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Takaya K, Kishi K. Identification of a new human senescent skin cell marker ribonucleoside-diphosphate reductase subunit M2 B. Biogerontology 2024; 25:1239-1251. [PMID: 39261410 DOI: 10.1007/s10522-024-10135-5] [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: 07/17/2024] [Accepted: 08/26/2024] [Indexed: 09/13/2024]
Abstract
In skin aging, it has been hypothesized that aging fibroblasts accumulate within the epidermal basal layer, dermis, and subcutaneous fat, causing abnormal tissue remodeling and extracellular matrix dysfunction, thereby inducing an aging-related secretory phenotype (SASP). A new treatment for skin aging involves the specific elimination of senescent skin cells, especially fibroblasts within the dermis and keratinocytes in the basal layer. This requires the identification of specific protein markers of senescent cells, such as ribonucleoside-diphosphate reductase subunit M2 B (RRM2B), which is upregulated in various malignancies in response to DNA stress damage. However, the behavior and role of RRM2B in skin aging remain unclear. Therefore, we examined whether RRM2B functions as a senescence marker using a human dermal fibroblast model of aging. In a model of cellular senescence induced by replicative aging and exposure to ionizing radiation or UVB, RRM2B was upregulated at the gene and protein levels. This was correlated with decreased uptake of the senescence-associated β-galactosidase activity and proliferation marker bromodeoxyuridine. RRM2B upregulation was concurrent with the increased expression of SASP factor genes. Furthermore, using fluorescence flow cytometry, RRM2B-positive cells were recovered more frequently in the aging cell population. In aging human skin, RRM2B was also found to be more abundant in the dermis and epidermal basal layer than other proteins. Therefore, RRM2B may serve as a clinical marker to identify senescent skin cells.
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Affiliation(s)
- Kento Takaya
- Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Kazuo Kishi
- Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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2
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Jiang Y, Hu X, Pang M, Huang Y, Ren B, He L, Jiang L. RRM2‑mediated Wnt/β‑catenin signaling pathway activation in lung adenocarcinoma: A potential prognostic biomarker. Oncol Lett 2023; 26:417. [PMID: 37664657 PMCID: PMC10472049 DOI: 10.3892/ol.2023.14003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 07/17/2023] [Indexed: 09/05/2023] Open
Abstract
The present study aimed to investigate the role and mechanism of action of ribonucleotide reductase M2 (RRM2) in lung adenocarcinoma and its potential as a therapeutic target. Data of patients with lung adenocarcinoma from The Cancer Genome Atlas database were collected and analyzed to evaluate the potential of RRM2 as a biomarker. The expression of RRM2 was evaluated in the A549 cell line and its cisplatin-resistant A549/DDP cell line derivative by western blot and reverse transcription-quantitative PCR. The study also investigated cell proliferation and the mechanism by which RRM2 controls cellular cisplatin resistance using CCK-8 and colony-formation assays. In addition, cell migration was assessed using Transwell assays, and the cell cycle and apoptosis were examined using flow cytometry. RRM2 was highly expressed in lung adenocarcinoma and was associated with the clinical TMN stage. Functional enrichment analysis showed that RRM2 was enriched in the cell cycle. Immune cell infiltration analysis identified 12 types of immune cell that exhibited differences between patients expressing different levels of RRM2. Cellular assays revealed higher levels of RRM2 expression in A549/DDP cells than A549 cells, and its expression was induced by cisplatin. RRM2 knockdown decreased cell proliferation and migration, accelerated apoptosis and caused cell cycle arrest in the S-phase, increasing the sensitivity of A549 and A549/DDP cells to cisplatin through the Wnt/β-catenin signaling pathway. Overexpression of β-catenin reduced the effects of RRM2 knockdown on A549 cells. Lung adenocarcinoma growth may be influenced by RRM2 through the Wnt/β-catenin signaling pathway, suggesting a potential pathway for cancer progression.
