垂体生长激素腺瘤激素分泌与细胞内质网应激的相关性及临床意义研究  

The Correlation between Growth Hormone Secretion and Endoplasmic Reticulum Stress in Pituitary Growth Hormone Adenoma and Its Clinical Signification

作　　者：王子涵 雷琢玮[1] 江迁 王全基 李兴波 黄逸民 张卓 陈娟[1] 雷霆[1] WANG Zi-han;LEI Zhuo-wei;JI-ANG Qian;WANG Quan-ji;LI Xing-bo;HUANG Yi-min;ZHANG Zhuo;CHEN Juan;LEI Ting(Department of Neurosurgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China)

机构地区：[1]华中科技大学同济医学院附属同济医院神经外科,武汉430030

出　　处：《神经损伤与功能重建》2023年第4期187-192,共6页Neural Injury and Functional Reconstruction

基　　金：国家自然科学基金(No.82173136)。

摘　　要：目的:探讨垂体生长激素腺瘤中内质网应激与生长激素(GH)分泌之间的相关性及临床意义。方法:回顾性分析华中科技大学同济医学院附属同济医院神经外科2021年9月至2022年11月经鼻蝶入路手术切除垂体腺瘤治疗的垂体腺瘤患者20例的临床资料。收集肿瘤组织,制作切片采用免疫组化染色检测肿瘤组织内质网应激蛋白(GRP78、XBP-1s、p-eIF-2α)表达水平,并与患者术前GH水平进行相关性分析;提取患者肿瘤组织进行原代培养,使用内质网应激刺激剂衣霉素(Tm)、毒胡萝卜素(Tg),内质网应激抑制剂4-苯基丁酸(4-PBA)进行干预,检测生长激素腺瘤细胞GH分泌的改变及垂体特异性转录因子PiT-1转录及表达水平的变化。结果:①GRP-78、XBP-1s及p-eIF-2α的表达水平均与患者术前GH水平呈显著正相关(均P<0.0001);②内质网应激刺激剂Tm、Tg促进生长激素腺瘤细胞分泌GH(均P<0.001);③内质网应激抑制剂4-PBA可以明显降低Tm对生长激素腺瘤细胞GH分泌的促进作用(P<0.0001);④内质网应激刺激剂Tm、Tg促进生长激素腺瘤细胞PiT-1基因在转录水平的表达(Tm组P<0.001,Tg组P<0.0001)及翻译水平的表达(Tm组P=0.0093,Tg组P=0.0030);使用siRNA干扰生长激素腺瘤细胞PiT-1表达后,GH分泌下降(P<0.0001),且降低了Tm对GH分泌的促进作用;⑤内质网应激抑制剂4-PBA在转录(P<0.0001)及翻译水平(P<0.0001)均可以明显降低Tm对生长激素腺瘤细胞PiT-1基因表达的促进作用(P<0.0001)。结论:垂体生长激素腺瘤GH分泌水平与内质网应激水平之间呈明显正相关;内质网应激促进生长激素腺瘤细胞分泌GH,抑制内质网应激可减少生长激素腺瘤细胞分泌GH;内质网应激促进生长激素腺瘤细胞PiT-1的表达,抑制内质网应激减少生长激素腺瘤细胞PiT-1的表达。Objective:To investigate the correlation between endoplasmic reticulum(ER)stress and growth hormone(GH)secretion in pituitary GH adenomas and its mechanism.Methods:The clinical data of 20 patients with pituitary adenomas treated by transsphenoidal approach in the Department of Neurosurgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology from September 2021 to November 2022 were analyzed retrospectively.The tumor tissues were collected and sections were made for immunohistochemical staining.The correlation between the expression of ER stress protein and the preoperative GH level was analyzed.The tumor tissues of patients were extracted for primary culture and intervened with ER stress stimulants Tm、Tg and ER stress inhibitor 4-PBA to detect the changes of GH secretion and pituitary specific transcription factor(PiT-1)expression in GH adenoma cells.Results:(1)Expression levels of GRP-78,XBP-1s and p-eIF-2αwere all positively correlated with preoperative GH level(all P<0.0001).(2)ER stress stimulants Tm and Tg promoted the secretion of GH in GH adenoma cells(both P<0.001).(3)ER stress inhibitor 4-PBA could significant-ly reduce the promoting effect of Tm on GH secretion in GH adenoma cells(P<0.0001).(4)ER stress stimulators Tm and Tg promoted the expression of PiT-1 gene at both the transcriptional level(Tm group P<0.001,Tg group P<0.0001)and the translational level(Tm group P=0.0093,Tg group P<0.003)in GH adenoma cells.(5)ER stress inhibitor 4-PBA could significantly reduce the promoting effect of Tm on PiT-1 gene expression in GH adenoma cells at both transcriptional level(P<0.0001)and translation level(P<0.0001).Conclusion:There was a significant positive correlation between ER stress and GH secretion in pituitary GH adenomas.ER stress could promote GH secretion in GH adenoma cells,and inhibition of ER stress could reduce GH secretion.ER stress could promote PiT-1 expression in GH adenoma cells,and inhibition of ER stress could reduce PiT-1 expression in GH adenoma cells.

关 键 词：垂体瘤 内质网应激 生长激素 垂体特异性转录因子 

分 类 号：R741[医药卫生—神经病学与精神病学] R741.02[医药卫生—临床医学] R651.1