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Overexpression of neuromedin U is correlated with regional metastasis of head and neck squamous cell carcinoma.

ABSTRACT: Regional metastasis is an important prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). Neuromedin U (Nmu) is a secreted neuropeptide, named due to its potent uterine contraction?inducing activity. The aim of the present study was to analyze the significance of Nmu in the regional metastasis of HNSCC. The characteristics of 240 patients recruited from the Department of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan University (Wuhan, China) were summarized retrospectively. The positive rate of neck dissection was analyzed according to the material. The expression levels of Nmu in human tumor samples were analyzed using immunohistochemistry. Subsequently, the expression of Nmu was investigated using a tissue microassay to analyze the association between Nmu protein expression and Tumor Node Metastasis (TNM) status. The positive rate of neck dissection was 51.4% in the study sample. The expression levels of Nmu in primary tumors with regional metastasis were higher, compared with those without metastasis. There was increased protein expression of Nmu in the advanced tumor tissues. The data obtained in the present study demonstrated that the expression of Nmu was correlated with regional metastasis and TNM status. Overexpression of Nmu may be involved in the process of regional metastasis of HNSCC, and may serve as a novel and valuable biomarker for predicting regional metastasis in patients with HNSCC.

SUBMITTER: Wang L

PROVIDER: S-EPMC4940074 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Overexpression of neuromedin U is correlated with regional metastasis of head and neck squamous cell carcinoma.

Wang Lei L Chen Chen C Li Fen F Hua Qing-Quan QQ Chen Shiming S Xiao Bokui B Dai Mengyuan M Li Man M Zheng Anyuan A Yu Di D Hu Zhang Wei ZW Tao Zezhang Z

Molecular medicine reports 20160527 2

Regional metastasis is an important prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). Neuromedin U (Nmu) is a secreted neuropeptide, named due to its potent uterine contraction‑inducing activity. The aim of the present study was to analyze the significance of Nmu in the regional metastasis of HNSCC. The characteristics of 240 patients recruited from the Department of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan University (Wuhan, China) were sum ...[more]

PMID: 27279246

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Project description:DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells. However, our previous studies have revealed that DKK3 expression is predominantly observed in head and neck/oral squamous cell carcinoma (HNSCC/OSCC). Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion. From these data, it was hypothesized that DKK3 might exert an oncogenic function specific to HNSCC. In the present research, the DKK3 overexpression model was established, and its influences were investigated, together with molecular mechanism studies. The DKK3 expression profile in cancer cell lines was investigated, including HNSCC/OSCC, esophageal, gastric, colorectal, pancreatic, prostatic, and lung cancers. DKK3 overexpression was performed in HNSCC-derived cells by transfection of expression plasmid. The effects of DKK3 overexpression were assessed on cellular proliferation, migration, invasion, and in vivo tumor growth. The molecular mechanism of DKK3 overexpression was investigated by Western blotting and microarray analysis. DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc. However, reporter assays did not show TCF/LEF activation, suggesting that the increased malignant property of cancer cells was not driven by the Wnt/β-catenin pathway. For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt (S473) and c-Jun (Ser63) was elevated. The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion. From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration, and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K-Akt signaling.

Project description:While treatment failure in cases of head and neck squamous cell carcinoma (HNSCC) frequently takes the form of locoregional recurrences and distant metastasis, our understanding of the mechanisms of metastasis in HNSCC is limited. We initially performed the upstream and key nodes analysis together with whole gene microarray analysis characterized by distant metastatic potential in vivo with HNSCC cell lines and identified JunB, a member of the activator protein-1 (AP-1) family, as a key molecule in the regulation of the pathways related to distant metastasis in HNSCC. We have therefore tested the hypothesis that JunB plays a crucial role in distant metastasis in HNSCC.To study the role of JunB on metastatic potential of HNSCC, small interfering RNA (siRNA)-mediated knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (cas9) system (CRISPR/Cas9)-mediated knockout of JunB in HNSCC cells were established and the abilities of cell invasion and migration in vitro were examined. The efficacy of knockout of JunB was also examined using an experimental lung metastatic mouse model of HNSCC. In addition, to study if the role of JunB in HNSCC cell migration and invasiveness is related to epithelial-to-mesenchymal transition (EMT), cell morphology and expression of mesenchymal or epithelial marker on siRNA mediated JunB knockdown in HNSCC cells were examined with or without TGF-? stimulation.siRNA knockdown and sgRNA knockout of JunB in metastatic HNSCC cells significantly suppressed both cell invasion and migration in vitro. In addition, the knockout of JunB in metastatic HNSCC cells significantly repressed the incidence of lung metastases and prolonged the survival in vivo. However, we did not observe any change in cell morphology with the down-regulation of mesenchymal markers and up-regulation of epithelial markers in response to siRNA-mediated JunB knockdown in HNSCC cells.These results suggested that JunB could play an important role in promoting cell invasion, migration and distant metastasis in HNSCC via pathways other than EMT and that the down-regulation of JunB may become an effective strategy for patients with invasive HNSCC.

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Dataset Information

Overexpression of neuromedin U is correlated with regional metastasis of head and neck squamous cell carcinoma.

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Overexpression of neuromedin U is correlated with regional metastasis of head and neck squamous cell carcinoma.

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