Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, TN, India.
J Steroid Biochem Mol Biol. 2012 May;130(1-2):105-24. doi: 10.1016/j.jsbmb.2012.02.004. Epub 2012 Feb 22.
Gender bias in the incidence of thyroid cancer is well known, however, the underlying mechanism is largely unknown. The current study determines variations in the molecular characteristics of thyroid cancers between men and women. Normal and cancerous thyroid tissues were collected from a total of 125 men and women who underwent surgical thyroidectomy. Testosterone levels in serum and thyroid cancer tissues were elevated in women while it decreased in men compared to respective control groups; whereas, ligand binding activity increased in men and decreased in women. Androgen receptor (AR) mRNA expression increased in a majority of men while it decreased in a majority of women except those with follicular thyroid carcinoma (FTC). In thyroid cancers of women, Pearson's correlation analysis showed a positive correlation of AR mRNA with AR protein, CBP and Sp1, whereas AR mRNA showed a negative correlation with p53. In case of men, AR mRNA showed a positive correlation with AR and cyclin D1 proteins in papillary thyroid carcinoma (PTC); and CBP and Sp1 in follicular thyroid adenoma (FTA), whereas AR mRNA showed a positive correlation with p53. Our study identified for the first time that AR is posttranscriptionally regulated by miR-124a in thyroid cancer tissues. Further, our in vitro studies with a PTC cell line (NPA-87-1) showed miR-124a as the potent inhibitor of AR that impairs cell proliferation even in the presence of testosterone. Thus, the current study suggests that: (i) the varying pattern of testosterone level and AR status in thyroid tissues of men and women may predispose to the gender specific incidence of thyroid tumors and (ii) miR-124a plays a significant role in determining the AR gene expression pattern and thus, androgen mediated thyroid tumor growth.
性别导致甲状腺癌发病率的差异是众所周知的，但其中的潜在机制很大程度上仍是未知的。本研究旨在确定男性和女性甲状腺癌之间分子特征的变化。总共从 125 名接受甲状腺切除术的男性和女性中收集了正常和癌组织。与各自的对照组相比，女性的血清和甲状腺癌组织中的睾酮水平升高，而男性的则降低；而配体结合活性在男性中增加，在女性中降低。雄激素受体 (AR) mRNA 的表达在大多数男性中增加，而在大多数女性中减少，除了滤泡状甲状腺癌 (FTC) 患者。在女性甲状腺癌中，Pearson 相关分析显示 AR mRNA 与 AR 蛋白、CBP 和 Sp1 呈正相关，而与 p53 呈负相关。对于男性，AR mRNA 在乳头状甲状腺癌 (PTC) 中与 AR 和细胞周期蛋白 D1 蛋白呈正相关；在滤泡状甲状腺腺瘤 (FTA) 中与 CBP 和 Sp1 呈正相关，而与 p53 呈正相关。我们的研究首次发现 AR 在甲状腺癌组织中受 miR-124a 的转录后调控。此外，我们用 PTC 细胞系 (NPA-87-1) 进行的体外研究表明，miR-124a 是 AR 的有效抑制剂，即使在睾酮存在的情况下，也会损害细胞增殖。因此，本研究表明：(i) 男性和女性甲状腺组织中睾酮水平和 AR 状态的变化模式可能导致甲状腺肿瘤的性别特异性发病；(ii) miR-124a 在决定 AR 基因表达模式方面发挥着重要作用，从而影响雄激素介导的甲状腺肿瘤生长。