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Affiliation(s)
- Yongjie Jiang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Xing Hu
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Min Pang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Yuyan Huang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Bi Ren
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Liping He
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Li Jiang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
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Tang S, Leng M, Tan C, Zhu L, Pang Y, Zhang X, Chang YF, Lin W. Critical role for ribonucleoside-diphosphate reductase subunit M2 in ALV-J-induced activation of Wnt/β-catenin signaling via interaction with P27. J Virol 2023; 97:e0026723. [PMID: 37582207 PMCID: PMC10506463 DOI: 10.1128/jvi.00267-23] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 06/20/2023] [Indexed: 08/17/2023] Open
Abstract
Avian leukemia virus subgroup J (ALV-J) causes various diseases associated with tumor formation and decreased fertility and induced immunosuppressive disease, resulting in significant economic losses in the poultry industry globally. Virus usually exploits the host cellular machinery for their replication. Although there are increasing evidences for the cellular proteins involving viral replication, the interaction between ALV-J and host proteins leading to the pivotal steps of viral life cycle are still unclear. Here, we reported that ribonucleoside-diphosphate reductase subunit M2 (RRM2) plays a critical role during ALV-J infection by interacting with capsid protein P27 and activating Wnt/β-catenin signaling. We found that the expression of RRM2 is effectively increased during ALV-J infection, and that RRM2 facilitates ALV-J replication by interacting with viral capsid protein P27. Furthermore, ALV-J P27 activated Wnt/β-catenin signaling by promoting β-catenin entry into the nucleus, and RRM2 activated Wnt/β-catenin signaling by enhancing its phosphorylation at Ser18 during ALV-J infection. These data suggest that the upregulation of RRM2 expression by ALV-J infection favors viral replication in host cells via activating Wnt/β-catenin signaling. IMPORTANCE Our results revealed a novel mechanism by which RRM2 facilitates ALV-J growth. That is, the upregulation of RRM2 expression by ALV-J infection favors viral replication by interacting with capsid protein P27 and activating Wnt/β-catenin pathway in host cells. Furthermore, the phosphorylation of serine at position 18 of RRM2 was verified to be the important factor regulating the activation of Wnt/β-catenin signaling. This study provides insights for further studies of the molecular mechanism of ALV-J infection.
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Affiliation(s)
- Shuang Tang
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangdong Provincial Animal Virus Vector Vaccine Engineering Technology Research Center, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Mei Leng
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangdong Provincial Animal Virus Vector Vaccine Engineering Technology Research Center, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Chen Tan
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangdong Provincial Animal Virus Vector Vaccine Engineering Technology Research Center, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Lin Zhu
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangdong Provincial Animal Virus Vector Vaccine Engineering Technology Research Center, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Yanling Pang
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangdong Provincial Animal Virus Vector Vaccine Engineering Technology Research Center, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xinheng Zhang
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangdong Provincial Animal Virus Vector Vaccine Engineering Technology Research Center, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Yung-Fu Chang
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
| | - Wencheng Lin
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Guangdong Provincial Animal Virus Vector Vaccine Engineering Technology Research Center, College of Animal Science, South China Agricultural University, Guangzhou, China
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4
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Kałuzińska-Kołat Ż, Kołat D, Kośla K, Płuciennik E, Bednarek AK. Delineating the glioblastoma stemness by genes involved in cytoskeletal rearrangements and metabolic alterations. World J Stem Cells 2023; 15:302-322. [PMID: 37342224 PMCID: PMC10277965 DOI: 10.4252/wjsc.v15.i5.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/03/2023] [Accepted: 03/08/2023] [Indexed: 05/26/2023] Open
Abstract
Literature data on glioblastoma ongoingly underline the link between metabolism and cancer stemness, the latter is one responsible for potentiating the resistance to treatment, inter alia due to increased invasiveness. In recent years, glioblastoma stemness research has bashfully introduced a key aspect of cytoskeletal rearrangements, whereas the impact of the cytoskeleton on invasiveness is well known. Although non-stem glioblastoma cells are less invasive than glioblastoma stem cells (GSCs), these cells also acquire stemness with greater ease if characterized as invasive cells and not tumor core cells. This suggests that glioblastoma stemness should be further investigated for any phenomena related to the cytoskeleton and metabolism, as they may provide new invasion-related insights. Previously, we proved that interplay between metabolism and cytoskeleton existed in glioblastoma. Despite searching for cytoskeleton-related processes in which the investigated genes might have been involved, not only did we stumble across the relation to metabolism but also reported genes that were found to be implicated in stemness. Thus, dedicated research on these genes in GSCs seems justifiable and might reveal novel directions and/or biomarkers that could be utilized in the future. Herein, we review the previously identified cytoskeleton/metabolism-related genes through the prism of glioblastoma stemness.
