title: NMU signaling promotes endometrial cancer cell progression by modulating adhesion signaling.
abstract: 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.
authors: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
authors: Ting-Yu
authors: TY
authors: Lin
authors: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
authors: Fang-Ju
authors: FJ
authors: Wu
authors: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan 333, Taiwan.
authors: Chia-Lin
authors: CL
authors: Chang
authors: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
authors: Zhongyou
authors: Z
authors: Li
authors: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
authors: Ching-Wei
authors: CW
authors: Luo
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D003094:Collagen / Q000096:biosynthesis; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000473:pathology*; D004717:Endometrium / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D006820:Hyaluronic Acid / Q000096:biosynthesis; D039423:Integrin alpha1 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D008875:Middle Aged; D009479:Neuropeptides / Q000378:metabolism*; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D039423:Integrin alpha1; D009479:Neuropeptides; C107953:RAC1 protein, human; D017981:Receptors, Neurotransmitter; C082444:neuromedin U receptor; C056900:neuromedin U; C066737:RHOA protein, human; D006820:Hyaluronic Acid; D003094:Collagen; D019061:src-Family Kinases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
keywords: G protein-coupled receptor; NMUR2; adhesion signaling; endometrial cancer; neuromedin U