NMU signaling promotes endometrial cancer cell progression by modulating adhesion signaling
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Ting-Yu Lin1, Fang-Ju Wu1, Chia-Lin Chang2, Zhongyou Li1, Ching-Wei Luo1
1Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan
2Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan 333, Taiwan
Ching-Wei Luo, e-mail: [email protected]
Keywords: neuromedin U, NMUR2, endometrial cancer, adhesion signaling, G protein-coupled receptor
Received: August 05, 2015 Accepted: January 22, 2016 Published: February 03, 2016
Neuromedin U (NMU) was originally named based on its strong uterine contractile activity, but little is known regarding its signaling/functions in utero. We identified that NMU and one of its receptors, NMUR2, are not only present in normal uterine endometrium but also co-expressed in endometrial cancer tissues, where the NMU level is correlated with the malignant grades and survival of patients. Cell-based assays further confirmed that NMU signaling can promote cell motility and proliferation of endometrial cancer cells derived from grade II tumors. Activation of NMU pathway in these endometrial cancer cells is required in order to sustain expression of various adhesion molecules, such as CD44 and integrin alpha1, as well as production of their corresponding extracellular matrix ligands, hyaluronan and collagen IV; it also increased the activity of SRC and its downstream proteins RHOA and RAC1. Thus, it is concluded that NMU pathway positively controls the adhesion signaling-SRC-Rho GTPase axis in the tested endometrial cancer cells and that changes in cell motility and proliferation can occur when there is manipulation of NMU signaling in these cells either in vitro or in vivo. Intriguingly, this novel mechanism also explains how NMU signaling promotes the EGFR-driven and TGFβ receptor-driven mesenchymal transitions. Through the above axis, NMU signaling not only can promote malignancy of the tested endometrial cancer cells directly, but also helps these cells to become more sensitive to niche growth factors in their microenvironment.
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