Abstract
Thyroid cancer is the most common endocrine cancer, and has a high incidence of lymphatic metastasis. Vascular endothelial growth factor C (VEGFC) is essential for development of lymphatic vessels and lymphatic metastases during carcinogenesis. Steroid receptor coactivator-1 (SRC-1) interacts with nuclear receptors and transcription factors to promote tumor proliferation and metastasis. However, the correlation between SRC-1 and VEGFC levels in the lymphatic metastases of thyroid cancer remains unclear. We analyzed 20-paired specimens of thyroid cancer tissue and normal thyroid tissue and found increased levels of SRC-1 and VEGFC proteins in 13/20 and 15/20 thyroid cancer specimens, respectively, when compared with those levels in specimens of normal thyroid tissue. A high level of SRC-1 expression was positively correlated with VEGFC and lymphatic endothelial cell marker LYVE-1 expression. Papillary thyroid carcinoma cell line TPC-1 displayed high levels of SRC-1 and VEGFC expression and was selected for stable knockdown of SRC-1 in vitro. Inhibition of SRC-1 significantly reduced the VEGFC levels in TPC-1 cells. We found that SRC-1 binds to transcription factor NF-kB (p50/p65), and that this coactivation complex directly promoted VEGFC transcription, which could be abrogated by SRC-1 knockdown. Up-regulated NF-kB signaling was also confirmed in thyroid cancer tissues. In vivo studies showed that SRC-1 knockdown restricted tumor growth, reduced the numbers of LYVE-1-positive lymphatic vessels, and decreased the levels of VEGFC in tumor tissues. These results suggest a tumorigenic role for SRC-1 in thyroid cancer via its ability to regulate VEGFC expression.
Highlights
Thyroid cancer is the most common type of endocrine cancer and the sixth most common cancer in women
An analysis of expression levels identified a positive correlation between steroid receptor co-activator (SRC)-1 and Vascular endothelial growth factor C (VEGFC) levels in the thyroid cancer tissues, and showed that Steroid receptor coactivator-1 (SRC-1) levels were positively associated with VEGFC expression in the tumors (r2 = 0.6756; 95% CI: 0.4536–0.8187) (Figure 1C)
Because we found that VEGFC levels could be reduced by SRC-1 knockdown, we speculated that SRC-1 might interact with other transcription factors to form a co-activation complex that induces transcription of the VEGFC gene
Summary
Thyroid cancer is the most common type of endocrine cancer and the sixth most common cancer in women. More than 62,000 new cases of thyroid cancer were diagnosed in men and women during 2015, and its incidence continues to rise worldwide [1]. Differentiated papillary and follicular thyroid carcinomas are the most commonly diagnosed subtypes and have the best overall prognosis. Because the 10-year survival rate among patients with papillary thyroid cancer is 93%, therapeutic advances have been minimal during the past two decades [3]. Thyroid cancer commonly metastasizes to regional lymph nodes in the central and lateral compartments of the neck, and these metastases affect the patient’s prognosis. >3 cm extra nodal extension) in their cervical lymph nodes have higher rates of disease recurrence and cancer-related death, and this is especially true among patients aged 45 years and older [1,4] The patients who have a papillary thyroid cancer with macroscopic metastases (e.g. >3 cm extra nodal extension) in their cervical lymph nodes have higher rates of disease recurrence and cancer-related death, and this is especially true among patients aged 45 years and older [1,4]
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