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Affiliation(s)
- Żaneta Kałuzińska-Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland.
| | - Damian Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Katarzyna Kośla
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Elżbieta Płuciennik
- Department of Functional Genomics, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
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Miao Y, Su D, Fu Q, Chen T, Ji Y, Zhang F. Identification of CKS2 and RRM2 as potential markers of vitiligo using bioinformatics analysis. Medicine (Baltimore) 2022; 101:e31908. [PMID: 36401415 PMCID: PMC9678625 DOI: 10.1097/md.0000000000031908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Previous studies have attempted to elucidate the molecular mechanism of vitiligo; however, its pathogenesis remains unclear. This study aimed to explore biomarkers related to vitiligo through bioinformatic analysis. The microarray datasets GSE53146 and GSE65127 were downloaded from the Gene Expression Omnibus database. Firstly, differentially expressed genes (DEGs) in GSE53146 were screened, and then an enrichment analysis was performed. Secondly, the protein-protein interaction (PPI) network of DEGs was constructed using the STRING database, and the key genes were screened using the MCODE plugin in Cytoscape and verified using GSE65127. Finally, quantiseq was used to evaluate immune cell infiltration in vitiligo, then to observe the correlation between biomarkers and immune cells. In total, 544 DEGs were identified, including 342 upregulated and 202 downregulated genes. Gene Ontology (GO) enrichment showed that DEGs were related to inflammatory and immune responses, and Kyoto Encyclopedia of Genes and Genomes enrichment showed that DEGs were involved in many autoimmune diseases. In the PPI network, 7 key genes, CENPN, CKS2, PLK4, RRM2, TPX2, CCNA2, and CDC45 were identified by MCODE cluster and verified using the GSE65127 dataset. With an area under the curve (AUC) > 0.8 as the standard, 2 genes were screened, namely CKS2 and RRM2. Further immune infiltration analysis showed that M2 macrophages were involved in the pathogenesis of vitiligo, whereas CKS2 and RRM2 were both related to M2 macrophages. This study shows that CKS2 and RRM2 have potential as biomarkers of vitiligo and provides a theoretical basis for a better understanding of the pathogenesis of vitiligo.
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Affiliation(s)
- Yu Miao
- Department of Dermatology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Dongqiang Su
- Department of Dermatology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
- Department of Dermatology, Sixth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Qian Fu
- Department of Dermatology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Taoyu Chen
- Department of Dermatology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Yanqi Ji
- Department of Dermatology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Feng Zhang
- Department of Dermatology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
- Department of Dermatology, Sixth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
- * Correspondence: Feng Zhang, Department of Dermatology, Sixth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150023, China (e-mail: )
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Yu S, Han R, Gan R. The Wnt/β-catenin signalling pathway in Haematological Neoplasms. Biomark Res 2022; 10:74. [PMID: 36224652 PMCID: PMC9558365 DOI: 10.1186/s40364-022-00418-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/12/2022] [Accepted: 09/12/2022] [Indexed: 11/10/2022] Open
Abstract
Leukaemia and lymphoma are common malignancies. The Wnt pathway is a complex network of proteins regulating cell proliferation and differentiation, as well as cancer development, and is divided into the Wnt/β-catenin signalling pathway (the canonical Wnt signalling pathway) and the noncanonical Wnt signalling pathway. The Wnt/β-catenin signalling pathway is highly conserved evolutionarily, and activation or inhibition of either of the pathways may lead to cancer development and progression. The aim of this review is to analyse the mechanisms of action of related molecules in the Wnt/β-catenin pathway in haematologic malignancies and their feasibility as therapeutic targets.
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Affiliation(s)
- Siwei Yu
- Cancer Research Institute, Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P. R. China
| | - Ruyue Han
- Cancer Research Institute, Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P. R. China
| | - Runliang Gan
- Cancer Research Institute, Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P. R. China.
