Steroid receptor coactivator-1 interacts with NF-κB to increase VEGFC levels in human thyroid cancer

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.

Identification of a Five-Gene Signature and Establishment of a Prognostic Nomogram to Predict Progression-Free Interval of Papillary Thyroid Carcinoma

“…In accordance with our study, LYVE1 was previously reported to be downregulated in PTC tumors based on microarrays and this result was confirmed by qPCR and IHC (34). However, Gao et al reported that the expression of steroid receptor coactivator-1 (SRC-1), a potential oncogene, is positively associated with LYVE1 and associated with lymphatic metastasis in PTC (35). Thus, the role of LYVE1 in PTC and its relationship with lymph node metastasis remains to be elucidated.…”

Decreased 11β‐hydroxysteroid dehydrogenase 1 in lungs of steroid receptor coactivator (Src)‐1/‐2double‐deficient fetal mice is caused by impaired glucocorticoid and cytokine signaling

“…These findings provide evidence for a critical role of SRC‐1 and SRC‐2 in cytokine stimulation of 11β‐HSD1 expression in developing fetal lung. The decline in cytokine signaling in Src‐1/‐2 dKO, in turn, results in decreased NF‐κB activation, which was observed to be mediated by Src‐1/‐2 51,52 …”

“…Both SRC‐1 and SRC‐2 increase transcriptional activity of GR 80,81 and its binding to and activation of the C/EBPβ promoter (Figure 3E‐G), whereas, SRC‐1 transcriptionally activates C/EBPα 82 and NF‐κB 51,52 . These glucocorticoid and cytokine regulated pathways, thus, converge on transcriptional activation of C/EBPβ, C/EBPα and NF‐κB.…”

“…79 Both SRC-1 and SRC-2 increase transcriptional activity of GR 80,81 and its binding to and activation of the C/EBPβ promoter ( Figure 3E-G), whereas, SRC-1 transcriptionally activates C/EBPα 82 and NF-κB. 51,52 These glucocorticoid and cytokine regulated pathways, thus, converge on transcriptional activation of C/EBPβ, C/EBPα and NF-κB. NF-κB and C/EBP family members have been reported to synergistically activate IL-1-mediated induction of the genes encoding serum amyloid A (SAA2 and SAA3), 83,84 chemokines CCL3 and CCL4, 85 and COX-2.…”

“…The other regulatory pathway involves pro‐inflammatory cytokines (eg, IL‐1β and TNFα) (Figure 6, right panel), which we found to increase markedly in the fetal lung near term in an SRC‐1/‐2‐dependent manner (Figure 5). Expression of the genes encoding IL‐1β and TNFα are regulated, in part by increased NF‐κB transcriptional activity, 76,77 which is known to be SRC‐dependent 51,52 (Figure 6, upper right panel). Thus, we postulate that NF‐κB activation of IL‐1β and TNFα is impaired in Src‐1/‐2 d/d mice.…”