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Idris OA, Westgate D, Saadaie Jahromi B, Shebrain A, Zhang T, Ashour HM. PD-L1 Inhibitor Cosibelimab for Cutaneous Squamous Cell Carcinoma: Comprehensive Evaluation of Efficacy, Mechanism, and Clinical Trial Insights. Biomedicines 2025; 13:889. [PMID: 40299523 PMCID: PMC12024788 DOI: 10.3390/biomedicines13040889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 03/18/2025] [Accepted: 03/19/2025] [Indexed: 04/30/2025] Open
Abstract
Cutaneous squamous cell carcinoma (CSCC) is one of the most common non-melanoma skin cancers, and particularly challenging to treat in advanced or metastatic stages. Traditional therapies, including chemotherapy and radiation, often result in limited efficacy and severe side effects. Cosibelimab, a fully human monoclonal antibody targeting PD-L1, has emerged as a promising immunotherapy for advanced CSCC. In this review, we evaluate the therapeutic potential of cosibelimab by analyzing its mechanism of action, clinical trial data, and its role compared to other PD-1/PD-L1 inhibitors, such as pembrolizumab and cemiplimab. We synthesized the available preclinical and clinical data on cosibelimab, focusing on published Phase I and II trial results involving 76 patients. Objective response rates (ORRs), progression-free survival (PFS), overall survival (OS), and safety profiles were compared between cosibelimab, pembrolizumab, and cemiplimab. Mechanistic insights into cosibelimab's dual action, including PD-L1 blockade and antibody-dependent cellular cytotoxicity (ADCC), were also explored. Phase II trials demonstrated an ORR of 47.5%, with a median PFS of 12.9 months in advanced CSCC patients. Cosibelimab demonstrated a favorable safety profile, with predominantly mild to moderate adverse events. Comparative analysis with pembrolizumab and cemiplimab showed similar efficacy, although long-term survival data for cosibelimab is still emerging. Given its efficacy and safety, cosibelimab holds promise not only as a monotherapy but also for future exploration in combination regimens and broader oncologic indications. Future trials are required to validate its long-term outcomes, including overall survival, and to explore its use in combination therapies and neoadjuvant/adjuvant settings.
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Affiliation(s)
- Omer A. Idris
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI 49008, USA; (O.A.I.); (A.S.)
- Malate Institute for Medical Research, Malate Inc., Grandville, MI 49468, USA
| | - Diana Westgate
- Homer Stryker MD School of Medicine, Western Michigan University, Kalamazoo, MI 49008, USA
- Forefront Dermatology, Kalamazoo, MI 49007, USA
| | - Bahar Saadaie Jahromi
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI 49008, USA; (O.A.I.); (A.S.)
| | - Abdulaziz Shebrain
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI 49008, USA; (O.A.I.); (A.S.)
| | - Tiantian Zhang
- Department of Hematology and Hematopoietic Stem Cell Transplantation, Toni Stephenson Lymphoma Center, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Hossam M. Ashour
- Department of Integrative Biology, College of Arts and Sciences, University of South Florida, St. Petersburg, FL 33701, USA
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Heiskanen L, Nissinen L, Siljamäki E, Knuutila JS, Pellinen T, Kallajoki M, Heino J, Riihilä P, Kähäri VM. C5aR1 Promotes Invasion, Metastasis, and Poor Prognosis in Cutaneous Squamous Cell Carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00073-2. [PMID: 40056975 DOI: 10.1016/j.ajpath.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 01/31/2025] [Accepted: 02/11/2025] [Indexed: 03/18/2025]
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and the metastatic from is associated with a poor prognosis. Here, the role of the complement C5a receptor C5aR1 was examined in the progression and metastasis of cSCC. C5aR1 expression was increased in cSCC cells in a three-dimensional spheroid coculture model in the presence of fibroblasts, and treatment with recombinant C5a enhanced the invasion of cSCC cells. Staining for C5aR1 was detected on the surface of tumor cells at the invasive edge of human cSCC xenografts in vivo. Staining of metastatic and non-metastatic primary human cSCCs, premalignant and benign epidermal lesions, and normal skin for C5aR1 with multiplex immunofluorescence and chromogenic immunohistochemistry revealed increased expression of C5aR1 on the surface of tumor cells and fibroblasts in invasive cSCCs and recessive dystrophic epidermolysis bullosa-associated cSCCs compared with cSCC in situ, actinic keratoses, seborrheic keratoses, and normal skin. Increased expression of C5aR1 on the tumor cell surface and in fibroblasts was associated with metastatic risk and poor disease-specific survival of patients with primary cSCC. These findings suggest a role of C5a in cSCC cell invasion, and they identify C5aR1 as a novel biomarker for metastasis risk and poor prognosis in patients with cSCC. The results also suggest that C5aR1 could be a novel therapeutic target for the treatment of locally advanced and metastatic cSCC.
