Abstract
Endothelin-1 (ET-1), a member of endothelins family, binds to ETA receptor (ETAR) and ETB receptor to exert its role in multiple cellular processes. Although ET-1 and its receptors has been reported to be overexpressed in many cancers, and overexpression of ET-1 is able to trigger hepatocarcinogenesis in zebrafish, the functions of ET-1 and its receptors in hepatocellular carcinoma (HCC) cell migration and invasion remain unclear. In the present study, we found that ETAR was greatly expressed in HCC cells and HCC tissues. ETAR expression as well as ET-1 expression was associated with vascular invasion and tumor stage in HCC. Activation of ETAR by ET-1 dose-dependently promoted cell migration and invasion of HCC cells, while silencing of ETAR by siRNA or blocking of ETAR by specific inhibitor resulted in significant reduction in ET-1-mediated migration and invasion. Furthermore, ET-1 induced activation of ERK1/2 and AKT and increased MMP-3 production via ETAR. In addition, using inhibitors of ERK1/2 and AKT, we found that ERK1/2 and AKT pathways were both involved in ETAR-mediated migration, invasion, and MMP-3 production. Taken together, our findings suggest that activation of ETAR by ET-1 promotes HCC cell migration and invasion via activating ERK1/2 and AKT signaling pathways and upregulating MMP-3 expression. Thus, ETAR may play an important role in the progress of HCC.
Similar content being viewed by others
References
Bauvois B (2012) New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta 1825(1):29–36. doi:10.1016/j.bbcan.2011.10.001
Borzacchiello G, Mogavero S, Tortorella G, Catone G, Russo M (2010) Expression of endothelin-1 and endothelin receptor a in canine ovarian tumours. Reprod Domest Anim 45(6):e465–e468. doi:10.1111/j.1439-0531.2010.01580.x
Carducci MA, Jimeno A (2006) Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin Cancer Res 12(20 Pt 2):6296s–6300s. doi:10.1158/1078-0432.CCR-06-0929
Chen WQ, Zheng RS, Zhang SW (2013) Liver cancer incidence and mortality in China, 2009. Chin J Cancer 32(4):162–169. doi:10.5732/cjc.013.10027
Guise TA, Mohammad KS (2004) Endothelins in bone cancer metastases. Cancer Treat Res 118:197–212
Hoosein MM, Dashwood MR, Dawas K et al (2007) Altered endothelin receptor subtypes in colorectal cancer. Eur J Gastroenterol Hepatol 19(9):775–782. doi:10.1097/MEG.0b013e3282c563de
Hsieh WT, Yeh WL, Cheng RY et al (2014) Exogenous endothelin-1 induces cell migration and matrix metalloproteinase expression in U251 human glioblastoma multiforme. J Neurooncol 118(2):257–269. doi:10.1007/s11060-014-1442-1
Irani S, Salajegheh A, Gopalan V, Smith RA, Lam AK (2014) Expression profile of endothelin 1 and its receptor endothelin receptor A in papillary thyroid carcinoma and their correlations with clinicopathologic characteristics. Ann Diagn Pathol 18(2):43–48. doi:10.1016/j.anndiagpath.2013.11.001
Ishimoto S, Wada K, Tanaka N et al (2012) Role of endothelin receptor signalling in squamous cell carcinoma. Int J Oncol 40(4):1011–1019. doi:10.3892/ijo.2011.1258
Johansson N, Ahonen M, Kahari VM (2000) Matrix metalloproteinases in tumor invasion. Cell Mol Life Sci 57(1):5–15
Kar S, Yousem SA, Carr BI (1995) Endothelin-1 expression by human hepatocellular carcinoma. Biochem Biophys Res Commun 216(2):514–519. doi:10.1006/bbrc.1995.2652
Kawada K, Hasegawa S, Murakami T et al (2011) Molecular mechanisms of liver metastasis. Int J Clin Oncol 16(5):464–472. doi:10.1007/s10147-011-0307-2
Kitagawa N, Tsutsumi K, Niwa M et al (1994a) Expression of a functional endothelin (ETA) receptor in human meningiomas. J Neurosurg 80(4):723–731. doi:10.3171/jns.1994.80.4.0723
Kitagawa N, Tsutsumi K, Niwa M et al (1994b) A selective endothelin ETA antagonist, BQ-123, inhibits 125I-endothelin-1 (125I-ET-1) binding to human meningiomas and antagonizes ET-1-induced proliferation of meningioma cells. Cell Mol Neurobiol 14(2):105–118
Liakou P, Tepetes K, Germenis A et al (2012) Expression patterns of endothelin-1 and its receptors in colorectal cancer. J Surg Oncol 105(7):643–649. doi:10.1002/jso.23017
Lu JW, Liao CY, Yang WY et al (2014) Overexpression of endothelin 1 triggers hepatocarcinogenesis in zebrafish and promotes cell proliferation and migration through the AKT pathway. PLoS One 9(1):e85318. doi:10.1371/journal.pone.0085318
Maffei R, Bulgarelli J, Fiorcari S et al (2014) Endothelin-1 promotes survival and chemoresistance in chronic lymphocytic leukemia B cells through ETA receptor. PLoS One 9(6):e98818. doi:10.1371/journal.pone.0098818
Moraitis S, Langdon SP, Miller WR (1997) Endothelin expression and responsiveness in human ovarian carcinoma cell lines. Eur J Cancer 33(4):661–668
Pinto A, Merino M, Zamora P, Redondo A, Castelo B, Espinosa E (2012) Targeting the endothelin axis in prostate carcinoma. Tumour Biol 33(2):421–426. doi:10.1007/s13277-011-0299-6
Rosenblatt R, Valdman A, Cheng L et al (2009) Endothelin-1 expression in prostate cancer and high grade prostatic intraepithelial neoplasia. Anal Quant Cytol Histol 31(3):137–142
Teoh JP, Park KM, Wang Y et al (2014) Endothelin-1/endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis. Cell Signal 26(12):2885–2895. doi:10.1016/j.cellsig.2014.08.024
Unic A, Derek L, Hodak N et al (2011) Endothelins—clinical perspectives. Biochem Med 21(3):231–242
Wang R, Dashwood RH (2011) Endothelins and their receptors in cancer: identification of therapeutic targets. Pharmacol Res 63(6):519–524. doi:10.1016/j.phrs.2011.01.002
Wu MH, Lo JF, Kuo CH et al (2012) Endothelin-1 promotes MMP-13 production and migration in human chondrosarcoma cells through FAK/PI3K/Akt/mTOR pathways. J Cell Physiol 227(8):3016–3026. doi:10.1002/jcp.23043
Wu MH, Chen LM, Hsu HH et al (2013) Endothelin-1 enhances cell migration through COX-2 up-regulation in human chondrosarcoma. Biochim Biophys Acta 1830(6):3355–3364. doi:10.1016/j.bbagen.2013.03.014
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
None.
Rights and permissions
About this article
Cite this article
Cong, N., Li, Z., Shao, W. et al. Activation of ETA Receptor by Endothelin-1 Induces Hepatocellular Carcinoma Cell Migration and Invasion via ERK1/2 and AKT Signaling Pathways. J Membrane Biol 249, 119–128 (2016). https://doi.org/10.1007/s00232-015-9854-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00232-015-9854-1