|
1
|
Raj N, Karmakar A, Narayan G, Thummer RP. Small Molecules and Epigenetic Modifiers in Facilitating Pancreatic β-cell Formation: A Comprehensive Insight. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025. [PMID: 40178799 DOI: 10.1007/5584_2025_859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
Diabetes mellitus, arising due to inadequate insulin release or insulin resistance, can be addressed through β-cell replacement therapy. Given the limited availability of islet cadaveric donors, alternative strategies such as differentiation of stem cells into pancreatic β-cells or direct reprogramming of somatic cells into pancreatic β-cells are emerging as viable options. This chapter elucidates the pivotal role of small molecules and associated signaling pathways in in vivo pancreatic organogenesis, allowing their emulation in vitro to facilitate pancreatic development. Small molecules exhibit distinct advantages, such as cell-permeability and non-immunogenic properties, thereby generating efficient functional β-like cells. Recent investigations highlight alterations in epigenetic marks unique to pancreatic β-cells during cellular reprogramming and diabetes pathogenesis. The study further delineates the distinctive histone modifications and DNA methylation within pancreatic β-cells, underscoring their contributions to pancreas development.
Collapse
Affiliation(s)
- Naveen Raj
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Asmita Karmakar
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Gloria Narayan
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Rajkumar P Thummer
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
| |
Collapse
|
|
2
|
Iyer S, Tarique M, Sahay P, Giri S, Bava EP, Guan J, Jain T, Vaish U, Jin X, Moon S, Crossman DK, Dudeja V. Inhibition of hedgehog signaling ameliorates severity of chronic pancreatitis in experimental mouse models. Am J Physiol Gastrointest Liver Physiol 2025; 328:G342-G363. [PMID: 39499252 DOI: 10.1152/ajpgi.00212.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 11/07/2024]
Abstract
Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas with no specific cure. Research highlighting the pathogenesis and especially the therapeutic aspect remains limited. Aberrant activation of developmental pathways in adults has been implicated in several diseases. Hedgehog pathway is a notable embryonic signaling pathway, known to promote fibrosis of various organs when overactivated. The aim of this study is to explore the role of the hedgehog pathway in the progression of CP and evaluate its inhibition as a novel therapeutic strategy against CP. CP was induced in mice by repeated injections of l-arginine or caerulein in two separate models. Mice were administered with the FDA-approved pharmacological hedgehog pathway inhibitor, vismodegib during or after establishing the disease condition to inhibit hedgehog signaling. Various parameters of CP were analyzed to determine the effect of hedgehog pathway inhibition on the severity and progression of the disease. Our study shows that hedgehog signaling was overactivated during CP and its inhibition was effective in improving the histopathological parameters associated with CP. Vismodegib administration not only halted the progression of CP but was also able to resolve already-established fibrosis. In addition, inhibition of hedgehog signaling resulted in the reversal of pancreatic stellate cell activation ex vivo. Findings from our study justify conducting clinical trials using vismodegib against CP and, thus, could lead to the development of a novel therapeutic strategy for the treatment of CP.NEW & NOTEWORTHY Hedgehog signaling is activated in human and experimental models of CP. Inhibition of hedgehog signaling using an FDA-approved inhibitor, vismodegib, leads to the resolution of fibrosis and improves CP. This study has immense and immediate translational benefits.
Collapse
Affiliation(s)
- Srikanth Iyer
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Mohammad Tarique
- Department of Pediatrics, University of Missouri, Columbia, Missouri, United States
| | - Preeti Sahay
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Sagnik Giri
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Ejas P Bava
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - JiaShiung Guan
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Tejeshwar Jain
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Utpreksha Vaish
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Xiuwen Jin
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Sabrina Moon
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - David K Crossman
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Vikas Dudeja
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Birmingham Veteran Affairs Medical Center, Birmingham, Alabama, United States
| |
Collapse
|
|
3
|
Leclerc E, Pachkov M, Morisseau L, Tokito F, Legallais C, Jellali R, Nishikawa M, Abderrahmani A, Sakai Y. Investigation of the motif activity of transcription regulators in pancreatic β-like cell subpopulations differentiated from human induced pluripotent stem cells. Mol Omics 2024. [PMID: 39494575 DOI: 10.1039/d4mo00082j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2024]
Abstract
Pancreatic β-cells are composed of different subtypes that play a key role in the control of insulin secretion and thereby control glucose homeostasis. In vitro differentiation of human induced pluripotent stem cells (hiPSCs) into 3D spheroids leads to the generation of β-cell subtypes and thus to the development of islet-like structures. Using this cutting-edge cell model, the aim of the study was to decipher the signaling signature that underlines β-cell subtypes, with a focus on the search for the activity of motifs of important transcription regulators (TRs). The investigation was performed using data from previous single-cell sequencing analysis introduced into the integrated system for motif activity response analysis (ISMARA) of transcription regulators. We extracted the matrix of important TRs activated in the β-cell subpopulation and bi-hormonal-like β-cells. Based on these TRs and their targets, we built specific regulatory networks for main cell subpopulations. Our data confirmed the transcriptomic heterogeneity of the β-cell subtype lineage and suggested a mechanism that could account for the differentiation of β-cell subtypes during pancreas development. We do believe that our findings could be instrumental for understanding the mechanisms that affect the balance of β-cell subtypes, leading to impaired insulin secretion in type 2 diabetes.
