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Guglielmana V, Rossi D. Prognostic and predictive impact of NOTCH1 mutation in chronic lymphocytic leukemia: a systematic review. Leuk Lymphoma 2025; 66:584-593. [PMID: 39727347 DOI: 10.1080/10428194.2024.2441858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 11/25/2024] [Accepted: 12/09/2024] [Indexed: 12/28/2024]
Abstract
Mutations in the NOTCH1 oncogene are recurrently linked to chronic lymphocytic leukemia (CLL), found in approximately 10% of CLL cases at diagnosis. Although these mutations are associated with clinical outcomes, their significance in the context of treatment with anti-CD20 monoclonal antibodies, Bruton's tyrosine kinase inhibitors, and BCL2 inhibitors remains controversial. Consequently, testing for NOTCH1 mutations is not recommended outside of a clinical setting. This systematic literature review aims to consolidate the current understanding that NOTCH1 mutations are exploratory and not recommended for routine clinical practice.
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MESH Headings
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/mortality
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Receptor, Notch1/genetics
- Mutation
- Prognosis
- Biomarkers, Tumor/genetics
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Affiliation(s)
- Veronica Guglielmana
- Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
- Hematology Division and Bone Marrow Unit, IRCCS San Gerardo deiTintori, Monza, Italy
- Clinic of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Davide Rossi
- Clinic of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
- Institute of Oncology Research, Laboratory of Experimental Hematology, Bellinzona, Switzerland
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
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2
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Li X, Lin Y, An L. Genetic alterations and their prognostic impact in marginal zone lymphoma: a meta-analysis. Ann Hematol 2025; 104:1307-1315. [PMID: 39820428 PMCID: PMC12031998 DOI: 10.1007/s00277-024-06175-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 12/28/2024] [Indexed: 01/19/2025]
Abstract
This meta-analysis aimed to assess the impact of genetic mutations, particularly in the NOTCH2 and TNFAIP3 genes, on the prognostic outcomes of Marginal Zone Lymphoma (MZL) patients. Databases, including PubMed, Embase, and Cochrane Library, were explored up to October 2023. A total of 11 studies encompassing 2,314 records were included. Outcome measures were 5-year overall survival rates (OSR), progression-free survival rates (PFSR), and tumor progression rates (TPR). NOTCH2 and TNFAIP3 mutations were prominently identified across studies. In splenic MZL (SMZL) patients with NOTCH2 mutations, there was a significant decrease in the 5-year OSR (SMD: -11.11, 95% CI: -13.39 to -8.84, P < 0.01) and PFSR (SMD: -23.49, 95% CI: -28.85 to -18.14, P < 0.01). Similarly, TNFAIP3 mutations in SMZL patients demonstrated diminished 5-year OSR (SMD: -14.78, 95% CI: -18.01 to -11.56, P < 0.01) and PFSR (SMD: -21.06, 95% CI: -27.13 to -14.98, P < 0.01). For ocular adnexal MZL (OA-MZL) patients with NOTCH2 mutations, the 5-year OSR significantly declined (SMD: -23.40, 95% CI: -28.87 to -17.93, P < 0.01). Genetic mutations, notably in NOTCH2 and TNFAIP3 genes, have discernable negative implications on the prognosis of MZL patients. Recognizing these genetic markers can guide more personalized therapeutic interventions and inform clinical prognosis.
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Affiliation(s)
- Xijing Li
- Department of Pathology, Yantaishan Hospital, Yantai City, Shandong, 264003, China
| | - Yang Lin
- Department of Hematology, Yantai Yuhuangding Hospital, No. 20 Yudong Road, Zhifu District, Yantai City, Shandong, 264000, China
| | - Licai An
- Department of Hematology, Yantai Yuhuangding Hospital, No. 20 Yudong Road, Zhifu District, Yantai City, Shandong, 264000, China.
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Ma X, Xu J, Wang Y, Fleishman JS, Bing H, Yu B, Li Y, Bo L, Zhang S, Chen ZS, Zhao L. Research progress on gene mutations and drug resistance in leukemia. Drug Resist Updat 2025; 79:101195. [PMID: 39740374 DOI: 10.1016/j.drup.2024.101195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 12/05/2024] [Accepted: 12/20/2024] [Indexed: 01/02/2025]
Abstract
Leukemia is a type of blood cancer characterized by the uncontrolled growth of abnormal cells in the bone marrow, which replace normal blood cells and disrupt normal blood cell function. Timely and personalized interventions are crucial for disease management and improving survival rates. However, many patients experience relapse following conventional chemotherapy, and increasing treatment intensity often fails to improve outcomes due to mutated gene-induced drug resistance in leukemia cells. This article analyzes the association of gene mutations and drug resistance in leukemia. It explores genetic abnormalities in leukemia, highlighting recently identified mutations affecting signaling pathways, cell apoptosis, epigenetic regulation, histone modification, and splicing mechanisms. Additionally, the article discusses therapeutic strategies such as molecular targeting of gene mutations, alternative pathway targeting, and immunotherapy in leukemia. These approaches aim to combat specific drug-resistant mutations, providing potential avenues to mitigate leukemia relapse. Future research with these strategies holds promise for advancing leukemia treatment and addressing the challenges of drug-resistant mutations to improve patient outcomes.
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Affiliation(s)
- Xiangyu Ma
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, China
| | - Jiamin Xu
- Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
| | - Yanan Wang
- Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
| | - Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA
| | - Hao Bing
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, China
| | - Boran Yu
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, China
| | - Yanming Li
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, China
| | - Letao Bo
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA
| | - Shaolong Zhang
- Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA.
| | - Libo Zhao
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, China; Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China.
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Qu N, Li Z, Wei J, Yang Y, Meng Y, Gao Y. Bevacizumab increases cisplatin efficacy by inhibiting epithelial-mesenchymal transition via ALDH1 in cervical carcinoma. Int Immunopharmacol 2025; 145:113736. [PMID: 39662269 DOI: 10.1016/j.intimp.2024.113736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 11/25/2024] [Accepted: 11/26/2024] [Indexed: 12/13/2024]
Abstract
Cervical carcinoma has the highest incidence among gynaecological cancers in developing countries where the human papillomavirus (HPV) vaccine is not yet widely used. Cancer stem cells (CSCs) are the key factors affecting treatment efficacy and cancer prognosis. Aldehyde dehydrogenase 1 (ALDH1) is a marker of CSCs, and its expression is closely related to chemotherapy resistance in cervical carcinoma. Bevacizumab is the most widely used molecular targeted drug in the management of cervical carcinoma. We designed and performed a series of in vitro and in vivo experiments to investigate the inhibitory effects of these compounds on ALDH1 and the underlying mechanism involved. The results revealed that bevacizumab significantly inhibited epithelial-mesenchymal transition (EMT) in HeLa cervical cancer cells, as indicated by upregulation of E-cadherin and downregulation of N-cadherin and snail. Anoxic pressure was relieved, and tumour vascularization was inhibited in the tumour microenvironment. NOTCH1 plays a critical role in these processes. Through modulating these tumour biological characteristics via ALDH1, bevacizumab increases the sensitivity of cervical carcinoma to cisplatin, suggesting that bevacizumab in combination with standard chemotherapy may represent a new strategy for overcoming drug resistance. Abbreviation: HPV, human papillomavirus; CSCs, cancer stem cells; ALDH1, aldehyde dehydrogenase 1; EMT, epithelial-mesenchymal transition; OD, optical density; qRT-PCR, RNA analysis by quantitative real-time polymerase chain reaction; RIPA, radioimmunoprecipitation assay; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis; PVDF, polyvinylidene difluoride; ECL, electrochemiluminescence; NC, negative control; HE, haematoxylin and eosin; IHC, immunohistochemistry; DAB, 3, 3'-diaminobenzidine; IF, immunofluorescence; DAPI, 4,6-diamidino-2-phenylindole; VEGFA, vascular endothelial growth factor A; ROS, oxygen species; DFS, disease-free survival; OS, overall survival; HIF, hypoxia-inducible factor; PDGFs, platelet-derived growth factors; FGFs, fibroblast growth factors; PlGF, placenta growth factor; RTKs, receptor tyrosine kinases.
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Affiliation(s)
- Na Qu
- Department of Gynecology, Cancer Hospital of Dalian University of Technology (Liaoning Cancer Institute and Hospital), No. 44, Xiaoheyan Road, Shenyang 110042, Liaoning Province, China
| | - Zhuo Li
- Department of Gynecology, Cancer Hospital of Dalian University of Technology (Liaoning Cancer Institute and Hospital), No. 44, Xiaoheyan Road, Shenyang 110042, Liaoning Province, China
| | - Jing Wei
- Department of Gynecology, Cancer Hospital of Dalian University of Technology (Liaoning Cancer Institute and Hospital), No. 44, Xiaoheyan Road, Shenyang 110042, Liaoning Province, China
| | - Yuwei Yang
- Department of Gynecology, Cancer Hospital of Dalian University of Technology (Liaoning Cancer Institute and Hospital), No. 44, Xiaoheyan Road, Shenyang 110042, Liaoning Province, China
| | - Yiming Meng
- Central Laboratory, Cancer Hospital of Dalian University of Technology (Liaoning Cancer Institute and Hospital), No. 44, Xiaoheyan Road, Shenyang 110042, Liaoning Province, China
| | - Yuhua Gao
- Department of Gynecology, Cancer Hospital of Dalian University of Technology (Liaoning Cancer Institute and Hospital), No. 44, Xiaoheyan Road, Shenyang 110042, Liaoning Province, China.
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Lyu A, Nam SH, Humphrey RS, Horton TM, Ehrlich LIR. Cells and signals of the leukemic microenvironment that support progression of T-cell acute lymphoblastic leukemia (T-ALL). Exp Mol Med 2024; 56:2337-2347. [PMID: 39482533 PMCID: PMC11612169 DOI: 10.1038/s12276-024-01335-7] [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: 06/06/2024] [Revised: 07/30/2024] [Accepted: 08/11/2024] [Indexed: 11/03/2024] Open
Abstract
Current intensified chemotherapy regimens have significantly increased survival rates for pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL), but these treatments can result in serious adverse effects; furthermore, patients who are resistant to chemotherapy or who relapse have inferior outcomes, together highlighting the need for improved therapeutic strategies. Despite recent advances in stratifying T-ALL into molecular subtypes with distinct driver mutations, efforts to target the tumor-intrinsic genomic alterations critical for T-ALL progression have yet to translate into more effective and less toxic therapies. Ample evidence now indicates that extrinsic factors in the leukemic microenvironment are critical for T-ALL growth, infiltration, and therapeutic resistance. Considering the diversity of organs infiltrated by T-ALL cells and the unique cellular components of the microenvironment encountered at each site, it is likely that there are both shared features of tumor-supportive niches across multiple organs and site-specific features that are key to leukemia cell survival. Therefore, elucidating the distinct microenvironmental cues supporting T-ALL in different anatomic locations could reveal novel therapeutic targets to improve therapies. This review summarizes the current understanding of the intricate interplay between leukemia cells and the diverse cells they encounter within their tumor microenvironments (TMEs), as well as opportunities to therapeutically target the leukemic microenvironment.
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Affiliation(s)
- Aram Lyu
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA
| | - Seo Hee Nam
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
| | - Ryan S Humphrey
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
| | - Terzah M Horton
- Department of Pediatrics, Baylor College of Medicine/Dan L. Duncan Cancer Center and Texas Children's Cancer Center, Houston, TX, USA
| | - Lauren I R Ehrlich
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
- Department of Oncology, Livestrong Cancer Institutes, The University of Texas at Austin Dell Medical School, Austin, TX, USA.
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Charbat MA, Abdulhalim YH, Alrabeei MA, Abdo Hassan W. Role of Notch1 Signaling Pathway in Small Cell Lung Carcinoma. IRANIAN JOURNAL OF PATHOLOGY 2024; 19:365-375. [PMID: 40034926 PMCID: PMC11872034 DOI: 10.30699/ijp.2024.2013339.3184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 10/20/2024] [Indexed: 03/05/2025]
Abstract
Lung cancer is the leading cause of cancer-related death around the globe. It is generally divided into small-cell and non-small-cell lung carcinomas. Small-cell lung cancer (SCLC) is a malignant tumor characterized by rapid growth, high metastatic potential, and a frequent rate of relapse after chemotherapy. All the features may worse aggressiveness of this cancer and increase the possibility of unsuccessful therapeutic attempts. Notch1 signaling is a crucial molecular pathway in the regulation of many cellular functions, including cell-cell communication and gene regulation. Moreover, it was proposed previously that Notch1 might be oncogenic in various types of cancer, but the question arises as to why many SCLC cell lines do not express this pathway. This review aims to explore the role of this complex pathway in SCLC in both vitro and vivo studies and whether it has a tumor-promoting or suppressive effect. After an extensive literature review, it was found that the expression of Notch1 signaling in SCLC reduces its proliferative ability while promoting increased cell apoptosis. Furthermore, it reduces cell motility, invasion, and metastatic ability and enhances cell-cell adhesion by inhibiting epithelial-mesenchymal transition (EMT). Furthermore, it contributes to cell chemo-resistance by altering multidrug resistance-associated protein-1 (MRP-1), demonstrating an overall tumor-suppressive effect. Given these findings, induction of Notch1 using histone deacetylase inhibitor (HDACi) may be a potential future therapeutic strategy for SCLC management. Nevertheless, the effect of such a sophisticated signaling pathway in tumor carcinogenesis can't be generalized to all human cancers, and further studies are needed to better tailor therapeutic plans based on the specific cellular context.
