Dual inhibition of cMET and EGFR by microRNA-338-5p suppresses metastasis of esophageal squamous cell carcinoma.

Autor:	Cui D; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China., Zhu Y; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China., Yan D; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China., Lee NPY; Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China., Han L; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China., Law S; Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China., Tsao GSW; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China., Cheung ALM; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.
Jazyk:	angličtina
Zdroj:	Carcinogenesis [Carcinogenesis] 2021 Jul 16; Vol. 42 (7), pp. 995-1007.
DOI:	10.1093/carcin/bgab046
Abstrakt:	MicroRNAs, as a group of post-transcriptional regulators, regulate multiple pathological processes including metastasis during tumor development. Here, we demonstrated the metastasis-suppressive function of microRNA (miR)-338-5p in esophageal squamous cell carcinoma (ESCC). Overexpression of miR-338-5p had inhibitory effect on invasive ability of ESCC cells and extracellular matrix degradation, whereas silencing miR-338-5p had opposite effects. Mechanistically, miR-338-5p directly targeted the 3' untranslated regions of hepatocellular growth factor receptor cMet (cMET) and epidermal growth factor receptor (EGFR). As a result, miR-338-5p inhibited the downstream signaling cascades of cMET and EGFR and repressed cMET- and EGFR-mediated ESCC cell invasion. Re-expression of cMET or EGFR in miR-338-5p overexpressing ESCC cells was sufficient to derepress ESCC cell invasion both in vitro and in vivo. We further showed that such manipulation downregulated the expression and secretion of matrix metalloproteinases 2 and 9, which resulted in impaired extracellular matrix degradation and cell invasion. Most importantly, systemic delivery of miR-338-5p mimic significantly inhibited metastasis of ESCC cells in nude mice. Taken together, our results uncovered a previously unknown mechanism through which miR-338-5p suppresses ESCC invasion and metastasis by regulating cMET/EGFR-matrix metalloproteinase 2/9 axis and highlighted the potential significance of miR-338-5p-based therapy in treating patients with metastatic ESCC. (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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