Collapse
Affiliation(s)
- Eric Leclerc
- CNRS IRL 2820; Laboratory for Integrated Micro Mechatronic Systems, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba; Meguro-ku, Tokyo, 153-8505, Japan
| | - Mikhail Pachkov
- Biozentrum, University of Basel, Spitalstrasse 41, 4056 Basel, Switzerland
- SIB Swiss Institute of Bioinformatics, Quartier Sorge - Bâtiment Amphipôle, 1015 Lausanne, Switzerland
| | - Lisa Morisseau
- CNRS UMR 7338, Laboratoire de Biomécanique et Bioingénierie, Sorbonne universités, Université de Technologies de Compiègne, France
| | - Fumiya Tokito
- Department of Chemical System Engineering, Graduate School of Engineering, the University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Cecile Legallais
- CNRS UMR 7338, Laboratoire de Biomécanique et Bioingénierie, Sorbonne universités, Université de Technologies de Compiègne, France
| | - Rachid Jellali
- CNRS UMR 7338, Laboratoire de Biomécanique et Bioingénierie, Sorbonne universités, Université de Technologies de Compiègne, France
| | - Masaki Nishikawa
- Department of Chemical System Engineering, Graduate School of Engineering, the University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Amar Abderrahmani
- Univ. Lille, CNRS, Centrale Lille, Univ. Polytechnique Hauts-de-France, UMR 8520, IEMN, F-59000 Lille, France
| | - Yasuyuki Sakai
- CNRS IRL 2820; Laboratory for Integrated Micro Mechatronic Systems, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba; Meguro-ku, Tokyo, 153-8505, Japan
- Department of Chemical System Engineering, Graduate School of Engineering, the University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| |
Collapse
|
|
4
|
Parashar A, Jha D, Mehta V, Chauhan B, Ghosh P, Deb PK, Jaiswal M, Prajapati SK. Sonic hedgehog signalling pathway contributes in age-related disorders and Alzheimer's disease. Ageing Res Rev 2024; 96:102271. [PMID: 38492808 DOI: 10.1016/j.arr.2024.102271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/10/2024] [Accepted: 03/11/2024] [Indexed: 03/18/2024]
Abstract
Alzheimer's disease (AD) is caused by the aging process and manifested by cognitive deficits and progressive memory loss. During aging, several conditions, including hypertension, diabetes, and cholesterol, have been identified as potential causes of AD by affecting Sonic hedgehog (Shh) signalling. In addition to being essential for cell differentiation and proliferation, Shh signalling is involved in tissue repair and the prevention of neurodegeneration. Neurogenesis is dependent on Shh signalling; inhibition of this pathway results in neurodegeneration. Several protein-protein interactions that are involved in Shh signalling are implicated in the pathophysiology of AD like overexpression of the protein nexin-1 inhibits the Shh pathway in AD. A protein called Growth Arrest Specific-1 works with another protein called cysteine dioxygenase (CDO) to boost Shh signalling. CDO is involved in the development of the central nervous system (CNS). Shh signalling strengthened the blood brain barrier and therefore prevent the entry of amyloid beta and other toxins to the brain from periphery. Further, several traditional remedies used for AD and dementia, including Epigallocatechin gallate, yokukansan, Lycium barbarum polysaccharides, salvianolic acid, and baicalin, are known to stimulate the Shh pathway. In this review, we elaborated that the Shh signalling exerts a substantial influence on the pathogenesis of AD. In this article, we have tried to explore the various possible connections between the Shh signalling and various known pathologies of AD.
Collapse
Affiliation(s)
- Arun Parashar
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology & Management Sciences, Solan 173 212, India.
