FAK alleviates radiation-induced rectal injury by decreasing apoptosis
FAK alleviates radiation-induced rectal injury by decreasing apoptosis
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FAK 通过减少细胞凋亡减轻辐射引起的直肠损伤
DOI：
10.1016/j.taap.2018.10.007
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发表时间：
2018
影响因子：
3.8
通讯作者：
Liu Yong
中科院分区：
文献类型：
--
作者：
Li Jun-Jun;Tu Wen-Zhi;Chen Xu-Ming;Ying Hou-Yu;Chen Ying;Ge Yu-Long;Wang Jing;Xu Yi;Chen Ting-Feng;Zhang Xiao-Wei;Ye Jin-Jun;Liu Yong
放射性直肠损伤与放疗疗效密切相关。在这里，我们研究了粘着斑激酶（FAK）在放射性直肠损伤中的作用。在放射治疗前收集直肠癌患者的外周血样品。通过微阵列分析差异表达基因和拷贝数变异（CNVs）。使用CTCAE v3.0毒性分级评估急性直肠损伤。采用集落形成、线粒体膜电位、流式细胞术和蛋白质印迹法检测人小肠上皮隐窝细胞（HIEC）的放射敏感性。用15戈伊的单次剂量对C57 BL/6小鼠的直肠进行局部X射线照射。采用苏木精-伊红（H&E）染色、末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）、免疫组化（IHC）和实时荧光定量PCR（qRT-PCR）等方法观察FAK对放射损伤的影响。FAK mRNA水平与患者样本中直肠损伤严重程度呈负相关。位于8号染色体上的CNV扩增与FAK密切相关。进一步的功能测定显示，FAK沉默的HIEC细胞中γ H2 AX表达和凋亡相关蛋白水平增加。用FAK抑制剂处理的直肠粘膜中TUNEL、cl-caspase-3、cyto-c和bax/bcl-2表达的比率显著增加。这些结果表明，FAK减少辐射诱导的直肠损伤，减少细胞凋亡。
Radiation-induced rectal injury is closely related with radiotherapy efficiency. Here, we investigated the effect of focal adhesion kinase (FAK) in radiation-induced rectal injury. Peripheral blood samples of patients with rectal cancer were collected prior to radiotherapy. Differentially expressed genes and copy number variations (CNVs) were analyzed by microarray analysis. The CTCAE v3.0 toxicity grades were used to assess acute rectal injury. The radiosensitivity of human intestinal epithelial crypt (HIEC) cells were assayed by colony formation, mitochondrial membrane potential, flow cytometry and western blotting. The rectums of C57BL/6 mice were X-irradiated locally with a single dose of 15 Gy. The effect of FAK on radiation-induced injury was investigated by hematoxylin-eosin (H&E) staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR). FAK mRNA level was inversely correlated with rectal injury severity in patient samples. A CNV amplification located on chromosome 8 was closely related withFAK. Further functional assays revealed increased levels of γH2AX expression and apoptosis-related proteins in FAK-silenced HIEC cells. The ratio of TUNEL, cl-caspase-3, cyto-c and bax/bcl-2 expression in the rectum mucosa treated with a FAK inhibitor increased significantly. These results demonstrated that FAK reduced radiation-induced rectal injury by decreasing apoptosis.