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Rajasekar M, Suresh K, Theerthu A, Pugazhendhi R, Sivakumar K. Diosmin induces mitochondrial-mediated apoptosis and anti-inflammatory effects in Hep-2 cells: an integrated in vitro and in silico analysis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:7317-7329. [PMID: 39747464 DOI: 10.1007/s00210-024-03690-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 11/27/2024] [Indexed: 01/04/2025]
Abstract
The present study aims to explore the anticancer efficacy of Diosmin by inducing mitochondrial-mediated apoptosis in human epidermoid carcinoma cells (Hep-2). This is done by cell line assays and studying crucial inflammatory and apoptotic signaling molecules. The cytotoxicity property of Diosmin was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Marker expression study was done by western blotting for studying apoptotic markers like Bax, Bcl-2, p53, Bak, and Bcl-xl, proinflammatory cytokine (TNF-α), interleukins (IL-1, IL-6, IL-8), and signal transduction (STAT-3). The docking study confirms the affinity of Diosmin with apoptotic and important markers. Through the MTT assay, a dose-dependent cytotoxic effect of Diosmin was unveiled, with an IC50 value of effective inhibition of cell proliferation. Diosmin treatment resulted in noteworthy downregulation of Bcl-xl, Bak, Bcl-2, IL-1, 6, 8, TNF-α, and STAT-3 while upregulating the p53 and Bax expression levels, highlighting its inhibitory role in inducing apoptosis. Docking studies further exposed robust binding affinities between Diosmin and target apoptotic proteins, suggesting its efficacy in disrupting cellular functions and inflammatory signaling pathways in Hep-2 cells. The cytotoxic effects on Hep-2 cells and suggested activation of Bax, p53, and inhibition of Bcl-xl, Bak, Bcl-2, IL-1, 6, 8, TNF-α, as well as STAT-3 lead to the activation of mitochondrial-mediated apoptosis in Diosmin-treated Hep-2 cells. Further, its anti-inflammatory properties locate Diosmin as a conclusive compound for further studies for effective oral and other related squamous carcinoma treatments.
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Affiliation(s)
- Muthusamy Rajasekar
- Central Research Laboratory, Vinayaka Mission's Kirupananda Variyar Medical College and Hospitals, Vinayaka Mission's Research Foundation (Deemed to Be University), Salem, 636305, Tamil Nadu, India
| | - Kathiresan Suresh
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Chidambaram, 608002, Tamil Nadu, India.
| | - Azhamuthu Theerthu
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Chidambaram, 608002, Tamil Nadu, India
| | - Ravichandran Pugazhendhi
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Chidambaram, 608002, Tamil Nadu, India
| | - Kathiresan Sivakumar
- Department of Plant Science, Madurai Kamaraj University, Madurai, 625021, Tamil Nadu, India
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Karnuth B, Brundert A, Langer C, Masetto T, Müller C, Jüdt M, Stiegler Y, Stiegler H, Peter C, Grimmler M. Highly elevated sepsis biomarkers in advanced cholangiocarcinoma without sepsis: A case report and literature review. Medicine (Baltimore) 2025; 104:e42115. [PMID: 40419900 PMCID: PMC12114018 DOI: 10.1097/md.0000000000042115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 03/14/2025] [Accepted: 03/27/2025] [Indexed: 05/28/2025] Open
Abstract
RATIONALE Inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) are often elevated in liver cancer, making it difficult to monitor for bacterial infection. Hence, it is tempting to use more bacterial-specific sepsis markers such as procalcitonin (PCT) during immunosuppressive chemotherapy. This case study highlights the challenges of interpreting clinical chemistry sepsis biomarkers in patients with advanced cholangiocarcinoma (CCA). PATIENT CONCERNS A 55-year-old man presented with a liver mass on routine ultrasonography. MRI and CT showed multiple liver and bone metastases. The immunohistochemistry findings were consistent with an adenocarcinoma of the pancreaticobiliary system. After the diagnosis of primary hepatic CCA (NTM stage IV; FGFR2-SHROOM3 translocation) and 14 months of chemotherapy, the patient developed progressive liver lesions and new lung metastases. DIAGNOSES AND INTERVENTIONS During the last chemotherapy, PCT was highly elevated (>100 ng/mL), usually observed in severe sepsis or septic shock, whereas CRP was moderately elevated (<50 mg/L). The patient had mild leukopenia but no fever, systemic infection or septic shock. Blood and urine cultures were negative. OUTCOMES After referral to best supportive care, the patient died of liver failure. Retrospective blood analysis revealed high levels of soluble CD14 subtype, a bacterial sepsis marker known as presepsin. Calcitonin and IL-6 levels were above normal, consistent with advanced CCA, but not with a PCT/calcitonin-secreting tumor or systemic inflammation. LESSONS Oncologists are aware that CRP and IL-6 values can be elevated in liver cancer. Here, we further demonstrate that highly elevated, septic shock-like PCT values can occur even in the absence of bacterial sepsis. In addition, presepsin may be elevated, although mechanistically unrelated to PCT. Therefore, sepsis markers should be interpreted with caution and in the clinical context, not only in patients with neuroendocrine or hepatocellular carcinoma, which are known to secrete PCT and calcitonin, but also in patients with advanced CCA.
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Affiliation(s)
- Bianca Karnuth
- Medizinisches Versorgungszentrum für Labormedizin und Mikrobiologie Ruhr GmbH, Essen, Germany
| | - Almut Brundert
- Department of Medical Oncology, Evangelische Kliniken Essen-Mitte gGmbH, Essen, Germany
| | - Claus Langer
- Medizinisches Versorgungszentrum für Labormedizin und Mikrobiologie Ruhr GmbH, Essen, Germany
| | - Thomas Masetto
- Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- DiaSys Diagnostic Systems GmbH, Holzheim, Germany
| | - Christian Müller
- Department of Medical Oncology, Evangelische Kliniken Essen-Mitte gGmbH, Essen, Germany
| | - Maximilian Jüdt
- Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Yuriko Stiegler
- Medizinisches Versorgungszentrum für Labormedizin und Mikrobiologie Ruhr GmbH, Essen, Germany
| | - Hugo Stiegler
- Medizinisches Versorgungszentrum für Labormedizin und Mikrobiologie Ruhr GmbH, Essen, Germany
| | - Christoph Peter
- Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Matthias Grimmler
- Institute for Biomolecular Research, Hochschule Fresenius gGmbH, University of Applied Sciences, Idstein, Germany
- DiaServe Laboratories GmbH, Iffeldorf, Germany
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Ahmadi Asouri S, Aghadavood E, Mirzaei H, Abaspour A, Esmaeil Shahaboddin M. PIWI-interacting RNAs (PiRNAs) as emerging biomarkers and therapeutic targets in biliary tract cancers: A comprehensive review. Heliyon 2024; 10:e33767. [PMID: 39040379 PMCID: PMC11261894 DOI: 10.1016/j.heliyon.2024.e33767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 06/09/2024] [Accepted: 06/26/2024] [Indexed: 07/24/2024] Open
Abstract
Cancers affecting the biliary tract, such as gallbladder cancer and cholangiocarcinoma, make up a small percentage of adult gastrointestinal malignancies, but their incidence is on the rise. Due to the lack of dependable molecular biomarkers for diagnosis and prognosis, these cancers are often not detected until later stages and have limited treatment options. Piwi-interacting RNAs (piRNAs) are a type of small noncoding RNA that interacts with Piwi proteins and has been linked to various diseases, especially cancer. Manipulation of piRNA expression has the potential to serve as an important biomarker and target for therapy. This review uncovers the relationship between PIWI-interacting RNA (piRNA) and a variety of gastrointestinal cancers, including biliary tract cancer (BTC). It is evident that piRNAs have the ability to impact gene expression and regulate key genes and pathways related to the advancement of digestive cancers. Abnormal expression of piRNAs plays a significant role in the development and progression of digestive-related malignancies. The potential of piRNAs as potential biomarkers for diagnosis and prognosis, as well as therapeutic targets in BTC, is noteworthy. Nevertheless, there are obstacles and limitations that require further exploration to fully comprehend piRNAs' role in BTC and to devise effective diagnostic and therapeutic approaches using piRNAs. In summary, this review underscores the value of piRNAs as valuable biomarkers and promising targets for treating BTC, as we delve into the association between piRNAs and various gastrointestinal cancers, including BTC, and how piRNAs can impact gene expression and control essential pathways for digestive cancer advancement. The present research consists of a thorough evaluation presented in a storytelling style. The databases utilized to locate original sources were PubMed, MEDLINE, and Google Scholar, and the search was conducted using the designated keywords.
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Affiliation(s)
- Sahar Ahmadi Asouri
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Esmat Aghadavood
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Mirzaei
- Institute for Basic Sciences, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Alireza Abaspour
- Department of Pathobiology and Laboratory Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Mohammad Esmaeil Shahaboddin
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Institute for Basic Sciences, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
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Wang W, Lopez McDonald MC, Hariprasad R, Hamilton T, Frank DA. Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation. Cancers (Basel) 2024; 16:1387. [PMID: 38611065 PMCID: PMC11011165 DOI: 10.3390/cancers16071387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 03/25/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics.
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Affiliation(s)
- Weiyuan Wang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA 30322, USA; (W.W.); (M.C.L.M.); (T.H.)
| | - Melanie Cristina Lopez McDonald
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA 30322, USA; (W.W.); (M.C.L.M.); (T.H.)
| | | | - Tiara Hamilton
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA 30322, USA; (W.W.); (M.C.L.M.); (T.H.)
| | - David A. Frank
- Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA 30322, USA; (W.W.); (M.C.L.M.); (T.H.)
