Dataset Information

MiR-512-5p suppresses tumor growth by targeting hTERT in telomerase positive head and neck squamous cell carcinoma in vitro and in vivo.

ABSTRACT: Telomerase activation has very important implications for head and neck squamous cell carcinoma (HNSCC), but the regulatory mechanisms of telomerase in HNSCC remain unclear. In our present study, we found that miR-512-5P was markedly downregulated in telomerase-positive HNSCC cell lines. Both in vitro and in vivo assays revealed that miR-512-5P mimic attenuated HNSCC cell proliferation, and tumor growth in nude mice, which exerts its tumor suppressor function through elevated apoptosis, inhibition of the telomerase activity, decrease of telomere-binding proteins and shortening of telomere length by human telomerase reverse transcriptase (hTERT) downregulation. Furthermore, the dual-luciferase reporter gene assay results demonstrated that hTERT was a direct target of miR-512-5P. We conclude that the frequently miR-512-5P overexpression can regulate hTERT and function as a tumor suppressor in HNSCC. Therefore, miR-512-5P may serve as a potential therapeutic agent for miR-based HNSCC therapy.

SUBMITTER: Li J

PROVIDER: S-EPMC4530866 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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miR-512-5p suppresses tumor growth by targeting hTERT in telomerase positive head and neck squamous cell carcinoma in vitro and in vivo.

Li Jun J Lei Han H Xu Yong Y Tao Ze-Zhang ZZ

PloS one 20150810 8

Telomerase activation has very important implications for head and neck squamous cell carcinoma (HNSCC), but the regulatory mechanisms of telomerase in HNSCC remain unclear. In our present study, we found that miR-512-5P was markedly downregulated in telomerase-positive HNSCC cell lines. Both in vitro and in vivo assays revealed that miR-512-5P mimic attenuated HNSCC cell proliferation, and tumor growth in nude mice, which exerts its tumor suppressor function through elevated apoptosis, inhibiti ...[more]

PMID: 26258591

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Project description:This study demonstrated that miR‐335‐5p expression was reduced in HNSCC. miR‐335‐5p expression could inhibit HNSCC cell growth, metastasis, and promote cell apoptosis while it could suppress tumor growth in vivo. We identified MAP3K2 as a novel target of miR‐335‐5p and MAP3K2 overexpression partially rescued the inhibitory role of miR‐335‐5p. Hence, miR‐335‐5p might constitute a potential therapeutic target for HNSCC patients. Mounting evidence has indicated that aberrantly expressed microRNAs (miRNAs) play key roles in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). Previous studies have shown that miR‐335‐5p can serve as a tumor suppressor or an oncogene in cancer. However, the clinical importance and biological effects of miR‐335‐5p in HNSCC have not been determined. Here, we investigated the expression pattern, functional role, and mechanisms of miR‐335‐5p in HNSCC. We showed a decreased expression of miR‐335‐5p in HNSCC samples from the TCGA and GEO databases. Consistently, we detected a downregulation of miR‐335‐5p in HNSCC cell lines and patient tissues. The expression of miR‐335‐5p was inversely correlated with advanced clinical TNM stage and lymph node metastasis in HNSCC patients. miR‐335‐5p overexpression inhibited HNSCC cell proliferation and induced apoptosis, while miR‐335‐5p inhibition had the opposite effects. miR‐335‐5p overexpression suppressed tumor growth in mice. Bioinformatic analyses and functional assays identified MAP3K2 as a target of miR‐335‐5p, and we showed that miR‐335‐5p downregulated mitogen‐activated protein kinase kinase kinase 2 (MAP3K2) expression in HNSCC cells. We found an inverse association between MAP3K2 and miR‐335‐5p expression in 38 pairs of HNSCC tissues. Furthermore, the effect of miR‐335‐5p overexpression on growth and metastasis as well as cell apoptosis in HNSCC cells could be partially rescued by MAP3K2 expression. Collectively, our data show that miR‐335‐5p inhibits the development of HNSCC by regulating MAP3K2 expression. Thus, these findings offer novel insights into a potential therapeutic strategy for HNSCC patients.

Project description:BackgroundLocal or distant metastasis remains the main course of death in head and neck squamous cell carcinoma (HNSCC) patients. MicroRNAs (miRNAs) have been implicated in metastasis of HNSCC, but the mechanisms of their action are mainly undocumented. Through public head and neck cancer miRNA expression datasets, we found that miR-876-5p was a novel potential tumor suppressor targeting HNSCC metastasis.MethodsClinical significance and mechanism of miR-876-5P was systematically analyzed in HNSCC. Quantitative RT-PCR was used to evaluate miR-876-5p levels in HNSCC cell lines and in 20 pairs of HNSCC with associated regional nodal metastases and HNSCC without metastatic primary tumors. Scratch and invasion assays were evaluated to determine the role of miR-876-5p in the regulation of HNSCC cell migration and invasion, respectively. Western blotting was used to investigate the mechanism by which miR-876-5p suppresses HNSCC cell invasion and migration. Luciferase assays were performed to assess miR-876-5p binding to the vimentin gene. The animal model was used to support the in vitro experimental findings.ResultsMiR-876-5p mimics inhibited HNSCC cell migration and invasion. Vimentin protein and mRNA levels were decreased in the miR-876-5p mimics group but increased in the miR-876-5p inhibitors group, which demonstrated that miR-876-5p inhibits vimentin expression in HNSCC cells. By directly targeting the vimentin 3'-UTR, we used dual-luciferase reporter assays to verify that vimentin is a functional downstream target of miR-876-5p. Importantly, increased vimentin expression promoted cell migration and invasion, and co-transfection with miR-876-5p mimics and vimentin restored cell aggressiveness to the original level. Moreover, miR-876-5p overexpression significantly downregulated vimentin expression level and inhibited the distal metastasis of HNSCC cells in vivo.ConclusionsmiR-876-5p, which functions as a tumor suppressor in HNSCC, inhibits metastasis by targeting vimentin and provides a novel therapeutic target for HNSCC treatment.

Dataset Information

MiR-512-5p suppresses tumor growth by targeting hTERT in telomerase positive head and neck squamous cell carcinoma in vitro and in vivo.

Publications

miR-512-5p suppresses tumor growth by targeting hTERT in telomerase positive head and neck squamous cell carcinoma in vitro and in vivo.

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