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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Montagner A, Arleo A, Suzzi F, D’Assoro AB, Piscaglia F, Gramantieri L, Giovannini C. Notch Signaling and PD-1/PD-L1 Interaction in Hepatocellular Carcinoma: Potentialities of Combined Therapies. Biomolecules 2024; 14:1581. [PMID: 39766289 PMCID: PMC11674819 DOI: 10.3390/biom14121581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 12/03/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
Immunotherapy has shown significant improvement in the survival of patients with hepatocellular carcinoma (HCC) compared to TKIs as first-line treatment. Unfortunately, approximately 30% of HCC exhibits intrinsic resistance to ICIs, making new therapeutic combinations urgently needed. The dysregulation of the Notch signaling pathway observed in HCC can affect immune cell response, reducing the efficacy of cancer immunotherapy. Here, we provide an overview of how Notch signaling regulates immune responses and present the therapeutic rationale for combining Notch signaling inhibition with ICIs to improve HCC treatment. Moreover, we propose using exosomes as non-invasive tools to assess Notch signaling activation in hepatic cancer cells, enabling accurate stratification of patients who can benefit from combined strategies.
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Affiliation(s)
- Annapaola Montagner
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.A.); (F.S.); (F.P.); (C.G.)
- Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55902, USA;
| | - Andrea Arleo
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.A.); (F.S.); (F.P.); (C.G.)
| | - Fabrizia Suzzi
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.A.); (F.S.); (F.P.); (C.G.)
| | - Antonino B. D’Assoro
- Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55902, USA;
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.A.); (F.S.); (F.P.); (C.G.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Laura Gramantieri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Catia Giovannini
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.A.); (F.S.); (F.P.); (C.G.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
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Hefnawy A, Abdelhamid AS, Abdelaziz MM, Elzoghby AO, Khalil IA. Recent advances in nano-based drug delivery systems for treatment of liver cancer. J Pharm Sci 2024; 113:3145-3172. [PMID: 39151795 DOI: 10.1016/j.xphs.2024.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 08/13/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
Liver cancer is one of the aggressive primary tumors as evident by high rate of incidence and mortality. Conventional treatments (e.g. chemotherapy) suffer from various drawbacks including wide drug distribution, low localized drug concentration, and severe off-site toxicity. Therefore, they cannot satisfy the mounting need for safe and efficient cancer therapeutics, and alternative novel strategies are needed. Nano-based drug delivery systems (NDDSs) are among these novel approaches that can improve the overall therapeutic outcomes. NDDSs are designed to encapsulate drug molecules and target them specifically to liver cancer. Thus, NDDSs can selectively deliver therapeutic agents to the tumor cells and avoid distribution to off-target sites which should improve the safety profile of the active agents. Nonetheless, NDDSs should be well designed, in terms of the preparing materials, nanocarriers structure, and the targeting strategy, in order to accomplish these objectives. This review discusses the latest advances of NDDSs for cancer therapy with emphasis on the aforementioned essential design components. The review also entails the challenges associated with the clinical translation of NDDSs, and the future perspectives towards next-generation NDDSs.
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Affiliation(s)
- Amr Hefnawy
- Smyth Lab, College of Pharmacy, University of Texas at Austin, TX 78712, USA.
| | - Ahmed S Abdelhamid
- Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
| | - Moustafa M Abdelaziz
- Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA.
| | - Ahmed O Elzoghby
- Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Islam A Khalil
- Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City 12582, Giza, Egypt.
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Li X, Li Y, Zhang W, Jiang F, Lin L, Wang Y, Wu L, Zeng H, Zheng J. The IGF2BP3/Notch/Jag1 pathway: A key regulator of hepatic stellate cell ferroptosis in liver fibrosis. Clin Transl Med 2024; 14:e1793. [PMID: 39113232 PMCID: PMC11306284 DOI: 10.1002/ctm2.1793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/21/2024] [Accepted: 07/23/2024] [Indexed: 08/11/2024] Open
Abstract
INTRODUCTION Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), which involves various epigenetic modifications. OBJECTIVES N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotic cells, influences numerous physiological and pathological processes. Nevertheless, the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader gene mediating m6A modifications, in liver fibrosis remains unclear. METHODS AND RESULTS This study demonstrated that IGF2BP3 knockout reduces liver fibrosis by promoting HSC ferroptosis (FPT) and inactivating HSCs. Multi-omics analysis revealed that HSC-specific IGF2BP3 knockout decreased m6A content in Jagged1 (Jag1), a key component of the Notch signalling pathway. Furthermore, IGF2BP3 deficiency significantly reduced the expression of hairy and enhancer of split-1 (Hes1), a transcription factor in the Notch/Jag1 signalling pathway, with mRNA levels declining to 35%-62% and protein levels to 28%-35%. Additionally, it suppressed glutathione peroxidase 4 (GPX4) (decreased to approximately 31%-38%), a negative regulator of FPT, thereby facilitating HSC FPT progression and reducing profibrotic gene expression. CONCLUSION These findings uncover a novel IGF2BP3/Notch/Jag1 signalling pathway involving HSC FPT, suggesting promising targets for ameliorating liver fibrosis. KEY POINTS/HIGHLIGHTS IGF2BP3 deficiency inactivates Jag1 signalling. IGF2BP3 deficiency-mediated m6A modifications promote HSC ferroptosis. IGF2BP3 inhibition facilitates ferroptosis in HSCs via the Hes1/GPX4 axis. IGF2BP3 deficiency inactivates Jag1/Notch1/3/Hes1 signalling pathway inactivation, leading to the decrease in GPX4, which contributes to HSC ferroptosis.
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Affiliation(s)
- Xinmiao Li
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Yifei Li
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Weizhi Zhang
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Feng Jiang
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Lifan Lin
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Yining Wang
- School of Mental HealthWenzhou Medical UniversityWenzhouChina
| | - Lingling Wu
- Renji CollegeWenzhou Medical UniversityWenzhouChina
| | - Han Zeng
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Jianjian Zheng
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
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Chen J, Zhang S. The Role of Inflammation in Cholestatic Liver Injury. J Inflamm Res 2023; 16:4527-4540. [PMID: 37854312 PMCID: PMC10581020 DOI: 10.2147/jir.s430730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 10/06/2023] [Indexed: 10/20/2023] Open
Abstract
Cholestasis is a common clinical event in which bile formation and excretion are blocked, leading to retention of bile acids or bile salts; whether it occurs intra- or extrahepatically, primary or secondary, its pathogenesis is still unclear and is influenced by a combination of factors. In a variety of inflammatory and immune cells such as neutrophils, macrophages (intrahepatic macrophages are also known as Kupffer cells), mast cells, NK cells, and even T cells in humoral immunity and B cells in cellular immunity, inflammation can be a "second strike" against cholestatic liver injury. These cells, stimulated by a variety of factors such as bile acids, inflammatory chemokines, and complement, can be activated and accumulate in the cholestatic liver, and with the involvement of inflammatory mediators and modulation by cytokines, can lead to destruction of hepatocytes and bile duct epithelial cells and exacerbate (and occasionally retard) the progression of cholestatic liver disease. In this paper, we summarized the new research advances proposed so far regarding the relationship between inflammation and cholestasis, aiming to provide reference for researchers and clinicians in the field of cholestatic liver injury research.
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Affiliation(s)
- Jie Chen
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Shujun Zhang
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
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Wang Y, Deng B. Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers. Cancer Metastasis Rev 2023; 42:629-652. [PMID: 36729264 DOI: 10.1007/s10555-023-10084-4] [Citation(s) in RCA: 148] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 01/16/2023] [Indexed: 02/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy and one of the leading causes of cancer-related death. The biological process of HCC is complex, with multiple factors leading to the broken of the balance of inactivation and activation of tumor suppressor genes and oncogenes, the abnormal activation of molecular signaling pathways, the differentiation of HCC cells, and the regulation of angiogenesis. Due to the insidious onset of HCC, at the time of first diagnosis, less than 30% of HCC patients are candidates for radical treatment. Systematic antitumor therapy is the hope for the treatment of patients with middle-advanced HCC. Despite the emergence of new systemic therapies, survival rates for advanced HCC patients remain low. The complex pathogenesis of HCC has inspired researchers to explore a variety of biomolecular targeted therapeutics targeting specific targets. Correct understanding of the molecular mechanism of HCC occurrence is key to seeking effective targeted therapy. Research on biomarkers for HCC treatment is also advancing. Here, we explore the molecular mechanism that are associated with HCC development, summarize targeted therapies for HCC, and discuss potential biomarkers that may drive therapies.
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Affiliation(s)
- Yu Wang
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China
| | - Baocheng Deng
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China.
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Martinez Lyons A, Boulter L. NOTCH signalling - a core regulator of bile duct disease? Dis Model Mech 2023; 16:dmm050231. [PMID: 37605966 PMCID: PMC10461466 DOI: 10.1242/dmm.050231] [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] [Indexed: 08/23/2023] Open
Abstract
The Notch signalling pathway is an evolutionarily conserved mechanism of cell-cell communication that mediates cellular proliferation, fate determination and maintenance of stem/progenitor cell populations across tissues. Although it was originally identified as a critical regulator of embryonic liver development, NOTCH signalling activation has been associated with the pathogenesis of a number of paediatric and adult liver diseases. It remains unclear, however, what role NOTCH actually plays in these pathophysiological processes and whether NOTCH activity represents the reactivation of a conserved developmental programme that is essential for adult tissue repair. In this Review, we explore the concepts that NOTCH signalling reactivation in the biliary epithelium is a reiterative and essential response to bile duct damage and that, in disease contexts in which biliary epithelial cells need to be regenerated, NOTCH signalling supports ductular regrowth. Furthermore, we evaluate the recent literature on NOTCH signalling as a critical factor in progenitor-mediated hepatocyte regeneration, which indicates that the mitogenic role for NOTCH signalling in biliary epithelial cell proliferation has also been co-opted to support other forms of epithelial regeneration in the adult liver.
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Affiliation(s)
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
- CRUK Scottish Centre, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
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Kong M, Dong W, Kang A, Kuai Y, Xu T, Fan Z, Shi L, Sun D, Lu Y, Li Z, Xu Y. Regulatory role and translational potential of CCL11 in liver fibrosis. Hepatology 2023; 78:120-135. [PMID: 36651177 DOI: 10.1097/hep.0000000000000287] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 12/15/2022] [Indexed: 01/19/2023]
Abstract
BACKGROUND AND AIMS Myofibroblasts are considered the major effector cell type of liver fibrosis and primarily derived from hepatic stellate cells (HSCs). In the present study, we investigated the contribution of C-C motif chemokine (CCL11) to HSC-myofibroblast trans -differentiation and its implication in liver fibrosis. APPROACH AND RESULTS We report that CCL11 levels were elevated in HSCs, but not in hepatocytes or Kupffer cells, isolated from mice with liver fibrosis compared with the control mice. CCL11 levels were also up-regulated by 2 pro-fibrogenic growth factors TGF-β and platelet derived growth factor in cultured HSCs. Mechanistically, zinc finger factor 281 bound to the CCL11 promoter and mediated CCL11 trans -activation in HSCs. Depletion of CCL11 attenuated whereas treatment with recombinant CCL11 promoted HSC activation. Further, global CCL11 deletion ( CCL11-/- ) or HSC/myofibroblast-specific CCL11 knockdown mitigated fibrogenesis in mice. RNA-sequencing revealed that CCL11 might regulate HSC activation by stimulating the transcription of Jagged 1. Reconstitution of Jagged 1 restored the fibrogenic response in CCL11-/- mice. Finally, several targeting strategies that aimed at blockading CCL11 signaling, either by administration of an antagonist to its receptor C-C motif chemokine receptor 3 or neutralizing antibodies against CCL11/C-C motif chemokine receptor 3, ameliorated liver fibrosis in mice. CONCLUSIONS Our data unveil a previously unrecognized role for CCL11 in liver fibrosis and provide proof-of-concept evidence that targeting CCL11 can be considered as an effective therapeutic approach.