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Affiliation(s)
- Lauri Heiskanen
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland
| | - Liisa Nissinen
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland
| | - Elina Siljamäki
- Department of Life Technologies and InFLAMES Research Flagship, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Jaakko S Knuutila
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland
| | - Teijo Pellinen
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Markku Kallajoki
- Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland
| | - Jyrki Heino
- Department of Life Technologies and InFLAMES Research Flagship, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Pilvi Riihilä
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland
| | - Veli-Matti Kähäri
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland.
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Balduit A, Agostinis C, Bulla R. Beyond the Norm: The emerging interplay of complement system and extracellular matrix in the tumor microenvironment. Semin Immunol 2025; 77:101929. [PMID: 39793258 DOI: 10.1016/j.smim.2025.101929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/20/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025]
Abstract
Ground-breaking awareness has been reached about the intricate and dynamic connection between developing tumors and the host immune system. Being a powerful arm of innate immunity and a functional bridge with adaptive immunity, the complement system (C) has also emerged as a pivotal player in the tumor microenvironment (TME). Its "double-edged sword" role in cancer can find an explanation in the controversial relationship between C capability to mediate tumor cell cytolysis or, conversely, to sustain chronic inflammation and tumor progression by enhancing cell invasion, angiogenesis, and metastasis to distant organs. However, comprehensive knowledge about the actual role of C in cancer progression is impaired by several limitations of the currently available studies. In the current review, we aim to bring a fresh eye to the controversial role of C in cancer by analyzing the interplay between C and extracellular matrix (ECM) components as potential orchestrators of the TME. The interaction of C components with specific ECM components can determine C activation or inhibition and promote specific non-canonical functions, which can, in the tumor context, favor or limit progression based on the cancer setting. An in-depth and tumor-specific characterization of TME composition in terms of C components and ECM proteins could be essential to determine their potential interactions and become a key element for improving drug development, prognosis, and therapy response prediction in solid tumors.
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Affiliation(s)
- Andrea Balduit
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy
| | - Chiara Agostinis
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy
| | - Roberta Bulla
- Department of Life Sciences, University of Trieste, Trieste, Italy.
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Cao M, Zhang W, Chen J, Zhang Y. Identification of a coagulation-related gene signature for predicting prognosis in recurrent glioma. Discov Oncol 2024; 15:642. [PMID: 39527288 PMCID: PMC11555177 DOI: 10.1007/s12672-024-01520-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Recurrent gliomas rapidly progress and have high mortality and poor prognosis in the central nervous system. Therefore, further investigation of prognostic and therapeutic markers is needed. METHODS The mRNA expression, clinical data, and coagulation-related genes (CRGs) associated with recurrent glioma were obtained and calculated from the Chinese Glioma Genome Atlas and Kyoto Encyclopedia of Genes and Genomes databases. The significant CRGs were calculated by Weighted gene co-expression network analysis and PPI network. A prediction model was constructed using the least absolute shrinkage and selection operator regression analysis. Recurrent gliomas were stratified into high and low-risk groups based on the median risk score (RS). The Kaplan-Meier curve was used to analyze the difference in overall survival (OS) between these groups, while the receiver operating characteristic (ROC) curve was used to evaluate the accuracy of the gene model at 1-, 3-, and 5-years. Clinical factors, including age, gender, MGMT methylation status, radiotherapy, chemotherapy, and RS, were included in the univariate and multivariate regression analysis. A prognostic nomogram and calibration curve were established based on these factors. RESULTS Overall, seven CRGs associated with the prognosis were identified, including BTK, ITGB1, GNAI3, CFH, LYN, CFI, and F3. OS and survival rates were lower in the high-risk group compared with the low-risk group. The ROC curve demonstrated the area under the curve values >0.65 at 1-, 3-, and 5-years, confirming the reliability of the prognostic model. The univariate regression analysis indicated that tumor grade (grades 2, 3, and 4), histopathology (GBM or not), chemotherapy, IDH mutation, and 1p19q co-deletion status were independent prognostic indicators. Univariate and multivariate regression analyses indicated that RS was an independent prognostic factor for patients with recurrent glioma. Immune analysis revealed low infiltration of resting dendritic cells and high expression of programmed death receptor 1 in the high-risk group. CONCLUSION This study comprehensively investigated the correlation between CRGs and recurrent glioma prognosis, offering crucial insights for further research into glioma recurrence mechanisms and treatment strategies.
