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Cheng Y, Sun Q, Chen Y, Wang J, Chen Y, Yang Y, Zhang J, Cao Y, Li Z, Zhang Y. DTX3 suppresses bladder cancer cell invasion and metastasis by inhibiting the Notch signaling pathway. Int Immunopharmacol 2025; 153:114529. [PMID: 40127622 DOI: 10.1016/j.intimp.2025.114529] [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: 10/10/2024] [Revised: 03/06/2025] [Accepted: 03/18/2025] [Indexed: 03/26/2025]
Abstract
Deltex E3 ubiquitin ligase 3 (DTX3) was identified as a tumor suppressor in human cancers. However, whether DTX3 could suppress the progression of bladder cancer (BC) remains unknown. In this study, DTX3 downregulation in BC tissues was confirmed at mRNA and protein levels, and decreased DTX3 expression was associated with poor prognosis. DTX3 knockdown triggered aberrant epithelial-to-mesenchymal transition (EMT), principally via downregulation of E-cadherin and upregulation of N-cadherin, MMP9, Snail, and Slug. Gain- and loss-of-function assays indicated that DTX3 acted as a suppressor gene by inhibiting the migration and invasion of BC cells both in vivo and in vitro. Further analysis revealed that DTX3 inhibited Notch signaling pathway activity, and the Notch signaling inhibitor DAPT could partially reverse the effects of DTX3 knockdown on the metastatic abilities of BC cells. Mechanically, DTX3 bind to Notch intracellular domain (NICD) via its C-terminal RING finger domain (RFD), ubiquitinated, and degraded NICD, resulting in repression of the Notch pathway. Our findings reveal the key role of DTX3 in binding to NICD, promoting its ubiquitination and protein degradation, and suppressing the activation of the Notch signaling pathway to inhibit BC invasion and metastasis.
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Affiliation(s)
- Yu Cheng
- Department of Pathology, Cancer Research Laboratory, Chengde Medical University, Chengde, China
| | - Qi Sun
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ya Chen
- Department of Pathology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - JiaYu Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - YanJun Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - YuanZhong Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - JiangBo Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yun Cao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - ZhiYong Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
| | - YiJun Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
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Zhao H, Lin N, Ho VWS, Liu K, Chen X, Wu H, Chiu PK, Huang L, Dantes Z, Wong K, Chau H, Ko IC, Wong CH, Leung DK, Yuen SK, Wu D, Ding X, Ng CF, Teoh JY. Patient-Derived Bladder Cancer Organoids as a Valuable Tool for Understanding Tumor Biology and Developing Personalized Treatment. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2414558. [PMID: 39921252 PMCID: PMC11967763 DOI: 10.1002/advs.202414558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/15/2025] [Indexed: 02/10/2025]
Abstract
Bladder cancer (BC) is a heterogeneous disease with high recurrence rates and variable treatment responses. To address these clinical challenges, the world's first bladder cancer patient-derived organoids (PDOs) biobank is established based on an Asian population. Thirty-six BC-PDOs are generated from 56 patients and demonstrated that the BC-PDOs can replicate the histological and genomic features of parental tumors. Drug screening tests are conducted with a broad spectrum of conventional chemotherapeutic and targeted therapy drugs and identified differential drug sensitivities among the BC-PDOs. These in vitro results are consistently supported by the PDO xenograft animal studies and patients' clinical treatment outcomes, thereby verifying the predictive power of PDOs for drug responses in BC patients. By analyzing the genetic profiles of the PDOs, specific driver genes that correlate with drug sensitivity to two stand-of-care chemotherapeutics, cisplatin, and gemcitabine, are identified. Additionally, the practicality of PDOs in investigating the tumor microenvironment has been demonstrated. This study underscores the utility of PDOs in advancing the understanding of bladder cancer and the development of personalized therapeutic strategies. The BC-PDOs biobank provides an ideal preclinical platform for supporting the development of personalized treatment strategies for BC patients. This study also provides insights into the potential mechanisms of drug resistance, paves the way for subsequent region-specific research, and demonstrates the possibility of using PDO-related models to direct future research in developing drugs targeting tumor microenvironments.
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Affiliation(s)
- Hongda Zhao
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
- Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong Kong999077China
| | - Na Lin
- Department of Biomedical SciencesFaculty of Health SciencesUniversity of MacauTaipaMacaoSAR999078China
| | - Vincy Wing Sze Ho
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
- Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong Kong999077China
| | - Kang Liu
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
- Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong Kong999077China
| | - Xuan Chen
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
- Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong Kong999077China
| | - Hongwei Wu
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
- Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong Kong999077China
| | - Peter Ka‐Fung Chiu
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
| | - Linda Huang
- Invitrocue Hong Kong LtdHong KongSAR999077China
| | | | - Ka‐Leung Wong
- Department of Applied Biology and Chemical TechnologyThe Hong Kong Polytechnic UniversityHong Kong999077China
| | - Ho‐Fai Chau
- Department of Applied Biology and Chemical TechnologyThe Hong Kong Polytechnic UniversityHong Kong999077China
| | - Ivan Ching‐Ho Ko
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
| | - Chris Ho‐Ming Wong
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
| | - David Ka‐Wai Leung
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
| | - Steffi Kar‐Kei Yuen
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
| | - Dinglan Wu
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
| | - Xiaofan Ding
- Department of Biomedical SciencesFaculty of Health SciencesUniversity of MacauTaipaMacaoSAR999078China
| | - Chi Fai Ng
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
| | - Jeremy Yuen‐Chun Teoh
- S.H. Ho Urology CentreDepartment of SurgeryThe Chinese University of Hong KongHong Kong999077China
- Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong Kong999077China
- Department of UrologyMedical University of ViennaVienna1090Austria
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Hao H, Eberand BM, Larance M, Haltiwanger RS. Protein O-Fucosyltransferases: Biological Functions and Molecular Mechanisms in Mammals. Molecules 2025; 30:1470. [PMID: 40286076 PMCID: PMC11990869 DOI: 10.3390/molecules30071470] [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: 02/22/2025] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 04/29/2025] Open
Abstract
Domain-specific O-fucosylation is an unusual type of glycosylation, where the fucose is directly attached to the serine or threonine residues in specific protein domains via an O-linkage. O-fucosylated proteins play critical roles in a wide variety of biological events and hold important therapeutic values, with the most studied being the Notch receptors and ADAMTS proteins. O-fucose glycans modulate the function of the proteins they modify and are closely associated with various diseases including cancer. In mammals, alongside the well-documented protein O-fucosyltransferase (POFUT) 1-mediated O-fucosylation of epidermal growth factor-like (EGF) repeats and POFUT2-mediated O-fucosylation of thrombospondin type 1 repeats (TSRs), a new type of O-fucosylation was recently identified on elastin microfibril interface (EMI) domains, mediated by POFUT3 and POFUT4 (formerly FUT10 and FUT11). In this review, we present an overview of our current knowledge of O-fucosylation, integrating the latest findings and with a particular focus on its biological functions and molecular mechanisms.
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Affiliation(s)
- Huilin Hao
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30605, USA;
| | - Benjamin M. Eberand
- Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; (B.M.E.); (M.L.)
| | - Mark Larance
- Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; (B.M.E.); (M.L.)
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Chen SY, Zhang YL, Li XR, Wang JR, Li KP, Wan S, Yang JW, Wang H, Cao JL, Wang CY, Fan XP, Fu SJ, Ding LY, Che TJ, Yang L. BIN1 inhibited tumor growth, metastasis and stemness by ALDH1/NOTCH pathway in bladder carcinoma. Hereditas 2025; 162:29. [PMID: 40016843 PMCID: PMC11866615 DOI: 10.1186/s41065-025-00384-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 02/01/2025] [Indexed: 03/01/2025] Open
Abstract
BACKGROUND Bladder cancer (BLCA) represents one of the most prevalent urological malignancies worldwide. Bridging integrator 1 (BIN1), a well-characterized tumor suppressor that interacts with and inhibits oncogenic Myc transcription factors, has demonstrated crucial roles in various cancer types. However, its specific functions and underlying molecular mechanisms in BLCA development and progression remain poorly understood. This study aims to elucidate the role of BIN1 in regulating BLCA cell proliferation, metastasis, and cancer stem cell properties. METHODS Using urinary proteomics analysis, we identified BIN1 as a significantly dysregulated protein in BLCA. The clinical significance of BIN1 was further validated through comprehensive analyses of public databases. BIN1 expression levels defined distinct molecular and immunological subtypes of BLCA. Through proteomic profiling of BIN1-overexpressing UMUC3 cells and corresponding controls, we identified ALDH1 as a key downstream effector in the BIN1-regulated ALDH1/NOTCH signaling axis. We employed multiple experimental approaches, including Western blot analysis, quantitative RT-PCR, immunofluorescence staining, wound healing assays, transwell migration assays, colony formation assays, tumor sphere formation assays, flow cytometry, CCK8 proliferation assays, and cell transfection experiments. RESULTS We observed significant downregulation of BIN1 in both BLCA tissues and cell lines compared to normal adjacent tissues and SV-HUC-1 cells, respectively. BIN1 overexpression inhibited cancer cell proliferation by promoting apoptosis and suppressed epithelial-mesenchymal transition (EMT), thereby reducing local invasion and distant metastasis. Additionally, BIN1 regulated cancer stem cell properties through modulation of ALDH1 expression, with NOTCH2 acting as a crucial downstream mediator of ALDH1 signaling. CONCLUSION Our findings demonstrate that BIN1 functions as a tumor suppressor in BLCA and suggest its potential utility as both a diagnostic biomarker and therapeutic target for BLCA treatment.
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Affiliation(s)
- Si-Yu Chen
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Ya-Long Zhang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Xiao-Ran Li
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Ji-Rong Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Kun-Peng Li
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Shun Wan
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Jian-Wei Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Hao Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Jin-Long Cao
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Chen-Yang Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Xin-Peng Fan
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Sheng-Jun Fu
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Li-Yun Ding
- School of Physical Science and Technology, Lanzhou University, Lanzhou, China
| | - Tuan-Jie Che
- Baiyuan Company for Gene Technology, Lanzhou, China
| | - Li Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China.
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China.
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Zhang C, Weimann A, Stolzenburg JU, Neuhaus J, Berndt-Paetz M. Notch2/3-DLL4 interaction in urothelial cancer cell lines supports a tumorigenic role of Notch signaling pathways in bladder carcinoma. PLoS One 2025; 20:e0317709. [PMID: 39951484 PMCID: PMC11828355 DOI: 10.1371/journal.pone.0317709] [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: 06/13/2024] [Accepted: 01/02/2025] [Indexed: 02/16/2025] Open
Abstract
INTRODUCTION The Notch pathway plays an important role in many aspects of cancer biology and acts in a dichotomous way in bladder cancer. The mechanisms behind this behavior are still elusive. Here, we analyzed DLL4 and Notch receptor expression, interaction and downstream signaling in human bladder cancer cells. MATERIALS AND METHODS The expression levels of Notch pathway components (Notch1-4, DLL4, HES1, HEY1) were assessed in papillary (G1: RT-4) and non-papillary bladder cancer cell lines (G2-G4: RT-112, 647-V, T-24, KU-19-19, CAL-29) by qRT-PCR and immunofluorescence. Expression data were validated by analyzing data from open-source databases (CCLE; TCGA). The endogeneous interactions of Notch2/Notch3 receptors and the ligand DLL4 were studied by in situ proximity ligation assay. Activation of canonical Notch signaling was evaluated by stimulation with recombinant DLL4 protein. RESULTS All Notch targets were expressed, with Notch2 and Notch3 showing the highest expression levels. Endogeneous interactions between Notch2/3 and DLL4 were detected in all BCa cell lines. Amounts of Notch2/3-DLL4 complexes were high in RT-112 and CAL-29, while RT-4/647-V showed moderate and T-24, KU-19-19 low abundance. Proportion of (peri-) nuclear interaction complexes correlated negatively with Notch downstream targets. DLL4 stimulation resulted in canonical Notch pathway activation and increased tumor cell viability and proliferation in RT-4, 647-V, T-24 and KU-19-19 cells. DISCUSSION The Notch signaling pathway can discriminate between different receptors and may play an essential role in the progression of bladder carcinoma. We demonstrated for the first time direct interactions between DLL4 and Notch2/3 associated to activation of canonical downstream Notch signaling and increased tumor cell behavior in human bladder cancer cells. Our data support the view that the Notch2/3-DLL4 axis plays an oncogenic role in bladder cancer. Further analyses of Notch signaling in bladder cancer can promote the development of tailored anti-DLL4/Notch bladder cancer therapies in the future.