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Affiliation(s)
- Ming Kong
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, and Center for Experimental Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Wenhui Dong
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, and Center for Experimental Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Aoqi Kang
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, and Center for Experimental Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Yameng Kuai
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, and Center for Experimental Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Tongchang Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, and Center for Experimental Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Zhiwen Fan
- Department of Pathology, Nanjing Drum Tower Hospital Affiliated With Nanjing University, Nanjing, China
| | - Longqing Shi
- Department of Hepatobiliary Surgery, the First People's Hospital of Changzhou, The Third Hospital Affiliated With Soochow University, Changzhou, China
| | - Donglin Sun
- Department of Hepatobiliary Surgery, the First People's Hospital of Changzhou, The Third Hospital Affiliated With Soochow University, Changzhou, China
| | - Yunjie Lu
- Department of Hepatobiliary Surgery, the First People's Hospital of Changzhou, The Third Hospital Affiliated With Soochow University, Changzhou, China
| | - Zilong Li
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Yong Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, and Center for Experimental Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China
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Wang J, Liu H, Zhu L, Wang J, Luo X, Liu W, Ma Y. Prodigiosin from Serratia Marcescens in Cockroach Inhibits the Proliferation of Hepatocellular Carcinoma Cells through Endoplasmic Reticulum Stress-Induced Apoptosis. Molecules 2022; 27:7281. [PMID: 36364107 PMCID: PMC9653855 DOI: 10.3390/molecules27217281] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 08/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignant tumor, and the targeted therapy for HCC is very limited. Our previous study demonstrated that prodigiosin(PG), a secondary metabolite from Serratia marcescens found in the intestinal flora of cockroaches, inhibits the proliferation of HCC and increases the expression of CHOP, a marker protein for endoplasmic reticulum stress (ERS)-mediated apoptosis, in a dose-dependent manner. However, the mechanisms underlying the activity of PG in vivo and in vitro are unclear. This study explored the molecular mechanisms of PG-induced ERS against liver cancer in vitro and in vivo. The apoptosis of hepatocellular carcinoma cells induced by PG through endoplasmic reticulum stress was observed by flow cytometry, colony formation assay, cell viability assay, immunoblot analysis, and TUNEL assay. The localization of PG in cells was observed using laser confocal fluorescence microscopy. Flow cytometry was used to detect the intracellular Ca2+ concentration after PG treatment. We found that PG could promote apoptosis and inhibit the proliferation of HCC. It was localized in the endoplasmic reticulum of HepG2 cells, where it induces the release of Ca2+. PG also upregulated the expression of key unfolded response proteins, including PERK, IRE1α, Bip, and CHOP, and related apoptotic proteins, including caspase3, caspase9, and Bax, but down-regulated the expression of anti-apoptotic protein Bcl-2 in liver cancer. Alleviating ERS reversed the above phenomenon. PG had no obvious negative effects on the functioning of the liver, kidney, and other main organs in nude mice, but the growth of liver cancer cells was inhibited by inducing ERS in vivo. The findings of this study showed that PG promotes apoptosis of HCC by inducing ERS.
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Affiliation(s)
- Jie Wang
- School of Biosciences & Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510000, China
- Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, 280 Wai Huan Dong Road, Guangzhou Higher Education Mega Center, Guangzhou 510000, China
| | - Hancong Liu
- School of Biosciences & Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510000, China
- Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, 280 Wai Huan Dong Road, Guangzhou Higher Education Mega Center, Guangzhou 510000, China
| | - Liuchong Zhu
- School of Biosciences & Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510000, China
- Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, 280 Wai Huan Dong Road, Guangzhou Higher Education Mega Center, Guangzhou 510000, China
| | - Jingyi Wang
- School of Biosciences & Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510000, China
| | - Xiongming Luo
- School of Biosciences & Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510000, China
- Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, 280 Wai Huan Dong Road, Guangzhou Higher Education Mega Center, Guangzhou 510000, China
| | - Wenbin Liu
- School of Biosciences & Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510000, China
- Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, 280 Wai Huan Dong Road, Guangzhou Higher Education Mega Center, Guangzhou 510000, China
| | - Yan Ma
- School of Biosciences & Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510000, China
- Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, 280 Wai Huan Dong Road, Guangzhou Higher Education Mega Center, Guangzhou 510000, China
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He S, Qiao J, Wang L, Yu L. A novel immune-related gene signature predicts the prognosis of hepatocellular carcinoma. Front Oncol 2022; 12:955192. [PMID: 36185203 PMCID: PMC9520462 DOI: 10.3389/fonc.2022.955192] [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: 07/01/2022] [Accepted: 08/24/2022] [Indexed: 11/21/2022] Open
Abstract
Immune-related genes play a key role in regulating the cancer immune microenvironment, influencing the overall survival of patients with hepatocellular carcinoma (HCC). Along with the rapid development of immunotherapy, identifying immune-related genes with prognostic value in HCC has attracted increasing attention. Here, we aimed to develop a prognostic signature based on immune-related genes. By investigating the transcriptome landscape of 374 HCC and 160 non-HCC samples in silico, a total of 2251 differentially expressed genes were identified. Among which, 183 differentially expressed immune-related genes were subjected to a univariate Cox proportional hazard model to screen for genes with possible prognostic significance. A 10-gene prognostic signature, including HLA-G, S100A9, S100A10, DCK, CCL14, NRAS, EPO, IL1RN, GHR and RHOA, was generated employing a multivariate Cox proportional hazard model. Kaplan–Meier and Receiver Operator Characteristic (ROC) curves were used to evaluate the prognostic utility of the 10-gene signature. Moreover, the underlying mechanisms of these genes were analyzed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. According to the Tumor Immune Estimation Resource (TIMER) database, our prognostic signature was significantly associated with tumor-infiltrating B cells, CD4 T cells, dendritic cells, macrophages and neutrophils. Our study provides a novel prognostic signature based on immune-related genes associated with clinical outco mes of HCC.
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Vanaroj P, Chaijaroenkul W, Na-Bangchang K. Notch signaling in the pathogenesis, progression and identification of potential targets for cholangiocarcinoma (Review). Mol Clin Oncol 2022; 16:66. [PMID: 35154706 PMCID: PMC8825743 DOI: 10.3892/mco.2022.2499] [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: 09/03/2021] [Accepted: 01/03/2022] [Indexed: 11/05/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive type of bile duct cancer that is characterized by a high mortality rate due to its late diagnosis and ineffective treatment. The aim of the present systematic review was to analyze the association between Notch signaling and CCA in terms of its pathogenesis, progression and potential treatment targets. Relevant information was gathered from the PubMed, ScienceDirect and Scopus databases using the search terms 'cholangiocarcinoma' AND 'Notch signaling'. Of the 90 articles identified, 28 fulfilled the eligibility criteria and were included in the analysis. It was concluded that overexpression/upregulation of Notch ligands, such as Jagged1 and Notch receptors (Notch1, Notch2 and Notch3), as well as upregulation of the upstream Notch signaling pathway, promoted CCA development and progression. In addition, downregulation of Notch1 signaling through several possible interventions appears to be a promising strategy for inhibition of CCA development and progression. Therefore, the Notch signaling pathway may be considered as a potential target for CCA control.
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Affiliation(s)
- Peeranate Vanaroj
- Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, 12120 Thailand
| | - Wanna Chaijaroenkul
- Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, 12120 Thailand
| | - Kesara Na-Bangchang
- Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, 12120 Thailand.,Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University, Pathumthani, 12120 Thailand
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12
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Two distinct Notch signals, Delta-like 4/Notch1 and Jagged-1/Notch2, antagonistically regulate chemical hepatocarcinogenesis in mice. Commun Biol 2022; 5:85. [PMID: 35064244 PMCID: PMC8782997 DOI: 10.1038/s42003-022-03013-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 12/27/2021] [Indexed: 12/23/2022] Open
Abstract
Notch signaling is one of the most common drivers of carcinogenesis in many types of cancers, including hepatocellular carcinoma (HCC); however, it occasionally suppresses tumor progression. Moreover, it is virtually unknown how different sets of Notch ligands and receptors regulate the HCC development. In this study, we demonstrate that the expression of the Notch ligands, Delta-like 4 (Dll4) and Jagged-1 (Jag1), is upregulated during diethylnitrosamine-induced hepatocarcinogenesis. Dll4 is detected in the preneoplastic hepatocytes and HCC cells, but not in the normal hepatocytes, while Jag1 is expressed in the desmin-positive mesenchymal cells. Hepatocyte-specific Dll4 knockout abolishes the Notch1 signaling and suppresses the tumor progression. In contrast, Jag1 deletion induces the ectopic expression of Dll4 in hepatocytes along with the loss of Notch2 signaling, leading to the tumor progression. These results indicate that the two distinct Notch signals, Dll4/Notch1 and Jag1/Notch2, are antagonistic to each other, exerting opposite effects on HCC progression. Dll4/Notch1 signal promotes the progression of HCC, while Jag1/Notch2 signal antagonistically suppresses it in murine chemical hepatocarcinogenesis. Nakano et al. report that two distinct Notch signals regulate the progression of hepatocellular carcinoma (HCC) using tissue specific loss of function mouse mutants. They find Dll4/Notch1 signal promotes HCC progression, while the Jag1/Notch2 signal antagonistically suppresses it.
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13
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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: 20] [Impact Index Per Article: 5.0] [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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14
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Damrauer JS, Smith MA, Walter V, Thennavan A, Mose LE, Selitsky SR, Hoadley KA. Genomic characterization of rare molecular subclasses of hepatocellular carcinoma. Commun Biol 2021; 4:1150. [PMID: 34608257 PMCID: PMC8490450 DOI: 10.1038/s42003-021-02674-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 09/15/2021] [Indexed: 12/24/2022] Open
Abstract
Primary liver cancer, consisting of both cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC), is the second leading cause of cancer deaths worldwide. Our goal is to genomically characterize rare HCC subclasses to provide insight into disease biology. Leveraging The Cancer Genome Atlas (TCGA) to perform a combined analysis of CCA (n = 36) and HCC (n = 275), we integrated multiple genomic platforms, to assess transcriptional profiles, mutational signatures, and copy number patterns to uncover underlying etiology and linage specific patterns. We identified two molecular classes distinct from prototypical HCC tumors. The first, CCA-Like, although histologically indistinguishable from HCC, had enrichment of CCA mutations (IDH1, BAP1), mutational signatures, and transcriptional patterns (SOX9, KRT19). CCA-Like, however, retained a copy number landscape similar to HCC, suggesting a hepatocellular linage. The second, Blast-Like, is enriched in TP53 mutations, HBV infection, exposure related mutational signatures and transcriptionally similar to hepatoblasts. Although these subclasses are molecularly distinct, they both have a worse progression-free survival compared to classical HCC tumors, yet are clinically treated the same. The identification of and characterization of CCA-Like and Blast-Like subclasses advance our knowledge of HCC as well as represents an urgent need for the identification of class specific biomarkers and targeted therapy.