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Zhou J, Zhang M, Zhang Y, Shi X, Liu L, Yao R. Identification of Potential Prognostic Biomarker for Predicting Survival in Multiple Myeloma Using Bioinformatics Analysis and Experiments. Front Genet 2021; 12:722132. [PMID: 34567073 PMCID: PMC8461066 DOI: 10.3389/fgene.2021.722132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/11/2021] [Indexed: 12/21/2022] Open
Abstract
Multiple myeloma (MM) is a malignant disease of plasma cells, which remains incurable because of its unclear mechanism and drug resistance. Herein, we aimed to explore new biomarkers and therapeutic targets in MM. After screening differentially expressed genes (DEGs) in GSE6477 and GSE13591 dataset, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of DEGs using DAVID online database. The results indicated that the downregulated DEGs were mainly enriched in the immune-associated biological process. The protein–protein interaction network was constructed by STRING database, on which we performed module analysis and identified key genes. Gene set enrichment analysis (GSEA) and Kaplan–Meier analysis showed that RRM2 could be a novel biomarker in MM diagnosis. We further confirmed that novel RRM2 inhibitor osalmid inhibited MM cell proliferation and triggered cell cycle S phase arrest. Targeting RRM2 was expected to develop new therapeutic strategies for malignant MM.
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Affiliation(s)
- Jian Zhou
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Menghui Zhang
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yan Zhang
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xi Shi
- Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, China
| | - Linlin Liu
- College of Medical Imaging, Xuzhou Medical University, Xuzhou, China
| | - Ruosi Yao
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Xuzhou Ruihu Health Management and Consulting Co., Ltd., Xuzhou, China
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Yuan Y, Guo M, Gu C, Yang Y. The role of Wnt/β-catenin signaling pathway in the pathogenesis and treatment of multiple myeloma (review). Am J Transl Res 2021; 13:9932-9949. [PMID: 34650674 PMCID: PMC8507016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 06/07/2021] [Indexed: 06/13/2023]
Abstract
Multiple myeloma (MM) is a refractory hematological malignancy characterized by aberrant accumulation of plasma cells. Patients with MM are susceptible to becoming resistant to chemotherapy, eventually leading to relapse. Progression of MM is largely dependent on the bone marrow microenvironment. Stromal cells in the bone marrow microenvironment secrete Wnt ligands to activate Wnt signaling in MM, which is mediated through the transcription regulator β-catenin. In addition, Wnt/β-catenin pathway encourages osteoblast differentiation and bone formation, dysregulation of which is responsible for proliferation and drug resistance of MM cells. As a result, direct inhibition or silencing of β-catenin or associated genes in the Wnt/β-catenin pathway has been proposed to be an effective therapeutic anti-MM strategy. However, the underlying regulatory mechanism of the Wnt/β-catenin pathway in MM remains to be fully elucidated. Herein, we summarized research advances on the specific genes and molecular biology process of Wnt/β-catenin pathway involved in tumorigenesis of MM, as well as the interaction with bone marrow microenvironment. Additionally, comprehensive summaries of drugs or small molecule inhibitors acting on Wnt/β-catenin pathway and targeting MM were introduced. This review intends to provide an overview of theoretical supports for novel Wnt/β-catenin pathway based treatment strategies in MM.
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Affiliation(s)
- Yuxia Yuan
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineNanjing 210022, Jiangsu, China
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineNanjing 210023, Jiangsu, China
| | - Mengjie Guo
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineNanjing 210023, Jiangsu, China
| | - Chunyan Gu
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineNanjing 210022, Jiangsu, China
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineNanjing 210023, Jiangsu, China
| | - Ye Yang
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineNanjing 210022, Jiangsu, China
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineNanjing 210023, Jiangsu, China
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Liu W, Xie L, He YH, Wu ZY, Liu LX, Bai XF, Deng DX, Xu XE, Liao LD, Lin W, Heng JH, Xu X, Peng L, Huang QF, Li CY, Zhang ZD, Wang W, Zhang GR, Gao X, Wang SH, Li CQ, Xu LY, Liu W, Li EM. Large-scale and high-resolution mass spectrometry-based proteomics profiling defines molecular subtypes of esophageal cancer for therapeutic targeting. Nat Commun 2021; 12:4961. [PMID: 34400640 PMCID: PMC8368010 DOI: 10.1038/s41467-021-25202-5] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 07/26/2021] [Indexed: 02/07/2023] Open
Abstract
Esophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment. To define molecular subtypes of EC, we perform mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues, revealing a catalog of proteins and phosphosites that are dysregulated in ECs. The EC cohort is stratified into two molecular subtypes-S1 and S2-based on proteomic analysis, with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins, and being more aggressive. Moreover, we identify a subtype signature composed of ELOA and SCAF4, and construct a subtype diagnostic and prognostic model. Potential drugs are predicted for treating patients of S2 subtype, and three candidate drugs are validated to inhibit EC. Taken together, our proteomic analysis define molecular subtypes of EC, thus providing a potential therapeutic outlook for improving disease outcomes in patients with EC.
