Neuromedin U induces an invasive phenotype in CRC cells expressing the NMUR2 receptor

Abstract

Background Successful colorectal cancer (CRC) therapy often depends on the accurate identification of primary tumours with invasive potential. There is still a lack of identified pathological factors associated with disease recurrence that could help in making treatment decisions. Neuromedin U (NMU) is a secretory neuropeptide that was first isolated from the porcine spinal cord, and it has emerged as a novel factor involved in the tumorigenesis and/or metastasis of many types of cancers. Previously associated with processes leading to CRC cell invasiveness, NMU has the potential to be a marker of poor outcome, but it has not been extensively studied in CRC. Methods Data from The Cancer Genome Atlas (TCGA) were used to analyse NMU and NMU receptor (NMUR1 and NMUR2) expression in CRC tissues vs. normal tissues, and real-time PCR was used for NMU and NMU receptor expression analysis. NMU protein detection was performed by immunoblotting. Secreted NMU was immunoprecipitated from cell culture-conditioned media and analysed by immunoblotting and protein sequencing. DNA demethylation by 5-aza-CdR was used to analyse the regulation of NMUR1 and NMUR2 expression. NMU receptor activity was monitored by detecting calcium mobilisation in cells loaded with fluo-4, and ERK1/2 kinase activation was detected after treatment with NMU or receptor agonist. Cell migration and invasion were investigated using membrane filters. Integrin expression was evaluated by flow cytometry. Results The obtained data revealed elevated expression of NMU and NMUR2 in CRC tissue samples and variable expression in the analysed CRC cell lines. We have shown, for the first time, that NMUR2 activation induces signalling in CRC cells and that NMU increases the motility and invasiveness of NMUR2-positive CRC cells and increases prometastatic integrin receptor subunit expression. Conclusions Our results show the ability of CRC cells to respond to NMU via activation of the NMUR2 receptor, which ultimately leads to a shift in the CRC phenotype towards a more invasive phenotype.

Mimicking tumor cell heterogeneity of colorectal cancer in a patient-derived organoid-fibroblast model

“…In the ENAS condition we found upregulation of NMU, EREG and SNHG12 genes. NMU and EREG encode for Neuromedin U and Epiregulin, respectively, both of which are involved in tumor invasion and progression ( 50, 51 ). SNHG12 encodes for a long non-coding RNA, which can regulate tumor cell invasion and metastases in endometrial cancer ( 52 ).…”

Insights Into the Research Status of Neuromedin U: A Bibliometric and Visual Analysis From 1987 to 2021

“…However, in bladder cancer ( 46 ), endometrial carcinoma ( 47 , 48 ) and breast cancer ( 49 ), lung adenocarcinoma ( 50 ), NMU overexpression can promote tumor cell growth, enhance tumor formation and metastasis, and increase tumor drug resistance. The latest study found for the first time that NMUR2 activation promoted signaling in colorectal cancer (CRC) cells, and that NMU improves the mobility and invasiveness of NMUR2-positive CRC cells ( 51 ). The specific mechanisms behind these differing effects are not clear, but may be related to the tumor type, positive, and negative regulation of oncogenes, and the tumor microenvironment.…”

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“…NMU expression has been found to be elevated in various cancers, including hepatocellular cancer, pancreatic cancer, and colorectal cancer (CRC) 23,24,29 . It has been reported that NMU accelerates the migration and invasion of CRC cells by activating ERK1/2 kinases 23 .…”

“…NMU expression has been found to be elevated in various cancers, including hepatocellular cancer, pancreatic cancer, and colorectal cancer (CRC) 23,24,29 . It has been reported that NMU accelerates the migration and invasion of CRC cells by activating ERK1/2 kinases 23 . In this study, we hypothesized that NMU might promote malignant PTC progression through E2F targets, G2M checkpoints, epithelialmesenchymal transition, the IL6/JAK/STAT3 signaling pathway, the KRAS signaling pathway, and the IL2/STAT5 signaling pathway.…”

“…NMU mainly exerts physiological and pathophysiological effects by binding to neuromedin U receptors 1/2 18 , including smooth muscle contraction, feeding behavior, energy homeostasis, stress response, circadian rhythmicity, in ammation development, and tumorigenesis [19][20][21] . There is growing evidence that aberrant NMU expression can promote cancer development and progression [22][23][24] .…”