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Affiliation(s)
- Mohammed Ahmed Charbat
- College of Medicine, Sulaiman Al-Rajhi University, Al-bukayriyah, Kingdom of Saudi Arabia
| | | | | | - Wael Abdo Hassan
- Faculty of Medicine, Department of Pathology, Suez Canal University, Ismailia, Egypt
- Department of Basic Sciences, Sulaiman Al-Rajhi University, Al-bukayriyah, Kingdom of Saudi Arabia
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7
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Pedroza-Torres A, Romero-Córdoba SL, Montaño S, Peralta-Zaragoza O, Vélez-Uriza DE, Arriaga-Canon C, Guajardo-Barreto X, Bautista-Sánchez D, Sosa-León R, Hernández-González O, Díaz-Chávez J, Alvarez-Gómez RM, Herrera LA. Radio-miRs: a comprehensive view of radioresistance-related microRNAs. Genetics 2024; 227:iyae097. [PMID: 38963803 PMCID: PMC11304977 DOI: 10.1093/genetics/iyae097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 05/29/2024] [Indexed: 07/06/2024] Open
Abstract
Radiotherapy is a key treatment option for a wide variety of human tumors, employed either alone or alongside with other therapeutic interventions. Radiotherapy uses high-energy particles to destroy tumor cells, blocking their ability to divide and proliferate. The effectiveness of radiotherapy is due to genetic and epigenetic factors that determine how tumor cells respond to ionizing radiation. These factors contribute to the establishment of resistance to radiotherapy, which increases the risk of poor clinical prognosis of patients. Although the mechanisms by which tumor cells induce radioresistance are unclear, evidence points out several contributing factors including the overexpression of DNA repair systems, increased levels of reactive oxygen species, alterations in the tumor microenvironment, and enrichment of cancer stem cell populations. In this context, dysregulation of microRNAs or miRNAs, critical regulators of gene expression, may influence how tumors respond to radiation. There is increasing evidence that miRNAs may act as sensitizers or enhancers of radioresistance, regulating key processes such as the DNA damage response and the cell death signaling pathway. Furthermore, expression and activity of miRNAs have shown informative value in overcoming radiotherapy and long-term radiotoxicity, revealing their potential as biomarkers. In this review, we will discuss the molecular mechanisms associated with the response to radiotherapy and highlight the central role of miRNAs in regulating the molecular mechanisms responsible for cellular radioresistance. We will also review radio-miRs, radiotherapy-related miRNAs, either as sensitizers or enhancers of radioresistance that hold promise as biomarkers or pharmacological targets to sensitize radioresistant cells.
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Affiliation(s)
- Abraham Pedroza-Torres
- Programa Investigadoras e Investigadores por México, Consejo Nacional de Humanidades, Ciencias y Tecnologías, Mexico City C.P. 03940, Mexico
- Clínica de Cáncer Hereditario, Instituto Nacional de Cancerología, Mexico City C.P. 14080, Mexico
| | - Sandra L Romero-Córdoba
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City C.P. 04510, Mexico
- Departamento de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico City C.P. 14080, Mexico
| | - Sarita Montaño
- Laboratorio de Bioinformática, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Sinaloa (FCQB-UAS), Culiacán Rosales, Sinaloa C.P. 80030, Mexico
| | - Oscar Peralta-Zaragoza
- Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca, Morelos C.P. 62100, Mexico
| | - Dora Emma Vélez-Uriza
- Laboratorio de Traducción y Cáncer, Instituto Nacional de Cancerología, Mexico City C.P. 14080, Mexico
| | - Cristian Arriaga-Canon
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología–Instituto de Investigaciones Biomédicas–Universidad Nacional Autónoma de México (UNAM), Mexico City C.P. 14080, Mexico
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo León C.P. 64710, Mexico
| | - Xiadani Guajardo-Barreto
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología–Instituto de Investigaciones Biomédicas–Universidad Nacional Autónoma de México (UNAM), Mexico City C.P. 14080, Mexico
| | - Diana Bautista-Sánchez
- Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Rodrigo Sosa-León
- Clínica de Cáncer Hereditario, Instituto Nacional de Cancerología, Mexico City C.P. 14080, Mexico
| | - Olivia Hernández-González
- Laboratorio de Microscopia Electrónica, Instituto Nacional de Rehabilitación “Luis Guillermo Ibarraa Ibarra”, Mexico City C.P. 14389, Mexico
| | - José Díaz-Chávez
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología–Instituto de Investigaciones Biomédicas–Universidad Nacional Autónoma de México (UNAM), Mexico City C.P. 14080, Mexico
| | - Rosa María Alvarez-Gómez
- Clínica de Cáncer Hereditario, Instituto Nacional de Cancerología, Mexico City C.P. 14080, Mexico
| | - Luis A Herrera
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología–Instituto de Investigaciones Biomédicas–Universidad Nacional Autónoma de México (UNAM), Mexico City C.P. 14080, Mexico
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo León C.P. 64710, Mexico
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Pavlick DC, Frampton GM, Ross JR. Understanding variants of unknown significance and classification of genomic alterations. Oncologist 2024; 29:658-666. [PMID: 38982622 PMCID: PMC11299939 DOI: 10.1093/oncolo/oyae149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 04/16/2024] [Indexed: 07/11/2024] Open
Abstract
Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology.
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Affiliation(s)
- Dean C Pavlick
- Department of Computational Discovery, Foundation Medicine, Inc., Boston, MA, United States
| | - Garrett M Frampton
- Department of Computational Discovery, Foundation Medicine, Inc., Boston, MA, United States
| | - Jeffrey R Ross
- Department of Pathology, Foundation Medicine, Inc., Boston, MA, United States, and
- Departments of Pathology, Medicine (Oncology), and Urology, Upstate Medical University, Syracuse, NY, United States
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Vasei H, Foroughmand-Araabi MH, Daneshgar A. Weighted centroid trees: a general approach to summarize phylogenies in single-labeled tumor mutation tree inference. Bioinformatics 2024; 40:btae120. [PMID: 38984735 PMCID: PMC11520232 DOI: 10.1093/bioinformatics/btae120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 02/19/2024] [Accepted: 07/09/2024] [Indexed: 07/11/2024] Open
Abstract
MOTIVATION Tumor trees, which depict the evolutionary process of cancer, provide a backbone for discovering recurring evolutionary processes in cancer. While they are not the primary information extracted from genomic data, they are valuable for this purpose. One such extraction method involves summarizing multiple trees into a single representative tree, such as consensus trees or supertrees. RESULTS We define the "weighted centroid tree problem" to find the centroid tree of a set of single-labeled rooted trees through the following steps: (i) mapping the given trees into the Euclidean space, (ii) computing the weighted centroid matrix of the mapped trees, and (iii) finding the nearest mapped tree (NMTP) to the centroid matrix. We show that this setup encompasses previously studied parent-child and ancestor-descendent metrics as well as the GraPhyC and TuELiP consensus tree algorithms. Moreover, we show that, while the NMTP problem is polynomial-time solvable for the adjacency embedding, it is NP-hard for ancestry and distance mappings. We introduce integer linear programs for NMTP in different setups where we also provide a new algorithm for the case of ancestry embedding called 2-AncL2, that uses a novel weighting scheme for ancestry signals. Our experimental results show that 2-AncL2 has a superior performance compared to available consensus tree algorithms. We also illustrate our setup's application on providing representative trees for a large real breast cancer dataset, deducing that the cluster centroid trees summarize reliable evolutionary information about the original dataset. AVAILABILITY AND IMPLEMENTATION https://github.com/vasei/WAncILP.
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Affiliation(s)
- Hamed Vasei
- Department of Mathematical Sciences, Sharif University of Technology, Tehran 111559415, Iran
| | | | - Amir Daneshgar
- Department of Mathematical Sciences, Sharif University of Technology, Tehran 111559415, Iran
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10
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Zhao YX, Zhao HP, Zhao MY, Yu Y, Qi X, Wang JH, Lv J. Latest insights into the global epidemiological features, screening, early diagnosis and prognosis prediction of esophageal squamous cell carcinoma. World J Gastroenterol 2024; 30:2638-2656. [PMID: 38855150 PMCID: PMC11154680 DOI: 10.3748/wjg.v30.i20.2638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/26/2024] [Accepted: 05/13/2024] [Indexed: 05/27/2024] Open
Abstract
As a highly invasive carcinoma, esophageal cancer (EC) was the eighth most prevalent malignancy and the sixth leading cause of cancer-related death worldwide in 2020. Esophageal squamous cell carcinoma (ESCC) is the major histological subtype of EC, and its incidence and mortality rates are decreasing globally. Due to the lack of specific early symptoms, ESCC patients are usually diagnosed with advanced-stage disease with a poor prognosis, and the incidence and mortality rates are still high in many countries, especially in China. Therefore, enormous challenges still exist in the management of ESCC, and novel strategies are urgently needed to further decrease the incidence and mortality rates of ESCC. Although the key molecular mechanisms underlying ESCC pathogenesis have not been fully elucidated, certain promising biomarkers are being investigated to facilitate clinical decision-making. With the advent and advancement of high-throughput technologies, such as genomics, proteomics and metabolomics, valuable biomarkers with high sensitivity, specificity and stability could be identified for ESCC. Herein, we aimed to determine the epidemiological features of ESCC in different regions of the world, especially in China, and focused on novel molecular biomarkers associated with ESCC screening, early diagnosis and prognosis prediction.
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Affiliation(s)
- Yi-Xin Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - He-Ping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Meng-Yao Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Xi Qi
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Ji-Han Wang
- Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
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11
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Shi Q, Xue C, Zeng Y, Yuan X, Chu Q, Jiang S, Wang J, Zhang Y, Zhu D, Li L. Notch signaling pathway in cancer: from mechanistic insights to targeted therapies. Signal Transduct Target Ther 2024; 9:128. [PMID: 38797752 PMCID: PMC11128457 DOI: 10.1038/s41392-024-01828-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: 01/18/2024] [Revised: 03/31/2024] [Accepted: 04/15/2024] [Indexed: 05/29/2024] Open
Abstract
Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical Notch signaling transduction. Accumulating evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer types. Dysregulation of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies, closely linked to cancer proliferation, invasion, and metastasis. Furthermore, the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells, thereby enhancing cancer invasiveness. The regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive effects. Moreover, the Notch signaling pathway is implicated in conferring chemoresistance to tumor cells. Therefore, a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch signaling. This review focuses on the research progress of the Notch signaling pathway in cancers, providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of cancer. Additionally, the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy, aiming to offer new insights into therapeutic strategies for human malignancies.
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Affiliation(s)
- Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Shuwen Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Jinzhi Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yaqi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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12
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Ramsey KM, Barrick D. Unraveling paralog-specific Notch signaling through thermodynamics of ternary complex formation and transcriptional activation of chimeric receptors. Protein Sci 2024; 33:e4947. [PMID: 38511488 PMCID: PMC10962485 DOI: 10.1002/pro.4947] [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: 10/25/2023] [Revised: 02/07/2024] [Accepted: 02/11/2024] [Indexed: 03/22/2024]
Abstract
Notch signaling in humans is mediated by four paralogous receptors that share conserved architectures and possess overlapping, yet non-redundant functions. The receptors share a canonical activation pathway wherein upon extracellular ligand binding, the Notch intracellular domain (NICD) is cleaved from the membrane and translocates to the nucleus where its N-terminal RBP-j-associated molecule (RAM) region and ankyrin repeat (ANK) domain bind transcription factor CSL and recruit co-activator Mastermind-like-1 (MAML1) to activate transcription. However, different paralogs can lead to distinct outcomes. To better understand paralog-specific differences in Notch signaling, we performed a thermodynamic analysis of the Notch transcriptional activation complexes for all four Notch paralogs using isothermal titration calorimetry. Using chimeric constructs, we find that the RAM region is the primary determinant of stability of binary RAMANK:CSL complexes, and that the ANK regions are largely the determinants of MAML1 binding to pre-formed RAMANK:CSL complexes. Free energies of these binding reactions (ΔGRA and ΔGMAML) vary among the four Notch paralogs, although variations for Notch2, 3, and 4 offset in the free energy of the ternary complex (ΔGTC, where ΔGTC = ΔGRA + ΔGMAML). To probe how these affinity differences affect Notch signaling, we performed transcriptional activation assays with the paralogous and chimeric NICDs, and analyzed the results with an independent multiplicative model that quantifies contributions of the paralogous RAM, ANK, and C-terminal regions (CTR) to activation. This analysis shows that transcription activation correlates with ΔGTC, but that activation is further modified by CTR identity in a paralog-specific way.