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Liu CW, Peng HY, Siao AC, Tsuei YW, Lin YY, Shiah SG, Shih LJ, Yeh CC, Lee SW, Kao YH. Resistin stimulates PC-3 prostate cancer cell growth through stimulation of SOCS3 and SOCS5 genes. Exp Biol Med (Maywood) 2023; 248:1695-1707. [PMID: 37646261 PMCID: PMC10792425 DOI: 10.1177/15353702231191206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 05/08/2023] [Indexed: 09/01/2023] Open
Abstract
Resistin and suppressors of cytokine signaling (SOCSs) have been reported to regulate prostate cancer (PCa) cell proliferation and survival, respectively. Whether any of the SOCS molecules mediate the mitogenic effect of resistin on PCa cells is unknown. Using PC-3 human PCa cells, we found that resistin upregulates the expression of SOCS3 and SOCS5 mRNA, but not SOCS7 mRNA, in a dose- and time-dependent manner. The resistin-induced increases in SOCS3 and SOCS5 expression and cell proliferation were prevented by pretreatment with specific inhibitors of the TLR4, ERK, p38 MAPK, JNK, PI3K, and JAK2 proteins. However, pretreatment with a TLR2 inhibitor had no effect on resistin-mediated SOCS3 and SOCS5 expression. In addition, the effects of resistin on SOCS3, SOCS5, and SOCS7 mRNA levels were cell type-specific. Overexpression of either SOCS3 or SOCS5 enhanced further resistin-stimulated growth of PC-3 cells, whereas silencing SOCS3 or SOCS5 antagonized resistin-increased cell growth. Further PCa tissue analysis demonstrated higher levels of RETN, TLR4, SOCS3, and SOCS5 mRNAs in cancer tissues than benign prostate hyperplasia and indicated positive correlations among RETN, TLR4, and SOCS5. These data suggest that SOCS5, TLR4, and, to a lesser extent, SOCS3 can mediate the mitogenic effect of resistin on PC-3 PCa cells.
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Affiliation(s)
- Chi-Wei Liu
- Department of Life Sciences, National Central University, Taoyuan 320
- Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330
| | - Hsuan-Yu Peng
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 350
| | - An-Ci Siao
- Department of Life Sciences, National Central University, Taoyuan 320
| | - Yi-Wei Tsuei
- Department of Emergency Medicine, Taoyuan Armed Forces General Hospital, Taoyuan 325
| | - Yen-Yue Lin
- Department of Life Sciences, National Central University, Taoyuan 320
- Department of Emergency Medicine, Taoyuan Armed Forces General Hospital, Taoyuan 325
| | - Shine-Gwo Shiah
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 350
| | - Li-Jane Shih
- Medical Laboratory, Taoyuan Armed Forces General Hospital, Taoyuan 325
| | - Chien-Chih Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, Taoyuan Armed Forces General Hospital, Taoyuan 325
| | - Shih-Wei Lee
- Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330
- Department of Nursing, Yuanpei University of Medical Technology, Hsinchu 300
| | - Yung-Hsi Kao
- Department of Life Sciences, National Central University, Taoyuan 320
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7
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Zhao LM, Shi AD, Yang Y, Liu ZL, Hu XQ, Shu LZ, Tang YC, Zhang ZL. Advances in molecular and cell therapy for immunotherapy of cholangiocarcinoma. Front Oncol 2023; 13:1140103. [PMID: 37064120 PMCID: PMC10090456 DOI: 10.3389/fonc.2023.1140103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 03/17/2023] [Indexed: 03/31/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly malignant tumor of the hepatobiliary system that has failed to respond to many traditional therapies to a certain extent, including surgery, chemotherapy and radiotherapy. In recent years, the new therapeutic schemes based on immunology have fundamentally changed the systemic treatment of various malignant tumors to a certain extent. In view of the immunogenicity of CCA, during the occurrence and development of CCA, some immunosuppressive substances are released from cells and immunosuppressive microenvironment is formed to promote the escape immune response of its own cells, thus enhancing the malignancy of the tumor and reducing the sensitivity of the tumor to drugs. Some immunotherapy regimens for cholangiocarcinoma have produced good clinical effects. Immunotherapy has more precise characteristics and less adverse reactions compared with traditional treatment approaches. However, due to the unique immune characteristics of CCA, some patients with CCA may not benefit in the long term or not benefit at all after current immunotherapy. At present, the immunotherapy of CCA that have been clinically studied mainly include molecular therapy and cell therapy. In this article, we generalized and summarized the current status of immunotherapy strategies including molecular therapy and cell therapy in CCA in clinical studies, and we outlined our understanding of how to enhance the clinical application of these immunotherapy strategies.
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Affiliation(s)
- Li-ming Zhao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - An-da Shi
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Yan Yang
- Department of General Surgery, Shanxian Central Hospital, Heze, China
| | - Zeng-li Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
- Department of General Surgery, Qilu Hospital (Qingdao), Shandong University, Jinan, China
| | - Xiao-Qiang Hu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Li-Zhuang Shu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Yong-chang Tang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
- *Correspondence: Yong-chang Tang, ; Zong-li Zhang,
| | - Zong-li Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
- *Correspondence: Yong-chang Tang, ; Zong-li Zhang,
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8
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Circulating Tumor DNA Methylation Biomarkers for Characterization and Determination of the Cancer Origin in Malignant Liver Tumors. Cancers (Basel) 2023; 15:cancers15030859. [PMID: 36765815 PMCID: PMC9913861 DOI: 10.3390/cancers15030859] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/25/2023] [Accepted: 01/26/2023] [Indexed: 02/01/2023] Open
Abstract
Malignant liver tumors include primary malignant liver tumors and liver metastases. They are among the most common malignancies worldwide. The disease has a poor prognosis and poor overall survival, especially with liver metastases. Therefore, early detection and differentiation between malignant liver tumors are critical for patient treatment selection. The detection of cancer and the prediction of its origin is possible with a DNA methylation profile of the tumor DNA compared to that of normal cells, which reflects tissue differentiation and malignant transformation. New technologies enable the characterization of the tumor methylome in circulating tumor DNA (ctDNA), providing a variety of new ctDNA methylation biomarkers, which can provide additional information to clinical decision-making. Our review of the literature provides insight into methylation changes in ctDNA from patients with common malignant liver tumors and can serve as a starting point for further research.
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9
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Kim M, Delgado E, Ko S. DNA methylation in cell plasticity and malignant transformation in liver diseases. Pharmacol Ther 2023; 241:108334. [PMID: 36535346 PMCID: PMC9841769 DOI: 10.1016/j.pharmthera.2022.108334] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
The liver possesses extraordinary regenerative capacity mainly attributable to the ability of hepatocytes (HCs) and biliary epithelial cells (BECs) to self-replicate. This ability is left over from their bipotent parent cell, the hepatoblast, during development. When this innate regeneration is compromised due to the absence of proliferative parenchymal cells, such as during cirrhosis, HCs and BEC can transdifferentiate; thus, adding another layer of complexity to the process of liver repair. In addition, dysregulated lineage maintenance in these two cell populations has been shown to promote malignant growth in experimental conditions. Here, malignant transformation, driven in part by insufficient maintenance of lineage reprogramming, contributes to end-stage liver disease. Epigenetic changes are key drivers for cell fate decisions as well as transformation by finetuning overall transcription and gene expression. In this review, we address how altered DNA methylation contributes to the initiation and progression of hepatic cell fate conversion and cancer formation. We also discussed the diagnostic and therapeutic potential of targeting DNA methylation in liver cancer, its current limitations, and what future research is necessary to facilitate its contribution to clinical translation.
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Affiliation(s)
- Minwook Kim
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Evan Delgado
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
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10
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Yang M, Li M, Lyu Z, Yang Z. Implication of Ferroptosis in Cholangiocarcinoma: A Potential Future Target? Cancer Manag Res 2023; 15:335-342. [PMID: 37063167 PMCID: PMC10093512 DOI: 10.2147/cmar.s406150] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 03/30/2023] [Indexed: 04/18/2023] Open
Abstract
Cholangiocarcinoma (CCA), the second most common liver neoplasm, has a poor overall 5-year survival rate of less than 10%. A deeper understanding of the molecular pathogenesis contributing to CCA progression is essential for developing better therapeutic approaches to manage this disease. Ferroptosis, an oxidative iron-dependent form of regulated cell death, has been reported to be involved in tumorigenesis and progression. In particular, ferroptosis and inflammation, which are common issues in cholangiocarcinogenesis and CCA development, might be in concert with disease progression. Notably, the key feature of cancer cells is "iron addiction", which is crucial for the high metabolic demand in carcinogenesis and cancer progression. Additionally, iron metabolism is of great importance in ferroptosis. Moreover, that cancer cells are vulnerable to ferroptosis might be a possible mechanism of CCA development. Although the underlying mechanism of how ferroptosis is implicated in CCA development requires further investigation, developing a new strategy combined with a pro-ferroptotic treatment would be an exciting CCA treatment approach in the future.