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Affiliation(s)
- Ming Cao
- Department of Neurosurgery, WuXi Children's Hospital, Wuxi, 214000, China.
| | - Wenwen Zhang
- Department of Oncology, Wuxi Taihu Hospital, Wuxi, 214000, China
| | - Jie Chen
- Department of Neurosurgery, WuXi Children's Hospital, Wuxi, 214000, China
| | - Yuchen Zhang
- Department of Neurosurgery, WuXi Children's Hospital, Wuxi, 214000, China
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Liu G, He X, Zhao G, Lu Z. Complement regulation in tumor immune evasion. Semin Immunol 2024; 76:101912. [PMID: 39579520 DOI: 10.1016/j.smim.2024.101912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/18/2024] [Accepted: 11/18/2024] [Indexed: 11/25/2024]
Abstract
The complement system plays crucial roles in both innate and adaptive immune responses, facilitating the elimination of pathogens such as microorganisms and damaged cells, including cancer cells. It is tightly regulated and integrated with cell-mediated immunity. In the tumor microenvironment, the complement system performs both immune and nonimmune functions in tumor and immune cells through pathways that depend on or are independent of complement activation, thereby promoting immune evasion and tumor progression.
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Affiliation(s)
- Guijun Liu
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China
| | - Xuxiao He
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China
| | - Gaoxiang Zhao
- Department of Oncology, Cancer Institute of The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266061, China
| | - Zhimin Lu
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China.
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Nissinen L, Haalisto J, Riihilä P, Piipponen M, Kähäri VM. Clustering of RNA co-expression network identifies novel long non-coding RNA biomarkers in squamous cell carcinoma. Sci Rep 2024; 14:16864. [PMID: 39043845 PMCID: PMC11266547 DOI: 10.1038/s41598-024-67808-x] [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: 01/05/2024] [Accepted: 07/16/2024] [Indexed: 07/25/2024] Open
Abstract
Long non-coding RNAs (lncRNAs) have emerged as important players in cancer progression. Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer with increasing incidence worldwide. The prognosis of the metastatic cSCC is poor, and currently there are no established biomarkers to predict metastasis risk or specific therapeutic targets for advanced or metastatic cSCC. To elucidate the role of lncRNAs in cSCC, RNA sequencing of patient derived cSCC cell lines and normal human epidermal keratinocytes was performed. The correlation analysis of differentially expressed lncRNAs and protein-coding genes revealed six distinct gene clusters with one of the upregulated clusters featuring genes associated with cell motility. Upregulation of the expression of lncRNAs linked to cSCC cell motility in cSCC and head and neck SCC (HNSCC) cells was confirmed using qRT-PCR. Elevated expression of HOTTIP and LINC00543 was also noted in SCC tumors in vivo and was associated with poorer prognosis in HNSCC and lung SCC cohorts within TCGA data, respectively. Altogether, these findings uncover a novel set of lncRNAs implicated in cSCC cell locomotion. These lncRNAs may serve as potential novel biomarkers and as putative therapeutic targets for locally advanced and metastatic cSCC.
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Affiliation(s)
- Liisa Nissinen
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520, Turku, Finland
- FICAN West Cancer Centre Research Laboratory, University of Turku and Turku University Hospital, FI-20520, Turku, Finland
| | - Josefiina Haalisto
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520, Turku, Finland
- FICAN West Cancer Centre Research Laboratory, University of Turku and Turku University Hospital, FI-20520, Turku, Finland
| | - Pilvi Riihilä
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520, Turku, Finland
- FICAN West Cancer Centre Research Laboratory, University of Turku and Turku University Hospital, FI-20520, Turku, Finland
| | - Minna Piipponen
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520, Turku, Finland
- FICAN West Cancer Centre Research Laboratory, University of Turku and Turku University Hospital, FI-20520, Turku, Finland
| | - Veli-Matti Kähäri
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520, Turku, Finland.
- FICAN West Cancer Centre Research Laboratory, University of Turku and Turku University Hospital, FI-20520, Turku, Finland.
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Du YJ, Jiang Y, Hou YM, Shi YB. Complement factor I knockdown inhibits colon cancer development by affecting Wnt/β-catenin/c-Myc signaling pathway and glycolysis. World J Gastrointest Oncol 2024; 16:2634-2650. [DOI: 10.4251/wjgo.v16.i6.2634] [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: 10/27/2023] [Revised: 01/24/2024] [Accepted: 03/27/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Colon cancer (CC) occurrence and progression are considerably influenced by the tumor microenvironment. However, the exact underlying regulatory mechanisms remain unclear.
AIM To investigate immune infiltration-related differentially expressed genes (DEGs) in CC and specifically explored the role and potential molecular mechanisms of complement factor I (CFI).
METHODS Immune infiltration-associated DEGs were screened for CC using bioinformatics. Quantitative reverse transcription polymerase chain reaction was used to examine hub DEGs expression in the CC cell lines. Stable CFI-knockdown HT29 and HCT116 cell lines were constructed, and the diverse roles of CFI in vitro were assessed using CCK-8, 5-ethynyl-2’-deoxyuridine, wound healing, and transwell assays. Hematoxylin and eosin staining and immunohistochemistry staining were employed to evaluate the influence of CFI on the tumorigenesis of CC xenograft models constructed using BALB/c male nude mice. Key proteins associated with glycolysis and the Wnt pathway were measured using western blotting.