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Affiliation(s)
- Jeffrey S Damrauer
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Markia A Smith
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Vonn Walter
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - Aatish Thennavan
- Oral and Craniofacial Biomedicine Program, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA
| | - Lisle E Mose
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sara R Selitsky
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
- Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Katherine A Hoadley
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
- Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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15
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Xie Q, Guo H, He P, Deng H, Gao Y, Dong N, Niu W, Liu T, Li M, Wang S, Wu Y, Li J. Tspan5 promotes epithelial-mesenchymal transition and tumour metastasis of hepatocellular carcinoma by activating Notch signalling. Mol Oncol 2021; 15:3184-3202. [PMID: 33955149 PMCID: PMC8564648 DOI: 10.1002/1878-0261.12980] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 01/08/2021] [Accepted: 05/03/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to a high rate of tumour metastasis and disease recurrence. In physiological conditions, tetraspanins interact with specific partner proteins in tetraspanin-enriched microdomains and regulate their subcellular localization and function. However, the function of Tspan5 in pathological processes, particularly in cancer biology and its clinical significance, are still unclear. Here, we describe that a high expression of Tspan5 is significantly associated with some clinicopathological features including invasive length, vascular invasion, clinical stage and poor overall survival of HCC patients. Alterations of Tspan5 expression by lentivirus transductions in HCC cells demonstrated that Tspan5 promotes wound healing and cell migration in vitro and tumour metastasis of HCC cells in vivo. Mechanistic studies revealed that Tspan5 promoted cell migration and tumour metastasis by increasing the enzymatic maturation of ADAM10 and activating Notch signalling via the increase of the cleavage of the Notch1 receptor catalysed by the γ-secretase complex. Activation of Notch signalling by Tspan5 was shown further to enhance the epithelial-mesenchymal transition (EMT) and actin skeleton rearrangement of tumour cells. In clinical HCC samples, Tspan5 expression is strongly correlated with many key molecules acting in Notch signalling and EMT, highlighting the role of Tspan5 in the regulation of Notch signalling, EMT and tumour metastasis of HCC. Our findings provide new insights into the mechanism of tumour metastasis and disease progression of HCC and may facilitate the development of novel clinical intervention strategies against HCC.
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Affiliation(s)
- Qian Xie
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Huiling Guo
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Peirong He
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Huan Deng
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Yanjun Gao
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Ningning Dong
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Wenbo Niu
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Tiancai Liu
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Ming Li
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Suihai Wang
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Yingsong Wu
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
| | - Ji‐Liang Li
- Key Laboratory of Antibody Engineering of Guangdong Higher Education InstitutesSchool of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouChina
- Wenzhou Medical University Eye Hospital and School of Biomedical EngineeringChina
- Cancer Research CentreUniversity of Chinese Academy of Sciences Wenzhou InstituteChina
- Institute of Translational and Stratified MedicineUniversity of Plymouth Faculty of Medicine and DentistryUK
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16
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Song W, Zheng C, Liu M, Xu Y, Qian Y, Zhang Z, Su H, Li X, Wu H, Gong P, Li Y, Fan H. TRERNA1 upregulation mediated by HBx promotes sorafenib resistance and cell proliferation in HCC via targeting NRAS by sponging miR-22-3p. Mol Ther 2021; 29:2601-2616. [PMID: 33839325 DOI: 10.1016/j.ymthe.2021.04.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 01/31/2021] [Accepted: 04/06/2021] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most common malignancies and has an unfavorable prognosis. The hepatitis B virus-encoded X (HBx) protein is closely associated with hepatocarcinogenesis. Sorafenib is a unique targeted oral kinase inhibitor for advanced HCC. Long noncoding RNAs (lncRNAs) mediate HCC progression and therapeutic resistance by acting as competing endogenous RNAs (ceRNAs). However, the ceRNA regulatory mechanisms underlying sorafenib resistance in HBx-associated HCC remain largely unknown. In this study, we found that translation regulatory lncRNA 1 (TRERNA1) upregulation by HBx not only promoted HCC cell proliferation by regulating the cell cycle in vitro and in vivo but also correlated positively with poor prognosis in HCC. Importantly, TRERNA1 enhanced sorafenib resistance in HCC cells. RNA sequencing (RNA-seq) analysis indicated that NRAS proto-oncogene (NRAS) is a potential target of TRERNA1 that mediates aspects of hepatocellular carcinogenesis. TRERNA1 acts as a ceRNA to regulate NRAS expression by sponging microRNA (miR)-22-3p. In summary, we show that increased TRERNA1 expression induced by HBx reduces HCC cell sensitivity to sorafenib by activating the RAS/Raf/MEK/ERK signaling pathway. We reveal a novel regulatory mode by which the TRERNA1/miR-22-3p/NRAS axis mediates HCC progression and indicates that TRERNA1 might constitute a powerful tumor biomarker and therapeutic target in HCC.
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Affiliation(s)
- Wei Song
- Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing 210009, China; School of Life Science, Southeast University, Nanjing 210018, China; Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Chuqian Zheng
- Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing 210009, China
| | - Min Liu
- School of Life Science, Southeast University, Nanjing 210018, China
| | - Ying Xu
- School of Life Science, Southeast University, Nanjing 210018, China
| | - Yanyan Qian
- Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing 210009, China
| | - Zhihong Zhang
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Hongmeng Su
- School of Life Science, Southeast University, Nanjing 210018, China
| | - Xinxiu Li
- Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing 210009, China
| | - Huazhang Wu
- Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing 210009, China
| | - Pihai Gong
- Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing 210009, China
| | - Yiping Li
- Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing 210009, China
| | - Hong Fan
- Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing 210009, China.
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17
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Leone V, Ali A, Weber A, Tschaharganeh DF, Heikenwalder M. Liver Inflammation and Hepatobiliary Cancers. Trends Cancer 2021; 7:606-623. [PMID: 33674229 DOI: 10.1016/j.trecan.2021.01.012] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 12/17/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023]
Abstract
Immune regulation has an important role in cancer development, particularly in organs with continuous exposure to environmental pathogens, such as the liver and gastrointestinal tract. Chronic liver inflammation can lead to the development of hepatobiliary cancers, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or combined HCC (cHCC)-CCA. In this review, we discuss the link between oxidative stress and the hepatic immune compartments, as well as how these factors trigger hepatocyte damage, proliferation, and eventually cancer initiation and its sustainment. We further give an overview of new anticancer therapies based on immunomodulation.
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Affiliation(s)
- Valentina Leone
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Research Unit Radiation Cytogenetics, Helmholtz Zentrum München Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany
| | - Adnan Ali
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Achim Weber
- Department of Pathology and Molecular Pathology, Institute of Molecular Cancer Research (IMCR), University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland
| | - Darjus Felix Tschaharganeh
- Helmholtz-University Group Cell Plasticity and Epigenetic Remodeling, German Cancer Research Center (DKFZ) and Institute of Pathology University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
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18
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Giovannini C, Fornari F, Piscaglia F, Gramantieri L. Notch Signaling Regulation in HCC: From Hepatitis Virus to Non-Coding RNAs. Cells 2021; 10:cells10030521. [PMID: 33804511 PMCID: PMC8000248 DOI: 10.3390/cells10030521] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/23/2021] [Accepted: 02/24/2021] [Indexed: 12/12/2022] Open
Abstract
The Notch family includes evolutionary conserved genes that encode for single-pass transmembrane receptors involved in stem cell maintenance, development and cell fate determination of many cell lineages. Upon activation by different ligands, and depending on the cell type, Notch signaling plays pleomorphic roles in hepatocellular carcinoma (HCC) affecting neoplastic growth, invasion capability and stem like properties. A specific knowledge of the deregulated expression of each Notch receptor and ligand, coupled with resultant phenotypic changes, is still lacking in HCC. Therefore, while interfering with Notch signaling might represent a promising therapeutic approach, the complexity of Notch/ligands interactions and the variable consequences of their modulations raises concerns when performed in undefined molecular background. The gamma-secretase inhibitors (GSIs), representing the most utilized approach for Notch inhibition in clinical trials, are characterized by important adverse effects due to the non-specific nature of GSIs themselves and to the lack of molecular criteria guiding patient selection. In this review, we briefly summarize the mechanisms involved in Notch pathway activation in HCC supporting the development of alternatives to the γ-secretase pan-inhibitor for HCC therapy.
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Affiliation(s)
- Catia Giovannini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
- Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, 40138 Bologna, Italy;
- Correspondence: ; Tel.: +39-051-2144903; Fax: +39-051-2143902
| | - Francesca Fornari
- Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, 40138 Bologna, Italy;
- Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.G.)
- Department of Medical and Surgical Science (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Laura Gramantieri
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.G.)
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19
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Rodrigues PM, Olaizola P, Paiva NA, Olaizola I, Agirre-Lizaso A, Landa A, Bujanda L, Perugorria MJ, Banales JM. Pathogenesis of Cholangiocarcinoma. ANNUAL REVIEW OF PATHOLOGY 2021; 16:433-463. [PMID: 33264573 DOI: 10.1146/annurev-pathol-030220-020455] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.
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Affiliation(s)
- Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Nuno A Paiva
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Alona Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Ana Landa
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
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20
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O'Rourke CJ, Munoz-Garrido P, Andersen JB. Molecular Targets in Cholangiocarcinoma. Hepatology 2021; 73 Suppl 1:62-74. [PMID: 32304327 DOI: 10.1002/hep.31278] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/02/2020] [Accepted: 04/06/2020] [Indexed: 12/18/2022]
Abstract
Cholangiocarcinoma (CCA) encompasses a heterogeneous collection of malignancies for which diagnostic biomarkers are lacking and population screening is infeasible because of its status as a rare disease. Coupled with high postsurgical recurrence rates among the minority of patients diagnosed at resectable stages, systemic clinical management will inevitably be required for the majority of patients with CCA with recurrent and advanced disease. In this review, we discuss the therapeutic potential of different classes of molecular targets at various stages of development in CCA, including those targeted to the tumor epithelia (oncogenic, developmental, metabolic, epigenomic) and tumor microenvironment (angiogenesis, checkpoint regulation). Furthermore, we discuss the successes and failures of CCA-targeted therapies, emphasizing key lessons learned that should pave the way for future molecular target evaluation in this uncommon yet bona fide target-rich disease.
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Affiliation(s)
- Colm J O'Rourke
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Patricia Munoz-Garrido
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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21
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Matsumoto K, Luther KB, Haltiwanger RS. Diseases related to Notch glycosylation. Mol Aspects Med 2020; 79:100938. [PMID: 33341260 DOI: 10.1016/j.mam.2020.100938] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/30/2020] [Accepted: 12/03/2020] [Indexed: 12/15/2022]
Abstract
The Notch receptors are a family of transmembrane proteins that mediate direct cell-cell interactions and control numerous cell-fate specifications in humans. The extracellular domains of mammalian Notch proteins contain 29-36 tandem epidermal growth factor-like (EGF) repeats, most of which have O-linked glycan modifications: O-glucose added by POGLUT1, O-fucose added by POFUT1 and elongated by Fringe enzymes, and O-GlcNAc added by EOGT. The extracellular domain is also N-glycosylated. Mutations in the glycosyltransferases modifying Notch have been identified in several diseases, including Dowling-Degos Disease (haploinsufficiency of POFUT1 or POGLUT1), a form of limb-girdle muscular dystrophy (autosomal recessive mutations in POGLUT1), Spondylocostal Dysostosis 3 (autosomal recessive mutations in LFNG), Adams-Oliver syndrome (autosomal recessive mutations in EOGT), and some cancers (amplification, gain or loss-of-function of POFUT1, Fringe enzymes, POGLUT1, MGAT3). Here we review the characteristics of these diseases and potential molecular mechanisms.
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Affiliation(s)
- Kenjiroo Matsumoto
- Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA
| | - Kelvin B Luther
- Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA
| | - Robert S Haltiwanger
- Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA.