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Affiliation(s)
- Mingyu Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
| | - Meng Li
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
| | - Zhuozhen Lyu
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
| | - Zhen Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
- Correspondence: Zhen Yang, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, JingWu Road, Jinan, Shandong, 25000, People’s Republic of China, Tel +86 15168867123, Email
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11
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Johansson P, Laguna T, Ossowski J, Pancaldi V, Brauser M, Dührsen U, Keuneke L, Queiros A, Richter J, Martín-Subero JI, Siebert R, Schlegelberger B, Küppers R, Dürig J, Murga Penas EM, Carillo-de Santa Pau E, Bergmann AK. Epigenome-wide analysis of T-cell large granular lymphocytic leukemia identifies BCL11B as a potential biomarker. Clin Epigenetics 2022; 14:148. [PMID: 36376973 PMCID: PMC9664638 DOI: 10.1186/s13148-022-01362-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 10/20/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND The molecular pathogenesis of T-cell large granular lymphocytic leukemia (T-LGLL), a mature T-cell leukemia arising commonly from T-cell receptor αβ-positive CD8+ memory cytotoxic T cells, is only partly understood. The role of deregulated methylation in T-LGLL is not well known. We analyzed the epigenetic profile of T-LGLL cells of 11 patients compared to their normal counterparts by array-based DNA methylation profiling. For identification of molecular events driving the pathogenesis of T-LGLL, we compared the differentially methylated loci between the T-LGLL cases and normal T cells with chromatin segmentation data of benign T cells from the BLUEPRINT project. Moreover, we analyzed gene expression data of T-LGLL and benign T cells and validated the results by pyrosequencing in an extended cohort of 17 patients, including five patients with sequential samples. RESULTS We identified dysregulation of DNA methylation associated with altered gene expression in T-LGLL. Since T-LGLL is a rare disease, the samples size is low. But as confirmed for each sample, hypermethylation of T-LGLL cells at various CpG sites located at enhancer regions is a hallmark of this disease. The interaction of BLC11B and C14orf64 as suggested by in silico data analysis could provide a novel pathogenetic mechanism that needs further experimental investigation. CONCLUSIONS DNA methylation is altered in T-LGLL cells compared to benign T cells. In particular, BCL11B is highly significant differentially methylated in T-LGLL cells. Although our results have to be validated in a larger patient cohort, BCL11B could be considered as a potential biomarker for this leukemia. In addition, altered gene expression and hypermethylation of enhancer regions could serve as potential mechanisms for treatment of this disease. Gene interactions of dysregulated genes, like BLC11B and C14orf64, may play an important role in pathogenic mechanisms and should be further analyzed.
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Affiliation(s)
- Patricia Johansson
- grid.5718.b0000 0001 2187 5445Faculty of Medicine, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Virchowstr. 177, 45122 Essen, Germany
| | - Teresa Laguna
- grid.482878.90000 0004 0500 5302Computational Biology Group, Precision Nutrition and Cancer Research Program, IMDEA Food Institute, 28049 Madrid, Spain
| | - Julio Ossowski
- grid.9764.c0000 0001 2153 9986Institute for Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig Holstein, Campus Kiel, Kiel, Germany ,grid.10423.340000 0000 9529 9877Institute of Human Genetics, Medical School Hannover (MHH), Hannover, Germany
| | - Vera Pancaldi
- grid.468186.5Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, INSERM U1037, 31037 Toulouse, France ,grid.10097.3f0000 0004 0387 1602Barcelona Supercomputing Center, 08034 Barcelona, Spain
| | - Martina Brauser
- grid.5718.b0000 0001 2187 5445Faculty of Medicine, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Virchowstr. 177, 45122 Essen, Germany
| | - Ulrich Dührsen
- grid.5718.b0000 0001 2187 5445Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Lara Keuneke
- grid.9764.c0000 0001 2153 9986Institute for Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig Holstein, Campus Kiel, Kiel, Germany
| | - Ana Queiros
- grid.5841.80000 0004 1937 0247Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain
| | - Julia Richter
- grid.9764.c0000 0001 2153 9986Institute for Pathology, Christian-Albrechts-University Kiel and University Hospital Schleswig Holstein, Campus Kiel, Kiel, Germany
| | - José I. Martín-Subero
- grid.5841.80000 0004 1937 0247Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain ,grid.425902.80000 0000 9601 989XInstitució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
| | - Reiner Siebert
- grid.9764.c0000 0001 2153 9986Institute for Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig Holstein, Campus Kiel, Kiel, Germany ,grid.410712.10000 0004 0473 882XPresent Address: Institute of Human Genetics, University of Ulm and University Medical Center Ulm, Ulm, Germany
| | - Brigitte Schlegelberger
- grid.10423.340000 0000 9529 9877Institute of Human Genetics, Medical School Hannover (MHH), Hannover, Germany
| | - Ralf Küppers
- grid.5718.b0000 0001 2187 5445Faculty of Medicine, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Virchowstr. 177, 45122 Essen, Germany
| | - Jan Dürig
- grid.500068.bDepartment of Internal Medicine, University Hospital Essen, St. Josef-Krankenhaus, University Medicine Essen, Essen, Germany
| | - Eva M. Murga Penas
- grid.9764.c0000 0001 2153 9986Institute for Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig Holstein, Campus Kiel, Kiel, Germany
| | - Enrique Carillo-de Santa Pau
- grid.482878.90000 0004 0500 5302Computational Biology Group, Precision Nutrition and Cancer Research Program, IMDEA Food Institute, 28049 Madrid, Spain
| | - Anke K. Bergmann
- grid.10423.340000 0000 9529 9877Institute of Human Genetics, Medical School Hannover (MHH), Hannover, Germany
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12
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Gao Y, Ji W, Lu M, Wang Z, Jia X, Wang D, Cao P, Hu C, Sun X, Wang Z. Systemic pharmacological verification of Guizhi Fuling decoction in treating endometriosis-associated pain. JOURNAL OF ETHNOPHARMACOLOGY 2022; 297:115540. [PMID: 35870685 DOI: 10.1016/j.jep.2022.115540] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 07/03/2022] [Accepted: 07/11/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Guizhi Fuling decoction (GZFL decoction) is a famous formula in the Synopsis of the Golden Chamber, which has a long history in treating endometriosis. However, its exact mechanism remains unclear. AIM OF STUDY This study aims to explore the mechanism of GZFL decoction in treating endometriosis, especially in alleviating endometriosis-associated pain. MATERIALS AND METHODS A combination of system pharmacology and pharmacodynamics was used to explore the specific mechanism of GZFL decoction in the treatment of endometriosis-associated pain. First, the TCMSP database was used to search the components of the GZFL decoction; the parameter index was set as oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 0.18, while the active ingredients of the drug were screened out. The disease targets of endometriosis were obtained from the TTD, OMIM, Genecards, and DisGeNET databases; the keyword was "endometriosis pain". Network construction and analysis were performed using Cytoscape 3.7.2 software; the David database was used to enrich and analyze the pathways for alleviating endometriosis pain after GZFL decoction treatment. In addition, the network results were verified using experimental animal and cell research. RESULTS The results showed the following targets: 76 for the effective chemical components in the prescription, 1329 for disease pain, and 278 for the intersection of drugs and endometriosis pain. The enrichment results for these targets showed that the TNF-PI3K/Akt pathway exhibited research significance. In endometriosis rat models, the GZFL decoction reduced the volume of lesions and relieved pain symptoms. It also reduced the serum levels of IL-6, IL-1β, and TNF-α as well as their expression in the lesion tissues. The GZFL decoction also suppressed the activation of PI3K/Akt downstream signaling proteins. CONCLUSIONS GZFL decoction could reduce the volume of lesions, suppress inflammation, and decrease the sensitivity to pain in endometriosis rat models through inhibiting PI3K/Akt pathway. This study provides a possible target for traditional Chinese medicine in treating endometriosis-associated pain.
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Affiliation(s)
- Yang Gao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenjing Ji
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Man Lu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhiheng Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xurui Jia
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Dawei Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Peng Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chunping Hu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaoyan Sun
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| | - Zhigang Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
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13
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Satow R, Aiga Y, Watanabe T, Ishizuka N, Yoneda A, Fukami K. Zic family member 5 promotes survival in human pancreatic cancer and cholangiocarcinoma cells. Biochem Biophys Rep 2022; 31:101289. [PMID: 35669984 PMCID: PMC9166430 DOI: 10.1016/j.bbrep.2022.101289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are malignant tumors with poor prognosis because of the limited effectiveness of traditional chemotherapy and few effective molecular therapeutic agents. Here, we determined the essential roles of Zic family member 5 (ZIC5) in the survival of PDAC and CCA cells. The results showed that ZIC5 is strongly expressed in PDAC and CCA tissues, while ZIC5 expression is barely observed in most normal human adult tissues. Furthermore, ZIC5 expression is related to poor prognosis of patients with PDAC. ZIC5 knockdown via small interfering RNA decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3), a protein that is associated with PDAC and CCA aggressiveness. However, ZIC5 knockdown induced cell death regardless of STAT3 activation, which is promoted by interleukin (IL) −6, a factor associated with inflammation. Furthermore, knockdown of ZIC5 in PDAC and CCA cells additively or synergistically induced apoptosis with the anti-cancer drug gemcitabine. Thus, ZIC5 constitutes a potential therapeutic target for the treatment of PDAC and CCA.
ZIC5 is expressed in PDAC and CCA, while barely observed in normal adult tissues. ZIC5 expression is related to poor prognosis of patients with PDAC. ZIC5 knockdown induces apoptosis in several PDAC and CCA cell lines. Knockdown of ZIC5 additively or synergistically induces apoptosis with gemcitabine.
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Affiliation(s)
- Reiko Satow
- Corresponding author. Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-city, Tokyo, 192-0392, Japan.