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Affiliation(s)
- Kristen M. Ramsey
- T.C. Jenkins Department of BiophysicsJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Doug Barrick
- T.C. Jenkins Department of BiophysicsJohns Hopkins UniversityBaltimoreMarylandUSA
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13
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Perea J, García JL, Corchete LA, Martí M, Hernández-Villafranca S, Alcázar JA, Álvaro E, Hurtado E, Jiménez-Toscano M, Balaguer F, Ballestero A, López-Rojo I, Jiménez F, Sanz G, Melone S, Brandáriz L, Vivas A, Alvarellos A, González-Sarmiento R. Chromosomal breaks: another differential gap between early-onset and late-onset colorectal cancers. Br J Surg 2024; 111:znae041. [PMID: 38430195 DOI: 10.1093/bjs/znae041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/16/2024] [Accepted: 01/22/2024] [Indexed: 03/03/2024]
Affiliation(s)
- José Perea
- Molecular Medicine Unit-Department of Medicine, Institute of Biomedical Research of Salamanca (IBSAL) and Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-SACYL-CSIC, Salamanca, Spain
- Surgery Department, Vithas Arturo Soria Hospital, Madrid, Spain
| | - Juan Luis García
- Molecular Medicine Unit-Department of Medicine, Institute of Biomedical Research of Salamanca (IBSAL) and Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-SACYL-CSIC, Salamanca, Spain
| | - Luis A Corchete
- Haematology Department, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Cancer Research Centre-IBMCC (USAL-CSIC), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Marc Martí
- Colorectal Unit, Vall d'Hebrón University Hospital, Barcelona, Spain
| | | | - José A Alcázar
- Surgery Department, Clinic University Hospital, Salamanca, Spain
| | - Edurne Álvaro
- Surgery Department, Infanta Leonor University Hospital, Madrid, Spain
| | - Elena Hurtado
- Surgery Department, Gregorio Marañon University Hospital, Madrid, Spain
| | | | - Francesc Balaguer
- Gastroenterology Department, Clinic University Hospital, Barcelona, Spain
| | | | - Irene López-Rojo
- Surgery Department, MD Anderson Cancer Center Madrid, Madrid, Spain
| | | | - Gonzalo Sanz
- Surgery Department, San Carlos University Hospital, Madrid, Spain
| | - Sirio Melone
- Surgery Department, Alcorcon Foundation Hospital, Madrid, Spain
| | | | - Alfredo Vivas
- Surgery Department, 12 de Octubre University Hospital, Madrid, Spain
| | - Alicia Alvarellos
- Surgery Department, University Clinic of Navarra-Madrid, Madrid, Spain
| | - Rogelio González-Sarmiento
- Molecular Medicine Unit-Department of Medicine, Institute of Biomedical Research of Salamanca (IBSAL) and Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-SACYL-CSIC, Salamanca, Spain
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14
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Abdel-Mohsen MA, Badawy AM, Abu-Youssef MA, Yehia MA, Abou Shamaa LD, Mohamed SA. Influence of copper(I) nicotinate complex on the Notch1 signaling pathway in triple negative breast cancer cell lines. Sci Rep 2024; 14:2522. [PMID: 38291201 PMCID: PMC10827744 DOI: 10.1038/s41598-024-52952-1] [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: 07/07/2023] [Accepted: 01/25/2024] [Indexed: 02/01/2024] Open
Abstract
Triple negative breast cancer (TNBC) is a subtype of breast cancer which is characterized by its aggressiveness, poor and short overall survival. In this concept, there is a growing demand for metal-based compounds in TNBC therapy as copper complex that have a less toxic effect on normal cells and could stimulate apoptotic cell death. Additionally, Notch1 signaling pathway has received great attention as one of the most important potential targets for developing a novel therapeutic strategy. The present study is an attempt to assess the promising chemotherapeutic activities of copper(I) nicotinate (CNC) through its impact on the expression of downstream genes of Notch1 signaling pathway and the cell fate of TNBC. The co-treatment of TNBC cells with doxorubicin (Doxo) and CNC was also investigated. To approach the objective of the present study, TNBC cell lines; HCC1806 and MDAMB231, were utilized. MTT assay was used to determine the IC50 values of CNC and Doxo. After treatment, microtubule-associated protein light chain3 (LC3) were determined by flow cytometry. Additionally, qRT-PCR technique was used to detect the changes in genes levels that are involved Notch1 signaling pathway. Moreover, autophagosomes were monitored and imaged by Transmission electron microscopy. Treatment of TNBC cells with CNC modulated Notch1 signaling pathway in different manners with respect to the type of cells and the applied dose of CNC. The observed effects of CNC may reflect the possible anti-cancer activities of CNC in both types of TNBC. However, cell type and CNC dose should be considered.
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Affiliation(s)
- Mohamed A Abdel-Mohsen
- Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
| | - Asmaa M Badawy
- Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
| | - Morsy A Abu-Youssef
- Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Mona A Yehia
- Histochemistry and Cell Biology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Lobna D Abou Shamaa
- Immunology and Allergy Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Shymaa Abdullah Mohamed
- Molecular Biology Unit, Medical Technology Center and Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
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15
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Wang CW, Clémot M, Hashimoto T, Diaz JA, Goins LM, Goldstein AS, Nagaraj R, Banerjee U. A conserved mechanism for JNK-mediated loss of Notch function in advanced prostate cancer. Sci Signal 2023; 16:eabo5213. [PMID: 37934809 PMCID: PMC10802904 DOI: 10.1126/scisignal.abo5213] [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: 02/08/2022] [Accepted: 10/19/2023] [Indexed: 11/09/2023]
Abstract
Dysregulated Notch signaling is a common feature of cancer; however, its effects on tumor initiation and progression are highly variable, with Notch having either oncogenic or tumor-suppressive functions in various cancers. To better understand the mechanisms that regulate Notch function in cancer, we studied Notch signaling in a Drosophila tumor model, prostate cancer-derived cell lines, and tissue samples from patients with advanced prostate cancer. We demonstrated that increased activity of the Src-JNK pathway in tumors inactivated Notch signaling because of JNK pathway-mediated inhibition of the expression of the gene encoding the Notch S2 cleavage protease, Kuzbanian, which is critical for Notch activity. Consequently, inactive Notch accumulated in cells, where it was unable to transcribe genes encoding its target proteins, many of which have tumor-suppressive activities. These findings suggest that Src-JNK activity in tumors predicts Notch activity status and that suppressing Src-JNK signaling could restore Notch function in tumors, offering opportunities for diagnosis and targeted therapies for a subset of patients with advanced prostate cancer.
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Affiliation(s)
- Cheng-Wei Wang
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Marie Clémot
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Takao Hashimoto
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Johnny A. Diaz
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Lauren M. Goins
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Andrew S. Goldstein
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
- Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
- Molecular Biology Institute; University of California, Los Angeles, Los Angeles, CA, USA
| | - Raghavendra Nagaraj
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Utpal Banerjee
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
- Department of Biological Chemistry; University of California, Los Angeles, Los Angeles, CA, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA
- Molecular Biology Institute; University of California, Los Angeles, Los Angeles, CA, USA
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16
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Militi S, Nibhani R, Jalali M, Pauklin S. RBL2-E2F-GCN5 guide cell fate decisions during tissue specification by regulating cell-cycle-dependent fluctuations of non-cell-autonomous signaling. Cell Rep 2023; 42:113146. [PMID: 37725511 DOI: 10.1016/j.celrep.2023.113146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 05/30/2023] [Accepted: 08/31/2023] [Indexed: 09/21/2023] Open
Abstract
The retinoblastoma family proteins (RBs) and E2F transcription factors are cell-autonomous regulators of cell-cycle progression, but they also impact fate choice in addition to tumor suppression. The range of mechanisms involved remains to be uncovered. Here, we show that RBs, particularly RBL2/p130, repress WNT ligands such as WNT4 and WNT8A, thereby directing ectoderm specification between neural crest to neuroepithelium. RBL2 achieves this function through cell-cycle-dependent cooperation with E2Fs and GCN5 on the regulatory regions of WNT loci, which direct neuroepithelial versus neural crest specification by temporal fluctuations of WNT/β-catenin and DLL/NOTCH signaling activity. Thus, the RB-E2F bona fide cell-autonomous axis controls cell fate decisions, and RBL2 regulates field effects via WNT ligands. This reveals a non-cell-autonomous function of RBL2-E2F in stem cell and tissue progenitor differentiation that has broader implications for cell-cycle-dependent cell fate specification in organogenesis, adult stem cells, tissue homeostasis, and tumorigenesis.
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Affiliation(s)
- Stefania Militi
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford OX3 7LD, UK
| | - Reshma Nibhani
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford OX3 7LD, UK
| | - Morteza Jalali
- Anne McLaren Laboratory for Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford OX3 7LD, UK.
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17
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Hassan M, Shahzadi S, Malik A, Din SU, Yasir M, Chun W, Kloczkowski A. Oncomeric Profiles of microRNAs as New Therapeutic Targets for Treatment of Ewing's Sarcoma: A Composite Review. Genes (Basel) 2023; 14:1849. [PMID: 37895198 PMCID: PMC10606885 DOI: 10.3390/genes14101849] [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: 06/30/2023] [Revised: 09/07/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023] Open
Abstract
Ewing's sarcoma is a rare type of cancer that forms in bones and soft tissues in the body, affecting mostly children and young adults. Current treatments for ES are limited to chemotherapy and/or radiation, followed by surgery. Recently, microRNAs have shown favourable results as latent diagnostic and prognostic biomarkers in various cancers. Furthermore, microRNAs have shown to be a good therapeutic agent due to their involvement in the dysregulation of various molecular pathways linked to tumour progression, invasion, angiogenesis, and metastasis. In this review, comprehensive data mining was employed to explore various microRNAs that might have therapeutic potential as target molecules in the treatment of ES.
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Affiliation(s)
- Mubashir Hassan
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children Hospital, Columbus, OH 43205, USA;
| | - Saba Shahzadi
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children Hospital, Columbus, OH 43205, USA;
| | - Amal Malik
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54590, Pakistan;
| | - Salah ud Din
- Department of Bioinformatics, University of Okara, Okara 56130, Pakistan;
| | - Muhammad Yasir
- Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea; (M.Y.); (W.C.)
| | - Wanjoo Chun
- Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea; (M.Y.); (W.C.)
| | - Andrzej Kloczkowski
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
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18
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Maher N, Mouhssine S, Matti BF, Alwan AF, Gaidano G. Treatment Refractoriness in Chronic Lymphocytic Leukemia: Old and New Molecular Biomarkers. Int J Mol Sci 2023; 24:10374. [PMID: 37373521 PMCID: PMC10299596 DOI: 10.3390/ijms241210374] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/11/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Despite its indolent clinical course, therapy refractoriness and disease progression still represent an unmet clinical need. Before the advent of pathway inhibitors, chemoimmunotherapy (CIT) was the commonest option for CLL treatment and is still widely used in areas with limited access to pathway inhibitors. Several biomarkers of refractoriness to CIT have been highlighted, including the unmutated status of immunoglobulin heavy chain variable genes and genetic lesions of TP53, BIRC3 and NOTCH1. In order to overcome resistance to CIT, targeted pathway inhibitors have become the standard of care for the treatment of CLL, with practice-changing results obtained through the inhibitors of Bruton tyrosine kinase (BTK) and BCL2. However, several acquired genetic lesions causing resistance to covalent and noncovalent BTK inhibitors have been reported, including point mutations of both BTK (e.g., C481S and L528W) and PLCG2 (e.g., R665W). Multiple mechanisms are involved in resistance to the BCL2 inhibitor venetoclax, including point mutations that impair drug binding, the upregulation of BCL2-related anti-apoptotic family members, and microenvironmental alterations. Recently, immune checkpoint inhibitors and CAR-T cells have been tested for CLL treatment, obtaining conflicting results. Potential refractoriness biomarkers to immunotherapy were identified, including abnormal levels of circulating IL-10 and IL-6 and the reduced presence of CD27+CD45RO- CD8+ T cells.
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Affiliation(s)
- Nawar Maher
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, 28100 Novara, Italy; (N.M.); (S.M.)
| | - Samir Mouhssine
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, 28100 Novara, Italy; (N.M.); (S.M.)
| | - Bassam Francis Matti
- Department of Hematology and Bone Marrow Transplant, Hematology and Bone Marrow Transplant Center, Baghdad 00964, Iraq;
| | - Alaa Fadhil Alwan
- Department of Clinical Hematology, The National Center of Hematology, Mustansiriyah University, Baghdad 10015, Iraq;
| | - Gianluca Gaidano
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, 28100 Novara, Italy; (N.M.); (S.M.)
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19
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Sen P, Ghosh SS. The Intricate Notch Signaling Dynamics in Therapeutic Realms of Cancer. ACS Pharmacol Transl Sci 2023; 6:651-670. [PMID: 37200816 PMCID: PMC10186364 DOI: 10.1021/acsptsci.2c00239] [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: 11/29/2022] [Indexed: 05/20/2023]
Abstract
The Notch pathway is remarkably simple without the interventions of secondary messengers. It possesses a unique receptor-ligand interaction that imparts signaling upon cleavage of the receptor followed by the nuclear localization of its cleaved intracellular domain. It is found that the transcriptional regulator of the Notch pathway lies at the intersection of multiple signaling pathways that enhance the aggressiveness of cancer. The preclinical and clinical evidence supports the pro-oncogenic function of Notch signaling in various tumor subtypes. Owing to its oncogenic role, the Notch signaling pathway assists in enhanced tumorigenesis by facilitating angiogenesis, drug resistance, epithelial to mesenchymal transition, etc., which is also attributed to the poor outcome in patients. Therefore, it is extremely vital to discover a suitable inhibitor to downregulate the signal-transducing ability of Notch. The Notch inhibitory agents, such as receptor decoys, protease (ADAM and γ-secretase) inhibitors, and monoclonal/bispecific antibodies, are being investigated as candidate therapeutic agents. Studies conducted by our group exemplify the promising results in ablating tumorigenic aggressiveness by inhibiting the constituents of the Notch pathway. This review deals with the detailed mechanism of the Notch pathways and their implications in various malignancies. It also bestows us with the recent therapeutic advances concerning Notch signaling in the context of monotherapy and combination therapy.
