MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types
MAX dimerization (MXD) protein 3 (MXD3) is a member of the MXD family of basic-helix-loop-helix-leucine-zipper (bHLHZ) transcription factors that plays pivotal roles in cell cycle progression and cell proliferation. However, there is insufficient scientific evidence on the pathogenic roles of MXD3 i...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Computational and Structural Biotechnology Journal |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037021003780 |
| _version_ | 1818950486631383040 |
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| author | Szu-Yuan Wu Kuan-Chou Lin Bashir Lawal Alexander T.H Wu Ching-Zong Wu |
| author_facet | Szu-Yuan Wu Kuan-Chou Lin Bashir Lawal Alexander T.H Wu Ching-Zong Wu |
| author_sort | Szu-Yuan Wu |
| collection | DOAJ |
| description | MAX dimerization (MXD) protein 3 (MXD3) is a member of the MXD family of basic-helix-loop-helix-leucine-zipper (bHLHZ) transcription factors that plays pivotal roles in cell cycle progression and cell proliferation. However, there is insufficient scientific evidence on the pathogenic roles of MXD3 in various cancers and whether MXD3 plays a role in the immuno-oncology context of the tumor microenvironment, pathogenesis, prognosis, and therapeutic response of different tumors through certain common molecular mechanisms; thus, we saw a need to conduct the present in silico pan-cancer study. Using various computational tools, we interrogated the role of MXD3 in tumor immune infiltration, immune evasion, tumor progression, therapy response, and prognosis of cohorts from various cancer types. Our results indicated that MXD3 was aberrantly expressed in almost all The Cancer Genome Atlas (TCGA) cancer types and subtypes and was associated with the tumor stage, metastasis, and worse prognoses of various cohorts. Our results also suggested that MXD3 is associated with tumor immune evasion via different mechanisms involving T-cell exclusion in different cancer types and by tumor infiltration of immune cells in thymoma (THYM), liver hepatocellular carcinoma (LIHC), and head and neck squamous cell carcinoma (HNSC). Methylation of MXD3 was inversely associated with messenger (m)RNA expression levels and mediated dysfunctional T-cell phenotypes and worse prognoses of cohorts from different cancer types. Finally, we found that genetic alterations and oncogenic features of MXD3 were concomitantly associated with deregulation of the DBN1, RAB24, SLC34A1, PRELID1, LMAN2, F12, GRK6, RGS14, PRR7, and PFN3 genes and were connected to phospholipid transport and ion homeostasis. Our results also suggested that MXD3 expression is associated with immune or chemotherapeutic outcomes in various cancers. In addition, higher MXD3 expression levels were associated with decreased sensitivity of cancer cell lines to several mitogen-activated protein kinase kinase (MEK) inhibitors but led to increased activities of other kinase inhibitors, including Akt inhibitors. Interestingly, MXD3 exhibited higher predictive power for response outcomes and overall survival of immune checkpoint blockade sub-cohorts than three of seven standardized biomarkers. Altogether, our study strongly suggests that MXD3 is an immune-oncogenic molecule and could serve as a biomarker for cancer detection, prognosis, therapeutic design, and follow-up. |
| first_indexed | 2024-12-20T09:19:21Z |
| format | Article |
| id | doaj.art-f23462bf9b9a4c6281e1359d84a1d0ce |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-12-20T09:19:21Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-f23462bf9b9a4c6281e1359d84a1d0ce2022-12-21T19:45:20ZengElsevierComputational and Structural Biotechnology Journal2001-03702021-01-011949704983MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer typesSzu-Yuan Wu0Kuan-Chou Lin1Bashir Lawal2Alexander T.H Wu3Ching-Zong Wu4Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan; Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan; Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan; Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan; Graduate Institute of Business Administration, Fu Jen Catholic University, New Taipei City, Taiwan; Centers for Regional Anesthesia and Pain Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Cancer Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, TaiwanSchool of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan; Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei Medical University, Taipei, TaiwanGraduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, TaiwanThe PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; Taipei Heart Institute (THI), Taipei Medical University, Taipei, Taiwan; Corresponding authors at: The PhD Program of Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei, Taiwan (A.T.H. Wu). Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan (C.Z. Wu).School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan; Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan; Corresponding authors at: The PhD Program of Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei, Taiwan (A.T.H. Wu). Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan (C.Z. Wu).MAX dimerization (MXD) protein 3 (MXD3) is a member of the MXD family of basic-helix-loop-helix-leucine-zipper (bHLHZ) transcription factors that plays pivotal roles in cell cycle progression and cell proliferation. However, there is insufficient scientific evidence on the pathogenic roles of MXD3 in various cancers and whether MXD3 plays a role in the immuno-oncology context of the tumor microenvironment, pathogenesis, prognosis, and therapeutic response of different tumors through certain common molecular mechanisms; thus, we saw a need to conduct the present in silico pan-cancer study. Using various computational tools, we interrogated the role of MXD3 in tumor immune infiltration, immune evasion, tumor progression, therapy response, and prognosis of cohorts from various cancer types. Our results indicated that MXD3 was aberrantly expressed in almost all The Cancer Genome Atlas (TCGA) cancer types and subtypes and was associated with the tumor stage, metastasis, and worse prognoses of various cohorts. Our results also suggested that MXD3 is associated with tumor immune evasion via different mechanisms involving T-cell exclusion in different cancer types and by tumor infiltration of immune cells in thymoma (THYM), liver hepatocellular carcinoma (LIHC), and head and neck squamous cell carcinoma (HNSC). Methylation of MXD3 was inversely associated with messenger (m)RNA expression levels and mediated dysfunctional T-cell phenotypes and worse prognoses of cohorts from different cancer types. Finally, we found that genetic alterations and oncogenic features of MXD3 were concomitantly associated with deregulation of the DBN1, RAB24, SLC34A1, PRELID1, LMAN2, F12, GRK6, RGS14, PRR7, and PFN3 genes and were connected to phospholipid transport and ion homeostasis. Our results also suggested that MXD3 expression is associated with immune or chemotherapeutic outcomes in various cancers. In addition, higher MXD3 expression levels were associated with decreased sensitivity of cancer cell lines to several mitogen-activated protein kinase kinase (MEK) inhibitors but led to increased activities of other kinase inhibitors, including Akt inhibitors. Interestingly, MXD3 exhibited higher predictive power for response outcomes and overall survival of immune checkpoint blockade sub-cohorts than three of seven standardized biomarkers. Altogether, our study strongly suggests that MXD3 is an immune-oncogenic molecule and could serve as a biomarker for cancer detection, prognosis, therapeutic design, and follow-up.http://www.sciencedirect.com/science/article/pii/S2001037021003780MXD3Immuno-oncologyImmunotherapyChemotherapyGene expression profilingImmune-cell infiltration |
| spellingShingle | Szu-Yuan Wu Kuan-Chou Lin Bashir Lawal Alexander T.H Wu Ching-Zong Wu MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types Computational and Structural Biotechnology Journal MXD3 Immuno-oncology Immunotherapy Chemotherapy Gene expression profiling Immune-cell infiltration |
| title | MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types |
| title_full | MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types |
| title_fullStr | MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types |
| title_full_unstemmed | MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types |
| title_short | MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types |
| title_sort | mxd3 as an onco immunological biomarker encompassing the tumor microenvironment disease staging prognoses and therapeutic responses in multiple cancer types |
| topic | MXD3 Immuno-oncology Immunotherapy Chemotherapy Gene expression profiling Immune-cell infiltration |
| url | http://www.sciencedirect.com/science/article/pii/S2001037021003780 |
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