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Affiliation(s)
- Chuan Zhang
- Department of Urology, Research Laboratories, Leipzig University, Leipzig, Germany
- Department of Urology, Chengdu Fifth People’s Hospital affiliated to Chengdu University of T.C.M., Chengdu, China
| | - Annett Weimann
- Department of Urology, Research Laboratories, Leipzig University, Leipzig, Germany
| | | | - Jochen Neuhaus
- Department of Urology, Research Laboratories, Leipzig University, Leipzig, Germany
| | - Mandy Berndt-Paetz
- Department of Urology, Research Laboratories, Leipzig University, Leipzig, Germany
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Darmadi D, Saleh RO, Oghenemaro EF, Shakir MN, Hjazi A, Hassan ZF, Zwamel AH, Matlyuba S, Deorari M, Oudah SK. Role of SEL1L in the progression of solid tumors, with a special focus on its recent therapeutic potential. Cell Biol Int 2025; 49:16-32. [PMID: 39364680 DOI: 10.1002/cbin.12242] [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: 03/26/2024] [Revised: 07/24/2024] [Accepted: 09/02/2024] [Indexed: 10/05/2024]
Abstract
Since suppressor/enhancer of Lin-12-like (SEL1L) was cloned in 1997, various pieces of evidence from lower species suggest it plays a significant role in protein degradation via the ubiquitin-proteasome system. The relevance of SEL1L in many aspects of malignant transformation and tumorigenic events has been the subject of research, which has shown compelling in vitro and in vivo findings relating its altered expression to changes in tumor aggressiveness. The Endoplasmic Reticulum (ER) in tumor cells is crucial for preserving cellular proteostasis by inducing the unfolded protein response (UPR), a stress response. A crucial component of the UPR is ER-associated degradation (ERAD), which guards against ER stress-induced apoptosis and the removal of unfolded or misfolded proteins by the ubiquitin-proteasome system. As a protein stabilizer of HMG-CoA reductase degradation protein 1 (HRD1), one of the main components of ERAD, SEL1L plays an important role in ER homeostasis. Notably, the expression levels of these two proteins fluctuate independently in various cancer types, yet changes in their expression affect the levels of other associated proteins during cancer pathogenesis. Recent studies have also outlined the function of SEL1L in cancer medication resistance. This review explores the value of targeting SEL1L as a novel treatment approach for cancer, focusing on the molecular processes of SEL1L and its involvement in cancer etiology.
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Affiliation(s)
- Darmadi Darmadi
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | - Enwa Felix Oghenemaro
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Delta State University, Abraka, Nigeria
| | - Maha Noori Shakir
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | | | - Ahmed Hussein Zwamel
- Medical laboratory technique college, the Islamic University, Najaf, Iraq
- Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
| | - Sanoeva Matlyuba
- Department of Neurology, Vice rektor of Bukhara State Medical Institute, Bukhara, Uzbekistan
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Shamam Kareem Oudah
- College of Pharmacy/National University of Science and Technology, Dhi Qar, Iraq
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Matye D, Leak J, Woolbright BL, Taylor JA. Preclinical models of bladder cancer: BBN and beyond. Nat Rev Urol 2024; 21:723-734. [PMID: 38769130 DOI: 10.1038/s41585-024-00885-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2024] [Indexed: 05/22/2024]
Abstract
Preclinical modelling is a crucial component of advancing the understanding of cancer biology and therapeutic development. Several models exist for understanding the pathobiology of bladder cancer and evaluating therapeutics. N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced bladder cancer is a commonly used model that recapitulates many of the features of human disease. Particularly in mice, BBN is a preferred laboratory model owing to a high level of reproducibility, high genetic fidelity to the human condition, and its relative ease of use. However, important aspects of the model are often overlooked in laboratory studies. Moreover, the advent of new models has yielded a variety of methodologies that complement the use of BBN. Toxicokinetics, histopathology, molecular genetics and sex can differ between available models and are important factors to consider in bladder cancer modelling.
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Affiliation(s)
- David Matye
- School of Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Juliann Leak
- School of Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Benjamin L Woolbright
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - John A Taylor
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
- Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA.
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Wang G, Mao X, Wang W, Wang X, Li S, Wang Z. Bioprinted research models of urological malignancy. EXPLORATION (BEIJING, CHINA) 2024; 4:20230126. [PMID: 39175884 PMCID: PMC11335473 DOI: 10.1002/exp.20230126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 01/08/2024] [Indexed: 08/24/2024]
Abstract
Urological malignancy (UM) is among the leading threats to health care worldwide. Recent years have seen much investment in fundamental UM research, including mechanistic investigation, early diagnosis, immunotherapy, and nanomedicine. However, the results are not fully satisfactory. Bioprinted research models (BRMs) with programmed spatial structures and functions can serve as powerful research tools and are likely to disrupt traditional UM research paradigms. Herein, a comprehensive review of BRMs of UM is presented. It begins with a brief introduction and comparison of existing UM research models, emphasizing the advantages of BRMs, such as modeling real tissues and organs. Six kinds of mainstream bioprinting techniques used to fabricate such BRMs are summarized with examples. Thereafter, research advances in the applications of UM BRMs, such as culturing tumor spheroids and organoids, modeling cancer metastasis, mimicking the tumor microenvironment, constructing organ chips for drug screening, and isolating circulating tumor cells, are comprehensively discussed. At the end of this review, current challenges and future development directions of BRMs and UM are highlighted from the perspective of interdisciplinary science.
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Affiliation(s)
- Guanyi Wang
- Department of UrologyCancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research CenterZhongnan Hospital of Wuhan UniversityWuhanChina
- Department of Biomedical Engineering and Hubei Province Key Laboratory of Allergy and Immune Related DiseaseTaiKang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanChina
| | - Xiongmin Mao
- Department of UrologyCancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research CenterZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Wang Wang
- Department of UrologyCancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research CenterZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Xiaolong Wang
- Lewis Katz School of MedicineTemple UniversityPhiladelphiaPennsylvaniaUSA
| | - Sheng Li
- Department of UrologyCancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research CenterZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Zijian Wang
- Department of UrologyCancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research CenterZhongnan Hospital of Wuhan UniversityWuhanChina
- Department of Biomedical Engineering and Hubei Province Key Laboratory of Allergy and Immune Related DiseaseTaiKang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanChina
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Lin H, Fu L, Zhou X, Yu A, Chen Y, Liao W, Shu G, Zhang L, Tan L, Liang H, Wang Z, Deng Q, Wang J, Jin M, Chen Z, Wei J, Cao J, Chen W, Li X, Li P, Lu J, Luo J. LRP1 induces anti-PD-1 resistance by modulating the DLL4-NOTCH2-CCL2 axis and redirecting M2-like macrophage polarisation in bladder cancer. Cancer Lett 2024; 593:216807. [PMID: 38462037 DOI: 10.1016/j.canlet.2024.216807] [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: 10/31/2023] [Revised: 02/23/2024] [Accepted: 03/06/2024] [Indexed: 03/12/2024]
Abstract
The tumour microenvironment (TME) drives bladder cancer (BLCA) progression. Targeting the TME has emerged as a promising strategy for BLCA treatment in recent years. Furthermore, checkpoint blockade therapies are only beneficial for a minority of patients with BLCA, and drug resistance is a barrier to achieving significant clinical effects of anti-programmed cell death protein-1 (PD-1)/programmed death protein ligand-1 (PD-L1) therapy. In this study, higher low-density lipoprotein receptor-related protein 1 (LRP1) levels were related to a poorer prognosis for patients with various cancers, including those with higher grades and later stages of BLCA. Enrichment analysis demonstrated that LRP1 plays a role in the epithelial-mesenchymal transition (EMT), NOTCH signalling pathway, and ubiquitination. LRP1 knockdown in BLCA cells delayed BLCA progression both in vivo and in vitro. Furthermore, LRP1 knockdown suppressed EMT, reduced DLL4-NOTCH2 signalling activity, and downregulated M2-like macrophage polarisation. Patients with BLCA and higher LRP1 levels responded weakly to anti-PD-1 therapy in the IMvigor210 cohort. Moreover, LRP1 knockdown enhanced the therapeutic effects of anti-PD-1 in mice. Taken together, our findings suggest that LRP1 is a potential target for improving the efficacy of anti-PD-1/PD-L1 therapy by preventing EMT and M2-like macrophage polarisation by blocking the DLL4-NOTCH2 axis.
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Affiliation(s)
- Hansen Lin
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liangmin Fu
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xinwei Zhou
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Anze Yu
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuhang Chen
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wuyuan Liao
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guannan Shu
- Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, China
| | - Lizhen Zhang
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lei Tan
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hui Liang
- Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Zhu Wang
- Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Qiong Deng
- Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Jieyan Wang
- Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Meiyu Jin
- Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Zhenhua Chen
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jinhuan Wei
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiazheng Cao
- Department of Urology, Jiangmen Central Hospital, Haibang Street 23, Pengjiang District, Jiangmen, 529030, Guangdong Province, China
| | - Wei Chen
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaofei Li
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Pengju Li
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Jun Lu
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Junhang Luo
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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10
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Desponds E, Kioseoglou K, Zdimerova H, Ongaro M, Verdeil G, Leblond MM. Development of Traceable Mouse Models of Advanced and Metastatic Bladder Cancer. Cancers (Basel) 2024; 16:2245. [PMID: 38927950 PMCID: PMC11202260 DOI: 10.3390/cancers16122245] [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: 05/17/2024] [Revised: 06/11/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
Bladder cancer (BC) is the fourth most common cancer in men, with a poor patient prognosis for advanced disease. The poor survival of patients with muscle-invasive bladder cancer (MIBC) and metastatic status emphasizes the urgent need to develop new therapies. Lacking in the field of BC is the availability of relevant advanced BC mouse models, especially metastatic ones, that accurately recapitulate the complexities of human pathology to test and study new therapeutic strategies. Addressing this need, we developed a traceable mouse model of BC that expresses tumor-associated antigens within the context of advanced muscle-invasive BC. This novel system was achieved through the deletion of the tp53 and pten genes, alongside the incorporation of the fusion construct of Firefly luciferase (Luc) and the SIYRYYGL (SIY) T-cell antigen. We validate that the presence of the transgene did not impact on the development of the tumors while allowing us to measure tumor progression by bioluminescence. We show that the transgene did not influence the composition of the immune tumor microenvironment. More importantly, we report that this model was unresponsive to anti-PD-1 treatment, as in the majority of patients with BC. We also develop a new model based on the orthotopic injection of BC clonal cell lines derived from our first model. We demonstrate that this new model invades the muscle layer and has a metastasis development rate of 83%. The advantage of this model is that we can visualize tumor growth and metastasis development in vivo. These mouse models' characteristics, displaying many similarities with the human pathology, provide a valuable tool for tracking tumor progression, metastasis spread in vivo, and treatment resistance, as well as exploring fundamental and translational aspects of BC biology. This work contributes to the improvement in the landscape of mouse models of advanced BC for testing new therapeutic strategies.