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Affiliation(s)
- Plaboni Sen
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Siddhartha Sankar Ghosh
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Guwahati 781039, Assam, India
- Centre
for Nanotechnology, Indian Institute of
Technology Guwahati, Guwahati 781039, Assam, India
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20
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Samanta P, Bhowmik A, Biswas S, Sarkar R, Ghosh R, Pakhira S, Mondal M, Sen S, Saha P, Hajra S. Therapeutic Effectiveness of Anticancer Agents Targeting Different Signaling Molecules Involved in Asymmetric Division of Cancer Stem Cell. Stem Cell Rev Rep 2023:10.1007/s12015-023-10523-3. [PMID: 36952080 DOI: 10.1007/s12015-023-10523-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2023] [Indexed: 03/24/2023]
Abstract
Intra-tumoral heterogeneity is maintained by cancer stem cells (CSCs) with dysregulated self-renewal and asymmetric cell division (ACD). According to the cancer stem cell theory, by ACD a CSC can generate two daughter progenies with different fates such as one cancer stem cell and one differentiated cell. Therefore, this type of mitotic division supports vital process of the maintenance of CSC population. But this CSC pool reservation by ACD complicates the treatment of cancer patients, as CSCs give rise to aggressive clones which are prone to metastasis and drug-insensitivity. Hence, identification of therapeutic modalities which can target ACD of cancer stem cell is an intriguing part of cancer research. In this review, other than the discussion about the extrinsic inducers of ACD role of different proteins, miRNAs and lncRNAs in this type of cell division is also mentioned. Other than these, mode of action of the proven and potential drugs targeting ACD of CSC is also discussed here.
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Affiliation(s)
- Priya Samanta
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, Shyama Prasad Mukherjee Rd, Bakul Bagan, Bhowanipore, Kolkata, West Bengal, 700026, India
| | - Arijit Bhowmik
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, Shyama Prasad Mukherjee Rd, Bakul Bagan, Bhowanipore, Kolkata, West Bengal, 700026, India.
| | - Souradeep Biswas
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, Shyama Prasad Mukherjee Rd, Bakul Bagan, Bhowanipore, Kolkata, West Bengal, 700026, India
| | - Rupali Sarkar
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, Shyama Prasad Mukherjee Rd, Bakul Bagan, Bhowanipore, Kolkata, West Bengal, 700026, India
| | - Rituparna Ghosh
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, Shyama Prasad Mukherjee Rd, Bakul Bagan, Bhowanipore, Kolkata, West Bengal, 700026, India
| | - Shampa Pakhira
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, Shyama Prasad Mukherjee Rd, Bakul Bagan, Bhowanipore, Kolkata, West Bengal, 700026, India
| | - Mrinmoyee Mondal
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, Shyama Prasad Mukherjee Rd, Bakul Bagan, Bhowanipore, Kolkata, West Bengal, 700026, India
| | - Soummadeep Sen
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, Shyama Prasad Mukherjee Rd, Bakul Bagan, Bhowanipore, Kolkata, West Bengal, 700026, India
| | - Prosenjit Saha
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, Shyama Prasad Mukherjee Rd, Bakul Bagan, Bhowanipore, Kolkata, West Bengal, 700026, India
| | - Subhadip Hajra
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, Shyama Prasad Mukherjee Rd, Bakul Bagan, Bhowanipore, Kolkata, West Bengal, 700026, India.
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Shah H, Mistry M, Patel N, Vora H. Clinical significance of Notch receptors in triple negative breast cancer. Breast Dis 2023; 42:85-100. [PMID: 36970890 DOI: 10.3233/bd-220041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
BACKGROUND The Notch signaling pathway is an evolutionary conserved cell signaling pathway that plays an indispensable role in essential developmental processes. Aberrant activation of Notch pathway is known to initiate wide array of diseases and cancers. OBJECTIVE To evaluate the clinical significance of Notch receptors in Triple Negative Breast Cancer. METHODS We evaluated the association between Notch receptors and clinicopathological parameters including disease-free survival and overall survival of one hundred TNBC patients by immunohistochemistry. RESULTS Positive expression of nuclear Notch1 receptor (18%) was found be significantly correlated with positive lymph node (p = 0.009), high BR score (p = 0.02) and necrosis (p = 0.004) while cytoplasmic expression of Notch2 receptor (26%) was significantly correlated with metastasis (p = 0.05), worse DFS (p = 0.05) and poor OS (p = 0.02) in TNBC patients. Membrane (18%) and cytonuclear (3%) Notch3 expression were significantly associated with poorly differentiated tumors (p = 0.007), high BR score (p = 0.002) and necrosis (p = 0.03) respectively. However, cytoplasmic Notch3 and Notch4 expression were negatively correlated with poor prognostic factors. CONCLUSIONS Our data indicated that Notch receptors play a key role in promoting TNBC and mainly, Notch2 may contribute to poor prognosis of the disease. Hence, it is implicated that Notch2 may serve as a potential biomarker and therapeutic target for TNBC.
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Affiliation(s)
- Heer Shah
- Immunohematology Laboratory, Cancer Biology Department, The Gujarat Cancer & Research Institute, Ahmedabad, Gujarat, India
| | - Mittal Mistry
- Immunohematology Laboratory, Cancer Biology Department, The Gujarat Cancer & Research Institute, Ahmedabad, Gujarat, India
| | - Nupur Patel
- Immunohematology Laboratory, Cancer Biology Department, The Gujarat Cancer & Research Institute, Ahmedabad, Gujarat, India
| | - Hemangini Vora
- Immunohematology Laboratory, Cancer Biology Department, The Gujarat Cancer & Research Institute, Ahmedabad, Gujarat, India
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22
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Mfouo-Tynga IS, Mouinga-Ondeme AG. Photodynamic Therapy: A Prospective Therapeutic Approach for Viral Infections and Induced Neoplasia. Pharmaceuticals (Basel) 2022; 15:ph15101273. [PMID: 36297385 PMCID: PMC9608479 DOI: 10.3390/ph15101273] [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: 09/18/2022] [Revised: 10/08/2022] [Accepted: 10/11/2022] [Indexed: 11/07/2022] Open
Abstract
The recent COVID-19 pandemic outbreak and arising complications during treatments have highlighted and demonstrated again the evolving ability of microorganisms, especially viral resistance to treatment as they develop into new and strong strains. The search for novel and effective treatments to counter the effects of ever-changing viruses is undergoing. Although it is an approved procedure for treating cancer, photodynamic therapy (PDT) was first used against bacteria and has now shown potential against viruses and certain induced diseases. PDT is a multi-stage process and uses photosensitizing molecules (PSs) that accumulate in diseased tissues and eradicates them after being light-activated in the presence of oxygen. In this review, studies describing viruses and their roles in disrupting cell regulation mechanisms and signaling pathways and facilitating tumorigenesis were described. With the development of innovative “or smart” PSs through the use of nanoparticles and two-photon excitation, among other strategies, PDT can boost immune responses, inactivate viral infections, and eradicate neoplastic cells. Visualization and monitoring of biological processes can be achieved in real-time with nanomedicines and better tissue penetration strategies. After photodynamic inactivation of viruses, signaling pathways seem to be restored but the underlying mechanisms are still to be elucidated. Light-mediated treatments are suitable to manage both oncogenic viral infections and induced neoplasia.
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SOX8 Knockdown Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting the Notch Signaling Pathway. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9235837. [PMID: 36246971 PMCID: PMC9560839 DOI: 10.1155/2022/9235837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022]
Abstract
Castration-resistant prostate cancer (CRPC) is still challenging to treat. Dissatisfaction with androgen signal-targeted therapy forces people to look for other treatment strategies. Therefore, this study is aimed at exploring the role of SOX8/Notch signaling in CRPC. The upregulation of SOX8, Notch4, and Hes5 indicated a poor progression-free survival (PFS) in CRPC patients. The expression of these proteins was also upregulated in enzalutamide-resistant LNCaP cells (Enza-R). Moreover, knocking down SOX8 inhibited malignant biological behaviors and decreased the activation of Notch signaling in Enza-R cells. Importantly, knocking down SOX8 obviously reversed the enzalutamide resistance in Enza-R cells, while RO0429097 (a γ secretase inhibitor inactivates Notch signaling) exerted similar effects. At last, we found that both SOX8 knockdown and/or RO0429097 suppressed tumor growth and bone metastasis in vivo. Altogether, our study indicated that the SOX8/Notch signaling is involved in CRPC and that these enzymes are possible targets to develop novel treatment for CRPC.
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Kajiwara T, Nishina T, Nakasya A, Yamashita N, Yamashita R, Nakamura Y, Shiozawa M, Yuki S, Taniguchi H, Hara H, Ohta T, Esaki T, Shinozaki E, Takashima A, Moriwaki T, Denda T, Ohtsubo K, Sunakawa Y, Horita Y, Kawakami H, Kato T, Satoh T, Ando K, Mizutani T, Yasui H, Goto M, Okuyama H, Yamazaki K, Yoshino T, Hyodo I. NOTCH gene alterations in metastatic colorectal cancer in the Nationwide Cancer Genome Screening Project in Japan (SCRUM-Japan GI-SCREEN). J Cancer Res Clin Oncol 2022; 148:2841-2854. [PMID: 35622165 DOI: 10.1007/s00432-022-04064-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 05/09/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC. METHODS Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay. RESULTS The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39-0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC. CONCLUSION NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker.
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Affiliation(s)
- Takeshi Kajiwara
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama, Ehime, 791-0280, Japan.
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama, Ehime, 791-0280, Japan
| | - Akio Nakasya
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama, Ehime, 791-0280, Japan
| | - Natsumi Yamashita
- Clinical Research Center, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Riu Yamashita
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, Kitaadachi-gun, Japan
| | - Takashi Ohta
- Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, Japan
| | - Taito Esaki
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Eiji Shinozaki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Atsuo Takashima
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Toshikazu Moriwaki
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Koushiro Ohtsubo
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Yosuke Horita
- Department of Medical Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Hisato Kawakami
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Takeshi Kato
- Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Koji Ando
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomonori Mizutani
- Department of General Medicine, Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Hiroyuki Okuyama
- Department of Clinical Oncology, Kagawa University Hospital, Kita-gun, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shunto-gun, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Ichinosuke Hyodo
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama, Ehime, 791-0280, Japan
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Identification of Fusion Genes and Targets for Genetically Matched Therapies in a Large Cohort of Salivary Gland Cancer Patients. Cancers (Basel) 2022; 14:cancers14174156. [PMID: 36077692 PMCID: PMC9454424 DOI: 10.3390/cancers14174156] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/15/2022] [Accepted: 08/25/2022] [Indexed: 11/19/2022] Open
Abstract
Simple Summary Salivary gland cancer (SGC) is a rare and heterogeneous cancer for which limited treatment options are available in the palliative treatment setting. Characterization of the SGC genetic landscape to identify actionable aberrations is therefore important. This research aimed to comprehensively assess the prevalence of various types of actionable aberrations, including gene fusions, in a large cohort of patients with different SGC subtypes. The combined approach using RNA- and DNA-based targeted next-generation sequencing panels revealed the presence of gene fusions in half of the cases, including several fusions not previously described in SGC. Targets for genetically matched therapies were identified in 28.3–81.8% of cases, depending on the SGC subtype (overall 53.7% of the cases). This highlights the potential of molecular diagnostics to select systemic treatment in SGC. Abstract Introduction: Salivary gland cancer (SGC) is a rare cancer for which systemic treatment options are limited. Therefore, it is important to characterize its genetic landscape in search for actionable aberrations, such as NTRK gene fusions. This research aimed to identify these actionable aberrations by combining NGS-based analysis of RNA (gene fusions) and DNA (single and multiple nucleotide variants, copy number variants, microsatellite instability and tumor mutational burden) in a large cohort of SGC patients. Methods: RNA and DNA were extracted from archival tissue of 121 patients with various SGC subtypes. Gene fusion analysis was performed using a customized RNA-based targeted NGS panel. DNA was sequenced using a targeted NGS panel encompassing 523 cancer-related genes. Cross-validation of NGS-based NTRK fusion detection and pan-TRK immunohistochemistry (IHC) was performed. Results: Fusion transcripts were detected in 50% of the cases and included both known (MYB-NFIB, MYBL1-NFIB, CRTC1-MAML2) and previously unknown fusions (including transcripts involving RET, BRAF or RAD51B). Only one NTRK fusion transcript was detected, in a secretory carcinoma case. Pan-TRK IHC (clone EPR17341) was false positive in 74% of cases. The proportion of patients with targets for genetically matched therapies differed among subtypes (salivary duct carcinoma: 82%, adenoid cystic carcinoma 28%, mucoepidermoid carcinoma 50%, acinic cell carcinoma 33%). Actionable aberrations were most often located in PIK3CA (n = 18, 15%), ERBB2 (n = 15, 12%), HRAS and NOTCH1 (both n = 9, 7%). Conclusions: Actionable genetic aberrations were seen in 53.7% of all SGC cases on the RNA and DNA level, with varying percentages between subtypes.
