Oncogenic features of neuromedin U in breast cancer are associated with NMUR2 expression involving crosstalk with members of the WNT signaling pathway

Garczyk, Stefan; Klotz, Natalie; Szczepanski, Sabrina; Denecke, Bernd; Antonopoulos, Wiebke; Stillfried, Saskia von; Knüchel, Ruth; Rose, Michael; Dahl, Edgar

doi:10.18632/oncotarget.16121

Cited by 15 publications

(15 citation statements)

References 55 publications

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“…Although no experimental data has suggested a direct link between NMU and thyroid cancer, NMU has been shown to promote the development of various tumors, including breast cancer. Garczyk S et al have demonstrated that NMU may contribute to the progression of NMUR2-positive breast cancer [21] and enhance resistance to tumor immune responses in breast cancers with HER2 overexpression [22], suggesting NMU is a potential drug target for personalized strategies. Furthermore, NMU is involved in the development of endometrial, colorectal and gastric cancers, as well as acute myeloid leukemia caused by TP53 mutations [23][24][25][26].…”

Section: Discussionmentioning

confidence: 99%

Identification of Potential Biomarkers for Thyroid Cancer Using Bioinformatics Strategy: A Study Based on GEO Datasets

Shen

Dong

Liu

et al. 2020

BioMed Research International

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Background. The molecular mechanisms and genetic markers of thyroid cancer are unclear. In this study, we used bioinformatics to screen for key genes and pathways associated with thyroid cancer development and to reveal its potential molecular mechanisms. Methods. The GSE3467, GSE3678, GSE33630, and GSE53157 expression profiles downloaded from the Gene Expression Omnibus database (GEO) contained a total of 164 tissue samples (64 normal thyroid tissue samples and 100 thyroid cancer samples). The four datasets were integrated and analyzed by the RobustRankAggreg (RRA) method to obtain differentially expressed genes (DEGs). Using these DEGs, we performed gene ontology (GO) functional annotation, pathway analysis, protein-protein interaction (PPI) analysis and survival analysis. Then, CMap was used to identify the candidate small molecules that might reverse thyroid cancer gene expression. Results. By integrating the four datasets, 330 DEGs, including 154 upregulated and 176 downregulated genes, were identified. GO analysis showed that the upregulated genes were mainly involved in extracellular region, extracellular exosome, and heparin binding. The downregulated genes were mainly concentrated in thyroid hormone generation and proteinaceous extracellular matrix. Pathway analysis showed that the upregulated DEGs were mainly attached to ECM-receptor interaction, p53 signaling pathway, and TGF-beta signaling pathway. Downregulation of DEGs was mainly involved in tyrosine metabolism, mineral absorption, and thyroxine biosynthesis. Among the top 30 hub genes obtained in PPI network, the expression levels of FN1, NMU, CHRDL1, GNAI1, ITGA2, GNA14 and AVPR1A were associated with the prognosis of thyroid cancer. Finally, four small molecules that could reverse the gene expression induced by thyroid cancer, namely ikarugamycin, adrenosterone, hexamethonium bromide and clofazimine, were obtained in the CMap database. Conclusion. The identification of the key genes and pathways enhances the understanding of the molecular mechanisms for thyroid cancer. In addition, these key genes may be potential therapeutic targets and biomarkers for the treatment of thyroid cancer.

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Section: Discussionmentioning

confidence: 99%

Identification of Potential Biomarkers for Thyroid Cancer Using Bioinformatics Strategy: A Study Based on GEO Datasets

Shen

Dong

Liu

et al. 2020

BioMed Research International

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“…Studies have shown that overexpression of NMU is associated with tumorigenesis and development of various malignancies [12][13][14][15][16][17][18][19]. However, to date no studies have examined the association of NMU and HCC.…”

Section: Discussionmentioning

confidence: 99%

“…The neuropeptide has been demonstrated to be associated with a range of different physiological functions, including smooth muscle contraction, energy homeostasis, nociception, circadian control, bone remodeling, and immune regulation [9][10][11]. A limited number of studies had suggested that NMU may play an oncogenic role in the progression of various cancers, including lung cancer, pancreatic cancer, breast cancer, renal cancer, and endometrioid endometrial carcinoma, through promoting migration, invasion, glycolysis, a mesenchymal phenotype, a stem cell phenotype of cancer cells, and resistance to the anti-tumor immune response [12][13][14][15][16][17][18][19]. However, besides a report of NMU exacerbating non-alcoholic steatohepatitis (NASH) [20], the effects of NMU on liver diseases, especially on HCC, have not yet been studied.…”

