Dual inhibition of cMET and EGFR by microRNA-338-5p suppresses metastasis of esophageal squamous cell carcinoma
| Autor: | Nikki P. Lee, Liang Han, Di Cui, Yun Zhu, Simon Law, George S.W. Tsao, Annie L.M. Cheung, Dong Dong Yan |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Lung Neoplasms Esophageal Neoplasms Mice Nude Apoptosis Matrix metalloproteinase Metastasis Mice 03 medical and health sciences 0302 clinical medicine Growth factor receptor microRNA Tumor Cells Cultured medicine Animals Humans Gene silencing Neoplasm Invasiveness Secretion Epidermal growth factor receptor Cell Proliferation biology Chemistry General Medicine Proto-Oncogene Proteins c-met medicine.disease Xenograft Model Antitumor Assays digestive system diseases ErbB Receptors Gene Expression Regulation Neoplastic MicroRNAs 030104 developmental biology 030220 oncology & carcinogenesis Cancer research biology.protein Esophageal Squamous Cell Carcinoma Signal transduction |
| Zdroj: | Carcinogenesis. 42:995-1007 |
| ISSN: | 1460-2180 0143-3334 |
| DOI: | 10.1093/carcin/bgab046 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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