| | - Dhruv Jha
- Birla Institute of Technology, India
| | - Vineet Mehta
- Department of Pharmacology, Government College of Pharmacy, Rohru, District Shimla, Himachal Pradesh 171207, India
| | - Bonney Chauhan
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology & Management Sciences, Solan 173 212, India
| | - Pappu Ghosh
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology & Management Sciences, Solan 173 212, India
| | - Prashanta Kumar Deb
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology & Management Sciences, Solan 173 212, India
| | | | | |
Collapse
|
|
5
|
Dayer D, Bayati V, Ebrahimi M. Manipulation of Sonic Hedgehog Signaling Pathway in Maintenance, Differentiation, and Endocrine Activity of Insulin-Producing Cells: A Systematic Review. IRANIAN JOURNAL OF MEDICAL SCIENCES 2024; 49:65-76. [PMID: 38356490 PMCID: PMC10862108 DOI: 10.30476/ijms.2023.95425.2678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 10/30/2022] [Accepted: 11/01/2022] [Indexed: 02/16/2024]
Abstract
Background Some studies have evaluated the manipulation of the sonic hedgehog (Shh) signaling pathway to generate more efficient insulin-producing cells (IPCs). In a systematic review, we evaluated in vitro and in vivo studies on the effect of inhibition or activation of the Shh pathway on the production, differentiation, maintenance, and endocrine activity of IPCs. Methods A systematic review was conducted using all available experimental studies published between January 2000 and November 2022. The review aimed at determining the effect of Shh manipulation on the differentiation of stem cells (SCs) into IPCs. Keywords and phrases using medical subject headings were extracted, and a complete search was performed in Web of Science, Embase, ProQuest, PubMed, Scopus, and Cochrane Library databases. The inclusion criteria were manipulation of Shh in SCs, SCs differentiation into IPCs, and endocrine activity of mature IPCs. Articles with incomplete data and duplications were excluded. Results A total of 208 articles were initially identified, out of which 11 articles were included in the study. The effect of Shh inhibition in the definitive endoderm stage to produce functional IPCs were confirmed. Some studies showed the importance of Shh re-activation at late-stage differentiation for the generation of efficient IPCs. It is proposed that baseline concentrations of Shh in mature pancreatic β-cells affect insulin secretion and endocrine activities of the cells. However, Shh overexpression in pancreatic β-cells ultimately leads to improper endocrine function and inadequate glucose-sensing insulin secretion. Conclusion Accurate manipulation of the Shh signaling pathway can be an effective approach in the production and maintenance of functional IPCs.
Collapse
Affiliation(s)
- Dian Dayer
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Vahid Bayati
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Anatomy, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mina Ebrahimi
- Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| |
Collapse
|
|
6
|
Mohammed OA, Doghish AS, Saleh LA, Alghamdi M, Alamri MMS, Alfaifi J, Adam MIE, Alharthi MH, Alshahrani AM, Alhalafi AH, BinAfif WF, Rezigalla AA, Abdel-Reheim MA, El-Wakeel HS, Attia MA, Elmorsy EA, Al-Noshokaty TM, Nomier Y, Saber S. Itraconazole halts hepatocellular carcinoma progression by modulating sonic hedgehog signaling in rats: A novel therapeutic approach. Pathol Res Pract 2024; 253:155086. [PMID: 38176308 DOI: 10.1016/j.prp.2023.155086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 12/24/2023] [Accepted: 12/30/2023] [Indexed: 01/06/2024]
Abstract
Liver cancer stands as the fourth leading global cause of death, and its prognosis remains grim due to the limited effectiveness of current medical interventions. Among the various pathways implicated in the development of hepatocellular carcinoma (HCC), the hedgehog signaling pathway has emerged as a crucial player. Itraconazole, a relatively safe and cost-effective antifungal medication, has gained attention for its potential as an anticancer agent. Its primary mode of action involves inhibiting the hedgehog pathway, yet its impact on HCC has not been elucidated. The main objective of this study was to investigate the effect of itraconazole on diethylnitrosamine-induced early-stage HCC in rats. Our findings revealed that itraconazole exhibited a multifaceted arsenal against HCC by downregulating the expression of key components of the hedgehog pathway, shh, smoothened (SMO), and GLI family zinc finger 1 (GLI1), and GLI2. Additionally, itraconazole extended survival and improved liver tissue structure, attributed mainly to its inhibitory effects on hedgehog signaling. Besides, itraconazole demonstrated a regulatory effect on Notch1, and Wnt/β-catenin signaling molecules. Consequently, itraconazole displayed diverse anticancer properties, including anti-inflammatory, antiangiogenic, antiproliferative, and apoptotic effects, as well as the potential to induce autophagy. Moreover, itraconazole exhibited a promise to impede the transformation of epithelial cells into a more mesenchymal-like phenotype. Overall, this study emphasizes the significance of targeting the hedgehog pathway with itraconazole as a promising avenue for further exploration in clinical studies related to HCC treatment.
Collapse
Affiliation(s)
- Osama A Mohammed
- Department of Pharmacology, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo 11231, Egypt.
| | - Lobna A Saleh
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; Department of Pharmacology and Toxicology, Collage of Pharmacy, Taif University, Taif, Saudi Arabia.
| | - Mushabab Alghamdi
- Department of Internal Medicine, Division of Rheumatology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | - Mohannad Mohammad S Alamri
- Department of Family and Community Medicine, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | - Jaber Alfaifi
- Department of Child Health, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | - Masoud I E Adam
- Department of Medical Education and Internal Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | - Muffarah Hamid Alharthi
- Department of Family and Community Medicine, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | - Abdullah M Alshahrani
- Department of Family and Community Medicine, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | - Abdullah Hassan Alhalafi
- Department of Family and Community Medicine, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | - Waad Fuad BinAfif
- Department of Internal Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | - Assad Ali Rezigalla
- Department of Anatomy, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
| | - Hend S El-Wakeel
- Physiology Department, Benha Faculty of Medicine, Benha University, Qalubyia 13518, Egypt; Physiology Department, Al-Baha Faculty of Medicine, Al-Baha University, Al-Baha 65799, Saudi Arabia.