RESULTS Six key immune infiltration-related DEGs were screened, among which the expression of CFI, complement factor B, lymphoid enhancer binding factor 1, and SRY-related high-mobility-group box 4 was upregulated, whereas that of fatty acid-binding protein 1, and bone morphogenic protein-2 was downregulated. Furthermore, CFI could be used as a diagnostic biomarker for CC. Functionally, CFI silencing inhibited CC cell proliferation, migration, invasion, and tumor growth. Mechanistically, CFI knockdown downregulated the expression of key glycolysis-related proteins (glucose transporter type 1, hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2) and the Wnt pathway-related proteins (β-catenin and c-Myc). Further investigation indicated that CFI knockdown inhibited glycolysis in CC by blocking the Wnt/β-catenin/c-Myc pathway.
CONCLUSION The findings of the present study demonstrate that CFI plays a crucial role in CC development by influencing glycolysis and the Wnt/β-catenin/c-Myc pathway, indicating that it could serve as a promising target for therapeutic intervention in CC.
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Affiliation(s)
- Yong-Jun Du
- Department of Proctology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
| | - Yue Jiang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Yan-Mei Hou
- Department of Proctology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
| | - Yong-Bo Shi
- Department of Proctology, Zigong Hospital of Traditional Chinese Medicine, Zigong 643000, Sichuan Province, China
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Du YJ, Jiang Y, Hou YM, Shi YB. Complement factor I knockdown inhibits colon cancer development by affecting Wnt/β-catenin/c-Myc signaling pathway and glycolysis. World J Gastrointest Oncol 2024; 16:2646-2662. [PMID: 38994157 PMCID: PMC11236223 DOI: 10.4251/wjgo.v16.i6.2646] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 01/24/2024] [Accepted: 03/27/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Colon cancer (CC) occurrence and progression are considerably influenced by the tumor microenvironment. However, the exact underlying regulatory mechanisms remain unclear. AIM To investigate immune infiltration-related differentially expressed genes (DEGs) in CC and specifically explored the role and potential molecular mechanisms of complement factor I (CFI). METHODS Immune infiltration-associated DEGs were screened for CC using bioinformatics. Quantitative reverse transcription polymerase chain reaction was used to examine hub DEGs expression in the CC cell lines. Stable CFI-knockdown HT29 and HCT116 cell lines were constructed, and the diverse roles of CFI in vitro were assessed using CCK-8, 5-ethynyl-2'-deoxyuridine, wound healing, and transwell assays. Hematoxylin and eosin staining and immunohistochemistry staining were employed to evaluate the influence of CFI on the tumorigenesis of CC xenograft models constructed using BALB/c male nude mice. Key proteins associated with glycolysis and the Wnt pathway were measured using western blotting. RESULTS Six key immune infiltration-related DEGs were screened, among which the expression of CFI, complement factor B, lymphoid enhancer binding factor 1, and SRY-related high-mobility-group box 4 was upregulated, whereas that of fatty acid-binding protein 1, and bone morphogenic protein-2 was downregulated. Furthermore, CFI could be used as a diagnostic biomarker for CC. Functionally, CFI silencing inhibited CC cell proliferation, migration, invasion, and tumor growth. Mechanistically, CFI knockdown downregulated the expression of key glycolysis-related proteins (glucose transporter type 1, hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2) and the Wnt pathway-related proteins (β-catenin and c-Myc). Further investigation indicated that CFI knockdown inhibited glycolysis in CC by blocking the Wnt/β-catenin/c-Myc pathway. CONCLUSION The findings of the present study demonstrate that CFI plays a crucial role in CC development by influencing glycolysis and the Wnt/β-catenin/c-Myc pathway, indicating that it could serve as a promising target for therapeutic intervention in CC.
