Abstract
Background: Mucosa-associated lymphoma antigen 1 (MALT1) is an oncogene in subsets of diffuse large B cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue type (MALT) lymphoma. However, the role of MALT1 across cancers, especially in prostate cancer is still poorly understood. Methods: Here, we used several public datasets to evaluate MALT1 expression. Then, PCa cell lines and nude mice were used to investigate the cellular functions in vitro and in vivo. Microarray data were downloaded from The Cancer Genome Atlas and MALT1 was subjected to gene set enrichment analysis (GSEA) and Gene Ontology (GO) analysis to identify the biological functions and relevant pathways. Additionally, the correlations between MALT1 expression and mismatch repair (MMR) gene mutation, immune checkpoint gene expression, tumor mutational burden (TMB), and microsatellite instability (MSI) were investigated by Pearson correlation analysis. Moreover, the correlation between MALT1 expression and tumor immune infiltration was analyzed by the Tumor Immune Evaluation Resource (TIMER) database. Results: MALT1 overexpression was significantly correlated with MMR gene mutation levels and crucially promoted proliferation and colony genesis while reducing PCa cell apoptosis levels in vivo and in vitro. MALT1 expression showed strong correlations with immune checkpoint genes, TMB, and MSI in most cancers. The GO analysis indicated that MALT1-coexpressed genes were involved in heterotypic cell-cell adhesion, actin filament-based movement regulation, and action potential regulation. GSEA revealed that MALT1 expression was associated with several signaling pathways, including the NF-κB signaling, Wnt/β-catenin and TGF-β signaling pathways, in PCa. Additionally, MALT1 expression was significantly correlated with the infiltration of immune cells, including B cells, CD8+ T cells, dendritic cells and macrophages, and negatively correlated with CD4+ cell infiltration in PCa. Conclusion: MALT1 expression is higher in pancancer samples than in normal tissues. MALT1 promoted proliferation and colony genesis while reducing PCa cell apoptosis levels, and MALT1 suppression could inhibit xenograft tumor establishment in nude mice. Furthermore, MALT1 expression is closely related to the occurrence and development of multiple tumors in multiple ways. Therefore, MALT1 may be an emerging therapeutic target for a variety of cancers especially PCa.
Highlights
Prostate cancer (PCa), called prostate adenocarcinoma (PRAD), is the most common malignant cancer apart from lung cancer in males worldwide, and the second leading cause of male cancer-related death in worldwide (Gasnier and Parvizi, 2017; Bray et al, 2018)
RNA-seq data showed that compared to that in paired normal tissues, Mucosa-associated lymphoma antigen 1 (MALT1) was overexpressed in PRAD, cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), lung squamous cell carcinoma (LUSC), pancreatic adenocarcinoma (PAAD), and stomach adenocarcinoma (STAD) and was expressed at lower levels in kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LUAD), ovarian serous cystadenocarcinoma (OV), skin cutaneous melanoma (SKCM), and rectum adenocarcinoma (READ) (Figure 1B)
We studied the role of MALT1 in two PCa cell lines, PC-3 and LNCaP
Summary
Prostate cancer (PCa), called prostate adenocarcinoma (PRAD), is the most common malignant cancer apart from lung cancer in males worldwide, and the second leading cause of male cancer-related death in worldwide (Gasnier and Parvizi, 2017; Bray et al, 2018). There is an urgent need for a detailed investigation of the underlying mechanisms of PCa to discover novel molecular targets for gene therapy in order to thereby improve the prognosis of patients with PCa. Mucosa-associated lymphoma antigen 1 (MALT1), is a paracaspase that belongs to the caspase family of proteases and has arginine-specific cysteine protease activity (Ruland et al, 2003). Together with coactivator-associated arginine methyltransferase 1 (CARMA1, known as CARD11) and B cell lymphoma 10 (BCL10), MALT1 assembles the CARMA1/ Bcl10/MALT1 (CBM) complex that bridges proximal antigen receptor signaling events to the IkB kinase (IKK) complex, causes the degradation of inhibitor of κB (IKK), activates the NF-κB pathway (Turvey et al, 2014). The role of MALT1 across cancers, especially in prostate cancer is still poorly understood
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