Let-7a regulates EV secretion and mitochondrial oxidative phosphorylation by targeting SNAP23 in colorectal cancer
| Autor: | Qi Sheng Gu, Ji Kun Li, Dong Lan Cai, You Dong Liu, Xue Ni Liu, Bin Bin Zheng, Dong Wang Yan, Xiao Peng Zhuang, Hui Bin Ding, Liang Yu, Can Cao, Bing Jie Guan |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research SDHA medicine.disease_cause lcsh:RC254-282 Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation microRNA Extracellular medicine Animals Humans Oxidative phosphorylation Secretion Qc-SNARE Proteins Colorectal Cancer Chemistry Research Let-7a Qb-SNARE Proteins Extracellular vesicles lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Mitochondria Cell biology MicroRNAs 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell SNAP23 Female Signal transduction Colorectal Neoplasms Carcinogenesis |
| Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-16 (2021) Journal of Experimental & Clinical Cancer Research : CR |
| ISSN: | 1756-9966 |
| DOI: | 10.1186/s13046-020-01813-6 |
| Popis: | Background MicroRNAs (miRNAs) are abundant in tumor-derived extracellular vesicles (EVs) and the functions of extracellular miRNA to recipient cells have been extensively studied with tumorigenesis. However, the role of miRNA in EV secretion from cancer cells remains unknown. Methods qPCR and bioinformatics analysis were applied for determining extracellular let-7a expression from CRC patient serum and cells. Nanosight particle tracking analysis was performed for investigating the effect of let-7a on EV secretion. Luciferase reporter assays was used for identifying targeted genes synaptosome-associated protein 23 (SNAP23). In vitro and in vivo assays were used for exploring the function of let-7a/SNAP23 axis in CRC progression. Bioenergetic assays were performed for investigating the role of let-7a/SNAP23 in cellular metabolic reprogramming. Results let-7a miRNA was elevated in serum EVs from CRC patients and was enriched in CRC cell-derived EVs. We determined that let-7a could suppress EV secretion directly targeting SNAP23. In turn, SNAP23 promotes EV secretion of let-7a to downregulate the intracellular let-7a expression. In addition, we found a novel mechanism of let-7a/SNAP23 axis by regulating mitochondrial oxidative phosphorylation (OXPHOS) through Lin28a/SDHA signaling pathway. Conclusions Let-7a plays an essential role in not only inhibiting EV secretion, but also suppressing OXPHOS through SNAP23, resulting in the suppression of CRC progression, suggesting that let-7a/SNAP23 axis could provide not only effective tumor biomarkers but also novel targets for tumor therapeutic strategies. |
| Databáze: | OpenAIRE |
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