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22
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Zhao B, Hu S, Xiao Q, Fan S, Yu X, Li C, Dong P, Zheng J. Expression of NOTCH receptors and ligands and prognosis of hepatocellular carcinoma. Biomark Med 2020; 14:1631-1639. [PMID: 33336594 DOI: 10.2217/bmm-2020-0138] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Aim: To elucidate potential prognostic significance of NOTCH receptor and ligand expression in hepatocellular carcinoma. Materials & methods: NOTCH receptors and ligands were divided into increased and decreased expression groups by X-tile program. The association between NOTCH receptors/ligands and prognosis was analyzed by Kaplan-Meier method and log-rank test. Gene set enrichment analysis was performed to explore NOTCH receptors/ligands-related pathways via gsea-3.0. Results: DLL3 and DLL4 were independent prognostic factors for overall survival. Further studies showed that only DLL3 was significantly associated with tumor, node, metastasis stage. Gene set enrichment analysis analysis demonstrated that retinol metabolism, drug metabolism cytochrome P450 and tryptophan metabolism were significantly enriched in DLL3 expression phenotype. Conclusion: We demonstrate that DLL3 may be a prognostic biomarker in hepatocellular carcinoma.
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Affiliation(s)
- Binyu Zhao
- Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Medical College, Hangzhou Normal University, Hangzhou, 311100, China
| | - Shanshan Hu
- Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Qingqing Xiao
- Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Sinuo Fan
- Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xizhi Yu
- The Second Clinical College, Wenzhou Medical University, Wenzhou, 325000, China
| | - Chunxue Li
- Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Peihong Dong
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jianjian Zheng
- Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
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23
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Matsumori T, Kodama Y, Takai A, Shiokawa M, Nishikawa Y, Matsumoto T, Takeda H, Marui S, Okada H, Hirano T, Kuwada T, Sogabe Y, Kakiuchi N, Tomono T, Mima A, Morita T, Ueda T, Tsuda M, Yamauchi Y, Kuriyama K, Sakuma Y, Ota Y, Maruno T, Uza N, Marusawa H, Kageyama R, Chiba T, Seno H. Hes1 Is Essential in Proliferating Ductal Cell-Mediated Development of Intrahepatic Cholangiocarcinoma. Cancer Res 2020; 80:5305-5316. [PMID: 33067264 DOI: 10.1158/0008-5472.can-20-1161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 08/11/2020] [Accepted: 10/13/2020] [Indexed: 11/16/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is frequently driven by aberrant KRAS activation and develops in the liver with chronic inflammation. Although the Notch signaling pathway is critically involved in ICC development, detailed mechanisms of Notch-driven ICC development are still unknown. Here, we use mice whose Notch signaling is genetically engineered to show that the Notch signaling pathway, specifically the Notch/Hes1 axis, plays an essential role in expanding ductular cells in the liver with chronic inflammation or oncogenic Kras activation. Activation of Notch1 enhanced the development of proliferating ductal cells (PDC) in injured livers, while depletion of Hes1 led to suppression. In correlation with PDC expansion, ICC development was also regulated by the Notch/Hes1 axis and suppressed by Hes1 depletion. Lineage-tracing experiments using EpcamcreERT2 mice further confirmed that Hes1 plays a critical role in the induction of PDC and that ICC could originate from PDC. Analysis of human ICC specimens showed PDC in nonneoplastic background tissues, confirming HES1 expression in both PDC and ICC tumor cells. Our findings provide novel direct experimental evidence that Hes1 plays an essential role in the development of ICC via PDC. SIGNIFICANCE: This study contributes to the identification of the cells of origin that initiate ICC and suggests that HES1 may represent a therapeutic target in ICC.
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Affiliation(s)
- Tomoaki Matsumori
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuzo Kodama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. .,Department of Gastroenterology, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masahiro Shiokawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshihiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomonori Matsumoto
- Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Saiko Marui
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirokazu Okada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomonori Hirano
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeshi Kuwada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuko Sogabe
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Nobuyuki Kakiuchi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Teruko Tomono
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Atsushi Mima
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Toshihiro Morita
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tatsuki Ueda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Motoyuki Tsuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuki Yamauchi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Katsutoshi Kuriyama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yojiro Sakuma
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuji Ota
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takahisa Maruno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Norimitsu Uza
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology, Japanese Red Cross Hospital Osaka, Osaka, Japan
| | - Ryoichiro Kageyama
- Institute for Frontier Life and Medical Sciences, Kyoto University, Shogoin-Kawahara, Sakyo-Ku, Kyoto, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Kansai Electric Power Hospital, Osaka, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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24
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Rauff B, Malik A, Bhatti YA, Chudhary SA, Qadri I, Rafiq S. Notch signalling pathway in development of cholangiocarcinoma. World J Gastrointest Oncol 2020; 12:957-974. [PMID: 33005291 PMCID: PMC7509998 DOI: 10.4251/wjgo.v12.i9.957] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/03/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) comprises of extra-hepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma cancers as a result of inflammation of epithelium cell lining of the bile duct. The incidence rate is increasing dramatically worldwide with highest rates in Eastern and South Asian regions. Major risk factors involve chronic damage and inflammation of bile duct epithelium from primary sclerosing cholangitis, chronic hepatitis virus infection, gallstones and liver fluke infection. Various genetic variants have also been identified and as CCA develops on the background of biliary inflammation, diverse range of molecular mechanisms are involved in its progression. Among these, the Notch signalling pathway acts as a major driver of cholangiocarcinogenesis and its components (receptors, ligands and downstream signalling molecules) represent a promising therapeutic targets. Gamma-Secretase Inhibitors have been recognized in inhibiting the Notch pathway efficiently. A comprehensive knowledge of the molecular pathways activated by the Notch signalling cascade as well as its functional crosstalk with other signalling pathways provide better approach in developing innovative therapies against CCA.
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Affiliation(s)
- Bisma Rauff
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Arif Malik
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Yasir Ali Bhatti
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Shafiq Ahmad Chudhary
- Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore 54000, Pakistan
| | - Ishtiaq Qadri
- Department of Biology, Faculty of Science, King Abdulaziz University Jeddah Kingdom of Saudi Arabia
| | - Shafquat Rafiq
- Department of Gastrointestinal medicine, Croydon University Hospital, Croydon CR7 7YE, United Kingdom
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25
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Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C, Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR, Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens JC, Moncsek A, Ilyas SI, Heimbach J, Koerkamp BG, Bruix J, Forner A, Bridgewater J, Valle JW, Gores GJ. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17:557-588. [PMID: 32606456 PMCID: PMC7447603 DOI: 10.1038/s41575-020-0310-z] [Citation(s) in RCA: 1475] [Impact Index Per Article: 295.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2020] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.
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Affiliation(s)
- Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain.
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
| | - Jose J G Marin
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Shahid A Khan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Luke Boulter
- MRC-Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Rocio I R Macias
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Eugenio Gaudio
- Division of Human Anatomy, Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | | | - Mario Strazzabosco
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Universita Politecnica delle Marche, Ancona, Italy
| | | | - Laura Fouassier
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center of Autoimmune Liver Diseases, Department of Medicine and Surgery, San Gerardo Hospital, University of Milano, Bicocca, Italy
| | - Joachim C Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Sumera I. Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | | | | | - Jordi Bruix
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Alejandro Forner
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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26
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Zhu Y, Kwong LN. Insights Into the Origin of Intrahepatic Cholangiocarcinoma From Mouse Models. Hepatology 2020; 72:305-314. [PMID: 32096245 DOI: 10.1002/hep.31200] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/17/2020] [Accepted: 02/11/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Yan Zhu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Lawrence N Kwong
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
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27
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Jeevanandam J, Tan KX, Danquah MK, Guo H, Turgeson A. Advancing Aptamers as Molecular Probes for Cancer Theranostic Applications-The Role of Molecular Dynamics Simulation. Biotechnol J 2020; 15:e1900368. [PMID: 31840436 DOI: 10.1002/biot.201900368] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 12/06/2019] [Indexed: 12/24/2022]
Abstract
Theranostics cover emerging technologies for cell biomarking for disease diagnosis and targeted introduction of drug ingredients to specific malignant sites. Theranostics development has become a significant biomedical research endeavor for effective diagnosis and treatment of diseases, especially cancer. An efficient biomarking and targeted delivery strategy for theranostic applications requires effective molecular coupling of binding ligands with high affinities to specific receptors on the cancer cell surface. Bioaffinity offers a unique mechanism to bind specific target and receptor molecules from a range of non-targets. The binding efficacy depends on the specificity of the affinity ligand toward the target molecule even at low concentrations. Aptamers are fragments of genetic materials, peptides, or oligonucleotides which possess enhanced specificity in targeting desired cell surface receptor molecules. Aptamer-target binding results from several inter-molecular interactions including hydrogen bond formation, aromatic stacking of flat moieties, hydrophobic interaction, electrostatic, and van der Waals interactions. Advancements in Systematic Evolution of Ligands by Exponential Enrichment (SELEX) assay has created the opportunity to artificially generate aptamers that specifically bind to desired cancer and tumor surface receptors with high affinities. This article discusses the potential application of molecular dynamics (MD) simulation to advance aptamer-mediated receptor targeting in targeted cancer therapy. MD simulation offers real-time analysis of the molecular drivers of the aptamer-receptor binding and generate optimal receptor binding conditions for theranostic applications. The article also provides an overview of different cancer types with focus on receptor biomarking and targeted treatment approaches, conventional molecular probes, and aptamers that have been explored for cancer cells targeting.
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Affiliation(s)
- Jaison Jeevanandam
- Department of Chemical Engineering, Faculty of Engineering and Science, Curtin University, Miri, Sarawak, 98009, Malaysia
| | - Kei Xian Tan
- School of Materials Science & Engineering, Nanyang Technological University, Singapore, 639798
| | | | - Haobo Guo
- Department of Computer Science and Engineering, University of Tennessee, Chattanooga, TN, 37403, USA.,SimCenter, University of Tennessee, Chattanooga, TN, 37403, USA
| | - Andrew Turgeson
- Chemical Engineering Department, University of Tennessee, Chattanooga, TN, 37403, USA
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28
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O’Rourke CJ, Matter MS, Nepal C, Caetano-Oliveira R, Ton PT, Factor VM, Andersen JB. Identification of a Pan-Gamma-Secretase Inhibitor Response Signature for Notch-Driven Cholangiocarcinoma. Hepatology 2020; 71:196-213. [PMID: 31211856 PMCID: PMC6918012 DOI: 10.1002/hep.30816] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 06/04/2019] [Indexed: 12/19/2022]
Abstract
Cholangiocarcinoma (CCA) mortality rates are increasing as a result of rising incidence and limited curative treatment(s) for patients with advanced disease. NOTCH pathway reactivation has been reported in biliary malignancies to conflicting degrees, hindering prioritization of key therapeutic targets within the network and identification of candidate responder patients for NOTCH-directed therapies. We analyzed genomic data from 341 patients with CCA and identified NOTCH1 significantly increased in a subgroup characterized by distinct stromal infiltration. Network-wide imbalance of the NOTCH pathway was seen in CCA, including correlation of NOTCH1 with NOTCH3 and NOTCH ligands. Given the diversity of observed NOTCH receptor engagement, γ-secretase modulation was rationalized as a therapeutic option. Indeed, subcutaneous transplantation of sensitive and resistant CCA cell lines pretreated with a γ-secretase inhibitor (GSi) cocktail demonstrated the antineoplastic effects of GSi in a subset of CCA and led to the development of a 225-gene responder signature. This signature was validated in an independent cohort of 119 patients. Further, this signature was enriched in liver tumors initiated by hydrodynamic injections of activated-NOTCH as compared with the AKT-RAS-driven tumors. Candidate GSi-responder patients were characterized by distinct transcriptomes overlapping with previous hepatobiliary metastasis and stemness, unique stromal properties, and dysfunctional intratumoral immune infiltration. Pan-cancer analysis identified 41.9% of cancer types to harbor prospective GSi-responder patients, which was adapted into a 20-gene GSi-sensitivity score metric capable of discriminating nanomolar versus micromolar sensitivity to a cell-permeable GSi (Z-LLNle-CHO) across 60 diverse tumor lines (area under the curve = 1). Conclusion: We have established a GSi-responder signature with evidence across several patient cohorts, as well as in vitro and in vivo models, to enable precision medicine application of NOTCH-directed therapy in CCA as well as prospectively across diverse malignancies.