| | - Mohammed A Attia
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt; Department of Basic Medical Sciences , College of Medicine Almaarefa University Diriyiah, 13713, Riyadh, Saudi Arabia.
| | - Elsayed A Elmorsy
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt; Pharmacology and Therapeutics Department, Qassim College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia.
| | - Tohada M Al-Noshokaty
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt.
| | - Yousra Nomier
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt.
| |
Collapse
|
|
7
|
Propofol Inhibits Thyroid Cancer Cell Proliferation, Migration, and Invasion by Suppressing SHH and PI3K/AKT Signaling Pathways via the miR-141-3p/BRD4 Axis. JOURNAL OF HEALTHCARE ENGINEERING 2021; 2021:2704753. [PMID: 34956562 PMCID: PMC8702329 DOI: 10.1155/2021/2704753] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/10/2021] [Accepted: 11/23/2021] [Indexed: 01/26/2023]
Abstract
Objective This study explores the effect and mechanism of propofol for thyroid tumor. Methods Culture human normal thyroid cells Nthy-ori 3-1 and thyroid cancer cell line TPC-1. TPC-1 cells were divided into the propofol group (treated with propofol), miR-141-3p group (transfected with the miR-141-3p mimic), negative control group (transfected with miR-NC), miR-141-3p + pcDNA-BRD4 group (transfected with the miR-141-3p mimic and pcDNA-BRD4), miR-141-3p + pcDNA group (transfected with the miR-141-3p mimic and pcDNA), siBRD4 group (transfected with siBRD4), and si-control group (transfected with si-control). The detection of miR-141-3p and BRD4 expression in cells was done by RT-qPCR, and the dual-luciferase reporter gene method and western blotting were used to verify the targeting relationship between miR-141-3p and BRD4. MTT method was used to test cell proliferation, transwell method was used to test cell migration and invasion, and western blotting was used to test SHH, GLI1, p-PI3K, and p-AKT protein expression. Results Compared with Nthy-ori 3-1 cells, the expression of miR-141-3p in TPC-1 cells was markedly decreased. Propofol treatment and excessive expression of miR-141-3p could influence the phenotype of TPC-1 cells. BRD4 is one of the target genes of miR-141-3p, and its expression is negatively regulated by miR-141-3p. Overexpression of BRD4 can partially reverse the restraining effect of miR-141-3p on the TPC-1 cell phenotype. Both miR-141-3p and BRD4 can regulate the activity of SHH and PI3K/AKT signaling pathways. Conclusion Propofol can inhibit the activity of SHH and PI3K/AKT pathways by targeting downregulating BRD4 through miR-141-3p, thereby inhibiting the phenotype of TPC-1 cells.
Collapse
|
|
8
|
Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease. Cancers (Basel) 2021; 13:cancers13143410. [PMID: 34298625 PMCID: PMC8304605 DOI: 10.3390/cancers13143410] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The Hedgehog/GLI (Hh/GLI) pathway plays a major role during development and it is commonly dysregulated in many diseases, including cancer. This highly concerted series of ligands, receptors, cytoplasmic signaling molecules, transcription factors, and co-regulators is involved in regulating the biological functions controlled by this pathway. Activation of Hh/GLI in cancer is most often through a non-canonical method of activation, independent of ligand binding. This review is intended to summarize our current understanding of the Hh/GLI signaling, non-canonical mechanisms of pathway activation, its implication in disease, and the current therapeutic strategies targeting this cascade. Abstract The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO, HHIP, SUFU, PKA, CK1, GSK3β, etc.) that work in concert to repress (Ptch1, Ptch2, SUFU, PKA, CK1, GSK3β) or activate (Shh, Ihh, Dhh, SMO, GLI1–3) the signaling cascade. Not long after the initial discovery, dysregulation of the Hh/GLI signaling pathway was implicated in human disease. Activation of this signaling pathway is observed in many types of cancer, including basal cell carcinoma, medulloblastoma, colorectal, prostate, pancreatic, and many more. Most often, the activation of the Hh/GLI pathway in cancer occurs through a ligand-independent mechanism. However, in benign disease, this activation is mostly ligand-dependent. The upstream signaling component of the receptor complex, SMO, is bypassed, and the GLI family of transcription factors can be activated regardless of ligand binding. Additional mechanisms of pathway activation exist whereby the entirety of the downstream signaling pathway is bypassed, and PTCH1 promotes cell cycle progression and prevents caspase-mediated apoptosis. Throughout this review, we summarize each component of the signaling cascade, non-canonical modes of pathway activation, and the implications in human disease, including cancer.