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Affiliation(s)
- Yong-Jun Du
- Department of Proctology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
| | - Yue Jiang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Yan-Mei Hou
- Department of Proctology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
| | - Yong-Bo Shi
- Department of Proctology, Zigong Hospital of Traditional Chinese Medicine, Zigong 643000, Sichuan Province, China
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Zhao ZX, Li S, Liu LX. Thymoquinone affects hypoxia-inducible factor-1α expression in pancreatic cancer cells via HSP90 and PI3K/AKT/mTOR pathways. World J Gastroenterol 2024; 30:2793-2816. [PMID: 38899332 PMCID: PMC11185293 DOI: 10.3748/wjg.v30.i21.2793] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 04/14/2024] [Accepted: 05/08/2024] [Indexed: 06/03/2024] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is associated with some of the worst prognoses of all major cancers. Thymoquinone (TQ) has a long history in traditional medical practice and is known for its anti-cancer, anti-inflammatory, anti-fibrosis and antioxidant pharmacological activities. Recent studies on hypoxia-inducible factor-1α (HIF-1α) and PC have shown that HIF-1α affects the occurrence and development of PC in many aspects. In addition, TQ could inhibit the development of renal cancer by decreasing the expression of HIF-1α. Therefore, we speculate whether TQ affects HIF-1α expression in PC cells and explore the mechanism. AIM To elucidate the effect of TQ in PC cells and the regulatory mechanism of HIF-1α expression. METHODS Cell counting kit-8 assay, Transwell assay and flow cytometry were performed to detect the effects of TQ on the proliferative activity, migration and invasion ability and apoptosis of PANC-1 cells and normal pancreatic duct epithelial (hTERT-HPNE) cells. Quantitative real-time polymerase chain reaction and western blot assay were performed to detect the expression of HIF-1α mRNA and protein in PC cells. The effects of TQ on the HIF-1α protein initial expression pathway and ubiquitination degradation in PANC-1 cells were examined by western blot assay and co-immunoprecipitation. RESULTS TQ significantly inhibited proliferative activity, migration, and invasion ability and promoted apoptosis of PANC-1 cells; however, no significant effects on hTERT-HPNE cells were observed. TQ significantly reduced the mRNA and protein expression levels of HIF-1α in PANC-1, AsPC-1, and BxPC-3 cells. TQ significantly inhibited the expression of the HIF-1α initial expression pathway (PI3K/AKT/mTOR) related proteins, and promoted the ubiquitination degradation of the HIF-1α protein in PANC-1 cells. TQ had no effect on the hydroxylation and von Hippel Lindau protein mediated ubiquitination degradation of the HIF-1α protein but affected the stability of the HIF-1α protein by inhibiting the interaction between HIF-1α and HSP90, thus promoting its ubiquitination degradation. CONCLUSION The regulatory mechanism of TQ on HIF-1α protein expression in PC cells was mainly to promote the ubiquitination degradation of the HIF-1α protein by inhibiting the interaction between HIF-1α and HSP90; Secondly, TQ reduced the initial expression of HIF-1α protein by inhibiting the PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Zhan-Xue Zhao
- Department of General Surgery, Qinghai Provincial People's Hospital, Xining 810007, Qinghai Province, China
| | - Shuai Li
- Department of Clinical Pharmacy, The Affiliated Hospital of Qinghai University, Xining 810001, Qinghai Province, China
| | - Lin-Xun Liu
- Department of General Surgery, Qinghai Provincial People's Hospital, Xining 810007, Qinghai Province, China
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10
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Yang J, Wang C, Zhang Y, Cheng S, Wu M, Gu S, Xu S, Wu Y, Sheng J, Voon DCC, Wang Y. Clinical significance and immune infiltration analyses of a novel coagulation-related signature in ovarian cancer. Cancer Cell Int 2023; 23:232. [PMID: 37803446 PMCID: PMC10559580 DOI: 10.1186/s12935-023-03040-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/25/2023] [Indexed: 10/08/2023] Open
Abstract
Ovarian cancer (OV) is the most lethal gynecological malignancies worldwide. The coagulation cascade could induce tumor cell infiltration and contribute to OV progression. However, coagulation-related gene (CRG) signature for OV prognosis hasn't been determined yet. In this study, we evaluated the prognostic value of coagulation scores through receiver operating characteristics (ROC) analysis and K-M curves, among OV patients at our institution. Based on the transcriptome data of TCGA-OV cohort, we stratified two coagulation-related subtypes with distinct differences in prognosis and tumor immune microenvironment (p < 0.05). Moreover, from the 6406 differentially-expressed genes (DEGs) between the GTEx (n = 180) and TCGA-OV cohorts (n = 376), we identified 138 potential CRGs. Through LASSO-Cox algorithm, we finally distinguished a 3-gene signature (SERPINA10, CD38, and ZBTB16), with promising prognostic ability in both TCGA (p < 0.001) and ICGC cohorts (p = 0.040). Stepwise, we constructed a nomogram based on the clinical features and coagulation-related signature for overall survival prediction, with the C-index of 0.6761, which was evaluated by calibration curves. Especially, based on tissue microarrays analysis, Quantitative real-time fluorescence PCR (qRT-PCR), and Western Blot, we found that aberrant upregulation of CRGs was related to poor prognosis in OV at both mRNA and protein level (p < 0.05). Collectively, the coagulation-related signature was a robust prognostic biomarker, which could provide therapeutic benefits for chemotherapy/immunotherapy and assist clinical decision in OV patients.
