsequent investigation revealed that c-Met was a direct and functional target of miR-454 in osteosarcoma. Overexpression of miR-454 impaired c-Met-induced cell proliferation and invasion. Finally, miR-454 was found to be inversely correlated to c-Met expression in human osteosarcoma tissues. CONCLUSIONS:Reduced-expression of miR-454 in osteosarcoma cells promoted tumour growth by targeting c-Met, thus miR-454 may be a potential therapy target for this tumour.

SUBMITTER: Niu G

PROVIDER: S-EPMC6496886 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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miR-454 is down-regulated in osteosarcomas and suppresses cell proliferation and invasion by directly targeting c-Met.

Niu Guangfeng G Li Bin B Sun Jianmin J Sun Li L

Cell proliferation 20150416 3

<h4>Objectives</h4>Osteosarcoma is the most common primary bone malignancy of children and young adults. Increasing evidence has shown that microRNAs (miRNAs) are associated with cancer development, but, little is known concerning the role of miR-454 in osteosarcoma.<h4>Materials and methods</h4>qRT-PCR was performed to detect expression of miR-454 in osteosarcoma cell lines and tissues. To understand its role in osteosarcoma, we reintroduced expression of miR-454 in the MG-63 cell line by trans ...[more]

PMID: 25880599

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Project description:BackgroundGastric cancer is the fourth most common cancer in the world and the second most prevalent cause of cancer related death. The development of gastric cancer is mainly associated with H. Pylori infection leading to a focus in pathology studies on bacterial and environmental factors, and to a lesser extent on the mechanistic development of the tumour. MicroRNAs are small non-coding RNA molecules involved in post-transcriptional gene regulation. They are found to regulate genes involved in diverse biological functions and alterations in microRNA expression have been linked to the pathogenesis of many malignancies. The current study is focused on identifying microRNAs involved in gastric carcinogenesis and to explore their mechanistic relevance by characterizing their targets.ResultsInvitrogen NCode miRNA microarrays identified miR-449 to be decreased in 1-year-old Gastrin KO mice and in H. Pylori infected gastric tissues compared to tissues from wild type animals. Growth rate of gastric cell lines over-expressing miR-449 was inhibited by 60% compared to controls. FACS cell cycle analysis of miR-449 over-expressing cells showed a significant increase in the sub-G1 fraction indicative of apoptosis. ß-Gal assays indicated a senescent phenotype of gastric cell lines over-expressing miR-449. Affymetrix 133v2 arrays identified GMNN, MET, CCNE2, SIRT1 and CDK6 as miR-449 targets. Luciferase assays were used to confirm GMNN, MET, CCNE2 and SIRT1 as direct targets. We also show that miR-449 over-expression activated p53 and its downstream target p21 as well as the apoptosis markers cleaved CASP3 and PARP. Importantly, qPCR analyses showed a loss of miR-449 expression in human clinical gastric tumours compared to normal tissues.ConclusionsIn this study, we document a diminished expression of miR-449 in Gastrin KO mice and further confirmed its loss in human gastric tumours. We investigated the function of miR-449 by identifying its direct targets. Furthermore we show that miR-449 induces senescence and apoptosis by activating the p53 pathway.

Dataset Information

MiR-454 is down-regulated in osteosarcomas and suppresses cell proliferation and invasion by directly targeting c-Met.

Publications

miR-454 is down-regulated in osteosarcomas and suppresses cell proliferation and invasion by directly targeting c-Met.

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