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MALT1 promotes melanoma progression through JNK/c-Jun signaling.

ABSTRACT: Mucosa-associated lymphoma antigen 1 (MALT1) is a lymphoma oncogene that regulates signal transduction as a paracaspase and an adaptor protein. Yet, the role of MALT1 in other solid cancers such as melanoma is not well-understood. Here, we demonstrate that MALT1 is overexpressed in malignant melanoma cells, and predicts a poor disease-free survival. MALT1 inhibition via shRNA-mediated gene silencing or pharmacologically with MI-2 compound markedly reduced cell growth and migration of A2058 and A375 melanoma cell lines in vitro. Subcutaneous tumor growth analysis revealed that MALT1 gene silencing significantly reduced tumor growth and metastasis to the lung. Consistently, the subcutaneous tumors with MALT1 loss had increased cell apoptosis and decreased proliferation. In addition, these tumors showed signs of mesenchymal-epithelial transition as indicated by the upregulation of E-cadherin and downregulation of N-cadherin and ?1-intergrin. Further molecular analysis revealed that MALT1 is required for c-Jun and nuclear factor-?B (NF-?B) activation by tumor necrosis factor-?. Forced expression of the c-Jun upstream activator MKK7 reversed the cell growth and migration defects caused by MALT1 loss. In contrast, NF-?B activation via expression of p65ER, a fusion protein containing NF-?B p65 and the tamoxifen-responsive mutant estrogen receptor, induced minimal effects on cell proliferation, but diminished cell death induced by MALT1 loss and TRAIL treatment. Together, these findings demonstrate that MALT1 promotes melanoma cell proliferation and motility through JNK/c-Jun, and enhances melanoma cell survival through NF-?B, underscoring MALT1 as a potential therapeutic target and biomarker for malignant melanoma.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5541718 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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MALT1 promotes melanoma progression through JNK/c-Jun signaling.

Wang Y Y Zhang G G Jin J J Degan S S Tameze Y Y Zhang J Y JY

Oncogenesis 20170731 7

Mucosa-associated lymphoma antigen 1 (MALT1) is a lymphoma oncogene that regulates signal transduction as a paracaspase and an adaptor protein. Yet, the role of MALT1 in other solid cancers such as melanoma is not well-understood. Here, we demonstrate that MALT1 is overexpressed in malignant melanoma cells, and predicts a poor disease-free survival. MALT1 inhibition via shRNA-mediated gene silencing or pharmacologically with MI-2 compound markedly reduced cell growth and migration of A2058 and A ...[more]

PMID: 28759024

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Project description:BackgroundUtrophin (UTRN), as a tumor suppressor gene, is involved in various cancer progression. The function of UTRN in the melanoma process and the related molecular mechanisms are still unclear. Herein, we studied the function of UTRN in melanoma growth and the relevant molecular mechanisms.MethodsUsing the GEO database and UCSC Xena project, we compared the expression of UTRN in non-cancerous and melanoma tissues. Immunohistochemistry (IHC) staining, qRT-PCR and Western Blot (WB) were performed to evaluate UTRN expression in clinical samples. A total of 447 cases with UTRN expression data, patient characteristics and survival data were extracted from TCGA database and analyzed. After stable transduction and single cell cloning, the proliferation ability of A375 human melanoma cells was analyzed by Cell Counting Kit‑8 (CCK) and 5‑ethynyl‑2'‑deoxyuridine (EdU) incorporation assays. GSEA was performed to predict the mechanism by which UTRN regulated melanoma growth. Then WB analysis was used to assess the protein expression levels of pathway signaling in overexpression (EXP) melanoma cells. Epac activator 8-pCPT-2'-O-Me-cAMP was then used to evaluate the proliferation ability by activation of p38 and JNK/c-Jun signaling pathways.ResultsData from GEO and UCSC Xena project indicated that UTRN expression was decreased in melanoma. Experiment on clinical samples further confirmed our finding. TCGA results showed that a reduced expression of UTRN in 447 melanoma samples was associated with advanced clinical characteristics (T stage, Clark level, ulceration), shorter survival time and poorer prognosis. In addition, up-regulated UTRN expression inhibited melanoma cell proliferation when compared to control group. MAPK signaling pathway was presented in both KEGG and BioCarta databases by using GSEA tool. WB results confirmed the down-regulated expression of p38, JNK1 and c-Jun in EXP group when compared to control group. Epac activator 8-pCPT-2'-O-Me-cAMP treatment could partially rescue proliferation of tumor cells.ConclusionWe have demonstrated that reduced UTRN predicted poorer prognosis and UTRN inhibited melanoma growth via p38 and JNK1/c-Jun pathways. Therefore, UTRN could serve as a tumor suppressor and novel prognostic biomarker for melanoma patients.

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MALT1 promotes melanoma progression through JNK/c-Jun signaling.

Publications

MALT1 promotes melanoma progression through JNK/c-Jun signaling.

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