Collapse
|
|
9
|
Korzh S, Winata CL, Gong Z, Korzh V. The development of zebrafish pancreas affected by deficiency of Hedgehog signaling. Gene Expr Patterns 2021; 41:119185. [PMID: 34087472 DOI: 10.1016/j.gep.2021.119185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/29/2021] [Accepted: 05/07/2021] [Indexed: 10/21/2022]
Abstract
The pancreas development depends on complex regulation of several signaling pathways, including the Hedgehog (Hh) signaling via a receptor complex component, Smoothened, which deficiency blocks the Hh signaling. Such a defect in birds and mammals results in an annular pancreas. We showed that in developing zebrafish, the mutation of Smoothened or inhibition of Hh signaling by its antagonist cyclopamine caused developmental defects of internal organs, liver, pancreas, and gut. In particular, the pancreatic primordium was duplicated. The two exocrine pancreatic primordia surround the gut. This phenomenon correlates with a significant reduction of the gut's diameter, causing the annular pancreas phenotype.
Collapse
Affiliation(s)
- Svitlana Korzh
- -Department of Biological Sciences, National University of Singapore, Singapore
| | - Cecilia L Winata
- -International Institute of Molecular and Cell Biology in Warsaw, Poland
| | - Zhiyuan Gong
- -Department of Biological Sciences, National University of Singapore, Singapore.
| | - Vladimir Korzh
- -International Institute of Molecular and Cell Biology in Warsaw, Poland; -Institute of Molecular and Cell Biology, Singapore.
| |
Collapse
|
|
10
|
Yalcinkaya M, Kerksiek A, Gebert K, Annema W, Sibler R, Radosavljevic S, Lütjohann D, Rohrer L, von Eckardstein A. HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic β-cells in vitro by activation of Smoothened. J Lipid Res 2020; 61:492-504. [PMID: 31907205 DOI: 10.1194/jlr.ra119000509] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 12/18/2019] [Indexed: 01/20/2023] Open
Abstract
Loss of pancreatic β-cell mass and function as a result of sustained ER stress is a core step in the pathogenesis of diabetes mellitus type 2. The complex control of β-cells and insulin production involves hedgehog (Hh) signaling pathways as well as cholesterol-mediated effects. In fact, data from studies in humans and animal models suggest that HDL protects against the development of diabetes through inhibition of ER stress and β-cell apoptosis. We investigated the mechanism by which HDL inhibits ER stress and apoptosis induced by thapsigargin, a sarco/ER Ca2+-ATPase inhibitor, in β-cells of a rat insulinoma cell line, INS1e. We further explored effects on the Hh signaling receptor Smoothened (SMO) with pharmacologic agonists and inhibitors. Interference with sterol synthesis or efflux enhanced β-cell apoptosis and abrogated the anti-apoptotic activity of HDL. During ER stress, HDL facilitated the efflux of specific oxysterols, including 24-hydroxycholesterol (OHC). Supplementation of reconstituted HDL with 24-OHC enhanced and, in cells lacking ABCG1 or the 24-OHC synthesizing enzyme CYP46A1, restored the protective activity of HDL. Inhibition of SMO countered the beneficial effects of HDL and also LDL, and SMO agonists decreased β-cell apoptosis in the absence of ABCG1 or CYP46A1. The translocation of the SMO-activated transcription factor glioma-associated oncogene GLI-1 was inhibited by ER stress but restored by both HDL and 24-OHC. In conclusion, the protective effect of HDL to counter ER stress and β-cell death involves the transport, generation, and mobilization of oxysterols for activation of the Hh signaling receptor SMO.
Collapse
Affiliation(s)
- Mustafa Yalcinkaya
- Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland
| | - Anja Kerksiek
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | - Katrin Gebert
- Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland
| | - Wijtske Annema
- Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland
| | - Rahel Sibler
- Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland
| | - Silvija Radosavljevic
- Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland
| | - Dieter Lütjohann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | - Lucia Rohrer
- Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland
| | - Arnold von Eckardstein
- Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland
| |
Collapse
|
|
11
|
Li Y, Yu Q, Li R, Luo J, Yuan D, Song J, Sun Y, Long T, Yang Z. SPOP Regulates The Biological Mechanism Of Ovarian Cancer Cells Through The Hh Signaling Pathway. Onco Targets Ther 2019; 12:9239-9248. [PMID: 31819473 PMCID: PMC6847988 DOI: 10.2147/ott.s215940] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Accepted: 09/24/2019] [Indexed: 12/26/2022] Open
Abstract
Background Ovarian cancer is characterized by high metastatic potential and high mortality. More than 80% of primary ovarian malignancies are epithelial ovarian cancers. There is increasing evidence that Speckle-type POZ protein (SPOP) is highly correlated with the development of various types of cancer. However, the effects of SPOP on epithelial ovarian cancer and the associated molecular mechanisms remain unclear. Materials and methods We compared SPOP expression between epithelial ovarian cancer tissues and normal ovarian tissues by using immunohistochemical staining. To determine the role of SPOP in epithelial ovarian cancer cells, we overexpressed or knocked down SPOP in the epithelial ovarian cancer cell line OVCAR-3 using lentiviral vectors. Results Our results from the present study indicated that SPOP expression was significantly downregulated in human epithelial ovarian cancer and was associated with the FIGO stage and the histopathologic grading of the tumor. The overexpression and knockdown experiments revealed that SPOP inhibited proliferation while promoting apoptosis in ovarian cancer cells. Inhibition of SPOP mis-activated the Hedgehog (Hh) signaling pathway, thereby inhibiting apoptosis in ovarian cancer cells. Conclusion SPOP suppresses proliferation and promotes apoptosis in human ovarian cancer cells by inhibiting the Hh signaling pathway, offering the possibility of new approaches for the treatment of ovarian cancer.