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14
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Li H, Lan T, Liu H, Liu C, Dai J, Xu L, Cai Y, Hou G, Xie K, Liao M, Li J, Huang J, Yuan K, Wang G, Zeng Y, Wu H. IL-6-induced cGGNBP2 encodes a protein to promote cell growth and metastasis in intrahepatic cholangiocarcinoma. Hepatology 2022; 75:1402-1419. [PMID: 34758510 PMCID: PMC9306806 DOI: 10.1002/hep.32232] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 10/26/2021] [Accepted: 11/05/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS IL-6-induced tumor progression has been well established through the induction of antiapoptotic and proliferative genes. However, whether other mechanisms such as IL-6 regulation of circular RNAs (circRNAs) may also contribute to tumor development remains unknown. APPROACH AND RESULTS High-throughput RNA sequencing was used to identify the differentially expressed circRNAs on IL-6 stimulation in intrahepatic cholangiocarcinoma (ICC) cells. CircRNA GGNBP2 (derived from ggnbp2 gene, termed as cGGNBP2) was up-regulated by IL-6 treatment in a time and concentration-dependent manner. The biogenesis of cGGNBP2 was regulated by RNA-binding protein DEx-H Box Helicase 9, which was also mediated by IL-6 exposure. Mass spectrometry and western blotting identified a protein cGGNBP2-184aa encoded by cGGNBP2. cGGNBP2-184aa promoted ICC cell proliferation and metastasis in vitro and in vivo. Mechanistically, cGGNBP2-184aa directly interacted with signal transducers and activators of transduction-3 (STAT3), phosphorylated STAT3Tyr705 , and played a positive regulatory role in modulating IL-6/STAT3 signaling. IL-6/cGGNBP2-184aa/STAT3 formed a positive feedback loop to sustain constitutive activation of IL-6/STAT3 signaling. Elevated cGGNBP2 expression was correlated with poor prognosis of patients with ICC and was identified as an independent risk factor for patient prognosis. CONCLUSIONS Our study demonstrates that cGGNBP2-184aa, a protein encoded by IL-6-induced cGGNBP2, formed a positive feedback loop to facilitate ICC progression and may serve as an auxiliary target for clinical IL-6/STAT3-targeting treatments in ICC.
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Affiliation(s)
- Hui Li
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
- Department of Hepatobiliary Pancreatic Tumor CenterChongqing University Cancer HospitalChongqingChina
| | - Tian Lan
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Hailing Liu
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Chang Liu
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
| | - Junlong Dai
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
| | - Lin Xu
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Yunshi Cai
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Guimin Hou
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Kunlin Xie
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Mingheng Liao
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Jiaxin Li
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Jiwei Huang
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Kefei Yuan
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Genshu Wang
- Department of Hepatic Surgery and Liver Transplantation CenterThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Yong Zeng
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Hong Wu
- Department of Liver SurgeryLiver Transplantation DivisionWest China HospitalSichuan UniversityChengduChina
- Laboratory of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
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15
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Zeinalzadeh E, Valerievich Yumashev A, Rahman HS, Marofi F, Shomali N, Kafil HS, Solali S, Sajjadi-Dokht M, Vakili-Samiani S, Jarahian M, Hagh MF. The Role of Janus Kinase/STAT3 Pathway in Hematologic Malignancies With an Emphasis on Epigenetics. Front Genet 2021; 12:703883. [PMID: 34992627 PMCID: PMC8725977 DOI: 10.3389/fgene.2021.703883] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 08/12/2021] [Indexed: 12/12/2022] Open
Abstract
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway has been known to be involved in cell growth, cellular differentiation processes development, immune cell survival, and hematopoietic system development. As an important member of the STAT family, STAT3 participates as a major regulator of cellular development and differentiation-associated genes. Prolonged and persistent STAT3 activation has been reported to be associated with tumor cell survival, proliferation, and invasion. Therefore, the JAK-STAT pathway can be a potential target for drug development to treat human cancers, e.g., hematological malignancies. Although STAT3 upregulation has been reported in hematopoietic cancers, protein-level STAT3 mutations have also been reported in invasive leukemias/lymphomas. The principal role of STAT3 in tumor cell growth clarifies the importance of approaches that downregulate this molecule. Epigenetic modifications are a major regulatory mechanism controlling the activity and function of STAT3. So far, several compounds have been developed to target epigenetic regulatory enzymes in blood malignancies. Here, we discuss the current knowledge about STAT3 abnormalities and carcinogenic functions in hematopoietic cancers, novel STAT3 inhibitors, the role of epigenetic mechanisms in STAT3 regulation, and targeted therapies, by focusing on STAT3-related epigenetic modifications.
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Affiliation(s)
- Elham Zeinalzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaimaniyah, Iraq
- Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaimaniyah, Iraq
| | - Faroogh Marofi
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Navid Shomali
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Samadi Kafil
- German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), Heidelberg, Germany
| | - Saeed Solali
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Sajjadi-Dokht
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sajjad Vakili-Samiani
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), Heidelberg, Germany
| | - Majid Farshdousti Hagh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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16
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Sarantis P, Tzanetatou ED, Ioakeimidou E, Vallilas C, Androutsakos T, Damaskos C, Garmpis N, Garmpi A, Papavassiliou AG, Karamouzis MV. Cholangiocarcinoma: the role of genetic and epigenetic factors; current and prospective treatment with checkpoint inhibitors and immunotherapy. Am J Transl Res 2021; 13:13246-13260. [PMID: 35035673 PMCID: PMC8748131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 11/09/2021] [Indexed: 06/14/2023]
Abstract
Cholangiocarcinoma (CCA) represents 3% of all gastrointestinal cancers worldwide and is the second most common primary liver tumor after hepatocellular carcinoma. CCA is an aggressive tumor that involves the intrahepatic, perihilar and distal biliary tree, with a poor prognosis and an increasing incidence worldwide. Various genetic and epigenetic factors have been implicated in CCA development. Gene mutations involving apoptosis control and cell cycle evolution, histone modifications, methylation dysregulation and abnormal expression of non-coding RNA are the most important of these factors. Regarding treatment, surgical resection, cisplatin and gemcitabine have long been the most common treatment options, but 5-year survival (7-20%) is disappointing. For that reason, inhibitors and small molecules related to specific mutations and molecular pathways have been introduced. Among them, immunotherapy seems to be a promising treatment in CCA, with multiple regimens being under clinical trial studies. The combinatorial therapy of traditional CCA treatment with tyrosine kinase inhibitors and/or immunotherapy seem to be the future, depending on the molecular profile of each patient's tumor.
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Affiliation(s)
- Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Eleftheria Dikoglou Tzanetatou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Evangelia Ioakeimidou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Christos Vallilas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Theodoros Androutsakos
- Pathophysiology Department, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Christos Damaskos
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
- Renal Transplantation Unit, Laiko General Hospital11527 Athens, Greece
| | - Nikolaos Garmpis
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Athanasios G Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
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17
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Koustas E, Trifylli EM, Sarantis P, Papavassiliou AG, Karamouzis MV. Role of autophagy in cholangiocarcinoma: An autophagy-based treatment strategy. World J Gastrointest Oncol 2021; 13:1229-1243. [PMID: 34721764 PMCID: PMC8529918 DOI: 10.4251/wjgo.v13.i10.1229] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/28/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinomas (CCAs) are diverse biliary epithelial tumours involving the intrahepatic, perihilar and distal parts of the biliary tree. The three entirely variable entities have distinct epidemiology, molecular characteristics, prognosis and strategy for clinical management. However, many cholangiocarcinoma tumor-cells appear to be resistant to current chemotherapeutic agents. The role of autophagy and the therapeutic value of autophagy-based therapy are largely unknown in CCA. The multistep nature of autophagy offers a plethora of regulation points, which are prone to be deregulated and cause different human diseases, including cancer. However, it offers multiple targetable points for designing novel therapeutic strategies. Tumor cells have evolved to use autophagy as an adaptive mechanism for survival under stressful conditions such as energy imbalance and hypoxic region of tumors within the tumor microenvironment, but also to increase invasiveness and resistance to chemotherapy. The purpose of this review is to summarize the current knowledge regarding the interplay between autophagy and cholangiocarcinogenesis, together with some preclinical studies with agents that modulate autophagy in order to induce tumor cell death. Altogether, a combinatorial strategy, which comprises the current anti-cancer agents and autophagy modulators, would represent a positive CCA patient approach.
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Affiliation(s)
- Evangelos Koustas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Eleni-Myrto Trifylli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Michalis V Karamouzis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
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18
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The State of Immunotherapy in Hepatobiliary Cancers. Cells 2021; 10:cells10082096. [PMID: 34440865 PMCID: PMC8393650 DOI: 10.3390/cells10082096] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 08/02/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary cancers, including hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder carcinoma (GBC), are lethal cancers with limited therapeutic options. Curative-intent treatment typically involves surgery, yet recurrence is common and many patients present with advanced disease not amenable to an operation. Immunotherapy represents a promising approach to improve outcomes, but the immunosuppressive tumor microenvironment of the liver characteristic of hepatobiliary cancers has hampered the development and implementation of this therapeutic approach. Current immunotherapies under investigation include immune checkpoint inhibitors (ICI), the adoptive transfer of immune cells, bispecific antibodies, vaccines, and oncolytic viruses. Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two ICIs that have demonstrated utility in HCC, and newer immune checkpoint targets are being tested in clinical trials. In advanced CCA and GBC, PD-1 ICIs have resulted in antitumor responses, but only in a minority of select patients. Other ICIs are being investigated for patients with CCA and GBC. Adoptive transfer may hold promise, with reports of complete durable regression in metastatic CCA, yet this therapeutic approach may not be generalizable. Alternative approaches have been developed and promising results have been observed, but clinical trials are needed to validate their utility. While the treatment of hepatobiliary cancers involves unique challenges that these cancers present, the progress seen with ICIs and adoptive transfer has solidified immunotherapy as an important approach in these challenging patients with few other effective treatment options.