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Affiliation(s)
- Wei Liu
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
- College of Science, Heilongjiang Institute of Technology, Harbin, Heilongjiang, China
| | - Lei Xie
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Yao-Hui He
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
| | - Zhi-Yong Wu
- Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou, Guangdong, China
| | - Lu-Xin Liu
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Xue-Feng Bai
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, Heilongjiang, China
| | - Dan-Xia Deng
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Xiu-E Xu
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Lian-Di Liao
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Wan Lin
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Jing-Hua Heng
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Xin Xu
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Liu Peng
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Qing-Feng Huang
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Cheng-Yu Li
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Zhi-Da Zhang
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Wei Wang
- College of Science, Heilongjiang Institute of Technology, Harbin, Heilongjiang, China
| | - Guo-Rui Zhang
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, Heilongjiang, China
| | - Xiang Gao
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
| | - Shao-Hong Wang
- Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou, Guangdong, China
| | - Chun-Quan Li
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, Heilongjiang, China
| | - Li-Yan Xu
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China.
| | - Wen Liu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China.
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China.
| | - En-Min Li
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China.
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Kałuzińska Ż, Kołat D, Bednarek AK, Płuciennik E. PLEK2, RRM2, GCSH: A Novel WWOX-Dependent Biomarker Triad of Glioblastoma at the Crossroads of Cytoskeleton Reorganization and Metabolism Alterations. Cancers (Basel) 2021; 13:2955. [PMID: 34204789 PMCID: PMC8231639 DOI: 10.3390/cancers13122955] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/30/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma is one of the deadliest human cancers. Its malignancy depends on cytoskeleton reorganization, which is related to, e.g., epithelial-to-mesenchymal transition and metastasis. The malignant phenotype of glioblastoma is also affected by the WWOX gene, which is lost in nearly a quarter of gliomas. Although the role of WWOX in the cytoskeleton rearrangement has been found in neural progenitor cells, its function as a modulator of cytoskeleton in gliomas was not investigated. Therefore, this study aimed to investigate the role of WWOX and its collaborators in cytoskeleton dynamics of glioblastoma. Methodology on RNA-seq data integrated the use of databases, bioinformatics tools, web-based platforms, and machine learning algorithm, and the obtained results were validated through microarray data. PLEK2, RRM2, and GCSH were the most relevant WWOX-dependent genes that could serve as novel biomarkers. Other genes important in the context of cytoskeleton (BMP4, CCL11, CUX2, DUSP7, FAM92B, GRIN2B, HOXA1, HOXA10, KIF20A, NF2, SPOCK1, TTR, UHRF1, and WT1), metabolism (MTHFD2), or correlation with WWOX (COL3A1, KIF20A, RNF141, and RXRG) were also discovered. For the first time, we propose that changes in WWOX expression dictate a myriad of alterations that affect both glioblastoma cytoskeleton and metabolism, rendering new therapeutic possibilities.
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Affiliation(s)
- Żaneta Kałuzińska
- Department of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, Poland; (D.K.); (A.K.B.); (E.P.)