Collapse
Affiliation(s)
- Yanxi Li
- Department of Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Qiubo Yu
- Molecular Medical Testing Center, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Ruohan Li
- Department of Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Jing Luo
- Department of Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Dong Yuan
- Department of Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Jiao Song
- Department of Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Yixuan Sun
- Department of Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Tengfei Long
- Department of Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Zhu Yang
- Department of Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| |
Collapse
|
|
12
|
PDS5B regulates cell proliferation and motility via upregulation of Ptch2 in pancreatic cancer cells. Cancer Lett 2019; 460:65-74. [PMID: 31233836 DOI: 10.1016/j.canlet.2019.06.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 06/18/2019] [Accepted: 06/19/2019] [Indexed: 12/19/2022]
Abstract
Pds5b (precocious dissociation of sisters 5B) is involved in both tumorigenesis and cancer progression; however, the functions and molecular mechanisms of Pds5b in pancreatic cancer (PC) are unknown. Several approaches were conducted to investigate the molecular basis of Pds5b-related PC progression, including transfection, MTT, FACS, western blotting, wound healing assay, transwell chamber invasion assay, and immunohistochemical methods. Pds5b overexpression inhibited cell growth and induced apoptosis, whereas the inhibition of Pds5b promoted growth of PC cells. Moreover, Pds5b overexpression inhibited cell migration and invasion, while the downregulation of Pds5b enhanced cell motility. Furthermore, reduced Pds5b expression was associated with survival in PC patients. Mechanistically, Pds5b positively regulated the expression of Ptch2 to influence the Sonic hedgehog signaling pathway. Consistently, Ptch2 downregulation enhanced cell growth, migration, and invasion, while inhibiting cell apoptosis. Notably, the downregulation of Ptch2 abolished Pds5b-mediated anti-tumor activity in PC cells. Strikingly, Pds5b expression was positively associated with levels of Ptch2 in PC patient samples, suggesting that the Pds5b/Ptch2 axis regulates cell proliferation and invasion in PC cells. Our findings indicate that targeting Pds5b and Ptch2 may represent a novel therapeutic approach for PC.
Collapse
|
|
13
|
Teves ME, Strauss JF, Sapao P, Shi B, Varga J. The Primary Cilium: Emerging Role as a Key Player in Fibrosis. Curr Rheumatol Rep 2019; 21:29. [PMID: 31115730 DOI: 10.1007/s11926-019-0822-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW The myofibroblast is the culprit in the pathogenesis of fibrosis in systemic sclerosis (SSc). Activation of morphogen signaling pathways has been shown to be critically involved in organ fibrosis. Remarkably, the cellular receptors and key molecules from these signaling pathways are localized in the primary cilium. The primary cilium is a unique cellular organelle present in virtually all cells. This article summarizes recent studies evaluating the association between primary cilia and morphogen signaling driving myofibroblast transition and subsequent fibrosis. RECENT FINDINGS Emerging observations implicate dysfunctional primary cilia in fibrosis in many different tissues and organs. Primary cilia seem to be necessary for the initiation of the transition and sustained activation of myofibroblasts. We summarize recent progress in this field and propose the primary cilium as a potential mediator of fibrosis pathogenesis in SSc. Understanding the contributions of primary cilia in fibrosis may ultimately inform the development of entirely new approaches for fibrosis prevention and treatment.
Collapse
Affiliation(s)
- Maria E Teves
- Department of Obstetrics and Gynecology, School of Medicine, Virginia Commonwealth University, 1101 E Marshall Street, Richmond, VA, 23298, USA.
| | - Jerome F Strauss
- Department of Obstetrics and Gynecology, School of Medicine, Virginia Commonwealth University, 1101 E Marshall Street, Richmond, VA, 23298, USA
| | - Paulene Sapao
- Department of Obstetrics and Gynecology, School of Medicine, Virginia Commonwealth University, 1101 E Marshall Street, Richmond, VA, 23298, USA.,Department of Chemistry, Virginia Commonwealth University, Richmond, VA, USA
| | - Bo Shi
- Scleroderma Program, Division of Rheumatology, Northwestern University, 240 East Huron St., Chicago, IL, 60611, USA
| | - John Varga
- Scleroderma Program, Division of Rheumatology, Northwestern University, 240 East Huron St., Chicago, IL, 60611, USA.