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Affiliation(s)
- Jiani Yang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Chao Wang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yue Zhang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Shanshan Cheng
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Meixuan Wu
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Sijia Gu
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Shilin Xu
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yongsong Wu
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jindan Sheng
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Dominic Chih-Cheng Voon
- Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 9201192 Japan
- Institute of Frontier Sciences Initiative, Kanazawa University, Kanazawa, Ishikawa 9201192 Japan
| | - Yu Wang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
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11
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Hallam TM, Sharp SJ, Andreadi A, Kavanagh D. Complement factor I: Regulatory nexus, driver of immunopathology, and therapeutic. Immunobiology 2023; 228:152410. [PMID: 37478687 DOI: 10.1016/j.imbio.2023.152410] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/23/2023] [Accepted: 06/01/2023] [Indexed: 07/23/2023]
Abstract
Complement factor I (FI) is the nexus for classical, lectin and alternative pathway complement regulation. FI is an 88 kDa plasma protein that circulates in an inactive configuration until it forms a trimolecular complex with its cofactor and substrate whereupon a structural reorganization allows the catalytic triad to cleave its substrates, C3b and C4b. In keeping with its role as the master complement regulatory enzyme, deficiency has been linked to immunopathology. In the setting of complete FI deficiency, a consumptive C3 deficiency results in recurrent infections with encapsulated microorganisms. Aseptic cerebral inflammation and vasculitic presentations are also less commonly observed. Heterozygous mutations in the factor I gene (CFI) have been demonstrated to be enriched in atypical haemolytic uraemic syndrome, albeit with a very low penetrance. Haploinsufficiency of CFI has also been associated with decreased retinal thickness and is a strong risk factor for the development of age-related macular degeneration. Supplementation of FI using plasma purified or recombinant protein has long been postulated, however, technical difficulties prevented progression into clinical trials. It is only using gene therapy that CFI supplementation has reached the clinic with GT005 in phase I/II clinical trials for geographic atrophy.
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Affiliation(s)
- T M Hallam
- Gyroscope Therapeutics Limited, A Novartis Company, Rolling Stock Yard, London N7 9AS, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK
| | - S J Sharp
- Gyroscope Therapeutics Limited, A Novartis Company, Rolling Stock Yard, London N7 9AS, UK
| | - A Andreadi
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK
| | - D Kavanagh
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK; NIHR Newcastle Biomedical Research Centre, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
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12
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Joshi N, Bhat F, Bellad A, Sathe G, Jain A, Chavan S, Sirdeshmukh R, Pandey A. Urinary Proteomics for Discovery of Gastric Cancer Biomarkers to Enable Precision Clinical Oncology. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:361-371. [PMID: 37579183 PMCID: PMC10625469 DOI: 10.1089/omi.2023.0077] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/16/2023]
Abstract
For precision in clinical oncology practice, detection of tumor-derived peptides and proteins in urine offers an attractive and noninvasive alternative for diagnostic or screening purposes. In this study, we report comparative quantitative proteomic profiling of urine samples from patients with gastric cancer and healthy controls using tandem mass tags-based multiplexed mass spectrometry approach. We identified 1504 proteins, of which 246 were differentially expressed in gastric cancer cases. Notably, ephrin A1 (EFNA1), pepsinogen A3 (PGA3), sortilin 1 (SORT1), and vitronectin (VTN) were among the upregulated proteins, which are known to play crucial roles in the progression of gastric cancer. We also found other overexpressed proteins, including shisa family member 5 (SHISA5), mucin like 1 (MUCL1), and leukocyte cell derived chemotaxin 2 (LECT2), which had not previously been linked to gastric cancer. Using a novel approach for targeted proteomics, SureQuant, we validated changes in abundance of a subset of proteins discovered in this study. We confirmed the overexpression of vitronectin and sortilin 1 in an independent set of urine samples. Altogether, this study provides molecular candidates for biomarker development in gastric cancer, and the findings also support the promise of urinary proteomics for noninvasive diagnostics and personalized/precision medicine in the oncology clinic.
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Affiliation(s)
- Neha Joshi
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Firdous Bhat
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Anikha Bellad
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Gajanan Sathe
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Anu Jain
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Sandip Chavan
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ravi Sirdeshmukh
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Akhilesh Pandey
- Manipal Academy of Higher Education (MAHE), Manipal, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
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13
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Tsang DA, Tam SYC, Oh CC. Molecular Alterations in Cutaneous Squamous Cell Carcinoma in Immunocompetent and Immunosuppressed Hosts-A Systematic Review. Cancers (Basel) 2023; 15:1832. [PMID: 36980718 PMCID: PMC10046480 DOI: 10.3390/cancers15061832] [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: 01/25/2023] [Revised: 02/26/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
The characterization of cutaneous squamous cell carcinoma (cSCC) at the molecular level is lacking in the current literature due to the high mutational burden of this disease. Immunosuppressed patients afflicted with cSCC experience considerable morbidity and mortality. In this article, we review the molecular profile of cSCC among the immunosuppressed and immunocompetent populations at the genetic, epigenetic, transcriptomic, and proteometabolomic levels, as well as describing key differences in the tumor immune microenvironment between these two populations. We feature novel biomarkers from the recent literature which may serve as potential targets for therapy.