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Affiliation(s)
- Emma Desponds
- Department of Oncology, Lausanne University Hospital (CHUV), University of Lausanne, 1015 Lausanne, Switzerland; (E.D.); (K.K.); (H.Z.); (M.O.)
- Ludwig Institute for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland
| | - Konstantina Kioseoglou
- Department of Oncology, Lausanne University Hospital (CHUV), University of Lausanne, 1015 Lausanne, Switzerland; (E.D.); (K.K.); (H.Z.); (M.O.)
- Ludwig Institute for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland
| | - Hana Zdimerova
- Department of Oncology, Lausanne University Hospital (CHUV), University of Lausanne, 1015 Lausanne, Switzerland; (E.D.); (K.K.); (H.Z.); (M.O.)
- Ludwig Institute for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland
| | - Marco Ongaro
- Department of Oncology, Lausanne University Hospital (CHUV), University of Lausanne, 1015 Lausanne, Switzerland; (E.D.); (K.K.); (H.Z.); (M.O.)
- Ludwig Institute for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland
| | - Grégory Verdeil
- Department of Oncology, Lausanne University Hospital (CHUV), University of Lausanne, 1015 Lausanne, Switzerland; (E.D.); (K.K.); (H.Z.); (M.O.)
- Ludwig Institute for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland
| | - Marine M. Leblond
- Department of Oncology, Lausanne University Hospital (CHUV), University of Lausanne, 1015 Lausanne, Switzerland; (E.D.); (K.K.); (H.Z.); (M.O.)
- Ludwig Institute for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland
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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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Tang L, Xu H, Wu T, Wu W, Lu Y, Gu J, Wang X, Zhou M, Chen Q, Sun X, Cai H. Advances in tumor microenvironment and underlying molecular mechanisms of bladder cancer: a systematic review. Discov Oncol 2024; 15:111. [PMID: 38602556 PMCID: PMC11009183 DOI: 10.1007/s12672-024-00902-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 02/21/2024] [Indexed: 04/12/2024] Open
Abstract
Bladder cancer is one of the most frequent malignant tumors of the urinary system. The prevalence of bladder cancer among men and women is roughly 5:2, and both its incidence and death have been rising steadily over the past few years. At the moment, metastasis and recurrence of advanced bladder cancer-which are believed to be connected to the malfunction of multigene and multilevel cell signaling network-remain the leading causes of bladder cancer-related death. The therapeutic treatment of bladder cancer will be greatly aided by the elucidation of these mechanisms. New concepts for the treatment of bladder cancer have been made possible by the advancement of research technologies and a number of new treatment options, including immunotherapy and targeted therapy. In this paper, we will extensively review the development of the tumor microenvironment and the possible molecular mechanisms of bladder cancer.
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Affiliation(s)
- Liu Tang
- Department of Nursing, Jiangsu Cancer Hospital and The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Haifei Xu
- Department of Urology, Nantong Tumor Hospital and Tumor Hospital Affiliated to Nantong University, Nantong, China
| | - Tong Wu
- Department of Radiology, Nanjing Medical University The Fourth School of Clinical Medicine, Nanjing, Jiangsu, China
| | - Wenhao Wu
- Department of Radiology, Nanjing Medical University The Fourth School of Clinical Medicine, Nanjing, Jiangsu, China
| | - Yuhao Lu
- Department of Radiology, Nanjing Medical University The Fourth School of Clinical Medicine, Nanjing, Jiangsu, China
| | - Jijia Gu
- Department of Radiology, Nanjing Medical University The Fourth School of Clinical Medicine, Nanjing, Jiangsu, China
| | - Xiaoling Wang
- Department of Urology, Nantong Tumor Hospital and Tumor Hospital Affiliated to Nantong University, Nantong, China
| | - Mei Zhou
- Department of Nursing, Jiangsu Cancer Hospital and The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China.
| | - Qiuyang Chen
- Department of Radiology, Nanjing Medical University The Fourth School of Clinical Medicine, Nanjing, Jiangsu, China.
| | - Xuan Sun
- Department of Radiology, Nanjing Medical University The Fourth School of Clinical Medicine, Nanjing, Jiangsu, China.
| | - Hongzhou Cai
- Department of Urology, Jiangsu Cancer Hospital and The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China.
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13
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Saito S, Arai MA. Methodology for awakening the potential secondary metabolic capacity in actinomycetes. Beilstein J Org Chem 2024; 20:753-766. [PMID: 38633912 PMCID: PMC11022428 DOI: 10.3762/bjoc.20.69] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 03/27/2024] [Indexed: 04/19/2024] Open
Abstract
Secondary metabolites produced by actinomycete strains undoubtedly have great potential for use in applied research areas such as drug discovery. However, it is becoming difficult to obtain novel compounds because of repeated isolation around the world. Therefore, a new strategy for discovering novel secondary metabolites is needed. Many researchers believe that actinomycetes have as yet unanalyzed secondary metabolic activities, and the associated undiscovered secondary metabolite biosynthesis genes are called "silent" genes. This review outlines several approaches to further activate the metabolic potential of actinomycetes.
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Affiliation(s)
- Shun Saito
- Department of Biosciences and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
| | - Midori A Arai
- Department of Biosciences and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
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14
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Ramal M, Corral S, Kalisz M, Lapi E, Real FX. The urothelial gene regulatory network: understanding biology to improve bladder cancer management. Oncogene 2024; 43:1-21. [PMID: 37996699 DOI: 10.1038/s41388-023-02876-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/13/2023] [Accepted: 10/18/2023] [Indexed: 11/25/2023]
Abstract
The urothelium is a stratified epithelium composed of basal cells, one or more layers of intermediate cells, and an upper layer of differentiated umbrella cells. Most bladder cancers (BLCA) are urothelial carcinomas. Loss of urothelial lineage fidelity results in altered differentiation, highlighted by the taxonomic classification into basal and luminal tumors. There is a need to better understand the urothelial transcriptional networks. To systematically identify transcription factors (TFs) relevant for urothelial identity, we defined highly expressed TFs in normal human bladder using RNA-Seq data and inferred their genomic binding using ATAC-Seq data. To focus on epithelial TFs, we analyzed RNA-Seq data from patient-derived organoids recapitulating features of basal/luminal tumors. We classified TFs as "luminal-enriched", "basal-enriched" or "common" according to expression in organoids. We validated our classification by differential gene expression analysis in Luminal Papillary vs. Basal/Squamous tumors. Genomic analyses revealed well-known TFs associated with luminal (e.g., PPARG, GATA3, FOXA1) and basal (e.g., TP63, TFAP2) phenotypes and novel candidates to play a role in urothelial differentiation or BLCA (e.g., MECOM, TBX3). We also identified TF families (e.g., KLFs, AP1, circadian clock, sex hormone receptors) for which there is suggestive evidence of their involvement in urothelial differentiation and/or BLCA. Genomic alterations in these TFs are associated with BLCA. We uncover a TF network involved in urothelial cell identity and BLCA. We identify novel candidate TFs involved in differentiation and cancer that provide opportunities for a better understanding of the underlying biology and therapeutic intervention.
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Affiliation(s)
- Maria Ramal
- Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Sonia Corral
- Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Mark Kalisz
- Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Eleonora Lapi
- Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Francisco X Real
- Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
- CIBERONC, Madrid, Spain.
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
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15
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Paniri A, Hosseini MM, Amjadi-Moheb F, Tabaripour R, Soleimani E, Langroudi MP, Zafari P, Akhavan-Niaki H. The epigenetics orchestra of Notch signaling: a symphony for cancer therapy. Epigenomics 2023; 15:1337-1358. [PMID: 38112013 DOI: 10.2217/epi-2023-0270] [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: 12/20/2023] Open
Abstract
The aberrant regulation of the Notch signaling pathway, which is a fundamental developmental pathway, has been implicated in a wide range of human cancers. The Notch pathway can be activated by both canonical and noncanonical Notch ligands, and its role can switch between acting as an oncogene or a tumor suppressor depending on the context. Epigenetic modifications have the potential to modulate Notch and its ligands, thereby influencing Notch signal transduction. Consequently, the utilization of epigenetic regulatory mechanisms may present novel therapeutic opportunities for both single and combined therapeutics targeted at the Notch signaling pathway. This review offers insights into the mechanisms governing the regulation of Notch signaling and explores their therapeutic potential.
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Affiliation(s)
- Alireza Paniri
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, 4717647745,Iran
- Zoonoses Research Center, Pasteur Institute of Iran, 4619332976, Amol, Iran
| | | | - Fatemeh Amjadi-Moheb
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, 4717647745,Iran
| | - Reza Tabaripour
- Department of Cellular and Molecular Biology, Babol Branch, Islamic Azad University, Babol, 4747137381, Iran
| | - Elnaz Soleimani
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, 4717647745,Iran
| | | | - Parisa Zafari
- Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, 4691786953, Iran
| | - Haleh Akhavan-Niaki
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, 4717647745,Iran
- Zoonoses Research Center, Pasteur Institute of Iran, 4619332976, Amol, Iran
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16
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He Z, Zhong Y, Hu H, Li F. ZFP64 Promotes Gallbladder Cancer Progression through Recruiting HDAC1 to Activate NOTCH1 Signaling Pathway. Cancers (Basel) 2023; 15:4508. [PMID: 37760477 PMCID: PMC10527061 DOI: 10.3390/cancers15184508] [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: 08/07/2023] [Revised: 08/26/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
The lack of meaningful and effective early-stage markers remains the major challenge in the diagnosis of gallbladder cancer (GBC) and a huge barrier to timely treatment. Zinc finger protein 64 (ZFP64), a member of the zinc finger protein family, is considered to be a promising predictor in multiple tumors, but its potential effect in GBC still remains unclear. Here, we identified that ZFP64 was a vital regulatory protein in GBC. We found that ZFP64 expressed higher in GBC gallbladder carcinoma tissues than in normal tissues and was positively correlated with poor prognosis. Furthermore, ZFP64 was responsible for the migration, invasion, proliferation, anti-apoptosis, and epithelial mesenchymal transition (EMT) of GBC cells in vitro and in vivo. Mechanistically, through Co-IP assay, we confirmed that ZFP64 recruits HDAC1 localized to the promoter region of NUMB for deacetylation and therefore inhibits NUMB expression. The downregulation of NUMB enhanced the activation of the Notch1 signaling pathway, which is indispensable for the GBC-promotion effect of ZFP64 on GBC. In conclusion, ZFP64 regulated GBC progression and metastasis through upregulating the Notch1 signaling pathway, and thus ZFP64 is expected to become a new focus for a GBC prognostic marker and targeted therapy.
