Receptors of Sex Hormone in Papillary Thyroid Cancer and Its Influence on Angiogenesis and Clinical Progression

Recent studies illustrated the role of sex hormones and expression of their receptors in the incidence, presentation, and prognosis of thyroid cancer; otherwise, the mechanism between these receptors and thyroid cancer is not clear. The expression of sex hormone receptors in thyroid tumor tissues is required for the pathophysiological functioning of the sex hormones. A higher incidence of thyroid nodules and well-differentiated thyroid cancer is observed in women than in men. However, there is no clear consensus on the incidences of histologic variants of thyroid cancer arising in the thyroid nodules and gender-based variation in the therapeutic outcome of thyroid cancer. Both endogenous and exogenous androgen and estrogen hormones stimulate cell proliferation and angiogenesis as increased vascular endothelial growth factor (VEGF) expression, and thereby increase the chances of accumulation of random genetic errors. In addition, sex hormone receptors have been identified in normal, benign, and malignant thyroid tissues and in different thyroid cancer cell lines. The expression of these receptors modifies the proliferation of thyroid cancer cells through homologous upregulation of their own receptors, which is independent of the activity of thyroid-stimulating hormone (TSH). In this study, the levels of estrogen α and β, progesterone, and androgen receptor expression will be assessed in benign tissues and in tissues at different tumor-node-metastasis (TNM) and clinical stages of papillary thyroid carcinoma (PTC). We expect that increased sex hormone receptor expression may enhance thyroid tumorigenesis and angiogenesis in tumor tissues. The role of sex hormone–enhanced angiogenesis through thrombospondin-1 (TSP-1) regulation will be investigated. PTC cell lines CGTH W-3 and BHP-1-13 will be used in the sex hormones regulate TSP-1 studies. In addition, modulation of metastatic phenotype will be determined by using in vitro adhesion, migration, and invasion assays. The plasma concentrations of VEGF-C and VEGF-D and the expression levels of VEGF receptors and antiangiogenic factor TSP-1 in the vascular endothelium and tumor cells of PTC patients will also be studied. Immunohistochemical studies of sex hormone receptors and angiogenetic factors and their messenger RNA (mRNA) expression in fresh tissue samples will be conducted, and the findings will be compared with our thyroid cancer database. After stratification by age groups, gender-based TNM staging and longitudinal data on cancer recurrence, mortality, and disease-free status of the PTC patients will be compared with the data obtained from experiments. Univariate and multivariate statistical analyses will be conducted to determine the significance of various factors. Expression of sex hormone receptors and the possible underlying mechanism by which it acts as an angiogenetic factor will also be analyzed. The findings of this study will improve the understanding of the role of gender-associated angiogenetic factors in benign and PTC tumors, various clinical presentations of PTC, and therapeutic response in different TNM stages.

Project ID:PC10007-0391
External Project ID:NSC100-2314-B182-033