Dataset Information

MiR-328-3p promotes migration and invasion by targeting H2AFX in head and neck squamous cell carcinoma.

ABSTRACT: Migration and invasion are the initial step in the metastatic process, while metastasis is responsible for the poor prognosis of head and neck squamous cell carcinoma (HNSCC). Since miRNA has been found as an important regulator of gene expression at the post-transcriptional level in various diseases including carcinoma, exploring the role of miRNA in cancer metastasis will facilitate the target therapy of advanced HNSCC. MiR-328-3p has been reported to be an onco-miRNA or a tumor suppressor in several cancers. However, the role of miR-328-3p in HNSCC migration and invasion remains undefined. In this study, we first demonstrated that miR-328-3p enhanced migration and invasion of HNSCC in vitro, accompanying with a promotion of epithelial-mesenchymal transition (EMT) and mTOR activity. Meanwhile, we confirmed that miR-328-3p directly targeted the 3'UTR of H2A histone family, member X (H2AFX), which served as a tumor suppressor in migration and invasion of HNSCC. Moreover, H2AFX could partially reverse the migration and invasion of HNSCC caused by miR-328-3p. Overall, our results indicated that miR-328-3p enhanced migration and invasion of HNSCC through targeting H2AFX and activated the mTOR pathway.

SUBMITTER: Ma H

PROVIDER: S-EPMC8489127 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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miR-328-3p promotes migration and invasion by targeting H2AFX in head and neck squamous cell carcinoma.

Ma Huiling H Liu Chao C Zhang Shuiting S Yuan Wenhui W Hu Junli J Huang Donghai D Zhang Xin X Liu Yong Y Qiu Yuanzheng Y

Journal of Cancer 20210909 21

Migration and invasion are the initial step in the metastatic process, while metastasis is responsible for the poor prognosis of head and neck squamous cell carcinoma (HNSCC). Since miRNA has been found as an important regulator of gene expression at the post-transcriptional level in various diseases including carcinoma, exploring the role of miRNA in cancer metastasis will facilitate the target therapy of advanced HNSCC. MiR-328-3p has been reported to be an onco-miRNA or a tumor suppressor in ...[more]

PMID: 34659543

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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.

Project description:BackgroundTumor metastasis is responsible for approximately 90% of mortality in lung cancer. Understanding the molecular mechanisms of lung cancer metastasis is crucial for developing new treatment strategies. Cellular prion protein (PrPc), encoded by PRNP gene, was previously found to enhance lung cancer invasiveness. However, research on the post-transcriptional regulation of PRNP remains limited.MethodsDual-luciferase reporter assays identified miRNAs targeting the PRNP 3'-UTR, and RNA immunoprecipitation (RIP) confirmed the interaction between miR-193b-3p and PRNP mRNA. Promoter deletions and chromatin immunoprecipitation (ChIP) assays established c-Jun as a transcriptional repressor of miR-193b-3p. Functional validation of the c-Jun-miR-193b-3p-PrPc axis was conducted using transwell assays, LNA-in situ hybridization, RT-PCR, Western blot, and immunohistochemistry. Subcutaneous mouse xenograft models assessed the anti-tumor effects of miR-193b-3p in vivo.ResultsWe demonstrated that miR-193b-3p downregulates PrPc expression by directly targeting the 3'-UTR of PRNP. Overexpression of miR-193b-3p significantly suppressed PRNP expression at both mRNA and protein levels, and reduced lung cancer cell migration, invasion and proliferation, which was reversed by PrPc overexpression. Conversely, miR-193b-3p silencing enhanced PRNP expression as well as those oncogenic properties, which were mitigated by PRNP knockdown. Spearman correlation analysis revealed a significant negative association between miR-193b-3p and PrPc expression in lung cancer tissues (p = 0.017), and Kaplan-Meier survival analysis demonstrated that high PrPc (p = 0.039) or low miR-193b-3p (p = 0.027) expression correlated with poorer overall survival. Intra-tumoral injection of the miR-193b-3p mimic in mouse xenograft models significantly reduced tumor volume. In addition, c-Jun was identified as a transcriptional repressor of miR-193b-3p. Functional studies revealed that c-Jun knockdown inhibited lung cancer cell migration, invasion, and proliferation, effects that were reversed by either PrPc overexpression or miR-193b-3p inhibitor treatment. A significant association between PrPc and c-Jun expression in lung cancer tissues (p = 0.004) was observed. High expression of PrPc and/or c-Jun was found to be associated with poor overall survival of patients (p < 0.05).ConclusionsThis study is the first to uncover a novel regulatory pathway where c-Jun acts as a transcriptional repressor of miR-193b-3p, leading to PRNP upregulation, which promotes lung cancer migration and invasion. This previously unrecognized c-Jun-miR-193b-3p-PrPc axis also provides valuable insights for the potential development of new therapeutic strategies against lung cancer metastasis through RNA-targeting technology.

Project description:BackgroundWhile treatment failure in cases of head and neck squamous cell carcinoma (HNSCC) frequently takes the form of locoregional recurrences and distant metastasis, our understanding of the mechanisms of metastasis in HNSCC is limited. We initially performed the upstream and key nodes analysis together with whole gene microarray analysis characterized by distant metastatic potential in vivo with HNSCC cell lines and identified JunB, a member of the activator protein-1 (AP-1) family, as a key molecule in the regulation of the pathways related to distant metastasis in HNSCC. We have therefore tested the hypothesis that JunB plays a crucial role in distant metastasis in HNSCC.MethodsTo study the role of JunB on metastatic potential of HNSCC, small interfering RNA (siRNA)-mediated knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (cas9) system (CRISPR/Cas9)-mediated knockout of JunB in HNSCC cells were established and the abilities of cell invasion and migration in vitro were examined. The efficacy of knockout of JunB was also examined using an experimental lung metastatic mouse model of HNSCC. In addition, to study if the role of JunB in HNSCC cell migration and invasiveness is related to epithelial-to-mesenchymal transition (EMT), cell morphology and expression of mesenchymal or epithelial marker on siRNA mediated JunB knockdown in HNSCC cells were examined with or without TGF-β stimulation.ResultssiRNA knockdown and sgRNA knockout of JunB in metastatic HNSCC cells significantly suppressed both cell invasion and migration in vitro. In addition, the knockout of JunB in metastatic HNSCC cells significantly repressed the incidence of lung metastases and prolonged the survival in vivo. However, we did not observe any change in cell morphology with the down-regulation of mesenchymal markers and up-regulation of epithelial markers in response to siRNA-mediated JunB knockdown in HNSCC cells.ConclusionThese results suggested that JunB could play an important role in promoting cell invasion, migration and distant metastasis in HNSCC via pathways other than EMT and that the down-regulation of JunB may become an effective strategy for patients with invasive HNSCC.

Dataset Information

MiR-328-3p promotes migration and invasion by targeting H2AFX in head and neck squamous cell carcinoma.

Publications

miR-328-3p promotes migration and invasion by targeting H2AFX in head and neck squamous cell carcinoma.

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