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Kato T, Tanaka I, Huang H, Okado S, Imamura Y, Nomata Y, Takenaka H, Watanabe H, Kawasumi Y, Nakanishi K, Kadomatsu Y, Ueno H, Nakamura S, Mizuno T, Chen-Yoshikawa TF. Molecular Mechanisms of Tumor Progression and Novel Therapeutic and Diagnostic Strategies in Mesothelioma. Int J Mol Sci 2025; 26:4299. [PMID: 40362535 PMCID: PMC12072309 DOI: 10.3390/ijms26094299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 04/27/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Mesothelioma is characterized by the inactivation of tumor suppressor genes, with frequent mutations in neurofibromin 2 (NF2), BRCA1-associated protein 1 (BAP1), and cyclin-dependent kinase inhibitor 2A (CDKN2A). These mutations lead to disruptions in the Hippo signaling pathway and histone methylation, thereby promoting tumor growth. NF2 mutations result in Merlin deficiency, leading to uncontrolled cell proliferation, whereas BAP1 mutations impair chromatin remodeling and hinder DNA damage repair. Emerging molecular targets in mesothelioma include mesothelin (MSLN), oxytocin receptor (OXTR), protein arginine methyltransferase (PRMT5), and carbohydrate sulfotransferase 4 (CHST4). MSLN-based therapies, such as antibody-drug conjugates and immunotoxins, have shown efficacy in clinical trials. OXTR, upregulated in mesothelioma, is correlated with poor prognosis and represents a novel therapeutic target. PRMT5 inhibition is being explored in tumors with MTAP deletions, commonly co-occurring with CDKN2A loss. CHST4 expression is associated with improved prognosis, potentially influencing tumor immunity. Immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in some cases; however, resistance mechanisms remain a challenge. Advances in multi-omics approaches have improved our understanding of mesothelioma pathogenesis. Future research will aim to identify novel therapeutic targets and personalized treatment strategies, particularly in the context of epigenetic therapy and combination immunotherapy.
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Affiliation(s)
- Taketo Kato
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Ichidai Tanaka
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan;
| | - Heng Huang
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Shoji Okado
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Yoshito Imamura
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Yuji Nomata
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Hirofumi Takenaka
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Hiroki Watanabe
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Yuta Kawasumi
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Keita Nakanishi
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Yuka Kadomatsu
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Harushi Ueno
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Shota Nakamura
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Tetsuya Mizuno
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Toyofumi Fengshi Chen-Yoshikawa
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (T.K.); (H.H.); (S.O.); (Y.I.); (Y.N.); (H.T.); (H.W.); (Y.K.); (K.N.); (Y.K.); (H.U.); (S.N.); (T.M.)
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Iacomino N, Tarasco MC, Berni A, Ronchi J, Mantegazza R, Cavalcante P, Foti M. Non-Coding RNAs in Myasthenia Gravis: From Immune Regulation to Personalized Medicine. Cells 2024; 13:1550. [PMID: 39329732 PMCID: PMC11430632 DOI: 10.3390/cells13181550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/06/2024] [Accepted: 09/10/2024] [Indexed: 09/28/2024] Open
Abstract
Myasthenia gravis (MG) is an antibody-mediated autoimmune disorder characterized by altered neuromuscular transmission, which causes weakness and fatigability in the skeletal muscles. The etiology of MG is complex, being associated with multiple genetic and environmental factors. Over recent years, progress has been made in understanding the immunological alterations implicated in the disease, but the exact pathogenesis still needs to be elucidated. A pathogenic interplay between innate immunity and autoimmunity contributes to the intra-thymic MG development. Epigenetic changes are critically involved in both innate and adaptive immune response regulation. They can act as (i) pathological factors besides genetic predisposition and (ii) co-factors contributing to disease phenotypes or patient-specific disease course/outcomes. This article reviews the role of non-coding RNAs (ncRNAs) as epigenetic factors implicated in MG. Particular attention is dedicated to microRNAs (miRNAs), whose expression is altered in MG patients' thymuses and circulating blood. The long ncRNA (lncRNA) contribution to MG, although not fully characterized yet, is also discussed. By summarizing the most recent and fast-growing findings on ncRNAs in MG, we highlight the therapeutic potential of these molecules for achieving immune regulation and their value as biomarkers for the development of personalized medicine approaches to improve disease care.
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Affiliation(s)
- Nicola Iacomino
- Neurology 4–Neuroimmunology and Neuromuscolar Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (N.I.); (M.C.T.); (A.B.); (R.M.)
| | - Maria Cristina Tarasco
- Neurology 4–Neuroimmunology and Neuromuscolar Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (N.I.); (M.C.T.); (A.B.); (R.M.)
