Syntaphilin downregulation facilitates radioresistance via mediating mitochondria distribution in esophageal squamous cell carcinoma
| Autor: | Shichao Zhuo, Wenzhe Xu, Shanghui Guan, Di Huang, Xuan Chen, Yufeng Cheng, Pengxiang Chen, Xiaozheng Sun, Xue Chen |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Esophageal Neoplasms Down-Regulation Nerve Tissue Proteins Mitochondrion Radiation Tolerance Biochemistry 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Syntaphilin Cell Line Tumor Physiology (medical) Radioresistance Humans Gene silencing Radiosensitivity Cell Proliferation biology Chemistry Membrane Proteins digestive system diseases Mitochondria 030104 developmental biology Histone Cancer cell biology.protein Cancer research Esophageal Squamous Cell Carcinoma 030217 neurology & neurosurgery |
| Zdroj: | Free Radical Biology and Medicine. 165:348-359 |
| ISSN: | 0891-5849 |
| Popis: | Syntaphilin (SNPH) halts mitochondrial movements and regulates proliferation-motility phenotype switching of cancer cells. We sought to investigate the significance of SNPH-mediated mitochondria distribution in radioresistant (RR) phenotype switching in esophageal squamous cell carcinoma (ESCC). RR ESCC cells were established by long-term exposure to radiation. Effects of SNPH on proliferation, migration, mitochondrial distribution, radiation-induced oxidative damage and radiosensitivity were investigated by overexpressing or silencing SNPH. The mechanisms regulating SNPH expression and the potential molecules mediating the SNPH-re-expression-induced radiosensitization were explored. SNPH expression in specimens from 156 patients was analyzed to evaluate its clinical significance. We found that RR ESCC cells had a sparse mitochondrial network and lower SNPH level. SNPH reconstitution in RR ESCC cells inhibited migration, induced proliferation and mitochondrial aggregation, exacerbated the radiation-induced oxidative damage and ultimately promoted radiosensitization. Mechanistically, ubiquitin-proteasomal degradation and histone modification contributed to SNPH downregulation in RR ESCC cells. Subsequently, we found that CREB dephosphorylation facilitated the SNPH re-expression-induced radiosensitization. Furthermore, SNPH expression was correlated with the radiotherapeutic efficacy and served as an independent prognostic factor for survival of ESCC patients. Our study revealed that low SNPH expression was a novel indicator for radioresistance, and targeting SNPH could be a promising regimen to improve the radiotherapeutic efficiency in ESCC patients. |
| Databáze: | OpenAIRE |
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