Abstract
Recent studies have reported that T-cell differentiation protein 2 (MAL2) is an important regulator in cancers. Here, we downloaded data from multiple databases to analyze MAL2 expression and function in pan-cancers, especially in ovarian cancer (OC). Gene Expression Profiling Interactive Analysis (GEPIA) databases was used to examine MAL2 expression in 13 types of cancer. Kaplan–Meier plotter database was used to analyze the overall survival rate of MAL2 in pan-cancers. The Catalog of Somatic Mutations in Cancer (COSMIC), cBioPortal, and UCSC databases were used to examine MAL2 mutation in human cancers. Metascape, STRING, and GeneMANIA websites were used to explore MAL2 function in OC. Furthermore, ggplot2 package and ROC package were performed to analyze hub gene expression and undertake receiver operating characteristic (ROC) analysis. Drug sensitivity of MAL2 in OC was examined by the GSCALite database. In order to verify the results from databases above, real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting were conducted to detect the expression of MAL2 in OC cells. CRISPR/Cas9 system was used to knockout the MAL2 gene in the OC cell lines HO8910 and OVCAR3, using specific guide RNA targeting the exons of MAL2. Then, we performed proliferation, colony formation, migration, and invasion assays to investigate the impact of MAL2 in OC cell lines in vivo and in vitro. Epithelial-mesenchymal transition (EMT)-associated biomarkers were significantly altered in vitro via western blotting and qRT-PCR. Taken together, we observed that MAL2 was remarkably dysregulated in multiple cancers and was related to patient overall survival (OS), mutation, and drug sensitivity. Furthermore, experimental results showed that MAL2 deletion negatively regulated the proliferation, migration, invasion, and EMT of OC, indicating that MAL2 is a novel oncogene that can activate EMT, significantly promote both the proliferation and migration of OC in vitro and in vivo, and provide new clues for treatment strategies.
Highlights
The T-cell differentiation protein 2 (MAL2) gene, located on human chromosome 8q24, is a 19-kDa membrane protein with four transmembrane domains belonging to the MAL protein family (Fanayan et al, 2009) that participates in transporting apical vesicles
The data showed that MAL2 is highly expressed in pan-cancers, including bladder urothelial carcinoma (BLCA), invasive breast carcinoma (BRCA), cervical squamous cell carcinoma (CESC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian cancer (OC), pancreatic adenocarcinoma (PAAD), rectal adenocarcinoma (READ), stomach adenocarcinoma (STAD), thymoma (THYM), and uterine corpus endometrial carcinoma (UCEC), and was remarkably upregulated in two cancer types, involving OC and UCEC (Figure 1A)
Survival analysis revealed that a high expression of MAL2 was correlated with worse overall survival rate of BRCA (p 1.7e−05), OC (p 0.047), PAAD (p 0.00032), THYM (p 0.0039), and UCEC (p 8.8e−05), while CESC (p 0.27), LUAD (p 0.36), LUSC (p 0.073), and READ (p 0.23) showed no statistical significance of MAL2 for predicting prognosis of patients
Summary
The T-cell differentiation protein 2 (MAL2) gene, located on human chromosome 8q24, is a 19-kDa membrane protein with four transmembrane domains belonging to the MAL protein family (Fanayan et al, 2009) that participates in transporting apical vesicles. Through yeast two-hybrid expression screening of a human breast cancer library, MAL2 was identified as the molecular chaperone of tumor protein D52-like protein (TPD52) and MUC1 (Fanayan et al, 2009; Li et al, 2017). The latest studies revealed that a high expression of MAL2 can be detected in breast cancer tissues and cells (Bhandari et al, 2018) and that MAL2 participates in regulating cell proliferation, invasion, and metastasis; promotes the malignant progression of cancer; and is significantly associated with clinical pathology or prognosis. MAL2 has been reported to regulate liver polarization (López-Coral et al, 2020), which plays a role in regulating cell protein transport, which alters protein distribution and affects cell morphology, signaling pathways, and cell migration. There was no systematic research analyzing the role of MAL2 in human cancers
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