- Ph.D. Program in Neuroscience, University of Milano-Bicocca, 20900 Monza, Italy;
| | - Alessia Berni
- Neurology 4–Neuroimmunology and Neuromuscolar Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (N.I.); (M.C.T.); (A.B.); (R.M.)
| | - Jacopo Ronchi
- Ph.D. Program in Neuroscience, University of Milano-Bicocca, 20900 Monza, Italy;
- Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
- BicOMICs, University of Milano-Bicocca, 20900 Monza, Italy
| | - Renato Mantegazza
- Neurology 4–Neuroimmunology and Neuromuscolar Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (N.I.); (M.C.T.); (A.B.); (R.M.)
| | - Paola Cavalcante
- Neurology 4–Neuroimmunology and Neuromuscolar Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (N.I.); (M.C.T.); (A.B.); (R.M.)
| | - Maria Foti
- Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
- BicOMICs, University of Milano-Bicocca, 20900 Monza, Italy
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Wang F, Mei X, Yang Y, Zhang H, Li Z, Zhu L, Deng S, Wang Y. Non-coding RNA and its network in the pathogenesis of Myasthenia Gravis. Front Mol Biosci 2024; 11:1388476. [PMID: 39318549 PMCID: PMC11420011 DOI: 10.3389/fmolb.2024.1388476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 08/21/2024] [Indexed: 09/26/2024] Open
Abstract
Myasthenia Gravis (MG) is a chronic autoimmune disease that primarily affects the neuromuscular junction, leading to muscle weakness in patients with this condition. Previous studies have identified several dysfunctions in thymus and peripheral blood mononuclear cells (PBMCs), such as the formation of ectopic germinal centers in the thymus and an imbalance of peripheral T helper cells and regulatory T cells, that contribute to the initiation and development of MG. Recent evidences suggest that noncoding RNA, including miRNA, lncRNA and circRNA may play a significant role in MG progression. Additionally, the network between these noncoding RNAs, such as the competing endogenous RNA regulatory network, has been found to be involved in MG progression. In this review, we summarized the roles of miRNA, lncRNA, and circRNA, highlighted their potential application as biomarkers in diagnosing MG, and discussed their potential regulatory networks in the abnormal thymus and PBMCs during MG development.
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Affiliation(s)
- Fuqiang Wang
- Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, China
- Department of Thoracic Surgery, Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoli Mei
- Department of Thoracic Surgery, West China Hospital, West China School of Nursing, Sichuan University, Chengdu, China
| | - Yunhao Yang
- Department of Thoracic Surgery, Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Hanlu Zhang
- Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Zhiyang Li
- Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Lei Zhu
- Department of Thoracic Surgery, Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Senyi Deng
- Department of Thoracic Surgery, Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Yun Wang
- Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, China
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Okado S, Kato T, Hanamatsu Y, Emoto R, Imamura Y, Watanabe H, Kawasumi Y, Kadomatsu Y, Ueno H, Nakamura S, Mizuno T, Takeuchi T, Matsui S, Chen-Yoshikawa TF. CHST4 Gene as a Potential Predictor of Clinical Outcome in Malignant Pleural Mesothelioma. Int J Mol Sci 2024; 25:2270. [PMID: 38396947 PMCID: PMC10889779 DOI: 10.3390/ijms25042270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/07/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
Malignant pleural mesothelioma (MPM) develops primarily from asbestos exposures and has a poor prognosis. In this study, The Cancer Genome Atlas was used to perform a comprehensive survival analysis, which identified the CHST4 gene as a potential predictor of favorable overall survival for patients with MPM. An enrichment analysis of favorable prognostic genes, including CHST4, showed immune-related ontological terms, whereas an analysis of unfavorable prognostic genes indicated cell-cycle-related terms. CHST4 mRNA expression in MPM was significantly correlated with Bindea immune-gene signatures. To validate the relationship between CHST4 expression and prognosis, we performed an immunohistochemical analysis of CHST4 protein expression in 23 surgical specimens from surgically treated patients with MPM who achieved macroscopic complete resection. The score calculated from the proportion and intensity staining was used to compare the intensity of CHST4 gene expression, which showed that CHST4 expression was stronger in patients with a better postoperative prognosis. The median overall postoperative survival was 107.8 months in the high-expression-score group and 38.0 months in the low-score group (p = 0.044, log-rank test). Survival after recurrence was also significantly improved by CHST4 expression. These results suggest that CHST4 is useful as a prognostic biomarker in MPM.
