Chen Xuan, Xu Wenzhe, Zhuo Shichao, Chen Xue, Chen Pengxiang, Guan Shanghui, Huang Di, Sun Xiaozheng, Cheng Yufeng
Department of Radiation Oncology, Qilu Hospital of Shandong University, West Wenhua Rd. 107, Jinan, 250012, China.
Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, West Wenhua Rd. 107, Jinan, 250012, China.
Free Radic Biol Med. 2021 Mar;165:348-359. doi: 10.1016/j.freeradbiomed.2021.01.056. Epub 2021 Feb 9.
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.
Syntaxin结合蛋白（SNPH）可阻止线粒体移动，并调节癌细胞的增殖-运动表型转换。我们试图研究SNPH介导的线粒体分布在食管鳞状细胞癌（ESCC）放射抗性（RR）表型转换中的意义。通过长期暴露于辐射建立RR ESCC细胞。通过过表达或沉默SNPH来研究SNPH对增殖、迁移、线粒体分布、辐射诱导的氧化损伤和放射敏感性的影响。探索调节SNPH表达的机制以及介导SNPH重新表达诱导的放射增敏作用的潜在分子。分析156例患者标本中的SNPH表达，以评估其临床意义。我们发现RR ESCC细胞具有稀疏的线粒体网络和较低的SNPH水平。RR ESCC细胞中SNPH的重构抑制了迁移，诱导了增殖和线粒体聚集，加剧了辐射诱导的氧化损伤，并最终促进了放射增敏作用。从机制上讲，泛素-蛋白酶体降解和组蛋白修饰导致RR ESCC细胞中SNPH下调。随后，我们发现CREB去磷酸化促进了SNPH重新表达诱导的放射增敏作用。此外，SNPH表达与放射治疗疗效相关，并作为ESCC患者生存的独立预后因素。我们的研究表明，低SNPH表达是放射抗性的一个新指标，靶向SNPH可能是提高ESCC患者放射治疗效率的一个有前景的方案。