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19
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Fragkou N, Sideras L, Panas P, Emmanouilides C, Sinakos E. Update on the association of hepatitis B with intrahepatic cholangiocarcinoma: Is there new evidence? World J Gastroenterol 2021; 27:4252-4275. [PMID: 34366604 PMCID: PMC8316913 DOI: 10.3748/wjg.v27.i27.4252] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/12/2021] [Accepted: 06/18/2021] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a subgroup of cholangiocarcinoma that accounts for about 10%-20% of the total cases. Infection with hepatitis B virus (HBV) is one of the most important predisposing factors leading to the formation of iCCA. It has been recently estimated based on abundant epidemiological data that the association between HBV infection and iCCA is strong with an odds ratio of about 4.5. The HBV-associated mechanisms that lead to iCCA are under intense investigation. The diagnosis of iCCA in the context of chronic liver disease is challenging and often requires histological confirmation to distinguish from hepatocellular carcinoma. It is currently unclear whether antiviral treatment for HBV can decrease the incidence of iCCA. In terms of management, surgical resection remains the mainstay of treatment. There is a need for effective treatment modalities beyond resection in both first- and second-line treatment. In this review, we summarize the epidemiological evidence that links the two entities, discuss the pathogenesis of HBV-associated iCCA, and present the available data on the diagnosis and management of this cancer.
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Affiliation(s)
- Nikolaos Fragkou
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Lazaros Sideras
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Panteleimon Panas
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | | | - Emmanouil Sinakos
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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20
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Cigliano A, Chen X, Calvisi DF. Current challenges to underpinning the genetic basis for cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:511-526. [PMID: 33888034 PMCID: PMC8173760 DOI: 10.1080/17474124.2021.1915128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/07/2021] [Indexed: 12/23/2022]
Abstract
AREAS COVERED This review provides an overview regarding the current scenario and knowledge of the CCA genomic landscape and the potentially actionable molecular aberrations in each CCA subtype. EXPERT OPINION The establishment and advances of high-throughput methodologies applied to genetic and epigenetic profiling are changing many cancer types' therapeutic landscape , including CCA.The large body of data generated must be interpreted appropriately and eventually implemented in clinical practice. The following advancements toward precision medicine in CCA management will require designing better clinical trials with improved methods to stratify biliary tumor patients.
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Affiliation(s)
- Antonio Cigliano
- Department of Medical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Italy
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA
| | - Diego F. Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
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21
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Wang J, Ilyas S. Targeting the tumor microenvironment in cholangiocarcinoma: implications for therapy. Expert Opin Investig Drugs 2021; 30:429-438. [PMID: 33322977 PMCID: PMC8096665 DOI: 10.1080/13543784.2021.1865308] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 12/14/2020] [Indexed: 02/08/2023]
Abstract
Introduction: Cholangiocarcinomas (CCAs) are biliary epithelial tumors with rising incidence over the past 3 decades. Early diagnosis of CCAs remains a significant challenge and the majority of patients present at an advanced stage. CCAs are heterogeneous tumors and currently available standard systemic therapy options are of limited effectiveness. Immune checkpoint inhibition (ICI) has transformed cancer therapy across a spectrum of malignancies. However, the response rate to ICI has been relatively disappointing in CCAs owing to its desmoplastic tumor microenvironment (TME).Areas covered: Tumor microenvironment of CCAs consists of innate and adaptive cells, stromal cells, and extracellular components (cytokines, chemokines, exosomes, etc.). This intricate microenvironment has multiple immunosuppressive elements that promote tumor cell survival and therapeutic resistance. Accordingly, there is a need for the development of effective therapeutic strategies that target the TME. Herein, we review the components of the CCA TME, and potential therapies targeting the CCA TME.Expert opinion: CCAs are desmoplastic tumors with a dense tumor microenvironment. An enhanced understanding of the various components of the CCA TME is essential in the effort to develop novel biomarkers for patient stratification as well as combination therapeutic strategies that target the tumor plus the TME.
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Affiliation(s)
- Juan Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Sumera Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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22
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Armartmuntree N, Jusakul A, Sakonsinsiri C, Loilome W, Pinlaor S, Ungarreevittaya P, Yong CH, Techasen A, Imtawil K, Kraiklang R, Suwannakul N, Kaewlert W, Chaiprasert T, Thanan R, Murata M. Promoter hypermethylation of early B cell factor 1 (EBF1) is associated with cholangiocarcinoma progression. J Cancer 2021; 12:2673-2686. [PMID: 33854627 PMCID: PMC8040704 DOI: 10.7150/jca.52378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/14/2021] [Indexed: 01/20/2023] Open
Abstract
DNA hypermethylation in a promoter region causes gene silencing via epigenetic changes. We have previously reported that early B cell factor 1 (EBF1) was down-regulated in cholangiocarcinoma (CCA) tissues and related to tumor progression. Thus, we hypothesized that the DNA hypermethylation of EBF1 promoter would suppress EBF1 expression in CCA and induce its progression. In this study, the DNA methylation status of EBF1 and mRNA expression levels were analyzed in CCA and normal bile duct (NBD) tissues using a publicly available database of genome-wide association data. The results showed that the DNA methylation of EBF1 promoter region was significantly increased in CCA tissues compared with those of NBD. The degree of methylation was negatively correlated with EBF1 mRNA expression levels. Using methylation-specific PCR technique, the DNA methylation rates of EBF1 promoter region were investigated in CCA tissues (n=72). CCA patients with high methylation rates of EBF1 promoter region in the tumor tissues (54/72) had a poor prognosis. Higher methylation rates of EBF1 promoter region have shown in all CCA cell lines than that of an immortal cholangiocyte cell line (MMNK1). Upon treatment with the DNA methyltransferase inhibitor 5-Aza-dC, increased EBF1 expression levels and reduced DNA methylation rates were observed in CCA cells. Moreover, restoration of EBF1 expression in CCA cells led to inhibition of cell growth, migration and invasion. In addition, RNA sequencing analysis suggested that EBF1 is involved in suppression of numerous pathways in cancer. Taken together, DNA hypermethylation in the EBF1 promoter region suppresses EBF1 expression and induces CCA progression with aggressive clinical outcomes.
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Affiliation(s)
- Napat Armartmuntree
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chadamas Sakonsinsiri
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Somchai Pinlaor
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Piti Ungarreevittaya
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chern Han Yong
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Center Singapore, Singapore
| | - Anchalee Techasen
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Kanokwan Imtawil
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | | | - Nattawan Suwannakul
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie 514-8507, Japan
| | - Waleeporn Kaewlert
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Timpika Chaiprasert
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Raynoo Thanan
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Mariko Murata
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie 514-8507, Japan
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23
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Dees C, Pötter S, Zhang Y, Bergmann C, Zhou X, Luber M, Wohlfahrt T, Karouzakis E, Ramming A, Gelse K, Yoshimura A, Jaenisch R, Distler O, Schett G, Distler JH. TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis. J Clin Invest 2021; 130:2347-2363. [PMID: 31990678 DOI: 10.1172/jci122462] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 01/17/2020] [Indexed: 12/28/2022] Open
Abstract
Fibroblasts are key effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation may be initiated by external factors, prolonged activation can induce an "autonomous," self-maintaining profibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role in establishing this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, TGF-β induced the expression of DNA methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of STAT3 to promote fibroblast-to-myofibroblast transition, collagen release, and fibrosis in vitro and in vivo. Reestablishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGF-β-dependent fibroblast activation, and ameliorated experimental fibrosis in murine models. These findings identify a pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of targeted therapies in fibrotic diseases.
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Affiliation(s)
- Clara Dees
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Sebastian Pötter
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Yun Zhang
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Christina Bergmann
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Xiang Zhou
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Markus Luber
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Thomas Wohlfahrt
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Emmanuel Karouzakis
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland
| | - Andreas Ramming
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Kolja Gelse
- Department of Trauma Surgery - Orthopedic Surgery, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Rudolf Jaenisch
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Oliver Distler
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland
| | - Georg Schett
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Jörg Hw Distler
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
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24
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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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25
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Guo W, Ma J, Guo S, Wang H, Wang S, Shi Q, Liu L, Zhao T, Yang F, Chen S, Chen J, Zhao J, Yu C, Yi X, Yang Y, Ma J, Ni Q, Zhu G, Gao T, Li C. A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma. J Immunother Cancer 2020; 8:jitc-2020-001866. [PMID: 33298620 PMCID: PMC7733187 DOI: 10.1136/jitc-2020-001866] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2020] [Indexed: 01/05/2023] Open
Abstract
Background The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive. Methods The association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism. Results We first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8+T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8+T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1+CD8+T cells to tumor burden. Conclusions Together, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.