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Affiliation(s)
- Shoji Okado
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (S.O.); (T.K.); (Y.I.); (H.W.); (Y.K.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Taketo Kato
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (S.O.); (T.K.); (Y.I.); (H.W.); (Y.K.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Yuki Hanamatsu
- Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu 501-1194, Japan; (Y.H.); (T.T.)
| | - Ryo Emoto
- Department of Biostatistics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (R.E.); (S.M.)
| | - Yoshito Imamura
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (S.O.); (T.K.); (Y.I.); (H.W.); (Y.K.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Hiroki Watanabe
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (S.O.); (T.K.); (Y.I.); (H.W.); (Y.K.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Yuta Kawasumi
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (S.O.); (T.K.); (Y.I.); (H.W.); (Y.K.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Yuka Kadomatsu
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (S.O.); (T.K.); (Y.I.); (H.W.); (Y.K.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Harushi Ueno
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (S.O.); (T.K.); (Y.I.); (H.W.); (Y.K.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Shota Nakamura
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (S.O.); (T.K.); (Y.I.); (H.W.); (Y.K.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Tetsuya Mizuno
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (S.O.); (T.K.); (Y.I.); (H.W.); (Y.K.); (Y.K.); (H.U.); (S.N.); (T.M.)
| | - Tamotsu Takeuchi
- Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu 501-1194, Japan; (Y.H.); (T.T.)
| | - Shigeyuki Matsui
- Department of Biostatistics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (R.E.); (S.M.)
| | - Toyofumi Fengshi Chen-Yoshikawa
- Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; (S.O.); (T.K.); (Y.I.); (H.W.); (Y.K.); (Y.K.); (H.U.); (S.N.); (T.M.)
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Nicolì V, Coppedè F. Epigenetics of Thymic Epithelial Tumors. Cancers (Basel) 2023; 15:360. [PMID: 36672310 PMCID: PMC9856807 DOI: 10.3390/cancers15020360] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 12/30/2022] [Accepted: 01/02/2023] [Indexed: 01/08/2023] Open
Abstract
Thymic epithelial tumors (TETs) arise from the epithelial cells of the thymus and consist in the 1% of all adult malignancies, despite the fact that they are the most common lesions of the anterior mediastinum. TETs can be divided mainly into thymomas, thymic carcinomas, and the rarest ad aggressive neuroendocrine forms. Despite the surgical resection is quite resolving, the diagnosis of TETs is complicated by the absence of symptoms and the clinical presentation aggravated by several paraneoplastic disorders, including myasthenia gravis. Thus, the heterogeneity of TETs prompts the search for molecular biomarkers that could be helpful for tumor characterization and clinical outcomes prediction. With these aims, several researchers investigated the epigenetic profiles of TETs. In this manuscript, we narratively review the works investigating the deregulation of epigenetic mechanisms in TETs, highlighting the need for further studies combining genetic, epigenetic, and expression data to better characterize the different molecular subtypes and identify, for each of them, the most relevant epigenetic biomarkers of clinical utility.
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Affiliation(s)
- Vanessa Nicolì
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy
| | - Fabio Coppedè
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy
- Interdepartmental Research Center of Biology and Pathology of Aging, University of Pisa, 56126 Pisa, Italy
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SPLUNC1 regulates LPS-induced progression of nasopharyngeal carcinoma and proliferation of myeloid-derived suppressor cells. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:214. [PMID: 36175598 DOI: 10.1007/s12032-022-01816-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 07/29/2022] [Indexed: 10/14/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is one of the aggressive malignant tumors with high mortality, and the proliferation of myeloid-derived suppressor cells (MDSCs) could promote the metastasis of NPC through inhibiting the function of T cells. Meanwhile, SPLUNC1 was known to inhibit the malignant behavior of NPC cells, while the detailed function of SPLUNC1 in LPS-modified immune microenvironment of NPC remains unclear. To assess the impact of SPLUNC1 in immune microenvironment during the progression of NPC, NPC cells were exposed to LPS and then co-cultured with MDSCs for 48 h. RT-qPCR and western blot were performed to evaluate the mRNA and protein level of SPLUNC1, CXCL-2 and CXCR-2, respectively. The level of IL-1β, IL-6, TNF-α, PD-L1, Arg-1 and iNOS were tested by ELISA. Meanwhile, the expression of CD33+ was tested by flow cytometry. The expression of CXCL-2 and CXCR-2 in NPC cells was higher, compared to that in NP69 cells. In contrast, SPLUNC1 level in NPC cells was much lower than that in NP69 cells. SPLUNC1 level was negatively correlated with CXCL-2 and CXCR-2. Overexpression of SPLUNC1 reversed LPS-induced inflammatory responses and proliferation in NPC cells. In addition, SPLUNC1 upregulation could reverse LPS-induced proliferation of MDSCs in tumor microenvironment. Meanwhile, SPLUNC1 overexpression could regulate CXCL-2/CXCR-2 axis through decreasing CXCL-2 and CXCR-2 protein and mRNA expression. SPLUNC1 regulates LPS-induced progression of nasopharyngeal carcinoma and proliferation of MDSCs. Thus, our study might provide a theoretical basis for discovering new strategies against NPC.
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