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Abedin Y, Gabrilovich S, Alpert E, Rego E, Begum S, Zhao Q, Heller D, Einstein MH, Douglas NC. Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma. Int J Mol Sci 2022; 23:ijms23115980. [PMID: 35682660 PMCID: PMC9180633 DOI: 10.3390/ijms23115980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 05/22/2022] [Accepted: 05/23/2022] [Indexed: 02/04/2023] Open
Abstract
Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch family genes and proteins and to investigate the therapeutic effect of γ-secretase inhibitors (GSIs), indirect inhibitors of Notch signaling, in uLMS. We determined expression of Notch genes and proteins in benign uterine smooth muscle tissue, fibroids, and uLMS samples by immunostaining and in two uLMS cell lines, SK-UT-1B (uterine primary) and SK-LMS-1 (vulvar metastasis) by RT-PCR, Western blot and immunostaining. We exposed our cell lines to GSIs, DAPT and MK-0752, and measured expression of HES1, a downstream effector of Notch. Notch proteins were differentially expressed in uLMS. Expression of NOTCH3 and NOTCH4 was higher in uLMS samples than in benign uterine smooth muscle and fibroids. Expression of NOTCH4 was higher in SK-LMS-1 compared to SK-UT-1B. Exposure of SK-UT-1B and SK-LMS-1 to DAPT and MK-0752 decreased expression of HES1 and decreased uLMS cell viability in a dose- and time-dependent manner that was unique to each GSI. Our findings suggest that GSIs are potential therapeutics for uLMS, albeit with limited efficacy.
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Affiliation(s)
- Yasmin Abedin
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA; (S.G.); (E.A.); (E.R.); (S.B.); (Q.Z.); (D.H.); (M.H.E.); (N.C.D.)
- Correspondence:
| | - Sofia Gabrilovich
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA; (S.G.); (E.A.); (E.R.); (S.B.); (Q.Z.); (D.H.); (M.H.E.); (N.C.D.)
| | - Emily Alpert
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA; (S.G.); (E.A.); (E.R.); (S.B.); (Q.Z.); (D.H.); (M.H.E.); (N.C.D.)
| | - Erica Rego
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA; (S.G.); (E.A.); (E.R.); (S.B.); (Q.Z.); (D.H.); (M.H.E.); (N.C.D.)
| | - Salma Begum
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA; (S.G.); (E.A.); (E.R.); (S.B.); (Q.Z.); (D.H.); (M.H.E.); (N.C.D.)
| | - Qingshi Zhao
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA; (S.G.); (E.A.); (E.R.); (S.B.); (Q.Z.); (D.H.); (M.H.E.); (N.C.D.)
| | - Debra Heller
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA; (S.G.); (E.A.); (E.R.); (S.B.); (Q.Z.); (D.H.); (M.H.E.); (N.C.D.)
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA
| | - Mark H. Einstein
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA; (S.G.); (E.A.); (E.R.); (S.B.); (Q.Z.); (D.H.); (M.H.E.); (N.C.D.)
| | - Nataki C. Douglas
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA; (S.G.); (E.A.); (E.R.); (S.B.); (Q.Z.); (D.H.); (M.H.E.); (N.C.D.)
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Giuli MV, Mancusi A, Giuliani E, Screpanti I, Checquolo S. Notch signaling in female cancers: a multifaceted node to overcome drug resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 4:805-836. [PMID: 35582386 PMCID: PMC8992449 DOI: 10.20517/cdr.2021.53] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022]
Abstract
Drug resistance is one of the main challenges in cancer therapy, including in the treatment of female-specific malignancies, which account for more than 60% of cancer cases among women. Therefore, elucidating the underlying molecular mechanisms is an urgent need in gynecological cancers to foster novel therapeutic approaches. Notably, Notch signaling, including either receptors or ligands, has emerged as a promising candidate given its multifaceted role in almost all of the hallmarks of cancer. Concerning the connection between Notch pathway and drug resistance in the afore-mentioned tumor contexts, several studies focused on the Notch-dependent regulation of the cancer stem cell (CSC) subpopulation or the induction of the epithelial-to-mesenchymal transition (EMT), both features implicated in either intrinsic or acquired resistance. Indeed, the present review provides an up-to-date overview of the published results on Notch signaling and EMT- or CSC-driven drug resistance. Moreover, other drug resistance-related mechanisms are examined such as the involvement of the Notch pathway in drug efflux and tumor microenvironment. Collectively, there is a long way to go before every facet will be fully understood; nevertheless, some small pieces are falling neatly into place. Overall, the main aim of this review is to provide strong evidence in support of Notch signaling inhibition as an effective strategy to evade or reverse resistance in female-specific cancers.
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Affiliation(s)
- Maria V Giuli
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Angelica Mancusi
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Eugenia Giuliani
- Scientific Direction, San Gallicano Dermatological Institute IRCCS, Rome 00144, Italy
| | - Isabella Screpanti
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Saula Checquolo
- Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina 04100, Italy.,Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome 00161, Italy
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Chen YL, Lee KT, Wang CY, Shen CH, Chen SC, Chung WP, Hsu YT, Kuo YL, Chen PS, Cheung CHA, Chang CP, Shen MR, Hsu HP. Low expression of cytosolic NOTCH1 predicts poor prognosis of breast cancer patients. Am J Cancer Res 2022; 12:2084-2101. [PMID: 35693094 PMCID: PMC9185622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 03/29/2022] [Indexed: 06/15/2023] Open
Abstract
The incidence of breast cancer is increasing, and is one of the leading causes of cancer death worldwide. Dysregulation of NOTCH1 signaling is reported in breast cancer. In present study, bioinformatics was utilized to study the expression of NOTCH1 gene in breast cancer from public databases, including the Kaplan-Meier Plotter, PrognoScan, Human Protein Atlas, and cBioPortal. The relationship between NOTCH1 mRNA expression and survival of patients was inconsistent in public databases. In addition, we performed immunohistochemistry (IHC) staining of 135 specimens from our hospital. Lower cytoplasmic staining of NOTCH1 protein was correlated with cancer recurrence, bone metastasis, and a worse disease-free survival of patients, especially those with estrogen receptor-positive and human epidermal growth factor receptor 2-positive (HER2+) cancers. In TCGA breast cancer dataset, lower expression of NOTCH1 in breast cancer specimens was correlated with higher level of CCND1 (protein: cyclin D1). Decreased expression of NOTCH1 was correlated with lower level of CCNA1 (protein: cyclin A1), CCND2 (protein: cyclin D2), CCNE1 (protein: cyclin E1), CDK6 (protein: CDK6), and CDKN2C (protein: p18). In conclusion, NOTCH1 mRNA expression is not consistently correlated with clinical outcomes of breast cancer patients. Low cytoplasmic expression of NOTCH1 in IHC study is correlated with poor prognosis of breast cancer patients. Cytoplasmic localization of NOTCH1 protein failed to initial oncogenic signaling in present study. Expression of NOTCH1 mRNA was discordant with cell cycle-related genes. Regulation of NOTCH1 in breast cancer involves gene expression, protein localization and downstream signaling.
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Affiliation(s)
- Yi-Ling Chen
- Department of Health and Nutrition, Chia Nan University of Pharmacy and ScienceTainan 71710, Taiwan
| | - Kuo-Ting Lee
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainan 70403, Taiwan
| | - Chih-Yang Wang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung UniversityTainan 70101, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan 70101, Taiwan
| | - Che-Hung Shen
- National Institute of Cancer Research, National Health Research InstituteTainan 70456, Taiwan
| | - Sheau-Chiann Chen
- Department of Biostatistics, Vanderbilt University Medical CenterNashville, Tennessee 37232, United States
| | - Wei-Pang Chung
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityTainan 70101, Taiwan
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainan 70403, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung UniversityTainan, Taiwan
| | - Ya-Ting Hsu
- Division of Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainan 70403, Taiwan
| | - Yao-Lung Kuo
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainan 70403, Taiwan
| | - Pai-Sheng Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan 70101, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung UniversityTainan 70101, Taiwan
| | - Chun Hei Antonio Cheung
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan 70101, Taiwan
- Department of Pharmacology, College of Medicine, National Cheng Kung UniversityTainan 70101, Taiwan
| | - Chih-Peng Chang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan 70101, Taiwan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung UniversityTainan 70101, Taiwan
| | - Meng-Ru Shen
- Department of Pharmacology, College of Medicine, National Cheng Kung UniversityTainan 70101, Taiwan
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainan 70403, Taiwan
| | - Hui-Ping Hsu
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainan 70403, Taiwan
- Department of Biostatistics, Vanderbilt University Medical CenterNashville, Tennessee 37232, United States
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Wang PW, Su YH, Chou PH, Huang MY, Chen TW. Survival-related genes are diversified across cancers but generally enriched in cancer hallmark pathways. BMC Genomics 2022; 22:918. [PMID: 35508961 PMCID: PMC9066720 DOI: 10.1186/s12864-022-08581-x] [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: 04/22/2022] [Accepted: 04/22/2022] [Indexed: 11/28/2022] Open
Abstract
Background Pan-cancer studies have disclosed many commonalities and differences in mutations, copy number variations, and gene expression alterations among cancers. Some of these features are significantly associated with clinical outcomes, and many prognosis-predictive biomarkers or biosignatures have been proposed for specific cancer types. Here, we systematically explored the biological functions and the distribution of survival-related genes (SRGs) across cancers. Results We carried out two different statistical survival models on the mRNA expression profiles in 33 cancer types from TCGA. We identified SRGs in each cancer type based on the Cox proportional hazards model and the log-rank test. We found a large difference in the number of SRGs among different cancer types, and most of the identified SRGs were specific to a particular cancer type. While these SRGs were unique to each cancer type, they were found mostly enriched in cancer hallmark pathways, e.g., cell proliferation, cell differentiation, DNA metabolism, and RNA metabolism. We also analyzed the association between cancer driver genes and SRGs and did not find significant over-representation amongst most cancers. Conclusions In summary, our work identified all the SRGs for 33 cancer types from TCGA. In addition, the pan-cancer analysis revealed the similarities and the differences in the biological functions of SRGs across cancers. Given the potential of SRGs in clinical utility, our results can serve as a resource for basic research and biotech applications. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-022-08581-x.
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Affiliation(s)
- Po-Wen Wang
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan.,Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan
| | - Yi-Hsun Su
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan.,Industrial Development PhD Program of the College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan
| | - Po-Hao Chou
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan.,Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan
| | - Ming-Yueh Huang
- Institute of Statistical Science, Academia Sinica, Taipei, 11529, Taiwan
| | - Ting-Wen Chen
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan. .,Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan. .,Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan.
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Zheng Q, Zhang B, Li C, Zhang X. Overcome Drug Resistance in Cholangiocarcinoma: New Insight Into Mechanisms and Refining the Preclinical Experiment Models. Front Oncol 2022; 12:850732. [PMID: 35372014 PMCID: PMC8970309 DOI: 10.3389/fonc.2022.850732] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/14/2022] [Indexed: 11/19/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive tumor characterized by a poor prognosis. Therapeutic options are limited in patients with advanced stage of CCA, as a result of the intrinsic or acquired resistance to currently available chemotherapeutic agents, and the lack of new drugs entering into clinical application. The challenge in translating basic research to the clinical setting, caused by preclinical models not being able to recapitulate the tumor characteristics of the patient, seems to be an important reason for the lack of effective and specific therapies for CCA. So, there seems to be two ways to improve patient outcomes. The first one is developing the combination therapies based on a better understanding of the mechanisms contributing to the resistance to currently available chemotherapeutic agents. The second one is developing novel preclinical experimental models that better recapitulate the genetic and histopathological features of the primary tumor, facilitating the screening of new drugs for CCA patients. In this review, we discussed the evidence implicating the mechanisms underlying treatment resistance to currently investigated drugs, and the development of preclinical experiment models for CCA.
