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MiR-1207-5p suppresses laryngeal squamous cell carcinoma progression by downregulating SKA3 and inhibiting epithelial-mesenchymal transition.

ABSTRACT: Laryngeal squamous cell carcinoma (LSCC) is the second most common head and neck cancer. Previously, we discovered that miR-1207-5p was downregulated in LSCC. In this study, the clinical significance, function, and mechanism of miR-1207-5p in LSCC were investigated. Downregulation of miR-1207-5p was found to be strongly linked to the malignant progression of LSCC. Functional studies revealed that miR-1207-5p upregulation suppressed LSCC cell proliferation, invasion, migration, and xenograft tumor growth. Bioinformatics analysis revealed that miR-1207-5p target genes were involved in cell cycle regulation, proliferation, adhesion, and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Mechanistic studies revealed that miR-1207-5p interacts directly with the 3' untranslated region of spindle and kinetochore associated complex subunit 3 (SKA3) and downregulates SKA3 expression. Furthermore, SKA3 was found to be overexpressed in LSCC, and its high expression was associated with tumor progression and a poor prognosis. Rescue experiments demonstrated that miR-1207-5p inhibited the malignant phenotypes of LSCC via SKA3. Furthermore, miR-1207-5p upregulation or knockdown of SKA3 inhibited the epithelial-mesenchymal transition (EMT). Collectively, miR-1207-5p inhibited LSCC malignant progression by downregulating SKA3 and preventing EMT. These findings provide new insights into the mechanism of LSCC progression, as well as new potential biomarkers and therapeutic targets for LSCC diagnosis and treatment.

SUBMITTER: Wu Y

PROVIDER: S-EPMC8416975 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe investigation of underlying mechanism and the exploitation of novel therapies for metastatic prostate cancer (PCa) are still urgently needed. miR-199b-5p has been suggested to function as tumour suppressor in various human cancers. However, the clinical significance and role of miR-199b-5p in PCa remain unclear.MethodsThe current study sought to investigate the expression status of miR-199b-5p in PCa and the involved molecular mechanisms in PCa metastasis by using bioinformatics analyses, loss-and gain-of-functions and rescue experiments in vitro and in vivo.ResultsWe demonstrated that miR-199b-5p was significantly downregulated in metastatic PCa tissues and cells when compared with the normal prostate tissue, the localised disease, the weakly metastatic and androgen-dependent PCa cell and the normal prostate epithelial cell. We also found that miR-199b-5p drastically suppressed PCa cell proliferation, migration and invasion in vitro and inhibited xenografts tumour growth and metastasis in vivo. Mechanistically, our results showed that miR-199b-5p could inhibit discoidin domain receptor tyrosine kinase 1 (DDR1) expression by directly targeting its 3'-UTR, thereby hindering epithelial-mesenchymal transition (EMT)-associated traits, which were induced by DDR1 activating ERK signalling pathway. Moreover, PCa patients with low miR-199b-5p expression level had a remarkably shorter overall survival than those with high miR-199b-5p level, indicating an association of miR-199b-5p loss with poor prognosis in patients with PCa. Furthermore, DDR1 was upregulated in PCa, and significantly correlated with high Gleason score, advanced pathological stage, tumour metastasis and shorter overall survival.ConclusionsOur study, for the first time, provide evidence of a tumour-suppressive function of miR-199b-5p in the invasion and metastasis of PCa, supporting the translational exploitation of miR-199b-5p-based therapeutic approaches for PCa metastases. Also, the miR-199b-5p-DDR1-ERK signalling axis identified in this study represents a novel mechanism of regulating EMT in PCa metastases.

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MiR-1207-5p suppresses laryngeal squamous cell carcinoma progression by downregulating SKA3 and inhibiting epithelial-mesenchymal transition.

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