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Affiliation(s)
- Zhiqiang He
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Yuhan Zhong
- Laboratory of Liver Transplantation, Key Laboratory of Transplant Engineering and Immunology, National Health Commission (NHC), West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Haijie Hu
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Fuyu Li
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu 610041, China;
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17
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Yehya A, Youssef J, Hachem S, Ismael J, Abou-Kheir W. Tissue-specific cancer stem/progenitor cells: Therapeutic implications. World J Stem Cells 2023; 15:323-341. [PMID: 37342220 PMCID: PMC10277968 DOI: 10.4252/wjsc.v15.i5.323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/14/2023] [Accepted: 04/12/2023] [Indexed: 05/26/2023] Open
Abstract
Surgical resection, chemotherapy, and radiation are the standard therapeutic modalities for treating cancer. These approaches are intended to target the more mature and rapidly dividing cancer cells. However, they spare the relatively quiescent and intrinsically resistant cancer stem cells (CSCs) subpopulation residing within the tumor tissue. Thus, a temporary eradication is achieved and the tumor bulk tends to revert supported by CSCs' resistant features. Based on their unique expression profile, the identification, isolation, and selective targeting of CSCs hold great promise for challenging treatment failure and reducing the risk of cancer recurrence. Yet, targeting CSCs is limited mainly by the irrelevance of the utilized cancer models. A new era of targeted and personalized anti-cancer therapies has been developed with cancer patient-derived organoids (PDOs) as a tool for establishing pre-clinical tumor models. Herein, we discuss the updated and presently available tissue-specific CSC markers in five highly occurring solid tumors. Additionally, we highlight the advantage and relevance of the three-dimensional PDOs culture model as a platform for modeling cancer, evaluating the efficacy of CSC-based therapeutics, and predicting drug response in cancer patients.
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Affiliation(s)
- Amani Yehya
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Joe Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Sana Hachem
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Jana Ismael
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon.
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18
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Zhou MJ, Yang JJ, Ma TY, Feng GX, Wang XL, Wang LY, Ge YZ, Gao R, Liu HL, Shan L, Kong L, Chen XH. Increased retinoic acid signaling decreases lung metastasis in salivary adenoid cystic carcinoma by inhibiting the noncanonical Notch1 pathway. Exp Mol Med 2023; 55:597-611. [PMID: 36879115 PMCID: PMC10073150 DOI: 10.1038/s12276-023-00957-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 12/16/2022] [Accepted: 12/22/2022] [Indexed: 03/08/2023] Open
Abstract
MYB-NFIB fusion and NOTCH1 mutation are common hallmark genetic events in salivary gland adenoid cystic carcinoma (SACC). However, abnormal expression of MYB and NOTCH1 is also observed in patients without MYB-NFIB fusion and NOTCH1 mutation. Here, we explore in-depth the molecular mechanisms of lung metastasis through single-cell RNA sequencing (scRNA-seq) and exome target capture sequencing in two SACC patients without MYB-NFIB fusion and NOTCH1 mutation. Twenty-five types of cells in primary and metastatic tissues were identified via Seurat clustering and categorized into four main stages ranging from near-normal to cancer-based on the abundance of each cell cluster in normal tissue. In this context, we identified the Notch signaling pathway enrichment in almost all cancer cells; RNA velocity, trajectory, and sub-clustering analyses were performed to deeply investigate cancer progenitor-like cell clusters in primary tumor-associated lung metastases, and signature genes of progenitor-like cells were enriched in the "MYC_TARGETS_V2" gene set. In vitro, we detected the NICD1-MYB-MYC complex by co-immunoprecipitation (Co-IP) and incidentally identified retinoic acid (RA) as an endogenous antagonist of genes in the "MYC_TARGETS_V2" gene set. Following this, we confirmed that all-trans retinoic acid (ATRA) suppresses the lung metastasis of SACC by correcting erroneous cell differentiation mainly caused by aberrant NOTCH1 or MYB expression. Bioinformatic, RNA-seq, and immunohistochemical (IHC) analyses of primary tissues and metastatic lung tissues from patients with SACC suggested that RA system insufficiency partially promotes lung metastasis. These findings imply the value of the RA system in diagnosis and treatment.
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Affiliation(s)
- Meng-Jiao Zhou
- Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.,NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) and Comparative Medicine Center, Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Jia-Jie Yang
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, 100069, China
| | - Ting-Yao Ma
- Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Ge-Xuan Feng
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, 100069, China
| | - Xue-Lian Wang
- Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Li-Yong Wang
- The Central Laboratory for Molecular Biology, Capital Medical University, Beijing, 100069, China
| | - Yu-Ze Ge
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, 100069, China
| | - Ran Gao
- NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) and Comparative Medicine Center, Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Hong-Liang Liu
- SHANDONG Longfine PHARMACEUTICAL CO., LTD, Shandong, 272622, China
| | - Lin Shan
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, 100069, China
| | - Lu Kong
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, 100069, China.
| | - Xiao-Hong Chen
- Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
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19
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Guo M, Niu Y, Xie M, Liu X, Li X. Notch signaling, hypoxia, and cancer. Front Oncol 2023; 13:1078768. [PMID: 36798826 PMCID: PMC9927648 DOI: 10.3389/fonc.2023.1078768] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/19/2023] [Indexed: 02/04/2023] Open
Abstract
Notch signaling is involved in cell fate determination and deregulated in human solid tumors. Hypoxia is an important feature in many solid tumors, which activates hypoxia-induced factors (HIFs) and their downstream targets to promote tumorigenesis and cancer development. Recently, HIFs have been shown to trigger the Notch signaling pathway in a variety of organisms and tissues. In this review, we focus on the pro- and anti-tumorigenic functions of Notch signaling and discuss the crosstalk between Notch signaling and cellular hypoxic response in cancer pathogenesis, including epithelia-mesenchymal transition, angiogenesis, and the maintenance of cancer stem cells. The pharmacological strategies targeting Notch signaling and hypoxia in cancer are also discussed in this review.
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Affiliation(s)
- Mingzhou Guo
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Yang Niu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Min Xie
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiansheng Liu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiaochen Li
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China,*Correspondence: Xiaochen Li,
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20
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Alnajeebi AM, Alharbi HFH, Alelwani W, Babteen NA, Alansari WS, Shamlan G, Eskandrani AA. COVID-19 Candidate Genes and Pathways Potentially Share the Association with Lung Cancer. Comb Chem High Throughput Screen 2022; 25:2463-2472. [PMID: 34254909 DOI: 10.2174/1386207324666210712092649] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 04/19/2021] [Accepted: 04/21/2021] [Indexed: 01/27/2023]
Abstract
COVID-19 is considered as the most challenging in the current situation but lung cancer is also the leading cause of death in the global population. These two malignancies are among the leading human diseases and are highly complex in terms of diagnostic and therapeutic approaches as well as the most frequent and highly complex and heterogeneous in nature. Based on the latest update, it is known that the patients suffering from lung cancer, are considered to be significantly at higher risk of COVID-19 infection in terms of survival and there are a number of evidences which support the hypothesis that these diseases may share the same functions and functional components. Multi-level unwanted alterations such as (epi-)genetic alterations, changes at the transcriptional level, and altered signaling pathways (receptor, cytoplasmic, and nuclear level) are the major sources which promote a number of complex diseases and such heterogeneous level of complexities are considered as the major barrier in the development of therapeutics. With so many challenges, it is critical to understand the relationships and the common shared aberrations between them which is difficult to unravel and understand. A simple approach has been applied for this study where differential gene expression analysis, pathway enrichment, and network level understanding are carried out. Since, gene expression changes and genomic alterations are related to the COVID-19 and lung cancer but their pattern varies significantly. Based on the recent studies, it appears that the patients suffering from lung cancer and and simultaneously infected with COVID-19, then survival chance is lessened. So, we have designed our goal to understand the genes commonly overexpressed and commonly enriched pathways in case of COVID-19 and lung cancer. For this purpose, we have presented the summarized review of the previous works where the pathogenesis of lung cancer and COVID-19 infection have been focused and we have also presented the new finding of our analysis. So, this work not only presents the review work but also the research work. This review and research study leads to the conclusion that growth promoting pathways (EGFR, Ras, and PI3K), growth inhibitory pathways (p53 and STK11), apoptotic pathways (Bcl- 2/Bax/Fas), and DDR pathways and genes are commonly and dominantly altered in both the cases COVID-19 and lung cancer.
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Affiliation(s)
- Afnan M Alnajeebi
- College of Science, Department of Biochemistry, University of Jeddah, Jeddah, Saudi Arabia
| | - Hend F H Alharbi
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, KSA
| | - Walla Alelwani
- College of Science, Department of Biochemistry, University of Jeddah, Jeddah, Saudi Arabia
| | - Nouf A Babteen
- College of Science, Department of Biochemistry, University of Jeddah, Jeddah, Saudi Arabia
| | - Wafa S Alansari
- College of Science, Department of Biochemistry, University of Jeddah, Jeddah, Saudi Arabia
| | - Ghalia Shamlan
- Department of Food Science and Nutrition, College of Food and Agriculture Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Areej A Eskandrani
- Chemistry Department, Faculty of Science, Taibah University, Medina, Saudi Arabia
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21
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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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22
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Vasileva MV, Khromova NV, Kopnin BP, Dugina VB, Kopnin PB. Significance of NOTCH1 Expression in the Progression of Human Lung and Colorectal Cancers. BIOCHEMISTRY. BIOKHIMIIA 2022; 87:1199-1205. [PMID: 36273888 DOI: 10.1134/s0006297922100133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/26/2022] [Accepted: 08/27/2022] [Indexed: 06/16/2023]
Abstract
Lung and colorectal cancers are the most common types of cancer characterized by a poor prognosis and a high mortality rate. Mutations in the genes encoding components of the main intra- and extracellular signaling pathways, in particular the NOTCH1 gene (Notch1, a member of the Notch family of receptors), play one of the key roles in progression of these malignancies. Notch signaling is involved in maintaining homeostasis of the intestinal epithelium and structural and functional lung elements. Therefore, it is not surprising that the constitutive activity and hyperactivity of Notch signaling due to somatic mutations in genes coding for the products directly involved into its activation, could lead to the progression of these cancer types. The aim of our study was to investigate how the NOTCH1 downregulation via RNA interference (RNAi) affects the phenotype, characteristics, and Notch-dependent signaling of human A549 lung and HCT116 colorectal carcinoma cells. Several small harpin RNAs (shRNAs) were selected using the bioinformatic analysis and tested for their ability to suppress the NOTCH1 expression. The most efficient one was used to produce the A549 and HCT116 cells with NOTCH1 knockdown. The obtained cell lines demonstrated decreased proliferation rates, reduced colony-forming capacity under adhesive conditions, and decreased migration activity in a Boyden chamber. The NOTCH1 knockdown also significantly decreased expression of some Notch signaling target genes potentially involved in the acquisition and maintenance of more invasive and malignant cell phenotype. In vivo experiments in immunodeficient athymic female Balb/c nu/nu mice confirmed the results obtained in vitro: the NOTCH1 inhibition decreased the growth rates of the subcutaneous xenografts formed by A549 and HCT116 tumor cells. Therefore, downregulation of the gene encoding the Notch1 receptor potentially reduces malignant characteristics of human lung and colorectal carcinoma cells.
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Affiliation(s)
- Maria V Vasileva
- Blokhin National Medical Research Center of Oncology, Moscow, 115478, Russia
| | - Natalia V Khromova
- Blokhin National Medical Research Center of Oncology, Moscow, 115478, Russia
| | - Boris P Kopnin
- Blokhin National Medical Research Center of Oncology, Moscow, 115478, Russia
| | - Vera B Dugina
- Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russia
| | - Pavel B Kopnin
- Blokhin National Medical Research Center of Oncology, Moscow, 115478, Russia.
