PDF(Pubmed)
Abstract：
This study explored the role of 14-3-3σ in carbon ion-irradiated pancreatic adenocarcinoma (PAAD) cells and xenografts and clarified the underlying mechanism. The clinical significance of 14-3-3σ in patients with PAAD was explored using publicly available databases. 14-3-3σ was silenced or overexpressed and combined with carbon ions to measure cell proliferation, cell cycle, and DNA damage repair. Immunoblotting and immunofluorescence (IF) assays were used to determine the underlying mechanisms of 14-3-3σ toward carbon ion radioresistance. We used the BALB/c mice to evaluate the biological behavior of 14-3-3σ in combination with carbon ions. Bioinformatic analysis revealed that PAAD expressed higher 14-3-3σ than normal pancreatic tissues; its overexpression was related to invasive clinicopathological features and a worse prognosis. Knockdown or overexpression of 14-3-3σ demonstrated that 14-3-3σ promoted the survival of PAAD cells after carbon ion irradiation. And 14-3-3σ was upregulated in PAAD cells during DNA damage (carbon ion irradiation, DNA damaging agent) and promotes cell recovery. We found that 14-3-3σ resulted in carbon ion radioresistance by promoting RPA2 and RAD51 accumulation in the nucleus in PAAD cells, thereby increasing homologous recombination repair (HRR) efficiency. Blocking the HR pathway consistently reduced 14-3-3σ overexpression-induced carbon ion radioresistance in PAAD cells. The enhanced radiosensitivity of 14-3-3σ depletion on carbon ion irradiation was also demonstrated in vivo. Altogether, 14-3-3σ functions in tumor progression and can be a potential target for developing biomarkers and treatment strategies for PAAD along with incorporating carbon ion irradiation.
摘要：
本研究探讨了14-3-3σ在碳离子辐照的胰腺癌（PAAD）细胞和异种移植物中的作用，并阐明了其潜在机制。使用公开可用的数据库探索14-3-3σ在PAAD患者中的临床意义。14-3-3σ沉默或过表达，并与碳离子结合以测量细胞增殖，细胞周期,和DNA损伤修复。免疫印迹和免疫荧光（IF）测定用于确定14-3-3σ对碳离子辐射抗性的潜在机制。我们使用BALB/c小鼠评估了14-3-3σ与碳离子组合的生物学行为。生物信息学分析显示，PAAD表达高于正常胰腺组织14-3-3σ；其过表达与侵袭性临床病理特征有关，预后较差。14-3-3σ的敲低或过表达表明，14-3-3σ促进了碳离子照射后PAAD细胞的存活。并且14-3-3σ在DNA损伤期间在PAAD细胞中上调(碳离子照射，DNA损伤剂）并促进细胞恢复。我们发现14-3-3σ通过促进PAAD细胞核中RPA2和RAD51的积累而导致碳离子辐射抗性，从而提高同源重组修复(HRR)效率。阻断HR途径始终降低PAAD细胞中14-3-3σ过表达诱导的碳离子辐射抗性。在体内还证明了碳离子辐照下14-3-3σ消耗的增强的放射敏感性。总之,14-3-3σ在肿瘤进展中起作用，并且可以成为开发PAAD的生物标志物和治疗策略以及结合碳离子照射的潜在靶标。
