生长抑素受体2和生长抑素受体5在垂体催乳素腺瘤中的表达及其临床意义

Expression and clinical significance of somatostatin receptor 2 and 5 in pituitary prolactinomas

目的探讨生长抑素受体2(SSTR2)和生长抑素受体5(SSTR5)两个受体亚型在人垂体催乳素腺瘤中的表达及其临床意义。方法收集华中科技大学同济医学院附属同济医院神经外科经手术和病理结果证实的人垂体催乳素腺瘤标本16例及4例尸检获取的正常垂体组织,采用新型特异性SSTR2和SSTR5的单克隆抗体(UMB1和UMB4),分别进行免疫组织化学、蛋白质印迹法(Western blot)和免疫荧光染色的方法检测难治性垂体催乳素腺瘤标本中SSTR2及SSTR5的表达,再分析其表达水平与临床特征[性别、肿瘤大小、术前血清催乳素水平、肿瘤细胞核增殖抗原(Ki-67)增殖指数、肿瘤侵袭性]的相关性。使用GraphPad Prism(V. 7)进行数据分析。结果免疫组化染色在正常垂体组织中均可见SSTR2和SSTR5的散在表达,81.25%(13/16)的催乳素腺瘤病例样本中检测到SSTR5的表达,相反仅3例肿瘤标本检测到散在的SSTR2的免疫反应性,其中1例为生长激素和催乳素混合型多激素腺瘤;Western Blot结果证实免疫组化的结果,免疫荧光共染结果提示正常垂体组织中催乳素细胞并不表达SSTR2,但有SSTR5的表达。Pearson’s相关分析显示SSTR5的高表达与患者的性别(女性SSTR5 IRS 0.31±0.07比男性SSTR5 IRS 0.38±0.16,t=0.47,P>0.05)、肿瘤大小(R2=0.009,F=0.133,P>0.05)、术前血清催乳素水平(R2=0.026,F=0.348,P>0.05)、肿瘤Ki-67增殖指数(R2=0.060,F=0.887,P>0.05)无明显相关。结论垂体催乳素腺瘤高表达SSTR5,第2代生长抑素类似物帕瑞肽有助于多巴胺受体激动剂耐药型垂体催乳素腺瘤的替代治疗。

Objective To explore the expression of somatostatin receptor 2(SSTR2)and SSTR5 in pituitary prolactinomas and the clinical significance.Methods Totally,16 cases of human pituitary prolactinomas specimens obtained from Department of Neurosurgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology and 4 cases of normal pituitary tissues from autopsy confirmed by surgery and pathological examination were collected.Novel monoclonal antibodies specific to SSTR2 and SSTR5(UMB1 and UMB4)were used.The expression levels of SSTR2 and SSTR5 in pituitary prolactinoma specimens were detected by immunohistochemistry,Western blotting and immunofluorescence staining respectively,and clinical characteristics(gender,tumor size,preoperative serum prolactin level,tumor Ki-67 proliferation index,tumor aggressiveness)were analyzed.Statistical analysis were conducted with GraphPad Prism Ver.7.0.Results The immunohistochemistry revealed the scattered expression of SSTR2 and SSTR5 in normal pituitary tissues,and the expression of SSTR5 was detected in 81.5%(13/16)of cases of refractory prolactinomas,but only 3 cases of tumor specimens show scattered SSTR2 immunoreactivity,with mixed multi-hormone adenoma of growth hormone and prolactin in one case.Western blotting results confirmed the results of immunohistochemistry.The immunofluorescence co-staining results suggested lactotrophic cells in normal pituitary tissue did not express SSTR2,but they expressed SSTR5.Pearson′s correlation analysis showed that SSTR5 expression has no significant correlation with patients′gender(Female:SSTR5 IRS 0.31±0.07 vs.Male:SSTR5 IRS 0.38±0.16,t=0.47,P>0.05),tumor size(R square=0.009,F=0.133,P>0.05),preoperative serum prolactin level(R square=0.026,F=0.348,P>0.05),and tumor Ki-67 proliferation index(R square=0.060,F=0.887,P>0.05).Conclusion SSTR5 is highly expressed in pituitary prolactinomas,and somatostatin analogues targeting SSTR5 may be potential treatment options for dopamine receptor agonist-resistant pituitary prolactinomas.