Role of EGFL7/EGFR-signaling pathway in migration and invasion of growth hormone-producing pituitary adenomas
Currently, the primary therapeutic strategy for most growth hormone-producing pituitary adenomas (GHPA) is surgery. Due to the invasiveness of GHPA, high recurrence has limited the benefit of complete adenoma removal surgery. Epidermal growth factor-like domain 7 (EGFL7) is a secreted factor implicated in tumor angiogenesis, growth, invasiveness and metastasis in GHPA. Herein, we observed that the expression level of EGFL7 and p-EGFR in invasive GHPA was much higher than that of non-invasive GHPA. The overexpression of EGFL7 was positively correlated with activation of EGFR (p-EGFR). Noticeably, EGFL7 knockdown significantly inhibited activation of EGFR signaling cascades, including p-ERGR, p-AKT and p-ERK. Further studies showed that EGFL7 knockdown or pharmacological inhibition of EGFR-pathway, using EGFR inhibitor Tyrphostin AG-1478, significantly suppressed migration and invasion of GH3 and GT1-1 cells. In summary, our findings suggest that EGFL7 is a key factor for regulation of EGFR signaling pathway and plays an important role in migration and invasion of invasive GHPA.
KeywordsEGFL7 EGFR growth hormone-producing pituitary adenomas (GHPA) invasion tumorigenesis
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This work was supported by the National Natural Science Foundation of China (81502154), Research Special Fund For Public Welfare Industry of Health of China (201402008) and National High Technology Research and Development Program of China (2015AA020504).
- Campagnolo, L., Leahy, A., Chitnis, S., Koschnick, S., Fitch, M.J., Fallon, J.T., Loskutoff, D., Taubman, M.B., and Stuhlmann, H. (2005). EGFL7 is a chemoattractant for endothelial cells and is up-regulated in angiogenesis and arterial injury. Am J Pathol 167, 275–284.CrossRefPubMedPubMedCentralGoogle Scholar
- Dhandapani, S., Singh, H., Negm, H.M., Cohen, S., Anand, V.K., and Schwartz, T.H. (2016). Cavernous sinus invasion in pituitary adenomas: systematic review and pooled data meta-analysis of radiologic criteria and comparison of endoscopic and microscopic surgery. World Neurosurgery 96, 36–46.CrossRefPubMedGoogle Scholar
- Liu, Q., Wang, J., Yang, H., Gao, H., Li, C., Lan, X., and Zhang, Y. (2018). Attenuation of EGFL7 expression inhibits growth hormone–producing pituitary adenomas growth and invasion. Hum Gene Ther doi: 10.1089/hum.2017.200.Google Scholar
- Wang, J., Liu, Q., Gao, H., Wan, D., Li, C., Li, Z., and Zhang, Y. (2017b). EGFL7 participates in regulating biological behavior of growth hormone-secreting pituitary adenomas via Notch2/DLL3 signaling pathway. Tumour Biol 39, 1–11.Google Scholar