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LINC00461 facilitates HNSCC development and reduces chemosensitivity by impairing miR-195-mediated inhibition of HOXA10.

ABSTRACT: Homeobox A10 (HOXA10) has been regarded to serve as an oncogene in head and neck squamous cell carcinoma (HNSCC). This study was intended to explore the interaction among the long intergenic noncoding RNA 00461 (LINC00461), microRNA (miR)-195, and HOXA10, and to investigate its role in epithelial-mesenchymal transition (EMT) and chemoresistance in HNSCC. The effects of LINC00461, miR-195, and HOXA10 on the EMT and chemoresistance of HNSCC cells were analyzed by comprehensive analysis of gain- and loss-of-function techniques. The intimate relationships among LINC00461, miR-195, and HOXA10 were investigated by several procedures such as RNA-binding protein immunoprecipitation, RNA pull-down, and dual-luciferase reporter assays. A xenotransplantation tumor model in nude mice was established for the assessment of the tumorigenic ability of the cells in vivo. Our findings indicated that LINC00461 was highly expressed in HNSCC and its overexpression induced EMT and precipitated the chemoresistance of HNSCC cells to cisplatin. The LINC00461 could bind to miR-195 while miR-195 targeted HOXA10 independently. Moreover, LINC00461 impaired miR-195-mediated inhibition of HOXA10 to induce EMT and increase the chemoresistance in HNSCC. Tumor weight and volume were reduced by lentivirus-mediated elevation of miR-195 by inhibition of HOXA10, which could be annulled by LINC00461 overexpression. LINC00461 downregulates the expression of miR-195 to subsequently upregulate the expression of HOXA10, thereby promoting EMT and enhancing chemoresistance in HNSCC.

SUBMITTER: Guan Y

PROVIDER: S-EPMC8027536 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHead and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide. They are typically characterized by a high incidence of local recurrence, which is the most common cause of death in HNSCC patients. TP53 is the most frequently mutated gene in HNSCC and patients carrying TP53 mutations are associated with a higher probability to develop local recurrence. MiRNAs, which are among the mediators of the oncogenic activity of mt-p53 protein, emerge as an appealing tool for screening, diagnosis and prognosis of cancer. We previously identified a signature of 12 miRNAs whose aberrant expression associated with TP53 mutations and was prognostic for HNSCC. Among them miR-96-5p emerges as an oncogenic miRNAs with prognostic significance in HNSCC.MethodsTo evaluate the oncogenic role of miR-96-5p in a tumoral context, we performed colony formation, cell migration and cell viability assays in two HNSCC cell lines transfected for miR-96-5p mimic or inhibitor and treated with or without radio/chemo-therapy. In addition, to identify genes positively and negatively correlated to miR-96-5p expression in HNSCC, we analyzed the correlation between gene expression and miR-96-5p level in the subset of TCGA HNSCC tumors carrying missense TP53 mutations by Spearman and Pearson correlation. To finally identify targets of miR-96-5p, we used in silico analysis and the luciferase reporter assay to confirm PTEN as direct target.ResultsOur data showed that overexpression of miR-96-5p led to increased cell migration and radio-resistance, chemotherapy resistance in HNSCC cells. In agreement with these results, among the most statistically significant pathways in which miR-96-5p is involved, are focal Adhesion, extracellular matrix organization and PI3K-Akt-mTOR-signaling pathway. As a direct target of miR-96-5p, we identified PTEN, the main negative regulator of PI3K-Akt signalling pathway activation.ConclusionsThese results highlight a new mechanism of chemo/radio-resistance insurgence in HNSCC cells and support the possibility that miR-96-5p expression could be used as a novel promising biomarker to predict radiotherapy response and local recurrence development in HNSCC patients. In addition, the identification of pathways in which miR-96-5p is involved could contribute to develop new therapeutic strategies to overcome radio-resistance.

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LINC00461 facilitates HNSCC development and reduces chemosensitivity by impairing miR-195-mediated inhibition of HOXA10.

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