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Affiliation(s)
- Denise Ann Tsang
- Department of Dermatology, Singapore General Hospital, Singapore 169608, Singapore;
| | - Steve Y. C. Tam
- Education Resource Centre, Singapore General Hospital, Singapore 169608, Singapore
| | - Choon Chiat Oh
- Department of Dermatology, Singapore General Hospital, Singapore 169608, Singapore;
- Duke-NUS Medical School, Singapore 169608, Singapore
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14
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Rahmati Nezhad P, Riihilä P, Knuutila JS, Viiklepp K, Peltonen S, Kallajoki M, Meri S, Nissinen L, Kähäri VM. Complement Factor D Is a Novel Biomarker and Putative Therapeutic Target in Cutaneous Squamous Cell Carcinoma. Cancers (Basel) 2022; 14:cancers14020305. [PMID: 35053469 PMCID: PMC8773783 DOI: 10.3390/cancers14020305] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/31/2021] [Accepted: 01/04/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The incidence of the most common metastatic skin malignancy, cutaneous squamous cell carcinoma (cSCC), is growing worldwide, and the prognosis of the metastatic disease is poor. Presently, there are no biomarkers or therapeutic targets for high-risk cSCCs. Recent studies have demonstrated the essential role of autocrine complement synthesis in the progression of cSCC. Here, we have evaluated the role of complement Factor D (FD), the rate-limiting enzyme of the alternative complement pathway, in cSCC development. The results identify FD as a novel biomarker and putative therapeutic target for cSCC and propose the small-molecule FD inhibitor Danicopan as a highly specific drug candidate in the therapy of advanced cSCC. It is expected that the discovery of complement-associated molecular markers for cSCC progression would improve diagnosis, classification, prognostication, and targeted therapy of cSCC and its precursors in the future. Abstract Cutaneous squamous cell carcinoma (cSCC) is the most prevalent metastatic skin cancer. Previous studies have demonstrated the autocrine role of complement components in cSCC progression. We have investigated factor D (FD), the key enzyme of the alternative complement pathway, in the development of cSCC. RT-qPCR analysis of cSCC cell lines and normal human epidermal keratinocytes (NHEKs) demonstrated significant up-regulation of FD mRNA in cSCC cells compared to NHEKs. Western blot analysis also showed more abundant FD production by cSCC cell lines. Significantly higher FD mRNA levels were noted in cSCC tumors than in normal skin. Strong tumor cell-associated FD immunolabeling was detected in the invasive margin of human cSCC xenografts. More intense tumor cell-specific immunostaining for FD was seen in the tumor edge in primary and metastatic cSCCs, in metastases, and in recessive dystrophic epidermolysis bullosa-associated cSCCs, compared with cSCC in situ, actinic keratosis and normal skin. FD production by cSCC cells was dependent on p38 mitogen-activated protein kinase activity, and it was induced by interferon-γ and interleukin-1β. Blocking FD activity by Danicopan inhibited activation of extracellular signal-regulated kinase 1/2 and attenuated proliferation of cSCC cells. These results identify FD as a novel putative biomarker and therapeutic target for cSCC progression.
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Affiliation(s)
- Pegah Rahmati Nezhad
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland; (P.R.N.); (P.R.); (J.S.K.); (K.V.); (S.P.); (L.N.)
- FICAN West Cancer Centre, Research Laboratory, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland
| | - Pilvi Riihilä
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland; (P.R.N.); (P.R.); (J.S.K.); (K.V.); (S.P.); (L.N.)
- FICAN West Cancer Centre, Research Laboratory, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland
| | - Jaakko S. Knuutila
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland; (P.R.N.); (P.R.); (J.S.K.); (K.V.); (S.P.); (L.N.)
- FICAN West Cancer Centre, Research Laboratory, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland
| | - Kristina Viiklepp
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland; (P.R.N.); (P.R.); (J.S.K.); (K.V.); (S.P.); (L.N.)
- FICAN West Cancer Centre, Research Laboratory, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland
| | - Sirkku Peltonen
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland; (P.R.N.); (P.R.); (J.S.K.); (K.V.); (S.P.); (L.N.)
| | - Markku Kallajoki
- Department of Pathology, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland;
| | - Seppo Meri
- Department of Bacteriology and Immunology, The Translational Immunology Research Program, University of Helsinki, FI-00014 Helsinki, Finland;
| | - Liisa Nissinen
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland; (P.R.N.); (P.R.); (J.S.K.); (K.V.); (S.P.); (L.N.)
- FICAN West Cancer Centre, Research Laboratory, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland
| | - Veli-Matti Kähäri
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland; (P.R.N.); (P.R.); (J.S.K.); (K.V.); (S.P.); (L.N.)