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Affiliation(s)
- Qingfan Zheng
- Department of Hepatobiliary and Pancreas Surgery, the Second Hospital of Jilin University, Changchun, China
| | - Bin Zhang
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Changfeng Li
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xuewen Zhang
- Department of Hepatobiliary and Pancreas Surgery, the Second Hospital of Jilin University, Changchun, China
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31
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Gouda G, Gupta MK, Donde R, Behera L, Vadde R. Metabolic pathway-based target therapy to hepatocellular carcinoma: a computational approach. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA, VOLUME 2 2022:83-103. [DOI: 10.1016/b978-0-323-98807-0.00003-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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32
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Li Z, Yu F, Ye W, Mao L, Huang J, Shao Y, Yan J, Yu W, Jin J, Wang J. Clinical Features and Prognostic Significance of NOTCH1 Mutations in Diffuse Large B-Cell Lymphoma. Front Oncol 2021; 11:746577. [PMID: 34956871 PMCID: PMC8695434 DOI: 10.3389/fonc.2021.746577] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 11/12/2021] [Indexed: 01/06/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of large lymphoid B cell malignancy with distinct clinical and genetic features. Recently, NOTCH1 mutations were identified in DLBCL cases by Next-generation sequencing (NGS), but the clinical features and prognostic impact were not systematically studied. Here, NOTCH1 genes in 161 DLBCL samples were sequenced by NGS. The prognostic value of NOTCH1 mutations was assessed in the context of clinical and laboratory factors, such as international prognostic index (IPI), cell-of-origin classification, double expression of BCL2 and c-MYC. The combined data from three Western cohorts were used to validate these results. As a result, NOTCH1 mutations were found in 17(10.6%) patients, and three patients had a hotspot mutation of c.7541_7542delCT. The presence of NOTCH1 mutations was significantly associated with poor complete response and progression free survival(PFS), which was independent of established clinical and laboratory parameters. In addition, 30 (1.92%) of 1562 patients treated with R-CHOP regimen in those combined Western cohorts had NOTCH1 mutations. Meta-analysis of the Western cohorts confirmed that NOTCH1 mutations were also associated with poor PFS and OS. In conclusion, DLBCL patients with the NOTCH1 mutations have worse PFS and OS, and the NOTCH1 mutations can be used as an independent predictor for patients with DLBCL.
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Affiliation(s)
- Zhongqi Li
- The Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Fang Yu
- Department of Pathology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Wenle Ye
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China
| | - Liping Mao
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China
- The First Affiliated Hospital of Zhejiang University, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Jiansong Huang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China
- The First Affiliated Hospital of Zhejiang University, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Yang Shao
- Medical Department, Nanjing Geneseeq Technology Inc., Nanjing, China
| | - Junrong Yan
- Medical Department, Nanjing Geneseeq Technology Inc., Nanjing, China
| | - Wenjuan Yu
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China
- The First Affiliated Hospital of Zhejiang University, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China
- The First Affiliated Hospital of Zhejiang University, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- *Correspondence: Jinghan Wang, ; Jie Jin,
| | - Jinghan Wang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China
- The First Affiliated Hospital of Zhejiang University, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- *Correspondence: Jinghan Wang, ; Jie Jin,
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Three-Dimensional Culture Systems for Dissecting Notch Signalling in Health and Disease. Int J Mol Sci 2021; 22:ijms222212473. [PMID: 34830355 PMCID: PMC8618738 DOI: 10.3390/ijms222212473] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 12/12/2022] Open
Abstract
Three-dimensional (3D) culture systems opened up new horizons in studying the biology of tissues and organs, modelling various diseases, and screening drugs. Producing accurate in vitro models increases the possibilities for studying molecular control of cell–cell and cell–microenvironment interactions in detail. The Notch signalling is linked to cell fate determination, tissue definition, and maintenance in both physiological and pathological conditions. Hence, 3D cultures provide new accessible platforms for studying activation and modulation of the Notch pathway. In this review, we provide an overview of the recent advances in different 3D culture systems, including spheroids, organoids, and “organ-on-a-chip” models, and their use in analysing the crucial role of Notch signalling in the maintenance of tissue homeostasis, pathology, and regeneration.
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Palamaris K, Felekouras E, Sakellariou S. Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance. Cancers (Basel) 2021; 13:cancers13215532. [PMID: 34771695 PMCID: PMC8582651 DOI: 10.3390/cancers13215532] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/31/2021] [Accepted: 11/01/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma’s (PDAC) dismal prognosis is associated with its aggressive biological behavior and resistance to chemotherapy. Epithelial to mesenchymal transition (EMT) has been recognized as a key driver of PDAC progression and development of drug resistance. EMT is a transient and reversible process leading to transdifferentiation of epithelial cells into a more mesenchymal phenotype. It is regulated by multiple signaling pathways that control the activity of a transcription factors network. Activation of EMT in pre-invasive stages of PDAC has been accused for early dissemination. Furthermore, it contributes to the development of intratumoral heterogeneity and drug resistance. This review summarizes the available data regarding signaling networks regulating EMT and describes the integral role of EMT in different aspects of PDAC pathogenesis. Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by aggressive biological behavior and a lack of response to currently available chemotherapy. Emerging evidence has identified epithelial to mesenchymal transition (EMT) as a key driver of PDAC progression and a central regulator in the development of drug resistance. EMT is a reversible transdifferentiation process controlled by complex interactions between multiple signaling pathways such as TGFb, Wnt, and Notch, which converge to a network of specific transcription factors. Activation of EMT transcriptional reprogramming converts cancer cells of epithelial differentiation into a more mesenchymal phenotypic state. EMT occurrence in pre-invasive pancreatic lesions has been implicated in early PDAC dissemination. Moreover, cancer cell phenotypic plasticity driven by EMT contributes to intratumoral heterogeneity and drug tolerance and is mechanistically associated with the emergence of cells exhibiting cancer stem cells (CSCs) phenotype. In this review we summarize the available data on the signaling cascades regulating EMT and the molecular isnteractions between pancreatic cancer and stromal cells that activate them. In addition, we provide a link between EMT, tumor progression, and chemoresistance in PDAC.
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Affiliation(s)
- Kostas Palamaris
- 1ST Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Evangelos Felekouras
- 1ST Department of Surgery, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stratigoula Sakellariou
- 1ST Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Correspondence:
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Nadolny C, Zhang X, Chen Q, Hashmi SF, Ali W, Hemme C, Ahsan N, Chen Y, Deng R. Dysregulation and activities of ubiquitin specific peptidase 2b in the pathogenesis of hepatocellular carcinoma. Am J Cancer Res 2021; 11:4746-4767. [PMID: 34765291 PMCID: PMC8569343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/26/2021] [Indexed: 06/13/2023] Open
Abstract
Ubiquitin specific peptidase-2 (USP2) plays important roles in a myriad of cellular activities through deubiquitinating target proteins and its implications in various diseases, especially cancers, are starting to emerge. Our current understanding on USP2 expression in subjects with hepatocellular carcinoma (HCC) and its roles in the pathogenesis of HCC is limited. In this study, we found that USP2 protein and mRNA levels were significantly dysregulated in HCC tumor (HCC-T) when compared to adjacent non-tumor (HCC-NT) or normal liver tissues from both human and mouse HCC model. Among the USP2 isoforms, USP2b was the predominant isoform in the normal liver and markedly down-regulated in HCC-T tissues in both human and mice. Data from overexpression, chemical inhibition and knockout studies consistently demonstrated that USP2b promoted cell proliferation, colony formation and wound healing in HepG2 and Huh 7 cells. On the other hand, USP2b exhibited proapoptotic and pronecrtotic activities through enhancing bile acid-induced apoptosis and necrosis in both HepG2 and Huh 7 cells. Unbiased proteomic analysis of USP2-knockout (KO) and parental HepG2 cells resulted in identification of USP2-regulated downstream target proteins involved in cell proliferation, apoptosis, and tumorigenesis, including serine/threonine kinase 4 (STK4), epidermal growth factor receptor (EGFR), dipeptidyl peptidase 4 (DPP4) and fatty acid binding protein 1 (FABP1). In conclusion, USP2b expression was dysregulated in subjects with HCC and contributed to the pathogenesis of HCC by promoting cell proliferation and exerting proapoptotic and pronecrotic activities. The findings provide the molecular basis for developing therapies for HCC through modulating USP2b expression or activities.
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Affiliation(s)
- Christina Nadolny
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island7 Greenhouse Road, Kingston, RI 02881, USA
| | - Xinmu Zhang
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island7 Greenhouse Road, Kingston, RI 02881, USA
| | - Qiwen Chen
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island7 Greenhouse Road, Kingston, RI 02881, USA
| | - Syed F Hashmi
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island7 Greenhouse Road, Kingston, RI 02881, USA
| | - Winifer Ali
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island7 Greenhouse Road, Kingston, RI 02881, USA
| | - Christopher Hemme
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island7 Greenhouse Road, Kingston, RI 02881, USA
| | - Nagib Ahsan
- COBRE Center for Cancer Research Development, Proteomics Core Facility, Rhode Island HospitalProvidence, RI 02903, USA
- Division of Biology and Medicine, Brown UniversityProvidence, RI 02903, USA
- Department of Chemistry and Biochemistry, University of Oklahoma101 Stephenson Parkway, Norman, OK 73019, USA
| | - Yuan Chen
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island7 Greenhouse Road, Kingston, RI 02881, USA
| | - Ruitang Deng
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island7 Greenhouse Road, Kingston, RI 02881, USA
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Liu S, Gu L, Wu N, Song J, Yan J, Yang S, Feng Y, Wang Z, Wang L, Zhang Y, Jin Y. Overexpression of DTL enhances cell motility and promotes tumor metastasis in cervical adenocarcinoma by inducing RAC1-JNK-FOXO1 axis. Cell Death Dis 2021; 12:929. [PMID: 34635635 PMCID: PMC8505428 DOI: 10.1038/s41419-021-04179-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 09/06/2021] [Accepted: 09/16/2021] [Indexed: 12/14/2022]
Abstract
Cervical adenocarcinoma is an important disease that affects young women and it has a high mortality and poor prognosis. Denticleless E3 ubiquitin protein ligase homolog (DTL) gene with oncogenic function has been evaluated in several cancers. Through this study, we aimed to clarify the clinical and molecular characteristics of cervical adenocarcinoma involving overexpression of DTL and elucidate its molecular mechanism. Bioinformatics analysis was performed through multiple databases. RNA sequencing was used to obtain differentially expressed genes after DTL was overexpressed in cells. The role of DTL in cervical adenocarcinoma was explored through in vitro and in vivo experiments. We found that DTL has an unfavorable prognostic implication for patients with cervical adenocarcinoma. Overexpression of DTL induced the migration and invasion of tumor cells in vitro and promoted intra-pulmonary metastasis in vivo. In addition, DTL activated JNK through RAC1 and upregulated FOXO1 to induce epithelial-mesenchymal transition, and the migration and invasion of tumor cells. Therefore, we conclude that overexpression of DTL enhanced cell motility and promoted tumor metastasis of cervical adenocarcinoma by regulating the RAC1-JNK-FOXO1 axis. These results suggest that DTL may become a potential therapeutic target for antitumor metastasis of cervical adenocarcinoma.
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Affiliation(s)
- Sijia Liu
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Lina Gu
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Nan Wu
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, Heilongjiang, 150081, China
| | - Jiayu Song
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Jiazhuo Yan
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Shanshan Yang
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Yue Feng
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Zhao Wang
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Le Wang
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Yunyan Zhang
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China.
| | - Yan Jin
- Key laboratory of preservation of human genetic resources and disease control in China (Harbin Medical University), Ministry of Education, Harbin, Heilongjiang, 150081, China.
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Abstract
MicroRNAs (miRNAs), a class of small noncoding RNA, posttranscriptionally regulate the expression of genes. Aberrant expression of miRNA is reported in various types of cancer. Since the first report of oncomiR-21 involvement in the glioma, its upregulation was reported in multiple cancers and was allied with high oncogenic property. In addition to the downregulation of tumor suppressor genes, the miR-21 is also associated with cancer resistance to various chemotherapy. The recent research is appraising miR-21 as a promising cancer target and biomarker for early cancer detection. In this review, we briefly explain the biogenesis and regulation of miR-21 in cancer cells. Additionally, the review features the assorted genes/pathways regulated by the miR-21 in various cancer and cancer stem cells.
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Putowski M, Giannopoulos K. Perspectives on Precision Medicine in Chronic Lymphocytic Leukemia: Targeting Recurrent Mutations-NOTCH1, SF3B1, MYD88, BIRC3. J Clin Med 2021; 10:jcm10163735. [PMID: 34442029 PMCID: PMC8396993 DOI: 10.3390/jcm10163735] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/13/2021] [Accepted: 08/19/2021] [Indexed: 12/15/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) is highly heterogeneous, with extremely variable clinical course. The clinical heterogeneity of CLL reflects differences in the biology of the disease, including chromosomal alterations, specific immunophenotypic patterns and serum markers. The application of next-generation sequencing techniques has demonstrated the high genetic and epigenetic heterogeneity in CLL. The novel mutations could be pharmacologically targeted for individualized approach in some of the CLL patients. Potential neurogenic locus notch homolog protein 1 (NOTCH1) signalling targeting mechanisms in CLL include secretase inhibitors and specific antibodies to block NOTCH ligand/receptor interactions. In vitro studies characterizing the effect of the splicing inhibitors resulted in increased apoptosis of CLL cells regardless of splicing factor 3B subunit 1 (SF3B1) status. Several therapeutic strategies have been also proposed to directly or indirectly inhibit the toll-like receptor/myeloid differentiation primary response gene 88 (TLR/MyD88) pathway. Another potential approach is targeting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inhibition of this prosurvival pathway. Newly discovered mutations and their signalling pathways play key roles in the course of the disease. This opens new opportunities in the management and treatment of CLL.
