Frisk T, Farnebo F, Zedenius J, Grimelius L, Höög A, Wallin G, Larsson C
Department of Molecular Medicine, Endocrine Tumor Unit, Karolinska Hospital, Stockholm, Sweden.
Eur J Endocrinol. 2000 Jun;142(6):643-9. doi: 10.1530/eje.0.1420643.
Mutations in the RET proto-oncogene are found in about one third of sporadic medullary thyroid carcinomas (MTCs), mostly affecting codon 918. Glial cell line derived neurotropic factor (GDNF) and its membrane-bound GDNF family receptor alpha (GFRalpha-1), as well as neurturin (NTN) and its membrane-bound receptor GFRalpha-2 form a complex with the RET product, a receptor tyrosine kinase, resulting in downstream signaling to the nucleus.
To elucidate the role of these RET ligands in MTC tumorigenesis, their expression was determined in 15 MTC samples, one papillary thyroid carcinoma (PTC) and three normal thyroid tissue specimens.
The mRNA expression of RET, GDNF, GFRalpha-1, NTN and GFRalpha-2 was investigated by mRNA in situ hybridization, and confirmed by reverse transcription-PCR analysis.
None of the five genes was expressed in the normal thyroids or in the PTC. All MTCs showed expression of RET, 13 expressed GDNF, 12 expressed GFRalpha-1 and 9 expressed NTN and GFRalpha-2. In 7 of the tumors RET, GDNF and GFRalpha-1 were expressed at high levels, and in five of these seven tumors NTN and GFRalpha-2 genes were also expressed at high levels. The high level of expression was preferentially seen in tumor cells adjacent to stroma and connective tissue. All MTCs without expression of the RET ligands harbored the RET codon 918 mutation.
The results suggest that this signaling pathway is important for MTC development, and that it may be activated by expression of the RET ligand complexes by the tumor cells themselves.
在大约三分之一的散发性甲状腺髓样癌（MTC）中发现RET原癌基因突变，主要影响密码子918。胶质细胞系源性神经营养因子（GDNF）及其膜结合型GDNF家族受体α（GFRalpha-1），以及神经营养素（NTN）及其膜结合型受体GFRalpha-2与RET产物（一种受体酪氨酸激酶）形成复合物，导致下游信号传导至细胞核。
为阐明这些RET配体在MTC肿瘤发生中的作用，在15例MTC样本、1例甲状腺乳头状癌（PTC）和3例正常甲状腺组织标本中测定了它们的表达。
通过mRNA原位杂交研究RET、GDNF、GFRalpha-1、NTN和GFRalpha-2的mRNA表达，并通过逆转录-PCR分析进行确认。
五个基因在正常甲状腺或PTC中均未表达。所有MTC均显示RET表达，13例表达GDNF，12例表达GFRalpha-1，9例表达NTN和GFRalpha-2。在7例肿瘤中，RET、GDNF和GFRalpha-1高水平表达，在这7例肿瘤中的5例中，NTN和GFRalpha-2基因也高水平表达。高水平表达在与基质和结缔组织相邻的肿瘤细胞中优先可见。所有未表达RET配体的MTC均携带RET密码子918突变。
结果表明该信号通路对MTC的发展很重要，并且可能由肿瘤细胞自身表达的RET配体复合物激活。