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Affiliation(s)
- Colm J. O’Rourke
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Matthias S. Matter
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | - Chirag Nepal
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Rui Caetano-Oliveira
- Pathology Department, University Hospital (CHUC), Coimbra, Portugal,Coimbra Institute for Clinical and Biomedical Research (iCBR), Coimbra, Portugal
| | - Phuongnga T. Ton
- Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Valentina M. Factor
- Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Jesper B. Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark,Corresponding author: Jesper B Andersen, Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen. Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark. Phone: +45 35325834.
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29
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Functions of FGFR2 corrupted by translocations in intrahepatic cholangiocarcinoma. Cytokine Growth Factor Rev 2019; 52:56-67. [PMID: 31899106 DOI: 10.1016/j.cytogfr.2019.12.005] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 12/18/2019] [Indexed: 12/23/2022]
Abstract
Cholangiocarcinoma, originating from the biliary duct, represents a subset of liver cancer. With about 8000 new cases of cholangiocarcinoma diagnosed annually in the U.S., these fall into three categories: intrahepatic, peri-hilar, and extrahepatic cholangiocarcinoma. Arising from the epithelium of the bile duct, intrahepatic cholangiocarcinoma (ICC) is a universally fatal malignancy with very few treatment options. The poor prognosis and lack of molecular targeted therapies highlights ICC as a critical unmet medical need. With advances in sequencing technology, numerous chromosomal translocations have been discovered as drivers in cancer initiation and progression. Particularly in ICC, chromosomal translocations involving Fibroblast Growth Factor Receptor 2 (FGFR2) have been frequently identified, resulting in the creation of oncogenic fusion proteins. At the N-terminus, these fusion proteins share a nearly-identical FGFR2 moiety retaining an intact kinase domain and, at the C-terminus, a dimerization/oligomerization domain provided by different partner genes, including: Periphilin 1 (PPHLN1), Bicaudal family RNA binding protein 1 (BICC1), Adenosylhomocysteinase Like 1 (AHCYL1), and Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3). A number of pre-clinical and clinical trials have shown the effectiveness of FGFR inhibitors in treating FGFR2 fusion-positive ICC patients. However, the efficacy of these inhibitors may be short-lived due to acquired resistance. In this review, we provide an overview of FGFR2 fusions, comparing their structures and mechanism of dimerization, examining the importance of FGFR2 as a partner gene, as well as highlighting the significance of alternative splicing of FGFR2 in these fusion proteins. In addition, we discuss various therapeutic options and their associated potencies in targeting these translocation-induced ICCs.
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30
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Zou Y, Yang R, Huang ML, Kong YG, Sheng JF, Tao ZZ, Gao L, Chen SM. NOTCH2 negatively regulates metastasis and epithelial-Mesenchymal transition via TRAF6/AKT in nasopharyngeal carcinoma. J Exp Clin Cancer Res 2019; 38:456. [PMID: 31699119 PMCID: PMC6836530 DOI: 10.1186/s13046-019-1463-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 10/21/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Clinically, distant metastasis after primary treatment remains a key problem in nasopharyngeal carcinoma (NPC). Thus, identification of the underlying mechanisms and development of novel therapeutic strategies are urgently needed. NOTCH has been shown to function as a tumor promotor that enhances angiogenesis, cancer invasion and metastasis in NPC. However, the precise roles of the four individual NOTCH receptors and their mechanisms of action are unclear. METHODS We used Western blot analysis, immunofluorescence, immunohistochemical analysis, phalloidin staining, mouse tumor metastatic dissemination models, gene set enrichment analysis, immunoprecipitation assays and a series of functional assays to determine the potential role of NOTCH2 in regulating NPC metastasis. RESULTS NOTCH2 expression in the NPC tissues of patients with cervical lymph node metastasis was lower than that of patients without cervical lymph node metastasis. Correspondingly, NOTCH2 expression was low in metastatic and poorly differentiated NPC cells. NOTCH2 expression correlated negatively with survival time in patients with NPC. Suppression of NOTCH2 expression promoted NPC cell metastasis, whereas NOTCH2 overexpression inhibited this process. Furthermore, NOTCH2 attenuated the TRAF6-AKT signaling axis via an interaction between the NOTCH2 intracellular domain (N2ICD) and TRAF6, which inhibited epithelial-mesenchymal transition (EMT) and eventually suppressed NPC metastasis. CONCLUSIONS These findings reveal that loss of NOTCH2 activates the TRAF6/AKT axis and promotes metastasis in NPC, suggesting that NOTCH2 may represent a therapeutic target for the treatment of NPC.
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Affiliation(s)
- You Zou
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jie-Fang Road, Wuhan, 430060 Hubei People’s Republic of China
| | - Rui Yang
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jie-Fang Road, Wuhan, 430060 Hubei People’s Republic of China
| | - Mao-Ling Huang
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jie-Fang Road, Wuhan, 430060 Hubei People’s Republic of China
| | - Yong-Gang Kong
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jie-Fang Road, Wuhan, 430060 Hubei People’s Republic of China
| | - Jian-Fei Sheng
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jie-Fang Road, Wuhan, 430060 Hubei People’s Republic of China
| | - Ze-Zhang Tao
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jie-Fang Road, Wuhan, 430060 Hubei People’s Republic of China
| | - Ling Gao
- Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Jinan, China
| | - Shi-Ming Chen
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jie-Fang Road, Wuhan, 430060 Hubei People’s Republic of China
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Guan C, He L, Chang Z, Gu X, Liang J, Liu R. ZNF774 is a potent suppressor of hepatocarcinogenesis through dampening the NOTCH2 signaling. Oncogene 2019; 39:1665-1680. [PMID: 31659254 DOI: 10.1038/s41388-019-1075-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 10/10/2019] [Accepted: 10/14/2019] [Indexed: 01/06/2023]
Abstract
Discerning oncogenic drivers from passengers remain a major effort in understanding of the essence of the initiation and development of hepatocellular carcinoma (HCC), which is the most common primary liver malignancy and the third leading cause of cancer mortality worldwide. Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. Genome-wide identification of the transcriptional targets of the ZNF774/NuRD complex by ChIP-seq indicated that ZNF774 represses a cohort of genes including NOTCH2 that are critically involved in the growth and mobility of HCC. We demonstrated that the ZNF774/NuRD complex inhibits the proliferation and invasion of HCC cells in vitro and suppresses HCC growth and metastasis in vivo. Importantly, the expression of ZNF774 is significantly downregulated in HCC, and low ZNF774 expression strongly correlated with high NOTCH2 expression, advanced pathological stages, and poor overall survival of the patients. Together, these results uncover a key role for the ZNF774/NuRD-NOTCH2 axis in hepatocarcinogenesis.
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Affiliation(s)
- Chengjian Guan
- General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.,Medical School of Chinese People's Liberation Army, Beijing, 100853, China.,Department of Hepatobiliary and Pancreatic Surgical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Lin He
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Zhenyu Chang
- Medical School of Chinese People's Liberation Army, Beijing, 100853, China.,Department of Hepatobiliary and Pancreatic Surgical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Xinjin Gu
- Medical School of Chinese People's Liberation Army, Beijing, 100853, China.,Department of Hepatobiliary and Pancreatic Surgical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Jing Liang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Rong Liu
- Medical School of Chinese People's Liberation Army, Beijing, 100853, China. .,Department of Hepatobiliary and Pancreatic Surgical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China.
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Chen C, Nelson LJ, Ávila MA, Cubero FJ. Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link. Cells 2019; 8:1172. [PMID: 31569444 PMCID: PMC6829385 DOI: 10.3390/cells8101172] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 09/18/2019] [Accepted: 09/25/2019] [Indexed: 02/07/2023] Open
Abstract
In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low-a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA.
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Affiliation(s)
- Chaobo Chen
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain.
- de Octubre Health Research Institute (imas12), 28040 Madrid, Spain.
- Department of General Surgery, Wuxi Xishan People's Hospital, Wuxi 214000, China.
| | - Leonard J Nelson
- Institute for Bioengineering (IBioE), School of Engineering, Faraday Building, The University of Edinburgh, Edinburgh EH9 3 JL, Scotland, UK.
| | - Matías A Ávila
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
- Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain.
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain.
- de Octubre Health Research Institute (imas12), 28040 Madrid, Spain.
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Xu Q, Lin D, Li X, Xiao R, Liu Z, Xiong W, Cai L, He F. Association between single nucleotide polymorphisms of NOTCH signaling pathway-related genes and the prognosis of NSCLC. Cancer Manag Res 2019; 11:6895-6905. [PMID: 31413635 PMCID: PMC6662170 DOI: 10.2147/cmar.s197747] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 06/12/2019] [Indexed: 12/12/2022] Open
Abstract
Objective In this study, we analyzed the association between genetic variants of genes in the NOTCH signaling pathway and the prognosis of non-small-cell lung cancer (NSCLC) in the Chinese population. We also explored the interaction between genetic and epidemiological factors for the test group. Methods We performed genotyping of 987 NSCLC patients. Then, we used Cox proportional hazard models to analyze the associations between single-nucleotide polymorphisms (SNPs) and the prognosis of NSCLC. We employed Stata software to test the heterogeneity of associations between subgroups, and we analyzed the additive and multiplicative interactions between SNPs and epidemiologic factors. Results This work revealed the important prognostic and predictive value of rs915894 in the NOTCH4 gene, which may be regarded as a promising prognosis biomarker of NSCLC. Cox regression analysis indicated that the C allele of rs915894 is associated with longer survival and decreased risk of death in NSCLC (codominant model: adjusted HR =0.83, 95% CI =0.70-0.99; dominant model: adjusted HR =0.83, 95% CI =0.71-0.98). Additional stepwise regression analysis suggested that this SNP is an independently favorable factor for the prognosis of NSCLC (dominant model: adjusted HR =0.85, 95% CI =0.72-0.99). This protective effect is more pronounced for patients who are not smokers, have a history of other lung diseases, or have a family history of cancer. We also detected statistically significant additive and multiplicative interactions between rs915894 and smoking, rs915894 and history of lung diseases, and rs915894 and family history of cancer, which all affect NSCLC survival. Conclusion This study demonstrated that rs915894 in NOTCH 4 may be a genetic marker for NSCLC prognosis in the Chinese population and that rs915894 may have an interactive relationship with epidemiologic factors.
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Affiliation(s)
- Qiuping Xu
- Medical Department, The Affiliated Hospital of Putian University, Putian, Fujian, People's Republic of China.,Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Danhua Lin
- Medical Department, The Affiliated Hospital of Putian University, Putian, Fujian, People's Republic of China
| | - Xu Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Rendong Xiao
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Zhiqiang Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Weimin Xiong
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Lin Cai
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Fei He
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, People's Republic of China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
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Neuroblastoma RAS Viral Oncogene Homolog (NRAS) Is a Novel Prognostic Marker and Contributes to Sorafenib Resistance in Hepatocellular Carcinoma. Neoplasia 2019; 21:257-268. [PMID: 30685691 PMCID: PMC6370713 DOI: 10.1016/j.neo.2018.11.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 10/28/2018] [Accepted: 11/27/2018] [Indexed: 01/06/2023] Open
Abstract
Inhibition of the RAS-RAF-ERK-pathway using sorafenib as a first-line and regorafenib as a second-line treatment approach is the only effective therapeutic strategy for advanced hepatocellular carcinoma (HCC). Recent studies suggest that wild-type KRAS and HRAS isoforms could majorly contribute to HCC progression and sorafenib resistance. In contrast, the role of neuroblastoma RAS viral oncogene homolog (NRAS) in HCC remained elusive. In this study, wild-type NRAS was found to be overexpressed in HCC cell lines, preclinical HCC models, and human HCC tissues. Moreover, NRAS overexpression correlated with poor survival and proliferation in vivo. However, si-RNA-pool–mediated NRAS knockdown showed only slight effects on HCC proliferation, clonogenicity, and AKT activity. We determined that KRAS upregulation served as a functional compensatory mechanism in the absence of NRAS, which was overcome by combined inhibition of NRAS and KRAS in HCC cells. Furthermore, NRAS expression was elevated in sorafenib-resistant compared to nonresistant HCC cells, and NRAS knockdown enhanced sorafenib efficacy in resistant cells. In summary, NRAS appears to be a prognostic marker in HCC and contributes to sorafenib resistance. Regarding potential therapeutic strategies, NRAS inhibition in HCC should be combined with KRAS inhibition to prevent KRAS-mediated rescue effects.
