Abstract
Relaxin is known to play an important role in animal pregnancies, including those of humans. It is suggested that relaxin induces aggressive cell growth and invasiveness in several types of cancer, including endometrial cancer. However, the mechanisms of relaxin remain largely unclear. In this study, we examined the effects of relaxin 2 (RLN2), the major circulating relaxin in humans, on human endometrial carcinoma cell lines. RLN2 treatment induced invasion in HEC-1B and Ishikawa cells. RLN2-induced cell invasion was significantly decreased by transfection of relaxin receptor 1 (RXFP1) siRNAs. The β-catenin inhibitor, XAV939, also significantly inhibited the RLN2-induced cell invasions. Both a decrease of cadherin expression and an increase of β-catenin phosphorylation were observed in response to the RLN2 treatment in HEC-1B and Ishikawa cells. We then examined RLN2 and RXFP1 expression in 80 human endometrioid endometrial carcinoma tissues. RLN2 immunoreactivity was detected in the human endometrial carcinoma cells and had a correlative tendency with histological grade and RXFP1. These results suggest that adherens junctions in cancer cells are weakened by the breakdown of the cadherin/catenin complex, which is induced by β-catenin phosphorylation via RLN2/RXFP1 signaling.
Highlights
Endometrial carcinoma is the most common gynecological malignancy of the female genital tract and, recently, its incidence has been increasing [1,2], especially that of endometrioid endometrial adenocarcinoma, which is the most common histological type
It is known to affect the brain, kidneys, connective tissue, reproductive system, and cardiovascular system through G protein-coupled receptors, such as relaxin family peptide 1 (RXFP1) and 2 (RXFP2), which activate cyclic adenosine monophosphate in response to RLN binding [8]
The significance of relaxin 2 (RLN2) and RXFP1 was examined by immunohistochemistry in 80 cases of endometrioid endometrial carcinoma (EEC) tissues
Summary
Endometrial carcinoma is the most common gynecological malignancy of the female genital tract and, recently, its incidence has been increasing [1,2], especially that of endometrioid endometrial adenocarcinoma, which is the most common histological type. High levels of RXFP1 are reported in uterine tissue [9,10,11] It is well-known that three peptide forms of RLN: RLN1, RLN2, and RLN3, exist in humans, the roles of two of the peptides, RLN1 and RLN3, remain unclear [12]. The loss of E-cadherin has been well-known to promote migration and invasiveness in several cancer cell types, including endometrial cancer [24,25,26] These findings suggest that the Wnt/β-catenin signaling pathway is the key pathway that is induced by RLN-RXFP to enable endometrial cancer invasion. In this study, we first examined the effects of RLN2 on Ishikawa and HEC-1B human endometrial cancer cell line invasiveness. The significance of RLN2 and RXFP1 was examined by immunohistochemistry in 80 cases of endometrioid endometrial carcinoma (EEC) tissues
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