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Hachim MY, Elemam NM, Ramakrishnan RK, Salameh L, Olivenstein R, Hachim IY, Venkatachalam T, Mahboub B, Al Heialy S, Hamid Q, Hamoudi R. Derangement of cell cycle markers in peripheral blood mononuclear cells of asthmatic patients as a reliable biomarker for asthma control. Sci Rep 2021; 11:11873. [PMID: 34088958 PMCID: PMC8178351 DOI: 10.1038/s41598-021-91087-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/20/2021] [Indexed: 12/14/2022] Open
Abstract
In asthma, most of the identified biomarkers pertain to the Th2 phenotype and no known biomarkers have been verified for severe asthmatics. Therefore, identifying biomarkers using the integrative phenotype-genotype approach in severe asthma is needed. The study aims to identify novel biomarkers as genes or pathways representing the core drivers in asthma development, progression to the severe form, resistance to therapy, and tissue remodeling regardless of the sample cells or tissues examined. Comprehensive reanalysis of publicly available transcriptomic data that later was validated in vitro, and locally recruited patients were used to decipher the molecular basis of asthma. Our in-silicoanalysis revealed a total of 10 genes (GPRC5A, SFN, ABCA1, KRT8, TOP2A, SERPINE1, ANLN, MKI67, NEK2, and RRM2) related to cell cycle and proliferation to be deranged in the severe asthmatic bronchial epithelium and fibroblasts compared to their healthy counterparts. In vitro, RT qPCR results showed that (SERPINE1 and RRM2) were upregulated in severe asthmatic bronchial epithelium and fibroblasts, (SFN, ABCA1, TOP2A, SERPINE1, MKI67, and NEK2) were upregulated in asthmatic bronchial epithelium while (GPRC5A and KRT8) were upregulated only in asthmatic bronchial fibroblasts. Furthermore, MKI76, RRM2, and TOP2A were upregulated in Th2 high epithelium while GPRC5A, SFN, ABCA1 were upregulated in the blood of asthmatic patients. SFN, ABCA1 were higher, while MKI67 was lower in severe asthmatic with wheeze compared to nonasthmatics with wheezes. SERPINE1 and GPRC5A were downregulated in the blood of eosinophilic asthmatics, while RRM2 was upregulated in an acute attack of asthma. Validation of the gene expression in PBMC of locally recruited asthma patients showed that SERPINE1, GPRC5A, SFN, ABCA1, MKI67, and RRM2 were downregulated in severe uncontrolled asthma. We have identified a set of biologically crucial genes to the homeostasis of the lung and in asthma development and progression. This study can help us further understand the complex interplay between the transcriptomic data and the external factors which may deviate our understanding of asthma heterogeneity.
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Affiliation(s)
- Mahmood Yaseen Hachim
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates.
- Center for Genomic Discovery, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates.
| | - Noha Mousaad Elemam
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Rakhee K Ramakrishnan
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Laila Salameh
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | | | - Ibrahim Yaseen Hachim
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Thenmozhi Venkatachalam
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Bassam Mahboub
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Saba Al Heialy
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
- Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada
| | - Qutayba Hamid
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Division of Surgery and Interventional Science, UCL, London, UK
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12
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Jin G, Wang K, Liu Y, Liu X, Zhang X, Zhang H. Proteomic Level Changes on Treatment in MCF-7/DDP Breast Cancer Drug- Resistant Cells. Anticancer Agents Med Chem 2021; 20:687-699. [PMID: 32053082 PMCID: PMC7403652 DOI: 10.2174/1871520620666200213102849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 11/07/2019] [Accepted: 12/05/2019] [Indexed: 01/23/2023]
Abstract
Background
LCL161, a SMAC’S small molecule mimetic, can bind to a variety of IAPs and activate Caspases. We found that on its own, LCL161induces apoptosis of drug-resistant breast cancer cells by binding to a variety of IAPs and activating Caspases. However, when LCL161 is used in combination with Caspase Inhibitors (CI), its capacity to induce apoptosis of breast cancer cells is enhanced. Objective
To carry out proteomic and bioinformatics analysis of LCL161 in combination with CI. We aim to identify the key proteins and mechanisms of breast cancer drug-resistant apoptosis, thereby aiding in the breast cancer drug resistance treatment and identification of drug targeting markers. Methods
Cell culture experiments were carried out to explore the effect of LCL161 combined with CI on the proliferation of breast cancer drug-resistant cells. Proteomic analysis was carried out to determine the protein expression differences between breast cancer drug-resistant cells and LCL161 combined with CI treated cells. Bioinformatics analysis was carried out to determine its mechanism of action. Validation of proteomics results was done using Parallel Reaction Monitoring (PRM). Results
Cell culture experiments showed that LCL161 in combination with CI can significantly promote the apoptosis of breast cancer drug-resistant cells. Up-regulation of 92 proteins and down-regulation of 114 proteins protein were noted, of which 4 were selected for further validation. Conclusion
Our results show that LCL161 combined with CI can promote the apoptosis of drug-resistant breast cancer cells by down-regulation of RRM2, CDK4, and ITGB1 expression through Cancer pathways, p53 or PI3K-AKT signaling pathway. In addition, the expression of CDK4, RRM2, and CDC20 can be down-regulated by the nuclear receptor pathway to affect DNA transcription and replication, thereby promoting apoptosis of breast cancer drug-resistant cells.