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23
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Sun X, Xin S, Li W, Zhang Y, Ye L. Discovery of Notch Pathway-Related Genes for Predicting Prognosis and Tumor Microenvironment Status in Bladder Cancer. Front Genet 2022; 13:928778. [PMID: 35846128 PMCID: PMC9279929 DOI: 10.3389/fgene.2022.928778] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/03/2022] [Indexed: 12/02/2022] Open
Abstract
Background: Notch signaling is a key regulator of immune cell differentiation and linked to autoimmune diseases, tumorigenesis and tumor-induced immunomodulation. An abnormally activated Notch signaling pathway contributes to almost all of the key features of cancer, including tumor angiogenesis, stemness, and epithelial-mesenchymal transition. Consequently, we investigated Notch pathway-related genes for developing prognostic marker and assessing immune status in bladder cancer. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to analyze RNA-seq data for bladder cancer. Cluster subtypes were identified using the NMF algorithm. In order to establish a prognostic risk signature, the least absolute shrinkage and selection operator (Lasso) and Cox regression analysis was utilized. GSEA was carried out to investigate the molecular mechanisms. Immune cell infiltration levels in bladder cancer were calculated using the CIBERSORT algorithm. External clinical tissue samples were used to validate the expression levels of signature genes. Results: Based on the NMF algorithm, bladder cancer samples were divided into two cluster subtypes and displayed different survival outcome and immune microenvironment. A six-gene risk signature (DTX3L, CNTN1, ENO1, GATA3, MAGEA1, and SORBS2) was independent for prognosis and showed good stability. The infiltration of immune cells and clinical variables were significantly different among the risk groups of patients. Response to immunotherapy also differed between different risk groups. Furthermore, the mRNA expression levels of the signature genes were verified in tissue samples by qRT-PCR. Conclusion: We established a 6-gene signature associated with Notch pathway in bladder cancer to effectively predict prognosis and reflect immune microenvironment status.
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Affiliation(s)
- Xianchao Sun
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shiyong Xin
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Weiyi Li
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ying Zhang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Ying Zhang, ; Lin Ye,
| | - Lin Ye
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Ying Zhang, ; Lin Ye,
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24
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Tang H, Li X, Jiang L, Liu Z, Chen L, Chen J, Deng M, Zhou F, Zheng X, Liu Z. RITA1 drives the growth of bladder cancer cells by recruiting TRIM25 to facilitate the proteasomal degradation of RBPJ. Cancer Sci 2022; 113:3071-3084. [PMID: 35701858 PMCID: PMC9459252 DOI: 10.1111/cas.15459] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 06/01/2022] [Accepted: 06/08/2022] [Indexed: 11/28/2022] Open
Abstract
Bladder cancer (BC) is one of the most prevalent malignancies worldwide, but it lacks effective targeted therapy due to its elusive molecular mechanism. Therefore, it is important to further investigate the molecular mechanisms that mediate BC progression. By performing a tumor tissue–based gene microarray and shRNA library screening, we found that recombination signal binding protein for immunoglobulin kappa J region (RBPJ) interacting and tubulin associated 1 (RITA1) is crucial for the growth of BC cells. Moreover, RITA1 is aberrantly highly expressed in BC tissues and is also correlated with poor prognosis in patients with BC. Mechanistically, we determined that RITA1 recruits tripartite motif containing 25 (TRIM25) to ubiquitinate RBPJ to accelerate its degradation via proteasome, which leads to the transcriptional inhibition of Notch1 downstream targets. Our results suggest that aberrant high expression of RITA1 drives the growth of BC cells via the RITA1/TRIM25/RBPJ axis and RITA1 may serve as a promising therapeutic target for BC.
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Affiliation(s)
- Huancheng Tang
- Department of Urology, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou, China.,State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiangdong Li
- Department of Urology, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou, China.,State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lijuan Jiang
- Department of Urology, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou, China.,State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zefu Liu
- Department of Urology, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou, China.,State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lei Chen
- Department of Urology, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou, China.,State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jiawei Chen
- Department of Urology, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou, China.,State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Minhua Deng
- Department of Urology, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou, China.,State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Fangjian Zhou
- Department of Urology, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou, China.,State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xianchong Zheng
- Department of Urology, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou, China.,State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhuowei Liu
- Department of Urology, Sun Yat-Sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou, China.,State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
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25
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Roles of Notch Signaling in the Tumor Microenvironment. Int J Mol Sci 2022; 23:ijms23116241. [PMID: 35682918 PMCID: PMC9181414 DOI: 10.3390/ijms23116241] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 05/24/2022] [Accepted: 05/30/2022] [Indexed: 11/16/2022] Open
Abstract
The Notch signaling pathway is an architecturally simple signaling mechanism, well known for its role in cell fate regulation during organ development and in tissue homeostasis. In keeping with its importance for normal development, dysregulation of Notch signaling is increasingly associated with different types of tumors, and proteins in the Notch signaling pathway can act as oncogenes or tumor suppressors, depending on the cellular context and tumor type. In addition to a role as a driver of tumor initiation and progression in the tumor cells carrying oncogenic mutations, it is an emerging realization that Notch signaling also plays a role in non-mutated cells in the tumor microenvironment. In this review, we discuss how aberrant Notch signaling can affect three types of cells in the tumor stroma-cancer-associated fibroblasts, immune cells and vascular cells-and how this influences their interactions with the tumor cells. Insights into the roles of Notch in cells of the tumor environment and the impact on tumor-stroma interactions will lead to a deeper understanding of Notch signaling in cancer and inspire new strategies for Notch-based tumor therapy.
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26
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Hao N, Yang D, Liu T, Liu S, Lu X, Chen L. Laminin-integrin a6b4 interaction activates notch signaling to facilitate bladder cancer development. BMC Cancer 2022; 22:558. [PMID: 35585515 PMCID: PMC9118635 DOI: 10.1186/s12885-022-09645-7] [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: 01/03/2022] [Accepted: 05/03/2022] [Indexed: 12/24/2022] Open
Abstract
Background Laminins are high-molecular weight (400 ~ 900 kDa) proteins in extracellular matrix, which serve as major component of the basal lamina, and play a crucial role in promoting tumor cell migration. This study aimed at characterizing the role of laminin in promoting cancer development, and elucidating the mechanism of tumor progression driven by laminin-Notch signaling in bladder cancer. Methods 2D collagen/laminin culture system was established and CCK-8/transwell assay was conducted to evaluate the proliferation/migration ability of Biu-87 and MB49 cells cultured on 2D gels. Activation of integrins-Notch1 signaling was determined by western blotting. Orthotopic bladder cancer mice model was established to assess the therapeutic effects of Notch inhibitor. Results Our study demonstrated that extracellular laminin can trigger tumor cell proliferation/migration through integrin α6β4/Notch1 signaling in bladder cancer. Inhibition of Telomere repeat-binding factor 3 (TRB3)/Jagged Canonical Notch Ligand 1 (JAG1) signaling suppressed Notch signals activation induced by laminin-integrin axis. In MB49 orthotopic bladder cancer mice model, Notch inhibitor SAHM1 efficiently improved tumor suppressive effects of chemotherapy and prolonged survival time of tumor-bearing mice. Conclusion In conclusion, we show that, in bladder cancer, extracellular laminin induced the activation of Notch pathway through integrin α6β4/TRB3/JAG3, and disclosed a novel role of laminin in bladder cancer cells proliferation or migration. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09645-7.
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Affiliation(s)
- Nan Hao
- Department of Urology, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530000, Guangxi, China
| | - Daming Yang
- Department of Urology, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530000, Guangxi, China
| | - Tianpei Liu
- Department of Urology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421200, Hunan, China
| | - Shucheng Liu
- Department of Urology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421200, Hunan, China
| | - Xinsheng Lu
- Department of Urology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421200, Hunan, China
| | - Libo Chen
- Department of Urology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421200, Hunan, China.
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27
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Wang JJ, Wang X, Xian YE, Chen ZQ, Sun YP, Fu YW, Wu ZK, Li PX, Zhou ES, Yang ZT. The JMJD3 histone demethylase inhibitor GSK-J1 ameliorates lipopolysaccharide-induced inflammation in a mastitis model. J Biol Chem 2022; 298:102017. [PMID: 35526564 PMCID: PMC9168612 DOI: 10.1016/j.jbc.2022.102017] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 11/26/2022] Open
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28
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Wiessner GB, Plumber SA, Xiang T, Mendelsohn CL. Development, regeneration and tumorigenesis of the urothelium. Development 2022; 149:dev198184. [PMID: 35521701 PMCID: PMC10656457 DOI: 10.1242/dev.198184] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The urothelium of the bladder functions as a waterproof barrier between tissue and outflowing urine. Largely quiescent during homeostasis, this unique epithelium rapidly regenerates in response to bacterial or chemical injury. The specification of the proper cell types during development and injury repair is crucial for tissue function. This Review surveys the current understanding of urothelial progenitor populations in the contexts of organogenesis, regeneration and tumorigenesis. Furthermore, we discuss pathways and signaling mechanisms involved in urothelial differentiation, and consider the relevance of this knowledge to stem cell biology and tissue regeneration.
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Affiliation(s)
- Gregory B. Wiessner
- Departments of Urology, Genetics and Development, Pathology and Cell Biology, Columbia Stem Cell Initiative and Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
- Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
| | - Sakina A. Plumber
- Departments of Urology, Genetics and Development, Pathology and Cell Biology, Columbia Stem Cell Initiative and Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
| | - Tina Xiang
- Departments of Urology, Genetics and Development, Pathology and Cell Biology, Columbia Stem Cell Initiative and Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
| | - Cathy L. Mendelsohn
- Departments of Urology, Genetics and Development, Pathology and Cell Biology, Columbia Stem Cell Initiative and Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
- Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
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29
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Therapeutic targeting m6A-guided miR-146a-5p signaling contributes to the melittin-induced selective suppression of bladder cancer. Cancer Lett 2022; 534:215615. [DOI: 10.1016/j.canlet.2022.215615] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/22/2022] [Accepted: 02/28/2022] [Indexed: 12/13/2022]
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30
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Wu Y, Niu D, Deng S, Lei X, Xie Z, Yang X. Tumor-derived or non-tumor-derived exosomal noncodingRNAs and signaling pathways in tumor microenvironment. Int Immunopharmacol 2022; 106:108626. [DOI: 10.1016/j.intimp.2022.108626] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/10/2022] [Accepted: 02/12/2022] [Indexed: 12/12/2022]
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31
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Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther 2022; 7:95. [PMID: 35332121 PMCID: PMC8948217 DOI: 10.1038/s41392-022-00934-y] [Citation(s) in RCA: 518] [Impact Index Per Article: 172.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/16/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.
