miR-96-5p targets PTEN expression affecting radio-chemosensitivity of HNSCC cells

Abstract

Background Head 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. Methods To 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. Results Our 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. Conclusions These 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. Electronic supplementary material The online version of this article (10.1186/s13046-019-1119-x) contains supplementary material, which is available to authorized users.

MicroRNA-96-5p promotes proliferation, invasion and EMT of oral carcinoma cells by directly targeting FOXF2

“…Chen et al indicated that miR-125b suppresses oral oncogenicity by targeting the anti-oxidative gene PRXL2A (Chen et al, 2019). Numerous studies have found that miR-96-5p not only affected cell proliferation, but was also closely associated with prognosis in cancers including ovarian cancer, HNSCC, hepatocellular carcinoma and colorectal cancer (Liu et al, 2019;Vahabi et al, 2019;Iwai et al, 2018;Ress et al, 2015).…”

“…Many human miRNAs have been confirmed to be dysregulated in OSCC, including miR-543, miR-4513, miR-31, miR-223 and miR-125b (Wang et al, 2019;Xu et al, 2019;Kao et al, 2019;Jiang et al, 2019;Chen et al, 2019). Up until now, miR-96-5p had been reported to function as an oncogene in ovarian cancer, HNSCC, hepatocellular carcinoma (Liu et al, 2019;Vahabi et al, 2019;Iwai et al, 2018), or function as a tumor suppressor in colorectal cancer (Ress et al, 2015), the functions of miR-96-5p in OSCC were rarely explored previously. Therefore, we investigated the functional roles and mechanisms of miR-96-5p in OSCC.…”

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

“…As for many human cancers, TP53 is the most frequently mutated gene in HNSCC [9,17]. In TCGA dataset, which includes 478 HNSCC molecularly well characterized cases we found that patients carrying TP53 mutation exhibited a signi cantly lower level of TMPRSS2 expression compared to the patients with intact TP53 gene ( Fig.…”

TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients

“…As for many human cancers, TP53 is the most frequently mutated gene in HNSCC [ 9 , 19 ]. In TCGA dataset, which includes 478 HNSCC molecularly well characterized cases we found that patients carrying TP53 mutation exhibited a significantly lower level of TMPRSS2 expression compared to the patients with intact TP53 gene (Fig.…”