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MiR-381 Mediates the Development of Head and Neck Squamous Cell Carcinoma via Targeting STC2.

ABSTRACT: ObjectivemiR-381 is implicated in the occurrence and development of various cancers, yet its role in head and neck squamous cell carcinoma (HNSCC) remains largely unknown. This study sought to research the direct target of miR-381 in HNSCC and investigate their roles in cancer progression.MethodsmiRNA and mRNA expression files of HNSCC were accessed from TCGA database and then processed for differential analysis. Bioinformatics databases were employed to predict the target mRNAs of the potential miRNA. qRT-PCR was conducted to determine the expression levels of the target miRNA and mRNA. Then, a series of in vitro experiments like CCK-8, colony formation assay, wound healing assay and ?transwell assay were performed to detect cell proliferation, migration and invasion. Dual-luciferase reporter gene assay was carried out for the further validation of the targeted relationship between the miRNA and mRNA.ResultsmiR-381 was observed to be greatly down-regulated in HNSCC cells, and its overexpression could inhibit cell proliferation, migration and invasion. Besides, dual-luciferase reporter gene assay confirmed that STC2 was a direct target of miR-381, and their expression levels were reversely correlated. Moreover, rescue experiments demonstrated that overexpressing STC2 could rescue the inhibitory effect of miR-381 overexpression on cell proliferation, migration and invasion. Also, we verified that miR-381/STC2 exerted its function on HNSCC proliferation by mediating the FAK/PI3K/Akt/mTOR signaling pathway.ConclusionmiR-381 suppresses cell proliferation, migration and invasion in HNSCC through targeting STC2, and participates in HNSCC development probably via the FAK/PI3K/Akt/mTOR signaling pathway.

SUBMITTER: Ma H

PROVIDER: S-EPMC7247612 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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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.

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Project description:BackgroundHead and neck squamous cell carcinoma (HNSCC) is among the most common malignant tumors worldwide. This study, investigated the role of microRNA (miR)-762 in regulating HNSCC progression.Materials and methodsThe expression levels of miR-762 in HNSCC tissues were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Statistical analyses were performed to investigate the association of miR-762 with clinicopathological features in patients with HNSCC. Cell proliferation and migration were examined by cell counting (CCK-8) and IncuCyte assays. Target genes of miR-762 were screened using bioinformatics tools and microarrays, and confirmed using a luciferase activity reporter assay, qRT-PCR and Western blot analysis. Recuse experiments were performed to detect whether target genes mediated the effects of miR-762 on HNSCC cells. The in vivo effects of miR-762 were verified using tumor xenografts.ResultsHNSCC clinical specimens showed high expression levels of miR-762, which positively correlated with tumor-node-metastasis (TNM) stage and poor prognosis of HNSCC. miR-762 overexpression promoted the proliferation and migration of HNSCC cells in vitro. In addition, overexpression of miR-762 upregulated the expression of phosphorylated AKT (p-AKT) and mesenchymal markers (N-cadherin and vimentin), but suppressed epithelial marker (E-cadherin) expression. miR-762 also promoted HNSCC tumor growth in vivo. PH domain and leucine-rich repeat protein phosphatase 2 (PHLPP2) and Forkhead box O4 (FOXO4) were direct target genes of miR-762. HNSCC tissues had low expression levels of PHLPP2 and FOXO4, showing a negative correlation with miR-762 expression. Moreover, silencing of PHLPP2 and FOXO4 mimicked the tumor-promotive effects of miR-762 on HNSCC cells. Notably, overexpression of PHLPP2 and FOXO4 abolished the pro-tumoral function of miR-762 on cell proliferation and migration.ConclusionmiR-762 promotes HNSCC progression by targeting PHLPP2 and FOXO4. Therefore, miR-762 might be a potential diagnostic or therapeutic target for HNSCC.

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MiR-381 Mediates the Development of Head and Neck Squamous Cell Carcinoma via Targeting STC2.

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