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Affiliation(s)
- Weinan Guo
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jinyuan Ma
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Sen Guo
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Huina Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Sijia Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.,Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qiong Shi
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lin Liu
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Tao Zhao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Fengfan Yang
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Shuyang Chen
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Jianru Chen
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jianhong Zhao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Chen Yu
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiuli Yi
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yuqi Yang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jingjing Ma
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qingrong Ni
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Guannan Zhu
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Tianwen Gao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Chunying Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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26
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Dysregulation of IL6/IL6R-STAT3-SOCS3 signaling pathway in IBD-associated colorectal dysplastic lesions as compared to sporadic colorectal adenomas in non-IBD patients. Pathol Res Pract 2020; 216:153211. [PMID: 32979687 DOI: 10.1016/j.prp.2020.153211] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/29/2020] [Accepted: 09/08/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND IL6-IL6R-STAT3-SOCS3 signaling pathway is known to play important roles in regulating intestinal epithelial homeostasis, in pathogenesis of inflammatory bowel disease (IBD), and in tumorigenesis of colorectal neoplasia. We studied the expressions of these factors in IBD-associated dysplasia and compared to sporadic colorectal adenomas in non-IBD individuals. MATERIALS AND METHODS The expression of IL6, IL6R, STAT3, and SOCS3 within dysplastic as well as background non-dysplastic epithelial cells was evaluated by immunohistochemistry in 26 sporadic colorectal adenomas in non-IBD patients, 32 adenoma-like and 30 non-adenoma-like dysplastic lesions in IBD (41 ulcerative colitis, 21 Crohn's disease) patients. The level of expression of each factor was arbitrarily scored as 0, 1, 2, and 3. RESULTS In both IBD and non-IBD lesions, neoplastic epithelium showed a higher expression of all factors, except the IL6R, as compared to non-neoplastic epithelium. For non-neoplastic epithelium between IBD and non-IBD settings, the colitic epithelium showed a similar IL6, lower IL6R, higher STAT3, and higher SOCS3 expression. As compared to non-IBD adenomas, IBD-associated dysplasia showed a significantly lower IL6, lower IL6R, higher STAT3, and lower SOCS3 expression. Most notably, a parallel-elevation pattern of STAT3/SOCS3 expressions was seen in non-IBD adenomas but an inverse-expression pattern of STAT3/SOCS3 seen in IBD dysplastic lesions. No significant differences existed between adenoma-like and non-adenoma-like lesions. CONCLUSIONS IL6/IL6R-STAT3-SOCS3 signaling pathway does not seem to be preferentially associated with IBD-associated dysplasia. However, the STAT3-SOCS3 interaction appears dysregulated in IBD, characterized by a loss of STAT3/SOCS3 balance,i.e., loss of the normal negative regulation of SOCS3.
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27
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Suppressive myeloid cells are expanded by biliary tract cancer-derived cytokines in vitro and associate with aggressive disease. Br J Cancer 2020; 123:1377-1386. [PMID: 32747748 PMCID: PMC7591861 DOI: 10.1038/s41416-020-1018-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/26/2020] [Accepted: 07/17/2020] [Indexed: 12/23/2022] Open
Abstract
Background BTC is an aggressive disease exacerbated by inflammation and immune suppression. Expansion of immunosuppressive cells occurs in biliary tract cancer (BTC), yet the role of BTC-derived cytokines in this process is unclear. Methods Activated signalling pathways and cytokine production were evaluated in a panel of human BTC cell lines. Human peripheral blood mononuclear cells (PBMCs) were cultured with BTC supernatants, with and without cytokine neutralising antibodies, and analysed by flow cytometry or immunoblot. A human BTC tissue microarray (TMA, n = 69) was stained for IL-6, GM-CSF, and CD33+S100a9+ cells and correlated with clinical outcomes. Results Immunomodulatory factors (IL-6, GM-CSF, MCP-1) were present in BTC supernatants. BTC supernatants expanded CD33dimCD11b+HLA-DRlow/− myeloid-derived suppressor cells (MDSCs) from human PBMCs. Neutralisation of IL-6 and GM-CSF in BTC supernatants inhibited activation of STAT3/5, respectively, in PBMCs, with heterogeneous effects on MDSC expansion in vitro. Staining of a BTC TMA revealed a positive correlation between IL-6 and GM-CSF, with each cytokine and more CD33+S100a9+ cells. Increased CD33+S100a9+ staining positively correlated with higher tumour grade, differentiation and the presence of satellite lesions. Conclusion BTC-derived factors promote suppressive myeloid cell expansion, and higher numbers of CD33+S100a9+ cells in resectable BTC tumours correlates with more aggressive disease.
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28
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Vedeld HM, Folseraas T, Lind GE. Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis - The promise of DNA methylation and molecular biomarkers. JHEP Rep 2020; 2:100143. [PMID: 32939446 PMCID: PMC7479288 DOI: 10.1016/j.jhepr.2020.100143] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/25/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly fatal malignancy of the bile ducts that arises in up to 20% of patients with primary sclerosing cholangitis (PSC). Current detection methods for CCA display suboptimal sensitivity and/or specificity, and there is no evidence-based screening strategy for CCA in patients with PSC. Consequently, CCA is often detected too late for surgical resection, contributing to the high mortality associated with this malignancy. Recently, biomarkers have emerged with potential to complement current detection methods, and/or be used for cancer surveillance in high-risk patient groups, including patients with PSC. Aberrant DNA methylation patterns represent promising biomarkers with great potential for CCA detection. Such aberrations are frequent in CCA, often occur early, and can be detected in liquid biopsies, including blood, bile and urine. This review summarises and highlights the most promising DNA methylation biomarkers identified for CCA detection so far, focusing on patients with PSC. Other promising molecular biomarkers for detection of PSC-associated CCA in liquid biopsies will also be briefly covered.
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Affiliation(s)
- Hege Marie Vedeld
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Guro Elisabeth Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
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29
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The deubiquitinase USP25 supports colonic inflammation and bacterial infection and promotes colorectal cancer. ACTA ACUST UNITED AC 2020; 1:811-825. [DOI: 10.1038/s43018-020-0089-4] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 05/28/2020] [Indexed: 12/19/2022]
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30
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Cubero FJ, Mohamed MR, Woitok MM, Zhao G, Hatting M, Nevzorova YA, Chen C, Haybaeck J, de Bruin A, Avila MA, Boekschoten MV, Davis RJ, Trautwein C. Loss of c-Jun N-terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma. Hepatol Commun 2020; 4:834-851. [PMID: 32490320 PMCID: PMC7262317 DOI: 10.1002/hep4.1495] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 02/07/2020] [Indexed: 12/12/2022] Open
Abstract
Targeted inhibition of the c-Jun N-terminal kinases (JNKs) has shown therapeutic potential in intrahepatic cholangiocarcinoma (CCA)-related tumorigenesis. However, the cell-type-specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remain largely unknown. Here, we aimed to investigate the relevance of JNK1 and JNK2 function in hepatocytes in two different models of experimental carcinogenesis, the dethylnitrosamine (DEN) model and in nuclear factor kappa B essential modulator (NEMO)hepatocyte-specific knockout (Δhepa) mice, focusing on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development. Moreover, regulation of essential genes was assessed by reverse transcription polymerase chain reaction, immunoblottings, and immunostainings. Additionally, specific Jnk2 inhibition in hepatocytes of NEMOΔhepa/JNK1Δhepa mice was performed using small interfering (si) RNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of Jnk1 and Jnk2 in hepatocytes diminished hepatocellular carcinoma (HCC) in both the DEN model and in NEMOΔhepa mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMOΔhepa (NEMOΔhepa/JNKΔhepa) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMOΔhepa/JNK1Δhepa mice recapitulated the phenotype of NEMOΔhepa/JNKΔhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMOΔhepa mice. We found that NEMOΔhepa/JNKΔhepa livers exhibited overexpression of the interleukin-6/signal transducer and activator of transcription 3 pathway in addition to epidermal growth factor receptor (EGFR)-rapidly accelerated fibrosarcoma (Raf)-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) cascade. The functional relevance was tested by administering lapatinib, which is a dual tyrosine kinase inhibitor of erythroblastic oncogene B-2 (ErbB2) and EGFR signaling, to NEMOΔhepa/JNKΔhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases, and effectively blocked EGFR-Raf-MEK-ERK signaling. Conclusion: We define a novel function of JNK1/2 in cholangiocyte hyperproliferation. This opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis.