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35
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M1-Polarized Macrophages Promote Self-Renewing Phenotype of Hepatic Progenitor Cells with Jagged1-Notch Signalling Involved: Relevance in Primary Sclerosing Cholangitis. J Immunol Res 2018; 2018:4807145. [PMID: 30671485 PMCID: PMC6323443 DOI: 10.1155/2018/4807145] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 09/28/2018] [Accepted: 10/22/2018] [Indexed: 02/06/2023] Open
Abstract
The immunologic interaction between parenchyma cells and encircling inflammatory cells is thought to be the most important mechanism of biliary damage and repair in primary sclerosing cholangitis (PSC). Monocytes/macrophages as master regulators of hepatic inflammation have been demonstrated to contribute to PSC pathogenesis. Macrophages coordinate with liver regeneration, and multiple phenotypes have been identified with diverse expressions of surface proteins and cytokine productions. We analyzed the expression of Notch ligand Jagged1 in polarized macrophages and investigated the relevance of Notch signalling activation in liver regeneration. M1 or M2 macrophages were generated from mouse bone marrow-derived macrophages (BMDMs) by classical or alternative activation, respectively. Then, the expression levels of Jagged1 (Jag1) of each phenotype were measured. The effects of polarized BMDMs on the expression of hepatic progenitor cell- (HPC-) specific markers and hairy and enhancer of split-1 (HES1) in HPCs in coculture were also analyzed. Monocyte-macrophage and Notch signalling-associated gene signatures were evaluated in the GEO database (access ID: GSE61260) by gene set enrichment analysis (GSEA). M1 macrophages were found associated with elevated Jag1 expression, which increased the fraction of HPC with self-renewing phenotypes (CD326+CD44+ or CD324+CD44+) and HES1 expression level in cocultured HPC. Blocking Jagged1 by siRNA or antibody in the coculture system attenuates HPC self-renewing phenotypes as well as HES1 expression in HPC. GSEA data show that macrophage activation and Notch signalling-associated gene signatures are enriched in PSC patients. These findings suggest that M1 macrophages promote an HPC self-renewing phenotype which is associated with Notch signalling activation within HPC. In the liver of PSC patients, the prevalence of activated macrophages, with M1 polarized accounting for the main part, is associated with increment of Notch signalling and enhancement of HPC self-renewal.
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36
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Chen Z, Guo P, Xie X, Yu H, Wang Y, Chen G. The role of tumour microenvironment: a new vision for cholangiocarcinoma. J Cell Mol Med 2018; 23:59-69. [PMID: 30394682 PMCID: PMC6307844 DOI: 10.1111/jcmm.13953] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 09/10/2018] [Indexed: 12/18/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a relatively rare malignant and lethal tumour derived from bile duct epithelium and the morbidity is now increasing worldwide. This disease is difficult to diagnose at its inchoate stage and has poor prognosis. Therefore, a clear understanding of pathogenesis and major influencing factors is the key to develop effective therapeutic methods for CCA. In previous studies, canonical correlation analysis has demonstrated that tumour microenvironment plays an intricate role in the progression of various types of cancers including CCA. CCA tumour microenvironment is a dynamic environment consisting of authoritative tumour stromal cells and extracellular matrix where tumour stromal cells and cancer cells can thrive. CCA stromal cells include immune and non‐immune cells, such as inflammatory cells, endothelial cells, fibroblasts, and macrophages. Likewise, CCA tumour microenvironment contains abundant proliferative factors and can significantly impact the behaviour of cancer cells. Through abominably intricate interactions with CCA cells, CCA tumour microenvironment plays an important role in promoting tumour proliferation, accelerating neovascularization, facilitating tumour invasion, and preventing tumour cells from organismal immune reactions and apoptosis. This review summarizes the recent research progress regarding the connection between tumour behaviours and tumour stromal cells in CCA, as well as the mechanism underlying the effect of tumour stromal cells on the growth of CCA. A thorough understanding of the relationship between CCA and tumour stromal cells can shed some light on the development of new therapeutic methods for treating CCA.
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Affiliation(s)
- Ziyan Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Pengyi Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Xiaozai Xie
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Haitao Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yi Wang
- Environmental and Public, Health School of Wenzhou Medical University, Wenzhou, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
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Hany H, Shalaby A, Al Kashef W, Kandil W, Shahin RA, El-Alfy H, Besheer T, Farag R, Mohamed M. Evaluation of the role of Notch1 expression in hepatic carcinogenesis with clinico-pathological correlation. Pathology 2018; 50:730-736. [PMID: 30389219 DOI: 10.1016/j.pathol.2018.08.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 08/14/2018] [Accepted: 08/22/2018] [Indexed: 02/07/2023]
Abstract
The role of Notch pathway in hepatocarcinogenesis is unclear with conflicting results reported from different researchers. This study aimed to investigate the exact role of Notch1 in hepatocarcinogenesis and its influence on survival and to determine the possibility of it being a target therapy. Differential immunohistochemical expression of Notch1 in 100 cases of hepatocellular carcinoma (HCC) and adjacent non-neoplastic liver tissue was performed. The results showed that expression of Notch1 was significantly higher in the non-neoplastic hepatic tissues than in HCC tissues (p < 0.001), but there was no significant difference in Notch1 expression between cirrhotic and non-cirrhotic liver tissue (p = 0.197). Notch1 expression was higher in low grade than in high grade HCC (p = 0.036). Notch1 expression showed reverse correlation with mitotic count (p = 0.008), and necrosis (p = 0.005). The disease free survival was shorter in patients displaying low levels of Notch1 expression (p = 0.045). The overall survival showed no significant difference between high and low levels of Notch1 expression; however, it was somewhat longer in patients with high Notch1 expression (p = 0.220). In conclusion, the tumour suppressor role of Notch1 was supported and the use of Notch1 agonists may have a role in improving the prognosis of HCC.
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Affiliation(s)
- Heba Hany
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Asem Shalaby
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt; Pathology Department, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
| | - Wagdi Al Kashef
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Wageha Kandil
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Rehab-Allah Shahin
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Hatem El-Alfy
- Tropical Disease Department, Mansoura University Hospital, Mansoura University, Mansoura, Egypt
| | - Tarek Besheer
- Tropical Disease Department, Mansoura University Hospital, Mansoura University, Mansoura, Egypt
| | - Raghda Farag
- Tropical Disease Department, Mansoura University Hospital, Mansoura University, Mansoura, Egypt
| | - Mie Mohamed
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Egypt
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Huang S, Park J, Qiu C, Chung KW, Li SY, Sirin Y, Han SH, Taylor V, Zimber-Strobl U, Susztak K. Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming. PLoS Biol 2018; 16:e2005233. [PMID: 30226866 PMCID: PMC6161902 DOI: 10.1371/journal.pbio.2005233] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 09/28/2018] [Accepted: 09/03/2018] [Indexed: 12/14/2022] Open
Abstract
While Notch signaling has been proposed to play a key role in fibrosis, the direct molecular pathways targeted by Notch signaling and the precise ligand and receptor pair that are responsible for kidney disease remain poorly defined. In this study, we found that JAG1 and NOTCH2 showed the strongest correlation with the degree of interstitial fibrosis in a genome-wide expression analysis of a large cohort of human kidney samples. Transcript analysis of mouse kidney disease models, including folic-acid (FA)-induced nephropathy, unilateral ureteral obstruction (UUO), or apolipoprotein L1 (APOL1)-associated kidney disease, indicated that Jag1 and Notch2 levels were higher in all analyzed kidney fibrosis models. Mice with tubule-specific deletion of Jag1 or Notch2 (Kspcre/Jag1flox/flox and Kspcre/Notch2flox/flox) had no kidney-specific alterations at baseline but showed protection from FA-induced kidney fibrosis. Tubule-specific genetic deletion of Notch1 and global knockout of Notch3 had no effect on fibrosis. In vitro chromatin immunoprecipitation experiments and genome-wide expression studies identified the mitochondrial transcription factor A (Tfam) as a direct Notch target. Re-expression of Tfam in tubule cells prevented Notch-induced metabolic and profibrotic reprogramming. Tubule-specific deletion of Tfam resulted in fibrosis. In summary, Jag1 and Notch2 play a key role in kidney fibrosis development by regulating Tfam expression and metabolic reprogramming.
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Affiliation(s)
- Shizheng Huang
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Jihwan Park
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Chengxiang Qiu
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Ki Wung Chung
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Szu-yuan Li
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Yasemin Sirin
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Seung Hyeok Han
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Verdon Taylor
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Ursula Zimber-Strobl
- Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health, Munich, Germany
| | - Katalin Susztak
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
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Kennedy L, Hargrove L, Demieville J, Karstens A, Jones H, DeMorrow S, Meng F, Invernizzi P, Bernuzzi F, Alpini G, Smith S, Akers A, Meadows V, Francis H. Blocking H1/H2 histamine receptors inhibits damage/fibrosis in Mdr2 -/- mice and human cholangiocarcinoma tumorigenesis. Hepatology 2018; 68:1042-1056. [PMID: 29601088 PMCID: PMC6165706 DOI: 10.1002/hep.29898] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 02/28/2018] [Accepted: 03/12/2018] [Indexed: 12/12/2022]
Abstract
Primary sclerosing cholangitis (PSC) patients are at risk of developing cholangiocarcinoma (CCA). We have shown that (1) histamine increases biliary hyperplasia through H1/H2 histamine receptors (HRs) and (2) histamine levels increase and mast cells (MCs) infiltrate during PSC and CCA. We examined the effects of chronic treatment with H1/H2HR antagonists on PSC and CCA. Wild-type and multidrug-resistant knockout (Mdr2-/- ) mice were treated by osmotic minipumps with saline, mepyramine, or ranitidine (10 mg/kg body weight/day) or a combination of mepyramine/ranitidine for 4 weeks. Liver damage was assessed by hematoxylin and eosin. We evaluated (1) H1/H2HR expression, (2) MC presence, (3) L-histidine decarboxylase/histamine axis, (4) cholangiocyte proliferation/bile duct mass, and (5) fibrosis/hepatic stellate cell activation. Nu/nu mice were implanted with Mz-ChA-1 cells into the hind flanks and treated with saline, mepyramine, or ranitidine. Tumor growth was measured, and (1) H1/H2HR expression, (2) proliferation, (3) MC activation, (4) angiogenesis, and (5) epithelial-mesenchymal transition (EMT) were evaluated. In vitro, human hepatic stellate cells were evaluated for H1HR and H2HR expression. Cultured cholangiocytes and CCA lines were treated with saline, mepyramine, or ranitidine (25 μM) before evaluating proliferation, angiogenesis, EMT, and potential signaling mechanisms. H1/H2HR and MC presence increased in human PSC and CCA. In H1/H2HR antagonist (alone or in combination)-treated Mdr2-/- mice, liver and biliary damage and fibrosis decreased compared to saline treatment. H1/H2HR antagonists decreased tumor growth, serum histamine, angiogenesis, and EMT. In vitro, H1/H2HR blockers reduced biliary proliferation, and CCA cells had decreased proliferation, angiogenesis, EMT, and migration. Conclusion: Inhibition of H1/H2HR reverses PSC-associated damage and decreases CCA growth, angiogenesis, and EMT; because PSC patients are at risk of developing CCA, using HR blockers may be therapeutic for these diseases. (Hepatology 2018).