- FICAN West Cancer Centre, Research Laboratory, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland
- Correspondence: ; Tel.: +358-2-3131600
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15
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Nyström A, Bruckner-Tuderman L, Kiritsi D. Dystrophic Epidermolysis Bullosa: Secondary Disease Mechanisms and Disease Modifiers. Front Genet 2021; 12:737272. [PMID: 34650598 PMCID: PMC8505774 DOI: 10.3389/fgene.2021.737272] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/25/2021] [Indexed: 12/30/2022] Open
Abstract
The phenotypic presentation of monogenetic diseases is determined not only by the nature of the causative mutations but also is influenced by manifold cellular, microenvironmental, and external factors. Here, heritable extracellular matrix diseases, including dystrophic epidermolysis bullosa (DEB), are no exceptions. Dystrophic epidermolysis bullosa is caused by mutations in the COL7A1 gene encoding collagen VII. Deficiency of collagen VII leads to skin and mucosal fragility, which progresses from skin blistering to severe fibrosis and cancer. Clinical and pre-clinical studies suggest that targeting of secondary disease mechanisms or employment of natural disease modifiers can alleviate DEB severity and progression. However, since many of these mechanisms are needed for tissue homeostasis, informed, selective targeting is essential for safe and efficacious treatment. Here, we discuss a selection of key disease modifiers and modifying processes active in DEB, summarize the still scattered knowledge of them, and reflect on ways forward toward their utilization for symptom-relief or enhancement of curative therapies.
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Affiliation(s)
- Alexander Nyström
- Department of Dermatology, Medical Faculty, Medical Center - University of Freiburg, Freiburg, Germany.,Freiburg Institute for Advanced Studies, Freiburg, Germany
| | - Leena Bruckner-Tuderman
- Department of Dermatology, Medical Faculty, Medical Center - University of Freiburg, Freiburg, Germany
| | - Dimitra Kiritsi
- Department of Dermatology, Medical Faculty, Medical Center - University of Freiburg, Freiburg, Germany
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16
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Liang D, Zhang Z. MicroRNA-27b-3p inhibits the proliferation and invasion of cutaneous squamous cell carcinoma by targeting EGFR and MMP-13. Oncol Lett 2021; 22:729. [PMID: 34429769 DOI: 10.3892/ol.2021.12990] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 05/19/2021] [Indexed: 12/13/2022] Open
Abstract
Cutaneous squamous cell carcinoma is a common malignant tumor. The aim of the present study was to examine the biological function of microRNA (miR)-27b-3p in cutaneous squamous cell carcinoma (CSCC) and its underlying mechanism. The relative expression levels of miR-27b-3p were determined in A-431, Colo-16 and NHEK/SVTERT3-5 cell lines. The regulatory effects of miR-27b-3p on the proliferation of CSCC cells were evaluated using MTT and colony formation assays. Transwell assays were conducted to examine the role of miR-27b-5p in the migratory and invasive abilities of CSCC cells. The levels of EGFR, MMP-13, Akt, phosphorylated (p)-Akt, cyclin D1, N-cadherin (CAD) and E-CAD were detected in CSCC cells using reverse transcription-quantitative PCR and western blot analysis. Binding between miR-27b-3p and the 3'-untranslated region (UTR) of EGFR or MMP-13 was assessed using a dual-luciferase reporter assay. miR-27b-3p was significantly downregulated in CSCC cell lines, compared with the skin keratinocyte cell line. Transfection with a miR-27b-3p mimic significantly reduced the proliferative, migratory and invasive abilities of CSCC cells in vitro. Moreover, miR-27b-3p mimic transfection downregulated the mRNA and protein levels of EGFR, MMP-13, cyclin D1, p-Akt and N-CAD, whilst upregulating E-CAD levels in CSCC cells. miR-27b-3p was found to target the EGFR and MMP-13 3'-UTRs, thus downregulating the expression of these molecules. The inhibition of CSCC proliferation by miR-27b-3p was effectively reversed by EGFR overexpression. Moreover, the inhibitory effect of miR-27b-3p on the migratory and invasive abilities of CSCC cells was abolished by MMP-13 overexpression. In conclusion, miR-27b-3p inhibits the proliferation, migration and invasion of CSCC cells by downregulating the expression of EGFR and MMP-13 and may represent a potential diagnostic marker and therapeutic option for CSCC.
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Affiliation(s)
- Daning Liang
- Medical Cosmetology Department, University of Chinese Academy of Sciences, Shenzhen Hospital, Shenzhen, Guangdong 518000, P.R. China
| | - Zhenning Zhang
- Medical Cosmetology Department, University of Chinese Academy of Sciences, Shenzhen Hospital, Shenzhen, Guangdong 518000, P.R. China
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