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Affiliation(s)
- Francisco Javier Cubero
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
- Department of Immunology, Ophthalmology, and ENTComplutense University School of MedicineMadridSpain
- 12 de Octubre Health Research InstituteMadridSpain
| | - Mohamed Ramadan Mohamed
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
- Department of Therapeutic ChemistryNational Research CenterGizaEgypt
| | - Marius M. Woitok
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
| | - Gang Zhao
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
| | - Maximilian Hatting
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
| | - Yulia A. Nevzorova
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
- Department of Genetics, Physiology, and MicrobiologyFaculty of BiologyComplutense UniversityMadridSpain
| | - Chaobo Chen
- Department of Immunology, Ophthalmology, and ENTComplutense University School of MedicineMadridSpain
| | - Johannes Haybaeck
- Department of PathologyOtto‐von‐Guericke UniversityMagdeburgGermany
- Diagnostic and Research Center for Molecular BioMedicineInstitute of PathologyMedical University of GrazGrazAustria
- Department of Pathology, Neuropathology, and Molecular PathologyMedical University of InnsbruckInnsbruckAustria
| | - Alain de Bruin
- Department of PathobiologyFaculty of Veterinary MedicineDutch Molecular Pathology CenterUtrecht UniversityUtrechtthe Netherlands
- Department of PediatricsUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | - Matias A. Avila
- Instituto de Investigación Sanitaria de NavarraPamplonaSpain
- Hepatology ProgramCenter for Applied Medical ResearchUniversity of NavarraPamplonaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
| | - Mark V. Boekschoten
- Nutrition, Metabolism, and Genomics GroupDivision of Human NutritionWageningen UniversityWageningenthe Netherlands
| | - Roger J. Davis
- Howard Hughes Medical InstituteUniversity of Massachusetts Medical SchoolWorcesterMA
| | - Christian Trautwein
- Department of Internal Medicine IIIUniversity Hospital RWTH AachenAachenGermany
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Zhang JW, Wang X, Li GC, Wang D, Han S, Zhang YD, Luo CH, Wang HW, Jiang WJ, Li CX, Li XC. MiR-30a-5p promotes cholangiocarcinoma cell proliferation through targeting SOCS3. J Cancer 2020; 11:3604-3614. [PMID: 32284757 PMCID: PMC7150463 DOI: 10.7150/jca.41437] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 03/03/2020] [Indexed: 12/30/2022] Open
Abstract
Background: MicroRNAs (miRNAs) play important roles in the occurrence and development of cancers. In this project, we aimed to explore the role and molecular mechanism of mir-30a-5p in cholangiocarcinoma (CCA). Materials and Methods: The expression profile and clinical significance of miR-30a-5p in CCA patients were investigated in 31 ICC and 52 ECC patients respectively. The role and mechanism of miR-30a-5p in CCA cells were investigated by up-regulating and inhibiting miR-30a-5p expression in vitro functional study. Results: The expression of miR-30a-5p was increased in both CCA tissues and cells. The inhibition of miR-30a-5p decreased cell proliferation and induced cell apoptosis while overexpression of miR-30a-5p achieved the opposite effect. Furthermore, SOCS3 was down-regulated in ICC and ECC tissues and negatively regulated by miR-30a-5p. Dual-luciferase reporter assay revealed that co-transfection of miR-30a-5p significantly inhibited the activity of firefly luciferase reporter carrying the wild-type 3'UTR of SOCS3. The inhibition of SOCS3 could largely rescue the inhibitory effect of miR-30a-5p inhibition on CCA cells proliferation. In clinical, up-regulated miR-30a-5p expression was correlated with large tumor size in both ICC and ECC cohorts. Conclusions: miR-30a-5p promoted CCA cells proliferation through targeting SOCS3. These findings suggested that miR-30a-5p could be a potential therapeutic target.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Chang Xian Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Nanjing, Jiangsu Province, China
| | - Xiang Cheng Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Nanjing, Jiangsu Province, China
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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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Qi Y, Wang D, Huang W, Wang B, Huang D, Xiong F, Chen X, Chen Y. CyclinD1 inhibits dicer and crucial miRNA expression by chromatin modification to promote the progression of intrahepatic cholangiocarcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:413. [PMID: 31590696 PMCID: PMC6781400 DOI: 10.1186/s13046-019-1415-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 09/06/2019] [Indexed: 12/15/2022]
Abstract
Background CyclinD1 is crucial for cell cycling and can regulate the expression of Dicer, a crucial regulator of microRNA maturation. However, little is known on how CyclinD1 regulates Dicer and miRNA expression, and the progression of intrahepatic cholangiocarcinoma (ICC). Methods The expression of CyclinD1 and Dicer in non-tumor cholangiocytes, ICC cells and tissues as well as their association with clinicopathological characteristics and survival were examined. The potential mechanisms by which CyclinD1 regulates Dicer and relative miRNA expression were determined by immunoprecipitation, ChIP sequence, BSP and luciferase reporter assays following induction of CyclinD1 over-expression or silencing and Dicer silencing. The impact of CyclinD1 and/or Dicer silencing on the growth of ICC was tested in vivo. Results Up-regulated CyclinD1 was associated with down-regulated Dicer expression in ICC tissues and poorer overall survival in patients with ICC. CyclinD1 interacted with the nuclear H3K9me3 and SUV39H1 and bound to the Dicer promoter to increase its CpG island methylation in ICC cells. Functionally, CyclinD1 silencing inhibited the malignancy of ICC cells, which were mitigated partially by Dicer silencing in ICC cells. Dicer silencing down-regulated miR-1914-5p and miR-541-5p expression, which targeted and promoted CyclinD1 and CDK6 expression in ICC cells. Conclusions Our findings uncover that CyclinD1 inhibits Dicer expression by chromatin modification to reduce miR-1914-5p/miR-541-5p expression, which positively-feedback enhances CyclinD1 and CDK6 expression and progression of ICC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1415-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yongqiang Qi
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Da Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Wenhua Huang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Bing Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Di Huang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Fei Xiong
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiaoping Chen
- Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
| | - Yongjun Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
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Rimassa L, Personeni N, Aghemo A, Lleo A. The immune milieu of cholangiocarcinoma: From molecular pathogenesis to precision medicine. J Autoimmun 2019; 100:17-26. [PMID: 30862450 DOI: 10.1016/j.jaut.2019.03.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 03/05/2019] [Indexed: 12/11/2022]
Abstract
Cholangiocarcinoma (CCA) is a deadly cancer of the biliary epithelium with limited therapeutic options. It is a heterogeneous group of cancer that could develop at any level from the biliary tree and is currently classified into intrahepatic, perihilar and distal based on its anatomical location. With incidence and mortality rates currently increasing, it is now the second most common type of primary liver cancer and represents up to 3% of all gastrointestinal malignancies. High-throughput genomics and epigenomics have greatly increased our understanding of CCA underlying biology, however its pathogenesis remains largely unknown. CCA is characterized by a highly desmoplastic microenvironment containing stromal cells, mainly cancer-associated fibroblasts, infiltrating tumor epithelium. Tumor microenvironment in CCA is a highly dynamic environment that, besides stromal and endothelial cells, encompass also an abundance of immune cells, of both the innate and adaptive immune system (including tumor-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes) and abundant proliferative factors. It is orchestrated by multiple soluble factors and signals, that eventually define a tumor growth-permissive microenvironment. Through complicate interactions with CCA cells, tumor microenvironment profoundly affects the proliferative and invasive abilities of epithelial cancer cells and plays an important role in accelerating neovascularization and preventing apoptosis of neoplastic cells. In this review, we discuss recent developments regarding the characteristics of the tumor microenvironment, the role of each cellular population, and their multiarticulate interaction with the malignant population. Further we discuss innovative treatment approaches, including immunotherapy, and how identification of CCA secreted factors by both the stromal component and immune cell subsets are leading towards a precision medicine in CCA.
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Affiliation(s)
- Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy
| | - Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano (MI), Italy.
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Gargiulo E, Paggetti J, Moussay E. Hematological Malignancy-Derived Small Extracellular Vesicles and Tumor Microenvironment: The Art of Turning Foes into Friends. Cells 2019; 8:cells8050511. [PMID: 31137912 PMCID: PMC6562645 DOI: 10.3390/cells8050511] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/24/2019] [Accepted: 05/25/2019] [Indexed: 02/07/2023] Open
Abstract
Small extracellular vesicles (small EVs) are commonly released by all cells, and are found in all body fluids. They are implicated in cell to cell short- and long-distance communication through the transfer of genetic material and proteins, as well as interactions between target cell membrane receptors and ligands anchored on small EV membrane. Beyond their canonical functions in healthy tissues, small EVs are strategically used by tumors to communicate with the cellular microenvironment and to establish a proper niche which would ultimately allow cancer cell proliferation, escape from the immune surveillance, and metastasis formation. In this review, we highlight the effects of hematological malignancy-derived small EVs on immune and stromal cells in the tumor microenvironment.
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Affiliation(s)
- Ernesto Gargiulo
- Tumor-Stroma Interactions, Department of Oncology, Luxembourg Institute of Health, 84, val fleuri, L-1526 Luxembourg, Luxembourg.
| | - Jerome Paggetti
- Tumor-Stroma Interactions, Department of Oncology, Luxembourg Institute of Health, 84, val fleuri, L-1526 Luxembourg, Luxembourg.
| | - Etienne Moussay
- Tumor-Stroma Interactions, Department of Oncology, Luxembourg Institute of Health, 84, val fleuri, L-1526 Luxembourg, Luxembourg.
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Braconi C, Roessler S, Kruk B, Lammert F, Krawczyk M, Andersen JB. Molecular perturbations in cholangiocarcinoma: Is it time for precision medicine? Liver Int 2019; 39 Suppl 1:32-42. [PMID: 30829432 DOI: 10.1111/liv.14085] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/26/2019] [Accepted: 02/26/2019] [Indexed: 12/11/2022]
Abstract
The complexity of cholangiocarcinoma (CCA) cellularity and the molecular perturbation mechanisms that underlie the diversity of growth patterns of this malignancy remain a clinical concern. Tumours of the biliary system display significant intrinsic chemoresistance, caused by significant stromal involvement and genome-wide tumour heterogeneity, hampering disease remission and palliation as well as promoting the metastatic behaviour. It is crucial to advance our present understanding of the risk and molecular pathogenesis of CCA. This will facilitate the delineation of patient subsets based on molecular perturbations and adjust for precision therapies.