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Affiliation(s)
- Lindsey Kennedy
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA
- Medicine, Texas A&M Health Science Center, Temple, Texas, USA
| | - Laura Hargrove
- Medicine, Texas A&M Health Science Center, Temple, Texas, USA
| | | | - Allen Karstens
- Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas, USA
| | - Hannah Jones
- Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas, USA
| | - Sharon DeMorrow
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA
- Medicine, Texas A&M Health Science Center, Temple, Texas, USA
| | - Fanyin Meng
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA
- Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas, USA
- Medicine, Texas A&M Health Science Center, Temple, Texas, USA
| | - Pietro Invernizzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | - Francesca Bernuzzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA
- Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas, USA
- Medicine, Texas A&M Health Science Center, Temple, Texas, USA
| | - Steven Smith
- Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas, USA
| | - Austin Akers
- Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas, USA
| | - Victoria Meadows
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA
| | - Heather Francis
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA
- Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas, USA
- Medicine, Texas A&M Health Science Center, Temple, Texas, USA
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40
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Giaimo BD, Borggrefe T. Introduction to Molecular Mechanisms in Notch Signal Transduction and Disease Pathogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1066:3-30. [DOI: 10.1007/978-3-319-89512-3_1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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41
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Wang J, Dong M, Xu Z, Song X, Zhang S, Qiao Y, Che L, Gordan J, Hu K, Liu Y, Calvisi DF, Chen X. Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice. Oncogene 2018; 37:3229-3242. [PMID: 29545603 PMCID: PMC6002343 DOI: 10.1038/s41388-018-0188-1] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 12/01/2017] [Accepted: 02/06/2018] [Indexed: 02/08/2023]
Abstract
Liver cancer comprises a group of malignant tumors, among which hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common. ICC is especially pernicious and associated with poor clinical outcome. Studies have shown that a subset of human ICCs may originate from mature hepatocytes. However, the mechanisms driving the trans-differentiation of hepatocytes into malignant cholangiocytes remain poorly defined. We adopted lineage tracing techniques and an established murine hepatocyte-derived ICC model by hydrodynamic injection of activated forms of AKT (myr-AKT) and Yap (YapS127A) proto-oncogenes. Wild-type, Notch1 flox/flox , and Notch2 flox/flox mice were used to investigate the role of canonical Notch signaling and Notch receptors in AKT/Yap-driven ICC formation. Human ICC and HCC cell lines were transfected with siRNA against Notch2 to determine whether Notch2 regulates biliary marker expression in liver tumor cells. We found that AKT/Yap-induced ICC formation is hepatocyte derived and this process is strictly dependent on the canonical Notch signaling pathway in vivo. Deletion of Notch2 in AKT/Yap-induced tumors switched the phenotype from ICC to hepatocellular adenoma-like lesions, while inactivation of Notch1 in hepatocytes did not result in significant histomorphological changes. Finally, in vitro studies revealed that Notch2 silencing in ICC and HCC cell lines down-regulates the expression of Sox9 and EpCAM biliary markers. Notch2 is the major determinant of hepatocyte-derived ICC formation in mice.
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MESH Headings
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- Animals
- Bile Duct Neoplasms/metabolism
- Bile Duct Neoplasms/pathology
- Bile Ducts, Intrahepatic/pathology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Cycle Proteins
- Cell Line, Tumor
- Cholangiocarcinoma/metabolism
- Cholangiocarcinoma/pathology
- Female
- Hepatocytes/metabolism
- Hepatocytes/pathology
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Male
- Mice, Transgenic
- Phosphoproteins/genetics
- Phosphoproteins/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Receptor, Notch1/genetics
- Receptor, Notch1/metabolism
- Receptor, Notch2/genetics
- Receptor, Notch2/metabolism
- Signal Transduction/physiology
- YAP-Signaling Proteins
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Affiliation(s)
- Jingxiao Wang
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Mingjie Dong
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA
- 307 Hospital of Academy of Military Medical Science, Beijing, China
| | - Zhong Xu
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Guizhou, China
| | - Xinhua Song
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Shanshan Zhang
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA
| | - Yu Qiao
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA
- Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Li Che
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA
| | - John Gordan
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA
| | - Kaiwen Hu
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yan Liu
- 307 Hospital of Academy of Military Medical Science, Beijing, China.
| | - Diego F Calvisi
- Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA.
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Soliman B, Salem A, Ghazy M, Abu-Shahba N, El Hefnawi M. Bioinformatics functional analysis of let-7a, miR-34a, and miR-199a/b reveals novel insights into immune system pathways and cancer hallmarks for hepatocellular carcinoma. Tumour Biol 2018; 40:1010428318773675. [PMID: 29775159 DOI: 10.1177/1010428318773675] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Let-7a, miR-34a, and miR-199 a/b have gained a great attention as master regulators for cellular processes. In particular, these three micro-RNAs act as potential onco-suppressors for hepatocellular carcinoma. Bioinformatics can reveal the functionality of these micro-RNAs through target prediction and functional annotation analysis. In the current study, in silico analysis using innovative servers (miRror Suite, DAVID, miRGator V3.0, GeneTrail) has demonstrated the combinatorial and the individual target genes of these micro-RNAs and further explored their roles in hepatocellular carcinoma progression. There were 87 common target messenger RNAs (p ≤ 0.05) that were predicted to be regulated by the three micro-RNAs using miRror 2.0 target prediction tool. In addition, the functional enrichment analysis of these targets that was performed by DAVID functional annotation and REACTOME tools revealed two major immune-related pathways, eight hepatocellular carcinoma hallmarks-linked pathways, and two pathways that mediate interconnected processes between immune system and hepatocellular carcinoma hallmarks. Moreover, protein-protein interaction network for the predicted common targets was obtained by using STRING database. The individual analysis of target genes and pathways for the three micro-RNAs of interest using miRGator V3.0 and GeneTrail servers revealed some novel predicted target oncogenes such as SOX4, which we validated experimentally, in addition to some regulated pathways of immune system and hepatocarcinogenesis such as insulin signaling pathway and adipocytokine signaling pathway. In general, our results demonstrate that let-7a, miR-34a, and miR-199 a/b have novel interactions in different immune system pathways and major hepatocellular carcinoma hallmarks. Thus, our findings shed more light on the roles of these miRNAs as cancer silencers.
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Affiliation(s)
- Bangly Soliman
- 1 Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,2 Informatics and Systems Department, Biomedical Informatics and Chemo-Informatics Group, Centre of Excellence for Advanced Sciences (CEAS), Division of Engineering Research, National Research Centre, Cairo, Egypt
| | - Ahmed Salem
- 1 Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Mohamed Ghazy
- 1 Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Nourhan Abu-Shahba
- 3 Stem Cells Research Group, Medical Centre of Excellence, Medical Molecular Genetics Department, National Research Centre, Cairo, Egypt
| | - Mahmoud El Hefnawi
- 2 Informatics and Systems Department, Biomedical Informatics and Chemo-Informatics Group, Centre of Excellence for Advanced Sciences (CEAS), Division of Engineering Research, National Research Centre, Cairo, Egypt.,4 Centre for Informatics, Nile University, Sheikh Zayed City, Egypt
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Abstract
Comprehensive genomic analyses have been performed for head and neck squamous cell carcinoma (HNSCC), revealing a significant rate of NOTCH1 mutations and identifying NOTCH1 as the second most frequently mutated gene after TP53. Most NOTCH1 mutations are considered inactivating, indicating that NOTCH1 is a tumor suppressor gene. On the other hand, cohorts from Asian populations with HNSCC have shown activating NOTCH1 mutations. HNSCC with NOTCH1 mutations have a worse prognosis than the NOTCH1 wild-type tumors. Additional data on other NOTCH family members have shown that NOTCH promotes HNSCC progression. NOTCH family members, including NOTCH pathway genes, are upregulated in HNSCC compared with normal tissues, and inhibition of the NOTCH pathway decreases cell proliferation and invasion. NOTCH activity in HNSCC is therefore contextual, and NOTCH in HNSCC is considered to have a bimodal role as a tumor suppressor and an oncogene. In this review, recent understandings of NOTCH pathway genes, including NOTCH genes, in HNSCC are described. In addition, the implications of NOTCH pathway alteration for HNSCC-specific NOTCH-targeted cancer therapy are explored.
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Affiliation(s)
- T Fukusumi
- 1 Moores Cancer Center, University of California, La Jolla, CA, USA
| | - J A Califano
- 1 Moores Cancer Center, University of California, La Jolla, CA, USA
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Zhang S, Wang J, Wang H, Fan L, Fan B, Zeng B, Tao J, Li X, Che L, Cigliano A, Ribback S, Dombrowski F, Chen B, Cong W, Wei L, Calvisi DF, Chen X. Hippo Cascade Controls Lineage Commitment of Liver Tumors in Mice and Humans. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:995-1006. [PMID: 29378174 DOI: 10.1016/j.ajpath.2017.12.017] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 12/11/2017] [Accepted: 12/28/2017] [Indexed: 02/05/2023]
Abstract
Primary liver cancer consists mainly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A subset of human HCCs expresses a ICC-like gene signature and is classified as ICC-like HCC. The Hippo pathway is a critical regulator of normal and malignant liver development. However, the precise function(s) of the Hippo cascade along liver carcinogenesis remain to be fully delineated. The role of the Hippo pathway in a murine mixed HCC/ICC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated. The authors demonstrated the inactivation of Hippo in AKT/Ras liver tumors leading to nuclear localization of Yap and TAZ. Coexpression of AKT/Ras with Lats2, which activates Hippo, or the dominant negative form of TEAD2 (dnTEAD2), which blocks Yap/TAZ activity, resulted in delayed hepatocarcinogenesis and elimination of ICC-like lesions in the liver. Mechanistically, Notch2 expression was found to be down-regulated by the Hippo pathway in liver tumors. Overexpression of Lats2 or dnTEAD2 in human HCC cell lines inhibited their growth and led to the decreased expression of ICC-like markers, as well as Notch2 expression. Altogether, this study supports the key role of the Hippo cascade in regulating the differentiation status of liver tumors.
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Affiliation(s)
- Shanshan Zhang
- Tumor Immunology and Gene Therapy Center, Second Military Medical University, Shanghai, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jingxiao Wang
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Second Clinical Medical School, Beijing University of Chinese Medicine, Beijing, China
| | - Haichuan Wang
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Lingling Fan
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
| | - Biao Fan
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China
| | - Billy Zeng
- Department of Pediatrics, University of California, San Francisco, California; Institute for Computational Health Sciences, University of California, San Francisco, California
| | - Junyan Tao
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
| | - Xiaolei Li
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
| | - Li Che
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
| | - Antonio Cigliano
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy
| | - Silvia Ribback
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - Frank Dombrowski
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - Bin Chen
- Department of Pediatrics, University of California, San Francisco, California; Institute for Computational Health Sciences, University of California, San Francisco, California
| | - Wenming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Second Military Medical University, Shanghai, China
| | - Diego F Calvisi
- Institute of Pathology, University of Greifswald, Greifswald, Germany.
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California.