| |
Collapse
|
|
14
|
Saini F, Argent RH, Grabowska AM. Sonic Hedgehog Ligand: A Role in Formation of a Mesenchymal Niche in Human Pancreatic Ductal Adenocarcinoma. Cells 2019; 8:E424. [PMID: 31072042 PMCID: PMC6563044 DOI: 10.3390/cells8050424] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 05/05/2019] [Accepted: 05/07/2019] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterised by desmoplasia, thought to support progression and chemotherapeutic resistance. The Hedgehog pathway is known to play an important role in this cancer. While the upregulation of Sonic hedgehog (Shh) in the epithelium of PDAC is known, we investigated its expression in the tumour microenvironment in order to find new targets for new chemotherapeutical approaches. Immunohistochemistry was used for the investigation of Shh and Vimentin in primary human pancreatic tissues. Gene (qRT-PCR) and protein (immunofluorescence) expression of Shh, αSMA (a marker of the mesenchymal phenotype) and periostin (a marker of mesenchymal cells within a mixed population) were investigated in in vitro cell models. Shh expression was significantly upregulated in the stromal and epithelial compartments of poorly-differentiated PDAC samples, with a strong correlation with the amount of stroma present. Characterisation of stromal cells showed that there was expression of Shh ligand in a mixed population comprising αSMA+ myofibroblasts and αSMA- mesenchymal stem cells. Moreover, we demonstrated the interaction between these cell lines by showing a higher rate of mesenchymal cell proliferation and the upregulation of periostin. Therefore, targeting stromal Shh could affect the equilibrium of the tumour microenvironment and its contribution to tumour growth.
Collapse
Affiliation(s)
- Francesca Saini
- Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK.
| | - Richard H Argent
- Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK.
| | - Anna M Grabowska
- Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK.
| |
Collapse
|
|
15
|
Liu Y, Gao S, Zhu J, Zheng Y, Zhang H, Sun H. Dihydroartemisinin induces apoptosis and inhibits proliferation, migration, and invasion in epithelial ovarian cancer via inhibition of the hedgehog signaling pathway. Cancer Med 2018; 7:5704-5715. [PMID: 30338663 PMCID: PMC6247066 DOI: 10.1002/cam4.1827] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 09/04/2018] [Accepted: 09/19/2018] [Indexed: 01/28/2023] Open
Abstract
Dihydroartemisinin (DHA), the primary of artemisinin extracted from the traditional Chinese medicine Artemisia annua, has been used in malaria treatment for a long time. Recently, many studies have indicated that, in addition to antimalarial effects, DHA also exhibits anticancer activity in certain types of neoplasms, including ovarian cancer. However, the precise anti‐ovarian cancer mechanism of DHA is still unclear. Abnormal activation of the hedgehog (Hh) pathway is closely related to tumorigenesis and progression of ovarian cancer. We performed this study to elucidate the effects of DHA on the biological behavior of ovarian cancer cells and to determine its effects on the Hh signaling pathway. CCK8 assays and flow cytometry were used to evaluate the effects of DHA on cell viability and apoptosis in both ovarian cancer cells and HOSEPICs (human ovarian surface epithelial cells) in response to DHA treatment. Transwell membrane chambers were used to analyze the effects of DHA on the migration and invasion of epithelial ovarian cancer cells following treatment with DHA. The impact of DHA on Hh signaling was analyzed by RT‐qPCR and Western blot. DHA significantly inhibited proliferation, migration, and invasion of ovarian cancer cells, and induced apoptosis in vitro. In contrast, DHA had few effects on cell proliferation and apoptosis in HOSEPICs. DHA inhibited the hedgehog signaling pathway. Furthermore, DHA inhibited purmorphamine (Hh signaling pathway agonist)‐induced cell proliferation, cell migration, and cell invasion and the inhibition of apoptosis. Importantly, DHA enhanced GANT61 (hedgehog signaling pathway inhibitor)‐induced apoptosis and the inhibition of cell viability, migratory capacity, and invasive ability. This study demonstrates that DHA inhibits cell viability, migration, and invasion, as well as induces apoptosis in epithelial ovarian cancer through suppression of the Hh signaling pathway.
Collapse
Affiliation(s)
- Yanmei Liu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Shujun Gao
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.,The Diagnosis and Treatment Center of Cervical Disease, Obstetrics and Gynecology, Hospital of Fudan University, Shanghai, China
| | - Jie Zhu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Ya Zheng
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Haiyan Zhang
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Hong Sun
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| |
Collapse
|
|
16
|
Abstract
Stellate cells are resident lipid-storing cells of the pancreas and liver that transdifferentiate to a myofibroblastic state in the context of tissue injury. Beyond having roles in tissue homeostasis, stellate cells are increasingly implicated in pathological fibrogenic and inflammatory programs that contribute to tissue fibrosis and that constitute a growth-permissive tumor microenvironment. Although the capacity of stellate cells for extracellular matrix production and remodeling has long been appreciated, recent research efforts have demonstrated diverse roles for stellate cells in regulation of epithelial cell fate, immune modulation, and tissue health. Our present understanding of stellate cell biology in health and disease is discussed here, as are emerging means to target these multifaceted cells for therapeutic benefit.