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32
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Meng J, Jiang YZ, Zhao S, Tao Y, Zhang T, Wang X, Zhang Y, Sun K, Yuan M, Chen J, Wei Y, Lan X, Chen M, David CJ, Chang Z, Guo X, Pan D, Chen M, Shao ZM, Kang Y, Zheng H. Tumor-derived Jagged1 promotes cancer progression through immune evasion. Cell Rep 2022; 38:110492. [PMID: 35263601 DOI: 10.1016/j.celrep.2022.110492] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 12/09/2021] [Accepted: 02/14/2022] [Indexed: 12/13/2022] Open
Abstract
Immune checkpoint inhibitor (ICI) therapy is generating remarkable responses in individuals with cancer, but only a small portion of individuals with breast cancer respond well. Here we report that tumor-derived Jagged1 is a key regulator of the tumor immune microenvironment. Jagged1 promotes tumorigenesis in multiple spontaneous mammary tumor models. Through Jagged1-induced Notch activation, tumor cells increase expression and secretion of multiple cytokines to help recruit macrophages into the tumor microenvironment. Educated macrophages crosstalk with tumor-infiltrating T cells to inhibit T cell proliferation and tumoricidal activity. In individuals with triple-negative breast cancer, a high expression level of Jagged1 correlates with increased macrophage infiltration and decreased T cell activity. Co-administration of an ICI PD-1 antibody with a Notch inhibitor significantly inhibits tumor growth in breast cancer models. Our findings establish a distinct signaling cascade by which Jagged1 promotes adaptive immune evasion of tumor cells and provide several possible therapeutic targets.
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Affiliation(s)
- Jingjing Meng
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Yi-Zhou Jiang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shen Zhao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yuwei Tao
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Tengjiang Zhang
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xuxiang Wang
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Yuan Zhang
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Keyong Sun
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Min Yuan
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Jin Chen
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Yong Wei
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Xun Lan
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Mo Chen
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Charles J David
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Zhijie Chang
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xiaohuan Guo
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Deng Pan
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Meng Chen
- National Cancer Data Center, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhi-Ming Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA; Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ 08544, USA.
| | - Hanqiu Zheng
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
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Shimizu R, Ohira T, Yagyu T, Yumioka T, Yamaguchi N, Iwamoto H, Morizane S, Hikita K, Honda M, Takenaka A, Kugoh H. Activation of PPARγ in bladder cancer via introduction of the long arm of human chromosome 9. Oncol Lett 2022; 23:92. [PMID: 35154423 PMCID: PMC8822417 DOI: 10.3892/ol.2022.13212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/05/2022] [Indexed: 11/07/2022] Open
Abstract
Bladder cancer is divided into two molecular subtypes, luminal and basal, which form papillary and nodular tumors, respectively, and are identifiable by gene expression profiling. Although loss of heterozygosity (LOH) of the long arm of human chromosome 9 (9q) has been observed in the early development of both types of bladder cancer, the functional significance of LOH remains to be clarified. The present study introduced human chromosome 9q into basal bladder cancer cell line, SCaBER, using microcell-mediated chromosome transfer to investigate the effect of LOH of 9q on molecular bladder cancer subtypes. These cells demonstrated decreased proliferation and migration capacity compared with parental and control cells. Conversely, transfer of human chromosome 4 did not change the cell phenotype. Expression level of peroxisome proliferator-activated receptor (PPAR)γ, a marker of luminal type, increased 3.0-4.4 fold in SCaBER cells altered with 9q compared with parental SCaBER cells. Furthermore, the expression levels of tumor suppressor PTEN, which regulates PPARγ, also increased in 9q-altered cells. These results suggested that human chromosome 9q may carry regulatory genes for PPARγ that are involved in the progression of neoplastic transformation of bladder cancer.
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Affiliation(s)
- Ryutaro Shimizu
- Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori 683‑8504, Japan
| | - Takahito Ohira
- Department of Molecular and Cellular Biology, Division of Genome and Cellular Function, Tottori University, Yonago, Tottori 683‑8503, Japan
| | - Takuki Yagyu
- Department of Molecular and Cellular Biology, Division of Genome and Cellular Function, Tottori University, Yonago, Tottori 683‑8503, Japan
| | - Tetsuya Yumioka
- Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori 683‑8504, Japan
| | - Noriya Yamaguchi
- Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori 683‑8504, Japan
| | - Hideto Iwamoto
- Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori 683‑8504, Japan
| | - Shuichi Morizane
- Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori 683‑8504, Japan
| | - Katsuya Hikita
- Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori 683‑8504, Japan
| | - Masashi Honda
- Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori 683‑8504, Japan
| | - Atsushi Takenaka
- Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori 683‑8504, Japan
| | - Hiroyuki Kugoh
- Department of Molecular and Cellular Biology, Division of Genome and Cellular Function, Tottori University, Yonago, Tottori 683‑8503, Japan
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Torab P, Yan Y, Ahmed M, Yamashita H, Warrick JI, Raman JD, DeGraff DJ, Wong PK. Intratumoral Heterogeneity Promotes Collective Cancer Invasion through NOTCH1 Variation. Cells 2021; 10:3084. [PMID: 34831307 PMCID: PMC8619970 DOI: 10.3390/cells10113084] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/29/2021] [Accepted: 11/08/2021] [Indexed: 12/20/2022] Open
Abstract
Cellular and molecular heterogeneity within tumors has long been associated with the progression of cancer to an aggressive phenotype and a poor prognosis. However, how such intratumoral heterogeneity contributes to the invasiveness of cancer is largely unknown. Here, using a tumor bioengineering approach, we investigate the interaction between molecular subtypes within bladder microtumors and the corresponding effects on their invasiveness. Our results reveal heterogeneous microtumors formed by multiple molecular subtypes possess enhanced invasiveness compared to individual cells, even when both cells are not invasive individually. To examine the molecular mechanism of intratumoral heterogeneity mediated invasiveness, live single cell biosensing, RNA interference, and CRISPR-Cas9 gene editing approaches were applied to investigate and control the composition of the microtumors. An agent-based computational model was also developed to evaluate the influence of NOTCH1 variation on DLL4 expression within a microtumor. The data indicate that intratumoral variation in NOTCH1 expression can lead to upregulation of DLL4 expression within the microtumor and enhancement of microtumor invasiveness. Overall, our results reveal a novel mechanism of heterogeneity mediated invasiveness through intratumoral variation of gene expression.
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Affiliation(s)
- Peter Torab
- Department of Mechanical Engineering, The Pennsylvania State University, University Park, PA 16802, USA;
| | - Yue Yan
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA; (Y.Y.); (M.A.)
| | - Mona Ahmed
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA; (Y.Y.); (M.A.)
| | - Hironobu Yamashita
- Department of Pathology and Laboratory Medicine, The Pennsylvania State University, Hershey, PA 17033, USA; (H.Y.); (J.I.W.); (D.J.D.)
| | - Joshua I. Warrick
- Department of Pathology and Laboratory Medicine, The Pennsylvania State University, Hershey, PA 17033, USA; (H.Y.); (J.I.W.); (D.J.D.)
- Penn State Health Milton S., Hershey Medical Center, Department of Surgery, Hershey, PA 17033, USA;
| | - Jay D. Raman
- Penn State Health Milton S., Hershey Medical Center, Department of Surgery, Hershey, PA 17033, USA;
| | - David J. DeGraff
- Department of Pathology and Laboratory Medicine, The Pennsylvania State University, Hershey, PA 17033, USA; (H.Y.); (J.I.W.); (D.J.D.)
- Penn State Health Milton S., Hershey Medical Center, Department of Surgery, Hershey, PA 17033, USA;
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, Hershey, PA 17033, USA
| | - Pak Kin Wong
- Department of Mechanical Engineering, The Pennsylvania State University, University Park, PA 16802, USA;
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA; (Y.Y.); (M.A.)
- Penn State Health Milton S., Hershey Medical Center, Department of Surgery, Hershey, PA 17033, USA;
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Zhdanovskaya N, Firrincieli M, Lazzari S, Pace E, Scribani Rossi P, Felli MP, Talora C, Screpanti I, Palermo R. Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives. Cancers (Basel) 2021; 13:cancers13205106. [PMID: 34680255 PMCID: PMC8533696 DOI: 10.3390/cancers13205106] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/03/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary The Notch signaling pathway regulates cell proliferation, apoptosis, stem cell self-renewal, and differentiation in a context-dependent fashion both during embryonic development and in adult tissue homeostasis. Consistent with its pleiotropic physiological role, unproper activation of the signaling promotes or counteracts tumor pathogenesis and therapy response in distinct tissues. In the last twenty years, a wide number of studies have highlighted the anti-cancer potential of Notch-modulating agents as single treatment and in combination with the existent therapies. However, most of these strategies have failed in the clinical exploration due to dose-limiting toxicity and low efficacy, encouraging the development of novel agents and the design of more appropriate combinations between Notch signaling inhibitors and chemotherapeutic drugs with improved safety and effectiveness for distinct types of cancer. Abstract Notch signaling guides cell fate decisions by affecting proliferation, apoptosis, stem cell self-renewal, and differentiation depending on cell and tissue context. Given its multifaceted function during tissue development, both overactivation and loss of Notch signaling have been linked to tumorigenesis in ways that are either oncogenic or oncosuppressive, but always context-dependent. Notch signaling is critical for several mechanisms of chemoresistance including cancer stem cell maintenance, epithelial-mesenchymal transition, tumor-stroma interaction, and malignant neovascularization that makes its targeting an appealing strategy against tumor growth and recurrence. During the last decades, numerous Notch-interfering agents have been developed, and the abundant preclinical evidence has been transformed in orphan drug approval for few rare diseases. However, the majority of Notch-dependent malignancies remain untargeted, even if the application of Notch inhibitors alone or in combination with common chemotherapeutic drugs is being evaluated in clinical trials. The modest clinical success of current Notch-targeting strategies is mostly due to their limited efficacy and severe on-target toxicity in Notch-controlled healthy tissues. Here, we review the available preclinical and clinical evidence on combinatorial treatment between different Notch signaling inhibitors and existent chemotherapeutic drugs, providing a comprehensive picture of molecular mechanisms explaining the potential or lacking success of these combinations.
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Affiliation(s)
- Nadezda Zhdanovskaya
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Mariarosaria Firrincieli
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
| | - Sara Lazzari
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Eleonora Pace
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Pietro Scribani Rossi
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Claudio Talora
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Isabella Screpanti
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Correspondence: (I.S.); (R.P.)
| | - Rocco Palermo
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
- Correspondence: (I.S.); (R.P.)
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Xue C, Chen X, Lin K, Tong Y, Wang X. Identification of Notch signaling pathway gene mutations as a prognostic biomarker for bladder cancer. Future Oncol 2021; 17:4307-4320. [PMID: 34338007 DOI: 10.2217/fon-2021-0110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Purpose: The authors aimed to identify Notch signaling pathway gene mutations as a prognostic biomarker for bladder cancer. Methods: First, critical Notch signaling pathway genes were screened using The Cancer Genome Atlas and validation sets. Second, immune infiltration, protein-protein interaction network, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis analyses were performed. Finally, potential immunotherapy drug targets were screened using T-cell receptors, B-cell receptors and CERES scores for bladder cancer. Results: The NOTCH7 gene was identified, with a significant difference in immune infiltration level between mutant and wild type in bladder cancer, mainly related to T cells. NOTCH7 was an immunotherapy prognostic factor, and IRF1 and B2M were the potential drug targets for NOTCH7 mutation in bladder cancer. Conclusion: NOTCH7 gene mutation can be used as an immunotherapy biomarker for bladder cancer.