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Affiliation(s)
- Maciej Putowski
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland;
- Correspondence: ; Tel.: +48-81-448-66-32
| | - Krzysztof Giannopoulos
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland;
- Department of Hematology, St. John’s Cancer Center, 20-090 Lublin, Poland
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Palmini G, Brandi ML. microRNAs and bone tumours: Role of tiny molecules in the development and progression of chondrosarcoma, of giant cell tumour of bone and of Ewing's sarcoma. Bone 2021; 149:115968. [PMID: 33892177 DOI: 10.1016/j.bone.2021.115968] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 03/26/2021] [Accepted: 04/15/2021] [Indexed: 12/15/2022]
Abstract
The increasing interest on microRNAs (miRNAs), small non-coding RNA molecules containing about 22 nucleotides, about their biological functions led researchers to discover that they are actively involved in several biological processes. In the last decades, miRNAs become one of the most topic of cancer research. miRNAs, thanks to their function, are the perfect molecules to modulate multiple signaling pathways and gene expression in cancer, with the consequent capacity to modulate cancerous processes, such as cellular proliferation, invasion, metastasis and chemoresistance in various tumours. In the last years, several studies have demonstrated the role of miRNAs in their pathophysiology, but little we know about the underlying mechanism that lead to bone tumours like chondrosarcoma (COS), giant cell tumour of bone (GCTB) and Ewing sarcoma (EWS) to still be highly aggressive and resistant tumours. An exploration of the role of miRNAs in the biology of them will permit to researchers to find new molecular mechanisms that can be used to develop new and more effective therapies against these bone tumours. Here we present a comprehensive study of the latest discoveries which have been performed in relation to the role of miRNAs in the neoplastic processes which characterize COS, EWS and GCTB, demonstrating how these tiny molecules can act as tumour promoters or as tumour suppressors and how they can be used for improving therapeutic approaches.
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Affiliation(s)
- Gaia Palmini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
| | - Maria Luisa Brandi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy; Fondazione Italiana Ricerca sulle Malattie dell'Osso, F.I.R.M.O Onlus, Florence, Italy.
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Zhang X, Bian H, Wei W, Wang Q, Chen J, Hei R, Chen C, Wu X, Yuan H, Gu J, Lu Y, Cai C, Zheng Q. DLX5 promotes osteosarcoma progression via activation of the NOTCH signaling pathway. Am J Cancer Res 2021; 11:3354-3374. [PMID: 34249467 PMCID: PMC8263696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 05/25/2021] [Indexed: 06/13/2023] Open
Abstract
The distal-less (dlx) homeobox transcription factors have been implicated roles in bone development. DLX5, in particular, was shown to play essential roles in osteoblast differentiation by targeting RUNX2, a master transcription factor for bone development. Interestingly, DLX5 has also been shown to play an oncogenic role in lung and other cancers, possibly via regulation of MYC expression. Given its dual roles in bone and cancer, this study aimed to investigate the effect of DLX5 on progression of osteosarcoma (OS), the primary bone cancer that is characterized by abnormal bone formation and osteoblast activity. Expression of DLX5 in OS cell lines was detected by quantitative real-time PCR (qRT-PCR) and western blot (WB). In vitro and in vivo assays were performed to investigate the oncogenic function of DLX5 in OS cells and xenograft models. Luciferase reporter assay was performed to determine the underlying mechanism of DLX5-mediated OS aggressiveness. The results showed that DLX5 was differentially expressed in OS cell lines, with significantly upregulated levels in HOS and MG-63 and relatively low levels in U2OS and 143B cell lines, compared with the normal bone cell line. DLX5 knockdown in HOS and MG-63 cell lines by siRNA inhibited OS cell growth and progression, and induced cell apoptosis and cell cycle changes both in vitro and in vivo. Meanwhile, DLX5 overexpression had the opposite effect on U2OS and 143B cell lines. Notably, a positive correlation between the expression patterns of NOTCH1 and DLX5 was also observed. The expression levels of NICD (NOTCH1 intracellular domain) and HES1 (classical target of NOTCH) were closely associated with DLX5 expression. Whereas knockdown of DLX5 in OS cells resulted in decreased expression of NOTCH1 and reduced cell proliferation and migration, which were rescued by overexpression of NOTCH1. We further analyzed DLX5 and NOTCH1 genes using JASPAR software and found two potential DLX5 binding sites within the NOTCH1 promoter. Dual-luciferase assay demonstrated that DLX5 specifically activates the NOTCH1 promoter and controls its expression. Taken together, our results support that DLX5 plays an oncogenic role in OS development, which can at least partially, be attributed to activation of the NOTCH signaling pathway.
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Affiliation(s)
- Xiaojing Zhang
- Department of Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu UniversityZhenjiang 212013, China
- Shenzhen Academy of Peptide Targeting Technology at Pingshan, and Shenzhen Tyercan Bio-Pharm Co., Ltd.Shenzhen 518118, China
| | - Huiqin Bian
- Department of Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu UniversityZhenjiang 212013, China
| | - Wei Wei
- Department of Orthopaedics, Zhongnan Hospital of Wuhan UniversityWuhan 430071, China
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan UniversityWuhan 430071, China
| | - Qian Wang
- Department of Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu UniversityZhenjiang 212013, China
| | - Jinnan Chen
- Department of Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu UniversityZhenjiang 212013, China
- Department of Internal Medicine, Rush University Medical CenterChicago, IL 60612, USA
| | - Ruoxuan Hei
- Department of Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu UniversityZhenjiang 212013, China
| | - Chen Chen
- Department of Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu UniversityZhenjiang 212013, China
| | - Xuan Wu
- Department of Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu UniversityZhenjiang 212013, China
| | - Haochun Yuan
- Department of Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu UniversityZhenjiang 212013, China
| | - Junxia Gu
- Department of Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu UniversityZhenjiang 212013, China
| | - Yaojuan Lu
- Shenzhen Academy of Peptide Targeting Technology at Pingshan, and Shenzhen Tyercan Bio-Pharm Co., Ltd.Shenzhen 518118, China
| | - Cheguo Cai
- Department of Orthopaedics, Zhongnan Hospital of Wuhan UniversityWuhan 430071, China
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan UniversityWuhan 430071, China
| | - Qiping Zheng
- Department of Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu UniversityZhenjiang 212013, China
- Shenzhen Academy of Peptide Targeting Technology at Pingshan, and Shenzhen Tyercan Bio-Pharm Co., Ltd.Shenzhen 518118, China
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Ma S, Wang J, Lin J, Jin S, He F, Mei J, Zhang H, Wang S, Li Q. Survivin promotes rheumatoid arthritis fibroblast-like synoviocyte cell proliferation, and the expression of angiogenesis-related proteins by activating the NOTCH pathway. Int J Rheum Dis 2021; 24:922-929. [PMID: 34096679 DOI: 10.1111/1756-185x.14150] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/08/2021] [Accepted: 05/12/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Survivin have been shown to play a crucial role in rheumatoid arthritis (RA); however, the regulatory mechanism of survivin in RA has not been fully elucidated. This study aims to investigate the effect of survivin on the proliferation and apoptosis of human RA fibroblast-like synoviocyte (RA-HFLS) cells in RA and its underlying mechanism through the NOTCH pathway. METHODS The RA synovial tissues of 65 RA patients with partial resection of synovium of knee joint by arthroscopy were collected. The expression of survivin in synovial tissue was detected by immunohistochemistry, and the correlation of survivin expression and clinical-pathological parameters of patients was analyzed. In vitro, the proliferation of HFLS and RA-HFLS were detected by MTT; the apoptosis of HFLS and RA-HFLS were detected by flow cytometry; the expression of survivin proteins, key protein factors (Notch1, Jagged1, Hes1) in the Notch pathway, and angiogenesis-related proteins (vascular endothelial growth factor receptor 1 [VEGFR1], Ang1, Ang2) were determined by western blot. RESULTS We found that survivin was highly expressed in RA synovial tissues and RA-HFLS cells, and was positively correlated with erythrocyte sedimentation rate, cyclic citrullinated peptide, C-reactive protein, Disease Activity Score of 28 joints and other pathological indexes. Knockdown survivin induces RA-HFLS cell apoptosis, suppresses proliferation and the expression of VEGFR1, Ang1, Ang2. In addition, blocking Notch pathway using FLI-06 significantly down-regulated survivin expression. When survivin is up-regulated, it promotes RA-HFLS cell proliferation, the expression of VEGFR1, Ang1, Ang2 and suppresses apoptosis by activating the NOTCH. CONCLUSION This study confirmed that survivin promotes RA-HFLS cell proliferation, the expression of angiogenesis-related proteins and suppresses apoptosis by activating the NOTCH pathway.
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Affiliation(s)
- Sha Ma
- Medical School, Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, China.,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.,Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Jing Wang
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Jun Lin
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Song Jin
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Fang He
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Jian Mei
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Hong Zhang
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Shuya Wang
- Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Qin Li
- Medical School, Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, China.,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.,Department of Rheumatology, The First People's Hospital of Yunnan Province, Kunming, China
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LSD1 as a Biomarker and the Outcome of Its Inhibitors in the Clinical Trial: The Therapy Opportunity in Tumor. JOURNAL OF ONCOLOGY 2021; 2021:5512524. [PMID: 33833800 PMCID: PMC8018836 DOI: 10.1155/2021/5512524] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/04/2021] [Accepted: 03/10/2021] [Indexed: 01/06/2023]
Abstract
Tumors are the foremost cause of death worldwide. As a result of that, there has been a significant enhancement in the investigation, treatment methods, and good maintenance practices on cancer. However, the sensitivity and specificity of a lot of tumor biomarkers are not adequate. Hence, it is of inordinate significance to ascertain novel biomarkers to forecast the prognosis and therapy targets for tumors. This review characterized LSD1 as a biomarker in different tumors. LSD1 inhibitors in clinical trials were also discussed. The recent pattern advocates that LSD1 is engaged at sauce chromatin zones linking with complexes of multi-protein having an exact DNA-binding transcription factor, establishing LSD1 as a favorable epigenetic target, and also gives a large selection of therapeutic targets to treat different tumors. This review sturdily backing the oncogenic probable of LSD1 in different tumors indicated that LSD1 levels can be used to monitor and identify different tumors and can be a useful biomarker of progression and fair diagnosis in tumor patients. The clinical trials showed that inhibitors of LSD1 have growing evidence of clinical efficacy which is very encouraging and promising. However, for some of the inhibitors such as GSK2879552, though selective, potent, and effective, its disease control was poor as the rate of adverse events (AEs) was high in tumor patients causing clinical trial termination, and continuation could not be supported by the risk-benefit profile. Therefore, we propose that, to attain excellent clinical results of inhibitors of LSD1, much attention is required in designing appropriate dosing regimens, developing in-depth in vitro/in vivo mechanistic works of LSD1 inhibitors, and developing inhibitors of LSD1 that are reversible, safe, potent, and selective which may offer safer profiles.
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Patni AP, Harishankar MK, Joseph JP, Sreeshma B, Jayaraj R, Devi A. Comprehending the crosstalk between Notch, Wnt and Hedgehog signaling pathways in oral squamous cell carcinoma - clinical implications. Cell Oncol (Dordr) 2021; 44:473-494. [PMID: 33704672 DOI: 10.1007/s13402-021-00591-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 01/17/2021] [Accepted: 01/19/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) is a malignant oral cavity neoplasm that affects many people, especially in developing countries. Despite several advances that have been made in diagnosis and treatment, the morbidity and mortality rates due to OSCC remain high. Accumulating evidence indicates that aberrant activation of cellular signaling pathways, such as the Notch, Wnt and Hedgehog pathways, occurs during the development and metastasis of OSCC. In this review, we have articulated the roles of the Notch, Wnt and Hedgehog signaling pathways in OSCC and their crosstalk during tumor development and progression. We have also examined possible interactions and associations between these pathways and treatment regimens that could be employed to effectively tackle OSCC and/or prevent its recurrence. CONCLUSIONS Activation of the Notch signaling pathway upregulates the expression of several genes, including c-Myc, β-catenin, NF-κB and Shh. Associations between the Notch signaling pathway and other pathways have been shown to enhance OSCC tumor aggressiveness. Crosstalk between these pathways supports the maintenance of cancer stem cells (CSCs) and regulates OSCC cell motility. Thus, application of compounds that block these pathways may be a valid strategy to treat OSCC. Such compounds have already been employed in other types of cancer and could be repurposed for OSCC.
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Affiliation(s)
- Anjali P Patni
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - M K Harishankar
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Joel P Joseph
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Bhuvanadas Sreeshma
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Rama Jayaraj
- College of Human and Human Sciences, Charles Darwin University, Ellangowan Drive, Darwin, Northern Territory, 0909, Australia
| | - Arikketh Devi
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India.
