DAXX/ATRX蛋白表达缺失导致胰腺神经内分泌肿瘤细胞对缺血具有抗性而对辐射敏感，并与经动脉放射性栓塞治疗反应的改善相关。
Loss of DAXX/ATRX Protein Expression Results in Ischemia Resistance and Radiation Sensitivity in Pancreatic Neuroendocrine Tumor Cells and Is Associated with Improved Response to Trans-Arterial Radioembolization.
作者信息
Puzzuoli Jessica C, Solivio Caleb, Yuan Gavin, Rizzo Anthony J, Graham Mindy K, Shenker Larissa, Vista Will, Gil Adam, Singh Himanshu, Alexander Erica, Gonzalez-Aguirre Adrian, Latzman Jonathan, Petre E Nadia, Yarmohammadi Hooman, Erinjeri Joseph P, Covey Anne, Chan Eric, Russell James, Bodei Lisa, Raj Nitya, Reidy-Lagunes Diane, Heaphy Christopher M, Ziv Etay
机构信息
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
出版信息
Neuroendocrinology. 2025 Jul 24:1-11. doi: 10.1159/000547041.
INTRODUCTION
Metastatic liver pancreatic neuroendocrine tumors (PNETs) can be treated with ischemia-based trans-arterial embolization/trans-arterial chemo-embolization or radiation-based trans-arterial radioembolization (TARE). Guidelines for treatment selection are limited. The purpose of this study was to measure the effect of loss of DAXX/ATRX protein expression on ischemia and radiation sensitivity in Bon-1 and QGP-1 cells, and to compare TARE response in PNETs with and without a DAXX/ATRX mutation.
METHODS
This was a laboratory investigation and retrospective review of an institutional database of TARE-treated PNET patients. Ischemia and radiation sensitivity were tested on Bon-1 and QGP-1 cells and CRISPR-generated DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts. Post-ischemia and postradiation cell viability, survival fraction, and caspase-3 expression were measured. Local progression-free survival (LPFS) was measured from time of TARE to local progression or death and estimated using Cox proportional hazards.
RESULTS
Post-ischemia DAXX (C16/C45) and ATRX (QAX12/QAX24) knockouts had increased cell viability compared with Bon-1 wild-type cells (p < 0.0001, days 3, 5) and QGP-1 wild-type cells (p < 0.0001, days 3, 5, 7). Postradiation C16/C45 and QAX12/QAX24 had decreased survival fraction compared with respective wild type (p < 0.0001, all cell lines). C16/C45 had decreased apoptotic activity post-ischemia and increased apoptotic activity postradiation compared with wild type (p < 0.0001, all cell lines). Presence of DAXX/ATRX mutation was associated with longer LPFS after TARE (p < 0.001). Median LPFS after TARE was 6 months in wild type compared with 22 months in patients with DAXX/ATRX mutation.
CONCLUSION
Loss of DAXX/ATRX protein expression is associated with ischemia resistance and radiation sensitivity in Bon-1 and QGP-1 cells and longer LPFS after TARE in PNET patients.
引言
转移性肝胰腺神经内分泌肿瘤（PNETs）可采用基于缺血的经动脉栓塞/经动脉化疗栓塞或基于放射的经动脉放射性栓塞（TARE）进行治疗。治疗选择的指南有限。本研究的目的是测量DAXX/ATRX蛋白表达缺失对Bon-1和QGP-1细胞缺血和放射敏感性的影响，并比较有和没有DAXX/ATRX突变的PNETs对TARE的反应。
方法
这是一项实验室研究，并对接受TARE治疗的PNET患者的机构数据库进行回顾性分析。在Bon-1和QGP-1细胞以及CRISPR技术构建的DAXX（C16/C45）和ATRX（QAX12/QAX24）基因敲除细胞中测试缺血和放射敏感性。测量缺血后和放射后细胞活力、存活分数和半胱天冬酶-3表达。从TARE时间到局部进展或死亡测量局部无进展生存期（LPFS），并使用Cox比例风险模型进行估计。
结果
与Bon-1野生型细胞（第3、5天，p<0.0001）和QGP-1野生型细胞（第3、5、7天，p<0.0001）相比，缺血后DAXX（C16/C45）和ATRX（QAX12/QAX24）基因敲除细胞的细胞活力增加。与各自的野生型相比，放射后C16/C45和QAX12/QAX24的存活分数降低（所有细胞系，p<0.0001）。与野生型相比，C16/C45在缺血后凋亡活性降低，在放射后凋亡活性增加（所有细胞系，p<0.0001）。DAXX/ATRX突变的存在与TARE后更长的LPFS相关（p<0.001）。野生型TARE后的中位LPFS为6个月，而DAXX/ATRX突变患者为22个月。
结论
DAXX/ATRX蛋白表达缺失与Bon-1和QGP-1细胞的缺血抗性和放射敏感性相关，并且与PNET患者TARE后更长的LPFS相关。
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