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Affiliation(s)
- Gongshen Jin
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu, Medical University, 287 Changhuai Road, Bengbu, Anhui 233030, China
| | - Kangwei Wang
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu, Medical University, 287 Changhuai Road, Bengbu, Anhui 233030, China
| | - Yonghong Liu
- First People's Hospital of Yuhang District, Hangzhou 310000, China
| | - Xianhu Liu
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu, Medical University, 287 Changhuai Road, Bengbu, Anhui 233030, China
| | - Xiaojing Zhang
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu, Medical University, 287 Changhuai Road, Bengbu, Anhui 233030, China
| | - Hao Zhang
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu, Medical University, 287 Changhuai Road, Bengbu, Anhui 233030, China
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Xie Y, Xue C, Guo S, Yang L. MicroRNA-520a Suppresses Pathogenesis and Progression of Non-Small-Cell Lung Cancer through Targeting the RRM2/Wnt Axis. Anal Cell Pathol (Amst) 2021; 2021:9652420. [PMID: 33859925 PMCID: PMC8026327 DOI: 10.1155/2021/9652420] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 01/14/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) regulate multiple cellular behaviors, and their aberrant expression is frequently associated with disease progression. This research focused on the effects of miR-520a on the development of non-small-cell lung cancer (NSCLC) and the molecules involved. Tumor and normal tissues from 24 patients with NSCLC were collected. Differentially expressed miRNAs between tumor tissues and normal tissues were screened using microarrays, and miR-520a was screened to be significantly poorly expressed in tumor samples. Artificial upregulation of miR-520a reduced proliferation, migration and invasion, and resistance to death of NSCLC A549 and H460 cells according to the MTT, EdU labeling, transwell, and flow cytometry assays, respectively. miR-520a upregulation suppressed growth and metastasis of xenograft tumors in vivo. The integrated bioinformatic analysis and dual luciferase assays suggested that miR-520a targeted ribonucleotide reductase subunit 2 (RRM2) mRNA and inactivated the Wnt/β-catenin signaling pathway in NSCLC cells. Upregulation of RRM2 enhanced the malignant behaviors of NSCLCs, but the oncogenic effects of RRM2 were blocked upon miR-520a overexpression. To conclude, this study evidenced that miR-520a inhibits NSCLC progression through suppressing RRM2 and the Wnt signaling pathway. This paper may offer novel insights into NSCLC treatment.
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Affiliation(s)
- Yi Xie
- Department of Respiratory Oncology, Shandong Provincial Chest Hospital, Jinan, 250013 Shandong, China
| | - Congyu Xue
- Department of Tuberculosis, Shandong Provincial Chest Hospital, Jinan, 250013 Shandong, China
| | - Shuai Guo
- Department of Respiratory Oncology, Shandong Provincial Chest Hospital, Jinan, 250013 Shandong, China
| | - Lei Yang
- Department of Tuberculosis, Shandong Provincial Chest Hospital, Jinan, 250013 Shandong, China
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Fan W, Shi R, Guan M, Chen P, Wu H, Su W, Wang Y, Li P. The Effects of Naringenin on miRNA-mRNA Profiles in HepaRG Cells. Int J Mol Sci 2021; 22:ijms22052292. [PMID: 33669020 PMCID: PMC7956767 DOI: 10.3390/ijms22052292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/15/2021] [Accepted: 02/20/2021] [Indexed: 12/12/2022] Open
Abstract
Naringenin, a natural flavonoid widely found in citrus fruits, has been reported to possess anti-oxidant, anti-inflammatory, and hepatoprotective properties as a natural dietary supplement. However, the regulatory mechanism of naringenin in human liver remains unclear. In the present study, messenger RNA sequencing (mRNA-seq), microRNA sequencing (miRNA-seq), and real-time qPCR were used to distinguish the expression differences between control and naringenin-treated HepaRG cells. We obtained 1037 differentially expressed mRNAs and 234 miRNAs. According to the target prediction and integration analysis in silico, we found 20 potential miRNA-mRNA pairs involved in liver metabolism. This study is the first to provide a perspective of miRNA–mRNA interactions in the regulation of naringenin via an integrated analysis of mRNA-seq and miRNA-seq in HepaRG cells, which further characterizes the nutraceutical value of naringenin as a food additive.