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Anusewicz D, Orzechowska M, Bednarek AK. Notch Signaling Pathway in Cancer-Review with Bioinformatic Analysis. Cancers (Basel) 2021; 13:cancers13040768. [PMID: 33673145 PMCID: PMC7918426 DOI: 10.3390/cancers13040768] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/26/2021] [Accepted: 02/08/2021] [Indexed: 01/19/2023] Open
Abstract
Simple Summary The Notch signaling pathway, which controls multiple cell differentiation processes during the embryonic stage and adult life, is associated with carcinogenesis and disease progression. The aim of the present study was to highlight cancer heterogeneity with respect to the Notch pathway. Our analysis concerns the effects of the Notch signaling at different levels, including core components and downstream target genes. We also demonstrate overall and disease-free survival results, pointing out the characteristics of particular Notch components. Depending on tissue context, Notch members can be either oncogenic or suppressive. We observed different expression profile core components and target genes that could be associated with distinct survival of patients. Advances in our understanding of the Notch signaling in cancer are very promising for the development of new treatment strategies for the benefit of patients. Abstract Notch signaling is an evolutionarily conserved pathway regulating normal embryonic development and homeostasis in a wide variety of tissues. It is also critically involved in carcinogenesis, as well as cancer progression. Activation of the Notch pathway members can be either oncogenic or suppressive, depending on tissue context. The present study is a comprehensive overview, extended with a bioinformatics analysis of TCGA cohorts, including breast, bladder, cervical, colon, kidney, lung, ovary, prostate and rectum carcinomas. We performed global expression profiling of the Notch pathway core components and downstream targets. For this purpose, we implemented the Uniform Manifold Approximation and Projection algorithm to reduce the dimensions. Furthermore, we determined the optimal cutpoint using Evaluate Cutpoint software to established disease-free and overall survival with respect to particular Notch members. Our results demonstrated separation between tumors and their corresponding normal tissue, as well as between tumors in general. The differentiation of the Notch pathway, at its various stages, in terms of expression and survival resulted in distinct profiles of biological processes such as proliferation, adhesion, apoptosis and epithelial to mesenchymal transition. In conclusion, whether oncogenic or suppressive, Notch signaling is proven to be associated with various types of malignancies, and thus may be of interest as a potential therapeutic target.
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Jing X, Ren D, Gao F, Chen Y, Wu X, Han Y, Han Q, Li L, Wang X, Tang W, Zhang Y. Gene deficiency or pharmacological inhibition of PDCD4-mediated FGR signaling protects against acute kidney injury. Acta Pharm Sin B 2021; 11:394-405. [PMID: 33643819 PMCID: PMC7893143 DOI: 10.1016/j.apsb.2020.10.024] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 09/23/2020] [Accepted: 10/13/2020] [Indexed: 12/28/2022] Open
Abstract
Recent studies have shown that programmed cell death 4 (PDCD4) modulates distinct signal transduction pathways in different pathological conditions. Despite acute and chronic immune responses elicited by ischemia contributing to the functional deterioration of the kidney, the contributions and mechanisms of PDCD4 in acute kidney injury (AKI) have remained unclear. Using two murine AKI models including renal ischemia/reperfusion injury (IRI) and cisplatin-induced AKI, we found that PDCD4 deficiency markedly ameliorated renal dysfunction and inflammatory responses in AKI mice. Consistently, upregulation of PDCD4 was also confirmed in the kidneys from patients with biopsy confirmed acute tubular necrosis from a retrospective cohort study. Moreover, we found that overexpression of Fgr, a member of the tyrosine kinase family, dramatically aggravated renal injury and counteracted the protective effects of PDCD4 deficiency in AKI mice. We discovered that FGR upregulated NOTCH1 expression through activating STAT3. Most importantly, we further found that systemic administration of ponatinib, a tyrosine kinase inhibitor, significantly ameliorated AKI in mice. In summary, we identified that PDCD4 served as an important regulator, at least in part, of FGR/NOTCH1-mediated tubular apoptosis and inflammation in AKI mice. Furthermore, our findings suggest that ponatinib-mediated pharmacologic targeting of this pathway had therapeutic potential for mitigating AKI.
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Affiliation(s)
- Xu Jing
- Department of Pharmacology, School of Basic Medical Science, Shandong University, Jinan 250012, China
- Department of Clinical Laboratory, the Second Hospital of Shandong University, Jinan 250033, China
| | - Dandan Ren
- Department of Pharmacology, School of Basic Medical Science, Shandong University, Jinan 250012, China
- Chengda Biology Co., Ltd., Shenyang 110179, China
| | - Fei Gao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Ye Chen
- Department of Pharmacology, School of Basic Medical Science, Shandong University, Jinan 250012, China
| | - Xiao Wu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Yue Han
- Department of Pharmacology, School of Basic Medical Science, Shandong University, Jinan 250012, China
| | - Qingsheng Han
- Department of Pharmacology, School of Basic Medical Science, Shandong University, Jinan 250012, China
| | - Liang Li
- Department of Pharmacology, School of Basic Medical Science, Shandong University, Jinan 250012, China
| | - Xiaojie Wang
- Department of Pharmacology, School of Basic Medical Science, Shandong University, Jinan 250012, China
| | - Wei Tang
- Department of Microbiology, School of Basic Medical Science, Shandong University, Jinan 250012, China
| | - Yan Zhang
- Department of Pharmacology, School of Basic Medical Science, Shandong University, Jinan 250012, China
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Karakaidos P, Rampias T. Monitoring of Active Notch Signaling in Mouse Bladder Urothelium. Methods Mol Biol 2021; 2346:121-134. [PMID: 33190186 DOI: 10.1007/7651_2020_339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Notch signaling plays a crucial role in differentiation and homeostasis in a wide variety of epithelia. The tumor suppressor role of Notch in bladder urothelium is well accepted as the inactivation of this pathway due to damaging mutations in its components is associated with neoplastic transformation. Monitoring Notch signaling is therefore critical to understand how the deregulation of cell-cell communication can lead to differentiation loss and carcinogenesis. In this chapter, we provide a method to visualize active Notch signaling by the detection of the nuclear levels of Notch intracellular domain in mouse urothelium. The technique outlined below is characterized by high sensitivity and specificity and has been successfully applied to human tumor specimens. In this context, this technique could be used to characterize the molecular profile of Notch-deficient tumors and analyze the clonal expansion dynamics and the heterogeneity patterns of Notch inactivation.
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Affiliation(s)
| | - Theodoros Rampias
- Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
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Notch Signaling and Human Papillomavirus-Associated Oral Tumorigenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1287:105-122. [PMID: 33034029 DOI: 10.1007/978-3-030-55031-8_8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The NOTCH pathway is critical for the development of many cell types including the squamous epithelium lining of cutaneous and mucosal surfaces. In genetically engineered mouse models, Notch1 acts as one of the first steps to commit basal keratinocytes to terminally differentiate. Similarly, in human head and neck squamous cell cancers (HNSCCs), NOTCH1 is often lost consistent with its essential tumor-suppressive role for initiating keratinocyte differentiation. However, constitutive NOTCH1 activity in the epithelium results in expansion of the spinous keratinocyte layers and impaired terminal differentiation is consistent with the role of NOTCH1 as an oncogene in other cancers, especially in T-cell acute lymphoblastic leukemia. We have previously observed that NOTCH1 plays a dual role as both a tumor suppressor and oncogene, depending on the mutational context of the tumor. Namely, gain or loss or NOTCH1 activity promotes the development of human papillomavirus (HPV)-associated cancers. The additional HPV oncogenes likely disrupt the tumor-suppressive activities of NOTCH and enable the oncogenic pathways activated by NOTCH to promote tumor growth. In this review, we detail the role of NOTCH pathway in head and neck cancers with a focus on HPV-associated cancers.
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Song G, Zhu X, Xuan Z, Zhao L, Dong H, Chen J, Li Z, Song W, Jin C, Zhou M, Xie H, Zheng S, Song P. Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma. Am J Cancer Res 2021; 11:2318-2333. [PMID: 33500727 PMCID: PMC7797690 DOI: 10.7150/thno.48739] [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: 05/27/2020] [Accepted: 11/14/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and its specific mechanism has not been fully elucidated. Inactivation of tumor suppressors may contribute to the occurrence, progression, and recurrence of HCC. DNA methylation is a crucial mechanism involved in regulating the occurrence of HCC. Herein, we aimed to identify the key methylation-related tumor suppressors as well as potential biomarkers and therapeutic targets in HCC. Methods: Combined analysis of TCGA and GEO databases was performed to obtain potential methylation-related tumor suppressors in HCC. Methyl-target sequencing was performed to analyze the methylation level of the GNA14 promoter. The diagnostic value of GNA14 as a predictor of HCC was evaluated in HCC tumor samples and compared with normal tissues. The functional role of GNA14 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro. Subcutaneous tumorigenesis, lung colonization, and orthotopic liver tumor model were performed to analyze the role of GNA14 in vivo. Results: The expression of GNA14 was found to be downregulated in HCC and it was negatively correlated with hepatitis B virus (HBV) infection, vascular invasion, and prognosis of HCC. DNA methylation was demonstrated to be responsible for the altered expression of GNA14 and was regulated by HBV-encoded X protein (HBx). GNA14 regulated the RB pathway by promoting Notch1 cleavage to inhibit tumor proliferation, and might inhibit tumor metastasis by inhibiting the expression of JMJD6. Conclusion: GNA14 could be regulated by HBx by modulating the methylation status of its promoter. We identified GNA14 as a potential biomarker and therapeutic target for HCC.
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Xing D, Fadare O. Molecular events in the pathogenesis of vulvar squamous cell carcinoma. Semin Diagn Pathol 2021; 38:50-61. [PMID: 33032902 PMCID: PMC7749059 DOI: 10.1053/j.semdp.2020.09.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 09/10/2020] [Indexed: 12/18/2022]
Abstract
Vulvar squamous cell carcinomas (VSCC), which constitute over 90% of vulvar malignancies in adults, are classifiable into 2 subgroups that are mostly clinicopathologically distinct, a classification that is fundamentally based whether or not the tumors are HPV-mediated. In this review, we aim to summarize the recent advances in the understanding of molecular events in the pathogenesis of VSCC, including common and targetable mutations, copy number alterations, epigenetics, noncoding RNAs, and tumor immune microenvironment, which may provide insight into the future management of the disease. These events show substantial differences between the 2 subgroups, although significant areas of overlap exist. Recurrent, driver mutations appear to be substantially more prevalent in HPV(-) VSCC. TP53 mutations are the most common somatic mutations in VSCC overall, and are notably predominant in the HPV(-) VSCC, where 30-88% show a mutation. TP53 mutations are associated with worse patient outcomes, and co-mutations between TP53 and either HRAS, PIK3CA or CDKN2A appear to define subsets with even worse outcomes. A wide variety of other somatic mutations have been identified, including a subset with different mutational frequencies between HPV(+) and HPV(-) VSCC. CDKN2A mutations are common, and have been identified in 21 to 55% of HPV(-) VSCC, and in 2 to 25% of HPV(+) VSCC. Hypermethylation of CDKN2A is the most frequently reported epigenetic alteration in VSCC and the expression of some microRNAs may be associated with patient outcomes. The PTEN/PI3K/AKT/mTOR pathway is commonly altered in HPV(+) VSCC, and is accordingly potentially targetable. HPV-positivity/p16 block expression by immunohistochemistry has been found to be an independent prognostic marker for improved survival in VSCC, and may have some predictive value in VSCC patients treated with definitive radiotherapy. 22-39.3% and 68% of VSCC show EGFR amplification and protein overexpression respectively, although the prognostic and predictive value of an EGFR alteration requires additional study. Recurrent chromosomal gains in VSCCs have been found at 1q, 2q, 3q, 4p, 5p, 7p, 8p, 8q, and 12q, and there may be differential patterns of alterations depending on HPV-status. At least one-third of VSCC patients may potentially benefit from immune checkpoint inhibition therapy, based on a high frequency of PD-L1 expression or amplification, or a high tumor mutational burden. Additional studies are ultimately required to better understand the global landscape of genetic and epigenetic alterations in VSCC, and to identify and test potential targets for clinical application.
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Affiliation(s)
- Deyin Xing
- Departments of Pathology, Oncology, Gynecology and Obstetrics, The Johns Hopkins Medical Institutions, Baltimore, MD, United States.
| | - Oluwole Fadare
- Department of Pathology, University of California San Diego Health, La Jolla, CA, United States
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Li Y, Li Y, Chen X. NOTCH and Esophageal Squamous Cell Carcinoma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1287:59-68. [PMID: 33034026 PMCID: PMC7895477 DOI: 10.1007/978-3-030-55031-8_5] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research on its mechanisms, prevention, and therapy. Recent studies have shown that NOTCH mutations are commonly seen in human ESCC. This chapter summarizes our current understanding of the NOTCH pathway in normal esophagus and in ESCC. In normal esophagus, NOTCH pathway regulates the development of esophageal squamous epithelium, in particular, squamous differentiation. Exposure to extrinsic and intrinsic factors, such as gastroesophageal reflux, alcohol drinking, and inflammation, downregulates the NOTCH pathway and thus inhibits squamous differentiation of esophageal squamous epithelial cells. In ESCC, NOTCH plays a dual role as both a tumor suppressor pathway and an oncogenic pathway. In summary, further studies are warranted to develop NOTCH activators for the prevention of ESCC and NOTCH inhibitors for targeted therapy of a subset of ESCC with activated NOTCH pathway.
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Affiliation(s)
- Yong Li
- Department of Thoracic Surgery, National Cancer Center, Cancer Hospital of Chinese Academy of Medical Sciences, Beijing, China
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA
| | - Yahui Li
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA
| | - Xiaoxin Chen
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA.
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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