Collapse
Affiliation(s)
- Mara H Sherman
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon 97201, USA;
| |
Collapse
|
|
17
|
Wang Z, Teng D, Li Y, Hu Z, Liu L, Zheng H. A six-gene-based prognostic signature for hepatocellular carcinoma overall survival prediction. Life Sci 2018; 203:83-91. [PMID: 29678742 DOI: 10.1016/j.lfs.2018.04.025] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 03/16/2018] [Accepted: 04/16/2018] [Indexed: 01/09/2023]
Abstract
AIMS The purpose of this study was to propose a pipeline to identify prognostic signature for HCC overall survival (OS) prediction based on HCC gene expression datasets from The Cancer Genome Atlas (TCGA). RESULTS Differential expression analysis identified 3573 genes aberrantly expressed (DEGs) in HCC samples. Univariate cox regression analysis obtained 1605 and 1067 HCC OS and relapse free survival (RFS) related genes, which are abbreviated as OS-Gene and RFS-Gene respectively. Besides, there are 55 overlaps among DEGs, OS-Genes and RFS-Genes. Further prioritization of the 55 overlapping genes through Sure Independence Screening (SIS) resulted in 6 genes, including SRL, TTC26, CPSF2, TAF3, C16orf46 and CSN1S1, and the prognostic signature is the weighted combination of their expression values. Kaplan-Meier analysis based on the prognostic score (PS) of every sample indicates higher PS is associated with better HCC OS. Robustness of the prognostic signature was evaluated through another HCC gene expression datasets from the Gene Expression Omnibus (GEO). What's more, univariate and multivariate cox regression analysis indicate significant associations between stage/PS and HCC OS. CONCLUSIONS Our study provides a pipeline for the identification of prognostic signature for HCC OS prediction, which should also be suit for other types of cancers.
Collapse
Affiliation(s)
- Zhenglu Wang
- Pathology Department, Tianjin First Center Hospital, Tianjin, PR China; Biobank, Tianjin First Center Hospital, Tianjin, PR China
| | - Dahong Teng
- Transplantation Department, Tianjin First Center Hospital, PR China
| | - Yan Li
- Biobank, Tianjin First Center Hospital, Tianjin, PR China
| | - Zhandong Hu
- Pathology Department, Tianjin First Center Hospital, Tianjin, PR China
| | - Lei Liu
- Key Lab for Critical Care Medicine of the Ministry of Health, Tianjin First Center Hospital, Tianjin, PR China; Tianjin Key Laboratory of Organ Transplantation, Tianjin, PR China
| | - Hong Zheng
- Transplantation Department, Tianjin First Center Hospital, PR China; Tianjin Key Laboratory of Organ Transplantation, Tianjin, PR China.
| |
Collapse
|
|
18
|
Della Corte CM, Viscardi G, Papaccio F, Esposito G, Martini G, Ciardiello D, Martinelli E, Ciardiello F, Morgillo F. Implication of the Hedgehog pathway in hepatocellular carcinoma. World J Gastroenterol 2017; 23:4330-4340. [PMID: 28706416 PMCID: PMC5487497 DOI: 10.3748/wjg.v23.i24.4330] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 04/13/2017] [Accepted: 05/19/2017] [Indexed: 02/06/2023] Open
Abstract
The prognosis for patients who are diagnosed with advanced stage hepatocellular carcinoma (HCC) is poor because there are few treatment options. Recent research has focused on the identification of novel molecular entities that can be targeted to inhibit oncogenic signals that are involved in the carcinogenesis, proliferation and progression of HCC. Among all of the pathways that are involved in the development of HCC, Hedgehog (HH) signalling has demonstrated a substantial role in hepatocarcinogenesis and HCC progression. HH plays a physiological role in embryogenesis, through the induction of the differentiation of hepatocytes from endodermal progenitors. The re-activation of the HH pathway in chronic damaged liver is a mechanism of fibrotic degeneration and is implicated in various stages of HCC development. HH activation sustains the sub-population of immature liver epithelial cells that are involved in the pathogenesis of cirrhosis and HCC, and HH itself is a mediator of the alcohol-derived malignant transformation of liver cells. High levels of expression of HH protein markers in liver tumour tissues are correlated with aggressive histological and biological features and a poor clinical outcome. In vitro and in vivo inhibition models of the HH pathway confirm that HH is essential in maintaining tumour growth, metastasis and a mesenchymal phenotype.
Collapse
|
|
19
|
Lim J, Porter J, Varia H, Pettit S. Annular pancreas causing duodenal obstruction in an adult. BMJ Case Rep 2017; 2017:bcr-2017-219839. [PMID: 28500113 DOI: 10.1136/bcr-2017-219839] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Affiliation(s)
- Jie Lim
- General Surgery, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UK
| | - Johnathan Porter
- General Surgery, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UK
| | - Haren Varia
- Radiology, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UK
| | - Stephen Pettit
- General Surgery, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UK
| |
Collapse
|