Faulkner Sam, Jobling Philip, Rowe Christopher W, Rodrigues Oliveira S M, Roselli Severine, Thorne Rick F, Oldmeadow Christopher, Attia John, Jiang Chen Chen, Zhang Xu Dong, Walker Marjorie M, Hondermarck Hubert
School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia.
Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia; School of Medicine & Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Department of Endocrinology, John Hunter Hospital, Callaghan, New South Wales, Australia.
Am J Pathol. 2018 Jan;188(1):229-241. doi: 10.1016/j.ajpath.2017.09.008. Epub 2017 Oct 14.
Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75, and the proneurotrophin receptor sortilin were analyzed with immunohistochemistry in a cohort of thyroid cancers (n = 128) and compared with adenomas and normal thyroid tissues (n = 62). TrkA was detected in 20% of thyroid cancers, compared with none of the benign samples (P = 0.0007). TrkA expression was independent of histologic subtypes but associated with lymph node metastasis (P = 0.0148), suggesting the involvement of TrkA in tumor invasiveness. Nerves in the tumor microenvironment were positive for TrkA. p75 was overexpressed in anaplastic thyroid cancers compared with papillary and follicular subtypes (P < 0.0001). Sortilin was overexpressed in thyroid cancers compared with benign thyroid tissues (P < 0.0001). Neurotrophin receptor expression was confirmed in a panel of thyroid cancer cell lines at the mRNA and protein levels. Functional investigations using the anaplastic thyroid cancer cell line CAL-62 found that siRNA against TrkA, p75, and sortilin decreased cell survival and cell migration through decreased SRC and ERK activation. Together, these data reveal TrkA, p75, and sortilin as potential therapeutic targets in thyroid cancer.
神经营养因子受体正成为肿瘤学中的新兴靶点，但其在甲状腺癌中的临床病理意义尚不清楚。在本研究中，采用免疫组织化学方法对一组甲状腺癌（n = 128）中的神经营养因子酪氨酸受体激酶TrkA（也称为NTRK1）、常见神经营养因子受体p75和前神经营养因子受体sortilin进行了分析，并与腺瘤和正常甲状腺组织（n = 62）进行了比较。20%的甲状腺癌中检测到TrkA，而良性样本中均未检测到（P = 0.0007）。TrkA表达与组织学亚型无关，但与淋巴结转移相关（P = 0.0148），提示TrkA参与肿瘤侵袭。肿瘤微环境中的神经TrkA呈阳性。与乳头状和滤泡状亚型相比，未分化甲状腺癌中p75过表达（P < 0.0001）。与良性甲状腺组织相比，甲状腺癌中sortilin过表达（P < 0.0001）。在一组甲状腺癌细胞系中，在mRNA和蛋白质水平证实了神经营养因子受体的表达。使用未分化甲状腺癌细胞系CAL-62进行的功能研究发现，针对TrkA、p75和sortilin的siRNA通过降低SRC和ERK激活来降低细胞存活和细胞迁移。总之，这些数据揭示TrkA、p75和sortilin是甲状腺癌潜在的治疗靶点。
