Background: The incidence of thyroid cancer in women is 3–4-fold higher than in men. To characterize sex-specific molecular alterations in thyroid cancer, we examined the expression of sex-biased genes in normal thyroids and thyroid tumors. Methods: Ingenuity pathways analysis was used to define sex-biased gene networks using data from the Cancer Genome Atlas (TCGA). Confirmatory studies were performed through the analysis of histone lysine demethylases (KDMs) expression by real-time PCR and immunostaining. Results: In normal thyroids, 44 sex-biased genes were comparatively upregulated in male and 28 in female patients. The expressions of 37/72 (51%) sex-biased genes were affected in cancer tissues compared with normal thyroids. Gene network analyses revealed sex-specific patterns in the expressions of KDM5C, KDM5D, and KDM6A. In confirmatory studies, KDM5D mRNA and protein were detected only in males, whereas KDM5C and KDM6A were detected in samples from male and female patients. Nuclear staining with anti-KDMs was found in normal thyroids, but a loss of nuclear expression with a concomitant gain of cytoplasmic staining was observed in cancer tissues. Conclusions: Normal thyroids have a sex-specific molecular signature, and the development of thyroid cancer is associated with a differential expression of sex-biased genes. The sex-specific expression of KDMs, coupled with cancer-related alterations in their intracellular localization, may contribute to mechanisms underlying sex differences in thyroid tumorigenesis.
背景：女性甲状腺癌的发病率是男性的3至4倍。为阐明甲状腺癌中性别特异性分子改变，本研究检测了正常甲状腺与甲状腺肿瘤中性别偏向基因的表达情况。方法：利用癌症基因组图谱（TCGA）数据，通过Ingenuity通路分析定义性别偏向基因网络。通过实时荧光定量PCR和免疫染色分析组蛋白赖氨酸去甲基化酶（KDMs）表达进行验证研究。结果：在正常甲状腺组织中，男性患者有44个性别偏向基因相对上调，女性患者有28个。与正常甲状腺组织相比，37/72（51%）的性别偏向基因在癌组织中表达发生改变。基因网络分析显示KDM5C、KDM5D和KDM6A的表达呈现性别特异性模式。验证研究发现，KDM5D mRNA和蛋白仅在男性样本中检出，而KDM5C和KDM6A在男女患者样本中均有表达。正常甲状腺组织可见KDMs核染色，但在癌组织中观察到核表达缺失伴随胞质染色增强。结论：正常甲状腺具有性别特异性分子特征，甲状腺癌的发生发展与性别偏向基因的差异表达相关。KDMs的性别特异性表达及其在癌细胞内的定位改变，可能共同构成了甲状腺肿瘤发生中性别差异的潜在机制。
Sex-Specific Expression of Histone Lysine Demethylases (KDMs) in Thyroid Cancer
肿瘤(癌症)患者之家