Section: Introductionmentioning

confidence: 99%

The prognostic value of neuromedin U in patients with hepatocellular carcinoma

Han

Ruan

et al. 2020

BMC Cancer

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Background: Neuromedin U (NMU) is a neuropeptide belonging to the neuromedin family. Recently, significant associations between NMU and several cancers have been reported. However, no studies have examined the association between NMU and hepatocellular carcinoma (HCC). The purpose of this study was to examine the role of NMU in HCC. Methods: An enzyme-linked immunosorbent assay was used to measure the level of NMU protein in the sera of patients with hepatic hemangioma and HCC. NMU and cytokine mRNA expression was assessed in HCC samples via RT-qPCR. A tissue microarray consisting of 228 HCC peri-and intra-tumor tissues was used to detect NMU expression via immunohistochemical analysis. The association between NMU expression and overall survival (OS) and disease-free survival (DFS) was analyzed by Kaplan-Meier curves, the log-rank test, and Cox proportional hazard model. Results: The level of NMU protein was increased in the sera of HCC patients (p = 0.006). NMU was expressed in intercellular space, rather than in hepatocytes or HCC cells. The prognosis of HCC patients with high NMU expression in peri-tumor tissue was significantly poorer than that of patients with low NMU expression (OS: p = 0.002, DFS: p = 0.033). Peri-tumor NMU expression was also a significant independent prognostic factor for OS (hazard ratio: 1.541, 95% confidence interval: 1.092-2.175, p = 0.014). The level of NMU expression was positively associated with M2 macrophage percentage and the levels of type-2 inflammatory cytokines in HCC tissue. Conclusions: NMU may serve as a novel prognostic biomarker for HCC patients, although further validation is needed in the future. The activation of M2 macrophages and a type-2 inflammatory response may involve in the role of NMU in patients with HCC.

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“…The A260 nm/A280 nm ratio was generally between 1.9 and 2.0. Subsequently, cDNA was synthesized using 1μg of total RNA and the reverse transcription system (Promega) as described previously [ 32 ]. After cDNA synthesis, enzyme was heat inactivated by incubation for 5min at 95°C.…”

Section: Methodsmentioning

confidence: 99%

“…cDNAs were amplified by semi-quantitative real-time PCR using SYBR Green PCR mix (Bio-Rad Laboratories) and the iCycler IQ5 (Bio-Rad Laboratories) as described previously [ 32 ]. Gene-specific oligonucleotides were designed using Primer3web software (version 4.0.0) ( http://primer3.ut.ee/ ).…”

Section: Methodsmentioning

confidence: 99%

ARID1A-deficiency in urothelial bladder cancer: No predictive biomarker for EZH2-inhibitor treatment response?

et al. 2018

Self Cite

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Bladder cancer therapy relies on aggressive treatments highlighting the need for new, targeted therapies with reduced side effects. SWI/SNF complexes are mutated in ~20% across human cancers and dependency of SWI/SNF-deficient tumors on EZH2 has been uncovered recently. To systematically dissect the frequency of genetic alterations in SWI/SNF complexes potentially contributing to their inactivation, mutations and copy number variations in 25 SWI/SNF subunit genes were analyzed making use of publicly available sequencing data for 408 muscle-invasive bladder carcinoma samples. ARID1A truncating mutations were identified as the by far most common alterations of SWI/SNF complexes in urothelial bladder cancer. As current ARID1A protein expression data in bladder cancer are inconsistent and incomplete we examined if the frequency of truncating ARID1A mutations translates into a similar frequency of cases showing ARID1A protein loss. We applied a validated ARID1A antibody conducting a comprehensive immunohistochemistry-based expression analysis in urothelial bladder cancer (n = 362) including carcinoma in situ (CIS) cases. While observing increased median ARID1A protein levels in all carcinoma subgroups compared to normal urothelial controls (n = 21), the percentage of cases showing ARID1A protein loss was positively correlated with increasing stage and grade culminating in a rate of 14.1% in muscle-invasive disease. ARID1A-depletion did neither increase EZH2 protein or trimethylated H3K27 levels in vitro nor did ARID1A expression correlate with EZH2 or H3K27me3 amounts in human bladder carcinomas. Importantly, ARID1A-deficiency was neither associated with enhanced sensitivity towards inhibition of EZH2 enzymatic activity nor depletion of EZH2 protein. In summary, ARID1A truncating mutations, potentially translating into ARID1A protein loss in a subset of high-grade bladder cancers, are the most common SWI/SNF genetic alterations in bladder cancer. Our data do not support ARID1A-deficiency as predictive biomarker for EZH2-inhibitor treatment response in bladder cancer underlining the need for future bladder cancer-specific, drug screens for successfull discovery of ARID1A-deficiency-based targeted drugs.

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Oncogenic features of neuromedin U in breast cancer are associated with NMUR2 expression involving crosstalk with members of the WNT signaling pathway

Cited by 15 publications

References 55 publications

Identification of Potential Biomarkers for Thyroid Cancer Using Bioinformatics Strategy: A Study Based on GEO Datasets

Identification of Potential Biomarkers for Thyroid Cancer Using Bioinformatics Strategy: A Study Based on GEO Datasets

The prognostic value of neuromedin U in patients with hepatocellular carcinoma

ARID1A-deficiency in urothelial bladder cancer: No predictive biomarker for EZH2-inhibitor treatment response?

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