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Affiliation(s)
- Chong Xue
- Department of Urology, Zhejiang Greentown Cardiovascular Hospital, Hangzhou 310000, China
| | - Xin Chen
- Department of Urology, Zhejiang Greentown Cardiovascular Hospital, Hangzhou 310000, China
| | - KaoXing Lin
- Department of Urology, Zhejiang Greentown Cardiovascular Hospital, Hangzhou 310000, China
| | - YunGuang Tong
- School of Pharmacy, Zhejiang University, Hangzhou 310000, China.,Omigen Inc., Hangzhou 310000, China
| | - XinHong Wang
- Department of Urology, Zhejiang Greentown Cardiovascular Hospital, Hangzhou 310000, China
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Aggarwal V, Tuli HS, Varol M, Tuorkey M, Sak K, Parashar NC, Barwal TS, Sharma U, Iqubal A, Parashar G, Jain A. NOTCH signaling: Journey of an evolutionarily conserved pathway in driving tumor progression and its modulation as a therapeutic target. Crit Rev Oncol Hematol 2021; 164:103403. [PMID: 34214610 DOI: 10.1016/j.critrevonc.2021.103403] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/15/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Notch signaling, an evolutionarily conserved signaling cascade, is critical for normal biological processes of cell differentiation, development, and homeostasis. Deregulation of the Notch signaling pathway has been associated with tumor progression. Thus, Notch presents as an interesting target for a variety of cancer subtypes and its signaling mechanisms have been actively explored from the therapeutic viewpoint. However, besides acting as an oncogene, Notch pathway can possess also tumor suppressive functions, being implicated in inhibition of cancer development. Given such interesting dual and dynamic role of Notch, in this review, we discuss how the evolutionarily conserved Notch signaling pathway drives hallmarks of tumor progression and how it could be targeted for a promising treatment and management of cancer. In addition, the up-to-date information on the inhibitors currently under clinical trials for Notch targets is presented along with how NOTCH inhibitors can be used in conjunction with established chemotherapy/radiotherapy regimes.
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Affiliation(s)
- Vaishali Aggarwal
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, USA.
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133 207, Haryana, India.
| | - Mehmet Varol
- Department of Molecular Biology and Genetics, Faculty of Science, Mugla Sitki Kocman University, Mugla, TR48000, Turkey.
| | - Muobarak Tuorkey
- Division of Physiology, Zoology Department, Faculty of Science, Damanhour University, Damanhour, Egypt.
| | | | - Nidarshana Chaturvedi Parashar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133 207, Haryana, India.
| | - Tushar Singh Barwal
- Department of Zoology, Central University of Punjab, Village-Ghudda, 151 401, Punjab, India.
| | - Uttam Sharma
- Department of Zoology, Central University of Punjab, Village-Ghudda, 151 401, Punjab, India.
| | - Ashif Iqubal
- Department of Pharmacology, School of Pharmaceutical Education and Research (Formerly Faculty of Pharmacy), Jamia Hamdard (Deemed to be University), Delhi, India.
| | - Gaurav Parashar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133 207, Haryana, India.
| | - Aklank Jain
- Department of Zoology, Central University of Punjab, Village-Ghudda, 151 401, Punjab, India.
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Zhang C, Berndt-Paetz M, Neuhaus J. A Comprehensive Bioinformatics Analysis of Notch Pathways in Bladder Cancer. Cancers (Basel) 2021; 13:cancers13123089. [PMID: 34205690 PMCID: PMC8235546 DOI: 10.3390/cancers13123089] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/15/2021] [Accepted: 06/15/2021] [Indexed: 01/03/2023] Open
Abstract
Simple Summary The Notch pathway is important in embryology and numerous tumor diseases. However, its role in bladder cancer (BCa) has not been deeply investigated thus far. Gene expression data are available for BCa, and bioinformatics analysis can provide insights into a possible role of the Notch pathway in BCa development and prognosis. Using this information can help in better understanding the origin of BCa, finding novel biomarkers for prediction of disease progression, and potentially opening new avenues to improved treatment. Our analysis identified the Notch receptors NOTCH2/3 and their ligand DLL4 as potential drivers of BCa by direct interaction with basic cell functions and indirect by modulating the immune response. Abstract Background: A hallmark of Notch signaling is its variable role in tumor biology, ranging from tumor-suppressive to oncogenic effects. Until now, the mechanisms and functions of Notch pathways in bladder cancer (BCa) are still unclear. Methods: We used publicly available data from the GTEx and TCGA-BLCA databases to explore the role of the canonical Notch pathways in BCa on the basis of the RNA expression levels of Notch receptors, ligands, and downstream genes. For statistical analyses of cancer and non-cancerous samples, we used R software packages and public databases/webservers. Results: We found differential expression between control and BCa samples for all Notch receptors (NOTCH1, 2, 3, 4), the delta-like Notch ligands (DLL1, 3, 4), and the typical downstream gene hairy and enhancer of split 1 (HES1). NOTCH2/3 and DLL4 can significantly differentiate non-cancerous samples from cancers and were broadly altered in subgroups. High expression levels of NOTCH2/3 receptors correlated with worse overall survival (OS) and shorter disease-free survival (DFS). However, at long-term (>8 years) follow-up, NOTCH2 expression was associated with a better OS and DFS. Furthermore, the cases with the high levels of DLL4 were associated with worse OS but improved DFS. Pathway network analysis revealed that NOTCH2/3 in particular correlated with cell cycle, epithelial–mesenchymal transition (EMT), numbers of lymphocyte subtypes, and modulation of the immune system. Conclusions: NOTCH2/3 and DLL4 are potential drivers of Notch signaling in BCa, indicating that Notch and associated pathways play an essential role in the progression and prognosis of BCa through directly modulating immune cells or through interaction with cell cycle and EMT.
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Affiliation(s)
- Chuan Zhang
- Department of Urology, University of Leipzig, 04109 Leipzig, Germany; (C.Z.); (M.B.-P.)
- Department of Urology, Chengdu Fifth People’s Hospital Affiliated to the Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Mandy Berndt-Paetz
- Department of Urology, University of Leipzig, 04109 Leipzig, Germany; (C.Z.); (M.B.-P.)
| | - Jochen Neuhaus
- Department of Urology, University of Leipzig, 04109 Leipzig, Germany; (C.Z.); (M.B.-P.)
- Correspondence: ; Tel.: +49-341-971-7688
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Nandi A, Chakrabarti R. The many facets of Notch signaling in breast cancer: toward overcoming therapeutic resistance. Genes Dev 2021; 34:1422-1438. [PMID: 33872192 PMCID: PMC7608750 DOI: 10.1101/gad.342287.120] [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] [Indexed: 12/12/2022]
Abstract
In this review, Nandi et al. revisit the mechanisms by which Notch receptors and ligands contribute to normal mammary gland development and breast tumor progression. The authors also discuss combinatorial approaches aimed at disrupting Notch- and TME-mediated resistance that may improve prognosis in breast cancer patients. Breast cancer is the second leading cause of cancer-related death in women and is a complex disease with high intratumoral and intertumoral heterogeneity. Such heterogeneity is a major driving force behind failure of current therapies and development of resistance. Due to the limitations of conventional therapies and inevitable emergence of acquired drug resistance (chemo and endocrine) as well as radio resistance, it is essential to design novel therapeutic strategies to improve the prognosis for breast cancer patients. Deregulated Notch signaling within the breast tumor and its tumor microenvironment (TME) is linked to poor clinical outcomes in treatment of resistant breast cancer. Notch receptors and ligands are also important for normal mammary development, suggesting the potential for conserved signaling pathways between normal mammary gland development and breast cancer. In this review, we focus on mechanisms by which Notch receptors and ligands contribute to normal mammary gland development and breast tumor progression. We also discuss how complex interactions between cancer cells and the TME may reduce treatment efficacy and ultimately lead to acquired drug or radio resistance. Potential combinatorial approaches aimed at disrupting Notch- and TME-mediated resistance that may aid in achieving in an improved patient prognosis are also highlighted.
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Affiliation(s)
- Ajeya Nandi
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Rumela Chakrabarti
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting the γ-secretase complex. Cell Death Dis 2021; 12:562. [PMID: 34059639 PMCID: PMC8166826 DOI: 10.1038/s41419-021-03836-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 05/10/2021] [Accepted: 05/13/2021] [Indexed: 12/21/2022]
Abstract
Ciclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).
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Bhore N, Wang BJ, Wu PF, Lee YL, Chen YW, Hsu WM, Lee H, Huang YS, Yang DI, Liao YF. Dual-Specificity Phosphatase 15 (DUSP15) Modulates Notch Signaling by Enhancing the Stability of Notch Protein. Mol Neurobiol 2021; 58:2204-2214. [PMID: 33417224 DOI: 10.1007/s12035-020-02254-0] [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: 03/24/2020] [Accepted: 12/08/2020] [Indexed: 11/27/2022]
Abstract
Dual-specificity phosphatases (DUSPs) comprise a unique group of enzymes that dephosphorylate signaling proteins at both phospho-serine/threonine and phospho-tyrosine residues. Since Notch signaling is an essential pathway for neuronal cell fate determination and development that is also upregulated in Alzheimer's disease tissues, we sought to explore whether and how DUSPs may impact Notch processing. Our results show that overexpression of DUSP15 concomitantly and dose-dependently increased the steady-state levels of recombinant Notch (extracellular domain-truncated Notch, NotchΔE) protein and its cleaved product, Notch intracellular domain (NICD). The overall ratio of NotchΔE to NICD was unchanged by overexpression of DUSP15, suggesting that the effect is independent of γ-secretase. Interestingly, overexpression of DUSP15 also dose-dependently increased phosphorylated ERK1/2. Phosphorylated ERK1/2 is known to be positively correlated with Notch protein level, and we found that DUSP15-mediated regulation of Notch was dependent on ERK1/2 activity. Together, our findings reveal the existence of a previously unidentified DUSP15-ERK1/2-Notch signaling axis, which could potentially play a role in neuronal differentiation and neurological disease.
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Affiliation(s)
- Noopur Bhore
- Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, ICOB 238, 128 Sec. 2 Academia Rd, Taipei, 11529, Taiwan
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming University, Academia Sinica, Taipei, Taiwan
| | - Bo-Jeng Wang
- Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, ICOB 238, 128 Sec. 2 Academia Rd, Taipei, 11529, Taiwan
| | - Po-Fan Wu
- Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, ICOB 238, 128 Sec. 2 Academia Rd, Taipei, 11529, Taiwan
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Cheng Kung University, Academia Sinica, Taipei, Taiwan
| | - Yen-Lurk Lee
- TIGP in Molecular Medicine, National Yang-Ming University, Academia Sinica, Taipei, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yun-Wen Chen
- Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, ICOB 238, 128 Sec. 2 Academia Rd, Taipei, 11529, Taiwan
| | - Wen-Ming Hsu
- Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hsinyu Lee
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Yi-Shuian Huang
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming University, Academia Sinica, Taipei, Taiwan
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Cheng Kung University, Academia Sinica, Taipei, Taiwan
- TIGP in Molecular Medicine, National Yang-Ming University, Academia Sinica, Taipei, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Ding-I Yang
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming University, Academia Sinica, Taipei, Taiwan
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
| | - Yung-Feng Liao
- Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, ICOB 238, 128 Sec. 2 Academia Rd, Taipei, 11529, Taiwan.
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming University, Academia Sinica, Taipei, Taiwan.
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Cheng Kung University, Academia Sinica, Taipei, Taiwan.
