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.
Highlights
Endometrial cancer is the most common gynecological cancer in developed countries and the second most common in developing countries [1]
Regarding NMUR2, our preliminary gene quantification data suggests that its transcript level is elevated in the high graded tumors (Supplementary Figure S3), neither the NMUR2 expression data analyzed from the The Cancer Genome Atlas (TCGA) endometrial carcinoma cohort nor the NMUR2 protein staining summarized from an endometrial tissue microarray www.impactjournals.com/oncotarget showed a significant difference between normal and cancer tissues (Supplementary Figure S6)
Our findings suggest that the Neuromedin U (NMU) level may serve as a novel diagnosis marker when predicting the progression and disease outcome among endometrial cancer patients
Summary
Endometrial cancer is the most common gynecological cancer in developed countries and the second most common in developing countries [1]. Most endometrial cancer cases are found to be of the endometrioid type and are detected at the early grade, which results in a good prognosis after surgery, approximately 15% to 20% of patients will present with a high grade of endometrioid carcinoma or other malignant subtype, such as papillary serous carcinoma or clear cell carcinoma [3] This aggressive subset of cancers has high recurrent rates and contributes to the majority of deaths in patients [3, 4]. It has been shown that the gene amplification of HER2 (ERBB2) and overexpression of EGFR (ERBB1) are respectively associated with aggressive types (papillary serous and clear cell histologies) and a poor survival rate among patients with endometrial cancer [6] These findings suggest that this pathway may promote endometrial cancer malignancy. Inhibition of this pathway can impair proliferation in a diverse range of endometrial cancer cell lines in vitro [9, 10]
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