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45
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Notch signaling: its roles and therapeutic potential in hematological malignancies. Oncotarget 2018; 7:29804-23. [PMID: 26934331 PMCID: PMC5045435 DOI: 10.18632/oncotarget.7772] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/11/2016] [Indexed: 01/07/2023] Open
Abstract
Notch is a highly conserved signaling system that allows neighboring cells to communicate, thereby controlling their differentiation, proliferation and apoptosis, with the outcome of its activation being highly dependent on signal strength and cell type. As such, there is growing evidence that disturbances in physiological Notch signaling contribute to cancer development and growth through various mechanisms. Notch was first reported to contribute to tumorigenesis in the early 90s, through identification of the involvement of the Notch1 gene in the chromosomal translocation t(7;9)(q34;q34.3), found in a small subset of T-cell acute lymphoblastic leukemia. Since then, Notch mutations and aberrant Notch signaling have been reported in numerous other precursor and mature hematological malignancies, of both myeloid and lymphoid origin, as well as many epithelial tumor types. Of note, Notch has been reported to have both oncogenic and tumor suppressor roles, dependent on the cancer cell type. In this review, we will first give a general description of the Notch signaling pathway, and its physiologic role in hematopoiesis. Next, we will review the role of aberrant Notch signaling in several hematological malignancies. Finally, we will discuss current and potential future therapeutic approaches targeting this pathway.
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46
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Molecular and proteomic insight into Notch1 characterization in hepatocellular carcinoma. Oncotarget 2018; 7:39609-39626. [PMID: 27167202 PMCID: PMC5129957 DOI: 10.18632/oncotarget.9203] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 04/10/2016] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) ranks fifth in frequency worldwide amongst all human cancers causing one million deaths annually. Despite many promising treatment options, long-term prognosis remains dismal for the majority of patients who develop recurrence or present with advanced disease. Notch signaling is an evolutionarily conserved pathway crucial for the development and homeostasis of many organs including liver. Herein we showed that aberrant Notch1 is linked to HCC development, tumor recurrence and invasion, which might be mediated, at least in part, through the Notch1-E-Cadherin pathway. Collectively, these findings suggest that targeting Notch1 has important therapeutic value in hepatocellular carcinoma. In this regard, comparative analysis of the secretome of HepG2 and HepG2 Notch1 depleted cells identified novel secreted proteins related to Notch1 expression. Soluble E-Cadherin (sE-Cad) and Thrombospondin-1 (Thbs1) were further validated in human serum as potential biomarkers to predict response to Notch1 inhibitors for a tailored individualized therapy.
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Ren FH, Yang H, He RQ, Lu JN, Lin XG, Liang HW, Dang YW, Feng ZB, Chen G, Luo DZ. Analysis of microarrays of miR-34a and its identification of prospective target gene signature in hepatocellular carcinoma. BMC Cancer 2018; 18:12. [PMID: 29298665 PMCID: PMC5753510 DOI: 10.1186/s12885-017-3941-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 12/19/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Currently, some studies have demonstrated that miR-34a could serve as a suppressor of several cancers including hepatocellular carcinoma (HCC). Previously, we discovered that miR-34a was downregulated in HCC and involved in the tumorigenesis and progression of HCC; however, the mechanism remains unclear. The purpose of this study was to estimate the expression of miR-34a in HCC by applying the microarray profiles and analyzing the predicted targets of miR-34a and their related biological pathways of HCC. METHODS Gene expression omnibus (GEO) datasets were conducted to identify the difference of miR-34a expression between HCC and corresponding normal tissues and to explore its relationship with HCC clinicopathologic features. The natural language processing (NLP), gene ontology (GO), pathway and network analyses were performed to analyze the genes associated with the carcinogenesis and progression of HCC and the targets of miR-34a predicted in silico. In addition, the integrative analysis was performed to explore the targets of miR-34a which were also relevant to HCC. RESULTS The analysis of GEO datasets demonstrated that miR-34a was downregulated in HCC tissues, and no heterogeneity was observed (Std. Mean Difference(SMD) = 0.63, 95% confidence intervals(95%CI):[0.38, 0.88], P < 0.00001; Pheterogeneity = 0.08 I2 = 41%). However, no association was found between the expression value of miR-34a and any clinicopathologic characteristics. In the NLP analysis of HCC, we obtained 25 significant HCC-associated signaling pathways. Besides, we explored 1000 miR-34a-related genes and 5 significant signaling pathways in which CCND1 and Bcl-2 served as necessary hub genes. In the integrative analysis, we found 61 hub genes and 5 significant pathways, including cell cycle, cytokine-cytokine receptor interaction, notching pathway, p53 pathway and focal adhesion, which proposed the relevant functions of miR-34a in HCC. CONCLUSION Our results may lead researchers to understand the molecular mechanism of miR-34a in the diagnosis, prognosis and therapy of HCC. Therefore, the interaction between miR-34a and its targets may promise better prediction and treatment for HCC. And the experiments in vivo and vitro will be conducted by our group to identify the specific mechanism of miR-34a in the progress and deterioration of HCC.
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Affiliation(s)
- Fang-Hui Ren
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Hong Yang
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Rong-Quan He
- Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Jing-Ning Lu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Xing-Gu Lin
- Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Hai-Wei Liang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Yi-Wu Dang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Zhen-Bo Feng
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China.
| | - Dian-Zhong Luo
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China.
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Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation. Nat Commun 2017; 8:2214. [PMID: 29263426 PMCID: PMC5738441 DOI: 10.1038/s41467-017-02363-w] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 11/21/2017] [Indexed: 02/01/2023] Open
Abstract
Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that function in pathways critical to cancer cell growth. Tankyrase-mediated PARylation marks protein targets for proteasomal degradation. Here, we generate human knockout cell lines to examine cell function and interrogate the proteome. We show that either tankyrase 1 or 2 is sufficient to maintain telomere length, but both are required to resolve telomere cohesion and maintain mitotic spindle integrity. Quantitative analysis of the proteome of tankyrase double knockout cells using isobaric tandem mass tags reveals targets of degradation, including antagonists of the Wnt/β-catenin signaling pathway (NKD1, NKD2, and HectD1) and three (Notch 1, 2, and 3) of the four Notch receptors. We show that tankyrases are required for Notch2 to exit the plasma membrane and enter the nucleus to activate transcription. Considering that Notch signaling is commonly activated in cancer, tankyrase inhibitors may have therapeutic potential in targeting this pathway. Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that mark proteins for degradation, but there is a current lack of knowledge about their distinct functions and substrates. Here, the authors elucidate the cellular roles and substrates of these polymerases using comparative functional and proteomics analyses of tankyrase knockout cell lines.
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Morell CM, Fiorotto R, Meroni M, Raizner A, Torsello B, Cadamuro M, Spagnuolo G, Kaffe E, Sutti S, Albano E, Strazzabosco M. Notch signaling and progenitor/ductular reaction in steatohepatitis. PLoS One 2017; 12:e0187384. [PMID: 29140985 PMCID: PMC5687773 DOI: 10.1371/journal.pone.0187384] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 10/18/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Persistent hepatic progenitor cells (HPC) activation resulting in ductular reaction (DR) is responsible for pathologic liver repair in cholangiopathies. Also, HPC/DR expansion correlates with fibrosis in several chronic liver diseases, including steatohepatitis. Increasing evidence indicates Notch signaling as a key regulator of HPC/DR response in biliary and more in general liver injuries. Therefore, we aimed to investigate the role of Notch during HPC/DR activation in a mouse model of steatohepatitis. METHODS Steatohepatitis was generated using methionine-choline deficient (MCD) diet. For hepatocyte lineage tracing, R26R-YFP mice were infected with AAV8-TBG-Cre. RESULTS MCD diet promoted a strong HPC/DR response that progressively diffused in the lobule, and correlated with increased fibrosis and TGF-β1 expression. Notch signaling was unchanged in laser-capture microdissected HPC/DR, whereas Notch receptors were down regulated in hepatocytes. However, in-vivo lineage tracing experiments identified discrete hepatocytes showing Notch-1 activation and expressing (the Notch-dependent) Sox9. Stimulation of AML-12 hepatocyte-cell line with immobilized Jag1 induced Sox9 and down-regulated albumin and BSEP expression. TGF-β1 treatment in primary hepatic stellate cells (HSC) induced Jag1 expression. In MCD diet-fed mice, αSMA-positive HSC were localized around Sox9 expressing hepatocytes, suggesting that Notch activation in hepatocytes was promoted by TGF-β1 stimulated HSC. In-vivo Notch inhibition reduced HPC response and fibrosis progression. CONCLUSION Our data suggest that Notch signaling is an important regulator of DR and that in steatohepatitis, hepatocytes exposed to Jag1-positive HSC, contribute to pathologic DR by undergoing Notch-mediated differentiation towards an HPC-like phenotype. Given the roles of Notch in fibrosis and liver cancer, these data suggest mesenchymal expression of Jag1 as an alternative therapeutic target.
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Affiliation(s)
- Carola M. Morell
- International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | - Romina Fiorotto
- International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
- Liver Center, Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, United States of America
| | - Marica Meroni
- International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | - Aileen Raizner
- Liver Center, Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, United States of America
| | - Barbara Torsello
- International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | - Massimiliano Cadamuro
- International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | - Gaia Spagnuolo
- International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | - Eleanna Kaffe
- Liver Center, Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, United States of America
| | - Salvatore Sutti
- Department of Health Sciences, University “A. Avogadro” of East Piedmont, Novara, Italy
| | - Emanuele Albano
- Department of Health Sciences, University “A. Avogadro” of East Piedmont, Novara, Italy
| | - Mario Strazzabosco
- International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
- Liver Center, Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, United States of America
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50
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Yu J, Zanotti S, Walia B, Jellison E, Sanjay A, Canalis E. The Hajdu Cheney Mutation Is a Determinant of B-Cell Allocation of the Splenic Marginal Zone. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 188:149-159. [PMID: 29037852 DOI: 10.1016/j.ajpath.2017.09.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 08/25/2017] [Accepted: 09/21/2017] [Indexed: 12/27/2022]
Abstract
The neurogenic locus notch homolog protein (Notch)-2 receptor is a determinant of B-cell allocation, and gain-of-NOTCH2-function mutations are associated with Hajdu-Cheney syndrome (HCS), a disease presenting with osteoporosis and acro-osteolysis. We generated a mouse model reproducing the HCS mutation (Notch2HCS), and heterozygous global mutant mice displayed gain-of-Notch2 function. In the mutant spleen, the characteristic perifollicular rim marking the marginal zone (MZ), which is the interface between the nonlymphoid red pulp and the lymphoid white pulp, merged with components of the white pulp. As a consequence, the MZ of Notch2HCS mice occupied most of the splenic structure. To explore the mechanisms involved, lymphocyte populations from the bone marrow and spleen were harvested from heterozygous Notch2HCS mice and sex-matched control littermates and analyzed by flow cytometry. Notch2HCS mice had an increase in CD21/35highCD23- splenic MZ B cells of approximately fivefold and a proportional decrease in splenic follicular B cells (CD21/35intCD23+) at 1, 2, and 12 months of age. Western blot analysis revealed that Notch2HCS mutant splenocytes had increased phospho-Akt and phospho-Jun N-terminal kinase, and gene expression analysis of splenic CD19+ B cells demonstrated induction of Hes1 and Hes5 in Notch2HCS mutants. Anti-Notch2 antibodies decreased MZ B cells in control and Notch2HCS mice. In conclusion, Notch2HCS mutant mice have increased mature B cells in the MZ of the spleen.
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Affiliation(s)
- Jungeun Yu
- Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, Farmington, Connecticut
| | - Stefano Zanotti
- Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, Farmington, Connecticut; Department of Medicine, UConn Musculoskeletal Institute, Farmington, Connecticut
| | - Bhavita Walia
- Department of Genetics and Developmental Biology, UConn Health, Farmington, Connecticut
| | - Evan Jellison
- Department of Immunology, UConn Health, Farmington, Connecticut
| | - Archana Sanjay
- Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, Farmington, Connecticut.
| | - Ernesto Canalis
- Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, Farmington, Connecticut; Department of Medicine, UConn Musculoskeletal Institute, Farmington, Connecticut.
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