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Ferreira A, Aster JC. Notch signaling in cancer: Complexity and challenges on the path to clinical translation. Semin Cancer Biol 2021; 85:95-106. [PMID: 33862222 DOI: 10.1016/j.semcancer.2021.04.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 03/29/2021] [Accepted: 04/11/2021] [Indexed: 12/22/2022]
Abstract
Notch receptors participate in a conserved pathway in which ligands expressed on neighboring cells trigger a series of proteolytic cleavages that allow the intracellular portion of the receptor to travel to the nucleus and form a short-lived transcription complex that turns on target gene expression. The directness and seeming simplicity of this signaling mechanism belies the complexity of the outcomes of Notch signaling in normal cells, which are highly context and dosage dependent. This complexity is reflected in the diverse roles of Notch in cancers of various types, in which Notch may be oncogenic or tumor suppressive and may have a wide spectrum of effects on tumor cells and stromal elements. This review provides an overview of the roles of Notch in cancer and discusses challenges to clinical translation of Notch targeting agents as well as approaches that may overcome these hurdles.
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Affiliation(s)
- Antonio Ferreira
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, United States
| | - Jon C Aster
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, United States.
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Schulz GB, Elezkurtaj S, Börding T, Schmidt EM, Elmasry M, Stief CG, Kirchner T, Karl A, Horst D. Therapeutic and prognostic implications of NOTCH and MAPK signaling in bladder cancer. Cancer Sci 2021; 112:1987-1996. [PMID: 33686706 PMCID: PMC8088911 DOI: 10.1111/cas.14878] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 02/27/2021] [Accepted: 03/07/2021] [Indexed: 12/20/2022] Open
Abstract
Signaling pathways that drive bladder cancer (BC) progression may be promising and specific targets for systemic therapy. Here, we investigated the clinical significance and targetability of NOTCH and mitogen-activated protein kinase (MAPK) signaling for this aggressive malignancy. We assessed NOTCH1 and MAPK activity in 222 stage III and IV BC specimens of patients that had undergone radical cystectomy, and tested for clinical associations including cancer-specific and overall survival. We examined therapeutic effects of NOTCH and MAPK repression in a murine xenograft model of human bladder cancer cells and evaluated tumor growth and tumor cell plasticity. In BC, NOTCH1 and MAPK signaling marked two distinct tumor cell subpopulations. The combination of high NOTCH1 and high MAPK activity indicated poor cancer-specific and overall survival in univariate and multivariate analyses. Inhibition of NOTCH and MAPK in BC xenografts in vivo depleted targeted tumor cell subpopulations and revealed strong plasticity in signaling pathway activity. Combinatorial inhibition of NOTCH and MAPK signaling most strongly suppressed tumor growth. Our findings indicate that tumor cell subpopulations with high NOTCH and MAPK activity both contribute to tumor progression. Furthermore, we propose a new concept for BC therapy, which advocates specific and simultaneous targeting of these different tumor cell subpopulations through combined NOTCH and MAPK inhibition.
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Affiliation(s)
- Gerald B Schulz
- Department of Urology, Ludwig-Maximilians-Universität, Munich, Germany
| | - Sefer Elezkurtaj
- Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Teresa Börding
- Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | | | - Manal Elmasry
- Institute of Pathology, Ludwig-Maximilians-Universität, Munich, Germany
| | - Christian G Stief
- Department of Urology, Ludwig-Maximilians-Universität, Munich, Germany
| | - Thomas Kirchner
- Institute of Pathology, Ludwig-Maximilians-Universität, Munich, Germany
| | - Alexander Karl
- Department of Urology, Barmherzige Brüder, Munich, Germany
| | - David Horst
- Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Lodewijk I, Nunes SP, Henrique R, Jerónimo C, Dueñas M, Paramio JM. Tackling tumor microenvironment through epigenetic tools to improve cancer immunotherapy. Clin Epigenetics 2021; 13:63. [PMID: 33761971 PMCID: PMC7992805 DOI: 10.1186/s13148-021-01046-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/01/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Epigenetic alterations are known contributors to cancer development and aggressiveness. Additional to alterations in cancer cells, aberrant epigenetic marks are present in cells of the tumor microenvironment, including lymphocytes and tumor-associated macrophages, which are often overlooked but known to be a contributing factor to a favorable environment for tumor growth. Therefore, the main aim of this review is to give an overview of the epigenetic alterations affecting immune cells in the tumor microenvironment to provoke an immunosuppressive function and contribute to cancer development. Moreover, immunotherapy is briefly discussed in the context of epigenetics, describing both its combination with epigenetic drugs and the need for epigenetic biomarkers to predict response to immune checkpoint blockage. MAIN BODY Combining both topics, epigenetic machinery plays a central role in generating an immunosuppressive environment for cancer growth, which creates a barrier for immunotherapy to be successful. Furthermore, epigenetic-directed compounds may not only affect cancer cells but also immune cells in the tumor microenvironment, which could be beneficial for the clinical response to immunotherapy. CONCLUSION Thus, modulating epigenetics in combination with immunotherapy might be a promising therapeutic option to improve the success of this therapy. Further studies are necessary to (1) understand in depth the impact of the epigenetic machinery in the tumor microenvironment; (2) how the epigenetic machinery can be modulated according to tumor type to increase response to immunotherapy and (3) find reliable biomarkers for a better selection of patients eligible to immunotherapy.
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Affiliation(s)
- Iris Lodewijk
- Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales Y Tecnológicas (CIEMAT), 28040 Madrid, Spain
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, 28041 Madrid, Spain
| | - Sandra P. Nunes
- Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales Y Tecnológicas (CIEMAT), 28040 Madrid, Spain
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, 28041 Madrid, Spain
- Cancer Biology and Epigenetics Group – Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal
| | - Rui Henrique
- Cancer Biology and Epigenetics Group – Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal
- Department of Pathology, Portuguese Oncology Institute of Porto, 4200-072 Porto, Portugal
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar – University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group – Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar – University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
| | - Marta Dueñas
- Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales Y Tecnológicas (CIEMAT), 28040 Madrid, Spain
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, 28041 Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Jesús M. Paramio
- Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales Y Tecnológicas (CIEMAT), 28040 Madrid, Spain
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, 28041 Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
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Akil A, Gutiérrez-García AK, Guenter R, Rose JB, Beck AW, Chen H, Ren B. Notch Signaling in Vascular Endothelial Cells, Angiogenesis, and Tumor Progression: An Update and Prospective. Front Cell Dev Biol 2021; 9:642352. [PMID: 33681228 PMCID: PMC7928398 DOI: 10.3389/fcell.2021.642352] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 01/19/2021] [Indexed: 12/12/2022] Open
Abstract
The Notch signaling pathway plays an essential role in a wide variety of biological processes including cell fate determination of vascular endothelial cells and the regulation of arterial differentiation and angiogenesis. The Notch pathway is also an essential regulator of tumor growth and survival by functioning as either an oncogene or a tumor suppressor in a context-dependent manner. Crosstalk between the Notch and other signaling pathways is also pivotal in tumor progression by promoting cancer cell growth, migration, invasion, metastasis, tumor angiogenesis, and the expansion of cancer stem cells (CSCs). In this review, we provide an overview and update of Notch signaling in endothelial cell fate determination and functioning, angiogenesis, and tumor progression, particularly in the development of CSCs and therapeutic resistance. We further summarize recent studies on how endothelial signaling crosstalk with the Notch pathway contributes to tumor angiogenesis and the development of CSCs, thereby providing insights into vascular biology within the tumor microenvironment and tumor progression.
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Affiliation(s)
- Abdellah Akil
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Ana K. Gutiérrez-García
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Rachael Guenter
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - J. Bart Rose
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- O’Neal Comprehensive Cancer Center, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Adam W. Beck
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Herbert Chen
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- O’Neal Comprehensive Cancer Center, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Bin Ren
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- O’Neal Comprehensive Cancer Center, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
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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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Tsampoula M, Tarampoulous I, Antoniadou I, Koutmani Y, Gkikas D, Vekrellis K, Politis PK. Nuclear Receptor NR5A2 Promotes Neuronal Identity in the Adult Hippocampus. Mol Neurobiol 2021; 58:1952-1962. [PMID: 33411242 DOI: 10.1007/s12035-020-02222-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 11/19/2020] [Indexed: 12/01/2022]
Abstract
Neurogenesis in the dentate gyrus (DG) of the adult hippocampus is actively involved in brain homeostasis. Thus, identification of novel regulators in adult neurogenesis could significantly contribute to new therapies. We have recently unraveled the regulatory role of NR5A2 (also known as LRH1), a druggable orphan nuclear receptor, in embryonic neurogenesis. However, its involvement in adult neurogenesis is still an open question. Here we show that NR5A2 is differentially expressed in the DG of the adult hippocampus with neurons exhibiting higher levels of expression than adult neural stem/progenitor cells (aNSCs), suggesting a correlation with neuronal differentiation. Notably, NR5A2 overexpression in ex vivo cultured aNSCs induces expression of Prox1, a critical regulator of adult hippocampal neurogenesis. In agreement, NR5A2 is sufficient to reduce proliferation, increase neuronal differentiation, and promote axon outgrowth. Moreover, depletion of NR5A2 in DG cells in vivo caused a decrease in the number of NeuN as well as Calbindin-positive neurons, indicating its necessity for the maintenance of neuronal identity. Our data propose a regulatory role of NR5A2 in neuronal differentiation and fate specification of adult hippocampal NSCs.
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Affiliation(s)
- Matina Tsampoula
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
| | - Isaak Tarampoulous
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
| | - Ivi Antoniadou
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
| | - Yassemi Koutmani
- Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
| | - Dimitrios Gkikas
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
| | - Kostas Vekrellis
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
| | - Panagiotis K Politis
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece.
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Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis. Cells 2021; 10:cells10010094. [PMID: 33430387 PMCID: PMC7827494 DOI: 10.3390/cells10010094] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/23/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023] Open
Abstract
The Notch signaling pathway is a critical player in embryogenesis but also plays various roles in tumorigenesis, with both tumor suppressor and oncogenic activities. Mutations, deletions, amplifications, or over-expression of Notch receptors, ligands, and a growing list of downstream Notch-activated genes have by now been described for most human cancer types. Yet, it often remains unclear what may be the functional impact of these changes for tumor biology, initiation, and progression, for cancer therapy, and for personalized medicine. Emerging data indicate that Notch signaling can also contribute to increased aggressive properties such as invasion, tumor heterogeneity, angiogenesis, or tumor cell dormancy within solid cancer tissues; especially in epithelial cancers, which are in the center of this review. Notch further supports the “stemness” of cancer cells and helps define the stem cell niche for their long-term survival, by integrating the interaction between cancer cells and the cells of the tumor microenvironment (TME). The complexity of Notch crosstalk with other signaling pathways and its roles in cell fate and trans-differentiation processes such as epithelial-to-mesenchymal transition (EMT) point to this pathway as a decisive player that may tip the balance between tumor suppression and promotion, differentiation and invasion. Here we not only review the literature, but also explore genomic databases with a specific focus on Notch signatures, and how they relate to different stages in tumor development. Altered Notch signaling hereby plays a key role for tumor cell survival and coping with a broad spectrum of vital issues, contributing to failed therapies, poor patient outcome, and loss of lives.
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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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50
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Chestnut C, Subramaniam D, Dandawate P, Padhye S, Taylor J, Weir S, Anant S. Targeting Major Signaling Pathways of Bladder Cancer with Phytochemicals: A Review. Nutr Cancer 2020; 73:2249-2271. [DOI: 10.1080/01635581.2020.1856895] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Connor Chestnut
- Department of Urology, University of Kansas Medical Center, Kansas City, Kansas, USA
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | | | - Prasad Dandawate
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Subhash Padhye
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
- Interdisciplinary Science and Technology Research Academy, University of Pune, Pune, India
| | - John Taylor
- Department of Urology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Scott Weir
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
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