Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Am J Pathol. 2011 Sep;179(3):1415-24. doi: 10.1016/j.ajpath.2011.05.056. Epub 2011 Jul 16.
Telomere dysfunction and aberrant telomerase expression play important roles in tumorigenesis. In thyroid tumors, three possibly inhibitory splice variants of the active full-length isoform of human telomerase reverse transcriptase (hTERT) may be expressed. These variants might regulate telomerase activity and telomere length because it is the fraction of the full-length isoform, rather than the total transcript level, that correlates with enzymatic activity. Telomerase reactivation may be critical in the early stages of tumorigenesis, when progressive telomere shortening may be limiting cell viability. The aim of this study was to investigate the relationship between telomere length and hTERT splice variant expression patterns in benign and well-differentiated malignant thyroid tumors. Telomere lengths of 61 thyroid tumors were examined by fluorescence in situ hybridization, comparing tumors with adjacent normal thyroid tissue on the same slide. Expression patterns of hTERT splice variants were evaluated by quantitative and nested RT-PCR. Telomere length was inversely correlated with percentage of full-length hTERT expression rather than with total hTERT expression levels. Short telomeres and high fractions of full-length hTERT transcripts were associated with follicular and papillary thyroid carcinomas, whereas long telomeres and low levels of full-length hTERT were associated with benign thyroid nodules. Intermediate levels of full-length hTERT and telomere length were found in follicular variant of papillary thyroid carcinomas and follicular adenomas.
端粒功能障碍和异常端粒酶表达在肿瘤发生中起着重要作用。在甲状腺肿瘤中，可能表达人端粒酶逆转录酶（hTERT）的活性全长异构体的三个可能抑制性剪接变体。这些变体可能调节端粒酶活性和端粒长度，因为与酶活性相关的是全长异构体的分数，而不是总转录本水平。端粒酶的重新激活在肿瘤发生的早期阶段可能是关键的，因为渐进性的端粒缩短可能会限制细胞活力。本研究旨在探讨良性和分化良好的恶性甲状腺肿瘤中端粒长度和 hTERT 剪接变体表达模式之间的关系。通过荧光原位杂交检查了 61 个甲状腺肿瘤的端粒长度，并在同一张幻灯片上比较了肿瘤与相邻的正常甲状腺组织。通过定量和嵌套 RT-PCR 评估了 hTERT 剪接变体的表达模式。端粒长度与全长 hTERT 表达的百分比呈负相关，而与总 hTERT 表达水平无关。短端粒和全长 hTERT 转录物的高分数与滤泡性和乳头状甲状腺癌相关，而长端粒和全长 hTERT 的低水平与良性甲状腺结节相关。在甲状腺乳头状癌的滤泡变体和滤泡性腺瘤中发现了全长 hTERT 和端粒长度的中等水平。