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Affiliation(s)
| | | | | | | | | | | | | | - Peibo Li
- Correspondence: ; Tel.: +86-20-8411-2398; Fax: +86-20-8411-2398
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Ma C, Luo H, Cao J, Gao C, Fa X, Wang G. Independent prognostic implications of RRM2 in lung adenocarcinoma. J Cancer 2020; 11:7009-7022. [PMID: 33123291 PMCID: PMC7592001 DOI: 10.7150/jca.47895] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 10/03/2020] [Indexed: 12/16/2022] Open
Abstract
Background: Ribonucleoside-diphosphate reductase subunit M2 (RRM2) is the catalytic subunit of ribonucleotide reductase and modulates the enzymatic activity, which is essential for DNA replication and repair. However, the role of RRM2 in lung adenocarcinoma (LUAD) remains unclear. Methods: In this study, we explored the expression pattern and prognostic value of RRM2 in LUAD across TCGA, GEO, Oncomine, UALCAN, PrognoScan, and Kaplan-Meier Plotter, and confirmed its independent prognostic value via Cox analyses. LinkedOmics and GEPIA2 were applied to investigate co-expression and functional networks associated with RRM2. Besides, we used TIMER to assess the correlation between RRM2 and the main six types of tumor-infiltrating immune cells. Lastly, the correlations between immune signatures of immunomodulators, chemokines, and 28 tumor-infiltrating lymphocytes (TILs) and RRM2 were examined by tumor purity-corrected partial Spearman's rank correlation coefficient through TIMER portal. Results:RRM2 was found upregulated in tumor tissues in TCGA-LUAD, and validated in multiple independent cohorts. Moreover, whether in TCGA or other cohorts, high RRM2 expression was found to be associated with poor survival. Cox analyses showed that high RRM2 expression was an independent risk factor for overall survival, disease-specific survival, and progression-free survival of LUAD. Functional network analysis suggested that RRM2 regulates RNA transport, oocyte meiosis, spliceosome, ribosome biogenesis in eukaryotes, and cellular senescence signaling through pathways involving multiple cancer-related kinases and E2F family. Also, RRM2 expression correlated with infiltrating levels of B cells, CD4+ T cells, and neutrophils. Subsequent analysis found that B cells and dendritic cells could predict the outcome of LUAD. B cells were identified as an independent risk factor among six types of immune cells through Cox analyses. At last, the correlation analysis showed RRM2 correlated with 67.68% (624/922) of the immune signatures we performed. Conclusion: Our research showed that RRM2 could independently predict the prognosis of LUAD and was associated with immune infiltration. In particular, the tight relationship between RRM2 and B cell marker genes are the potential epicenter of the immune response and one of the critical factors affecting the prognosis. Our findings laid the foundation for further research on the immunomodulatory role of RRM2 in LUAD.
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Affiliation(s)
- Chao Ma
- Department of Cardiothoracic Surgery, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health.,Charité - Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany.,Department of Thoracic Surgery, the First Affiliated Hospital of Southern University of Sciences and Technology, Shenzhen People's Hospital, Shenzhen, China
| | - Huan Luo
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health.,Klinik für Augenheilkunde, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jing Cao
- Department of Human Anatomy, School of Basic Medicine, Zhengzhou University, Zhengzhou, China
| | - Chengshan Gao
- Department of Cardiothoracic Surgery, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xianen Fa
- Department of Cardiothoracic Surgery, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangsuo Wang
- Department of Thoracic Surgery, the First Affiliated Hospital of Southern University of Sciences and Technology, Shenzhen People's Hospital, Shenzhen, China
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