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Affiliation(s)
- Chiara Braconi
- Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.,Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Trust, Surrey and London, UK
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg and Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
| | - Beata Kruk
- Department of General, Transplant and Liver Surgery, Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Marcin Krawczyk
- Department of General, Transplant and Liver Surgery, Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland.,Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Jesper B Andersen
- Department of Health and Medical Sciences, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N, Denmark
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EF24 Suppresses Cholangiocellular Carcinoma Progression, Inhibits STAT3 Phosphorylation, and Induces Apoptosis via ROS-Mediated Oxidative Stress. JOURNAL OF ONCOLOGY 2019; 2019:8701824. [PMID: 30949204 PMCID: PMC6425401 DOI: 10.1155/2019/8701824] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 01/17/2019] [Accepted: 02/11/2019] [Indexed: 02/08/2023]
Abstract
Therapeutic options for advanced stage cholangiocellular carcinoma (CCC) are very limited as of today and patients carry an exceptionally poor overall prognosis. In recent years, increasing evidence has been accumulated to suggest that malignant cells widely show increased intrinsic ROS levels and exhibit altered redox profiles as compared to normal counterparts, opening up potential avenues for therapeutic intervention. This study provides preclinical experimental evidence of therapeutic activity of the curcumin analog EF24 in cholangiocarcinoma models. In CCC cell lines, EF24 inhibited cell viability and induced apoptosis through excessive ROS generation. Moreover, administration of EF24 led to depletion of total intracellular GSH levels, induced mitochondrial depolarization, and abrogated STAT3 phosphorylation. Of interest, these effects were readily averted by treating the cells with exogenous antioxidants such as N-acetyl cysteine (NAC) or glutathione monoethyl ester (GEE). In vivo, EF24, solubilized using a cyclodextrin formulation, significantly suppressed the growth of tumor xenografts without exhibiting any toxic adverse effects. Immunohistochemical analysis of extracted tumor tissues demonstrated reduced nuclear staining for Ki-67 and downregulation of phospho-STAT3 as well as strong staining for oxidative stress biomarker 8-OHdG. Therefore, the data presented here suggest EF24 as potential therapeutic compound against CCC which might act at least to some extent through ROS-induced oxidative damage, subsequently inducing apoptosis. Further evaluation of this approach should be carried out in future follow-up studies.
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Labib PL, Goodchild G, Pereira SP. Molecular Pathogenesis of Cholangiocarcinoma. BMC Cancer 2019; 19:185. [PMID: 30819129 PMCID: PMC6394015 DOI: 10.1186/s12885-019-5391-0] [Citation(s) in RCA: 201] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 02/20/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis. CONCLUSION Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.
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Affiliation(s)
- Peter L. Labib
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - George Goodchild
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - Stephen P. Pereira
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
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Kleinegger F, Hofer E, Wodlej C, Golob-Schwarzl N, Birkl-Toeglhofer AM, Stallinger A, Petzold J, Orlova A, Krassnig S, Reihs R, Niedrist T, Mangge H, Park YN, Thalhammer M, Aigelsreiter A, Lax S, Garbers C, Fickert P, Rose-John S, Moriggl R, Rinner B, Haybaeck J. Pharmacologic IL-6Rα inhibition in cholangiocarcinoma promotes cancer cell growth and survival. Biochim Biophys Acta Mol Basis Dis 2019; 1865:308-321. [DOI: 10.1016/j.bbadis.2018.11.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 10/25/2018] [Accepted: 11/07/2018] [Indexed: 02/08/2023]
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Bile Acid-Activated Receptors: GPBAR1 (TGR5) and Other G Protein-Coupled Receptors. Handb Exp Pharmacol 2019; 256:19-49. [PMID: 31302759 DOI: 10.1007/164_2019_230] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The BA-responsive GPCRs S1PR2 and TGR5 are almost ubiquitously expressed in human and rodent tissues. In the liver, S1PR2 is expressed in all cell types, while TGR5 is predominately found in non-parenchymal cells. In contrast to S1PR2, which is mainly activated by conjugated bile acids (BAs), all BAs serve as ligands for TGR5 irrespective of their conjugation state and substitution pattern.Mice with targeted deletion of either S1PR2 or TGR5 are viable and develop no overt phenotype. In liver injury models, S1PR2 exerts pro-inflammatory and pro-fibrotic effects and thus aggravates liver damage, while TGR5 mediates anti-inflammatory, anti-cholestatic, and anti-fibrotic effects. Thus, inhibitors of S1PR2 signaling and agonists for TGR5 have been employed to attenuate liver injury in rodent models for cholestasis, nonalcoholic steatohepatitis, and fibrosis/cirrhosis.In biliary epithelial cells, both receptors activate a similar signaling cascade resulting in ERK1/2 phosphorylation and cell proliferation. Overexpression of both S1PR2 and TGR5 was found in human cholangiocarcinoma tissue as well as in CCA cell lines, where stimulation of both GPCRs resulted in transactivation of the epidermal growth factor receptor and triggered cell proliferation as well as increased cell migration and invasiveness.This chapter will focus on the function of S1PR2 and TGR5 in different liver cell types and summarizes current knowledge on the role of these receptors in liver disease models.
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Bogenberger JM, DeLeon TT, Arora M, Ahn DH, Borad MJ. Emerging role of precision medicine in biliary tract cancers. NPJ Precis Oncol 2018; 2:21. [PMID: 30302397 PMCID: PMC6170410 DOI: 10.1038/s41698-018-0064-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 08/13/2018] [Accepted: 08/15/2018] [Indexed: 12/14/2022] Open
Abstract
Biliary tracts cancers (BTCs) are a diverse group of aggressive malignancies with an overall poor prognosis. Genomic characterization has uncovered many putative clinically actionable aberrations that can also facilitate the prognostication of patients. As such, comprehensive genomic profiling is playing a growing role in the clinical management of BTCs. Currently however, there is only one precision medicine approved by the US Food and Drug Administration (FDA) for the treatment of BTCs. Herein, we highlight the prevalence and prognostic, diagnostic, and predictive significance of recurrent mutations and other genomic aberrations with current clinical implications or emerging relevance to clinical practice. Some ongoing clinical trials, as well as future areas of exploration for precision oncology in BTCs are highlighted.
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Affiliation(s)
- James M. Bogenberger
- Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ USA
| | - Thomas T. DeLeon
- Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ USA
| | - Mansi Arora
- Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ USA
| | - Daniel H. Ahn
- Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ USA
| | - Mitesh J. Borad
- Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN USA
- Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ USA
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42
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Mahipal A, Kommalapati A, Tella SH, Lim A, Kim R. Novel targeted treatment options for advanced cholangiocarcinoma. Expert Opin Investig Drugs 2018; 27:709-720. [PMID: 30124336 DOI: 10.1080/13543784.2018.1512581] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Surgical resection remains the mainstay of potentially curative treatment in the early stages of cholangiocarcinoma, whereas for the advanced stage, systemic chemotherapeutics and experimental targeted therapies are the primary treatment options. The molecular heterogeneity of the tumor is based on location, liver dysfunction, and relative rarity of the disease and confers challenges for clinical trial enrollment. The advancements in the understanding of molecular pathogenesis of cholangiocarcinoma have led to the development of targeted therapies that are currently being evaluated in the clinical trials. AREAS COVERED This review summarizes the current understanding and future directions of targeted therapeutic options in the management of advanced cholangiocarcinoma. EXPERT OPINION Advanced cholangiocarcinoma has a dismal prognosis; improved understanding of the molecular pathogenesis and advancements in development of targeted therapy offers hope that we may improve outcomes in this rare, but highly lethal cancer. Among the newly discovered molecular alterations, targeting FGFR2 fusions, IDH1/2 mutations and HER2 receptors hold great promise for improving the future management of cholangiocarcinoma. Immunotherapy in combination with targeted agents and chemotherapy may improve outcomes. In addition, drugs targeting the MEK, EGFR, KRAS, BRAF, and ROS1 pathways and neo-angiogenesis may also provide new horizons in the management of cholangiocarcinoma.
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Affiliation(s)
- Amit Mahipal
- a Department of Medical Oncology , Mayo Clinic , Rochester , MN , USA
| | - Anuhya Kommalapati
- b Department of Internal Medicine , University of South Carolina School of Medicine , Columbia , SC , USA
| | - Sri Harsha Tella
- b Department of Internal Medicine , University of South Carolina School of Medicine , Columbia , SC , USA
| | - Alexander Lim
- c Department of Internal Medicine , University of South Florida , Tampa , FL , USA
| | - Richard Kim
- d Department of Gastrointestinal Oncology , H. Lee Moffitt Cancer Center , Tampa , FL , USA
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Jiang K, Centeno BA. Primary Liver Cancers, Part 2: Progression Pathways and Carcinogenesis. Cancer Control 2018; 25:1073274817744658. [PMID: 29353494 PMCID: PMC5933573 DOI: 10.1177/1073274817744658] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) and primary intrahepatic cholangiocarcinoma (ICC) have been increasing in incidence worldwide and are leading causes of cancer death. Studies of the molecular alterations leading to these carcinomas provide insights into the key mechanisms involved. A literature review was conducted to identify articles with information relevant to current understanding of the etiologies and molecular pathogenesis of HCC and ICC. Chronic inflammatory diseases are the key etiological risk factors for both HCC and ICC, although other diseases play a role, and for many ICCs, an underlying risk factor is not identified. Mutations in catenin beta 1 ( CTNBB1) and tumor protein 53 (P53) are the main genetic alterations in HCC. Isocitrate dehydrogenases 1 and 2 (IDH1/2), KRAS protooncogene GTPase (KRAS), a RAS Viral Oncogene Homolog in neoroblastoma (NRAS) and P53 are primary genetic alterations in ICC. In both diseases, the mutational landscape is dependent on the underlying etiology. The most significant etiologies and genetic processes involved in the carcinogenesis of HCC and ICC are reviewed.
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Affiliation(s)
- Kun Jiang
- 1 Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA.,2 Department of Oncologic Sciences, Morsani College of Medicine at University of South Florida, Tampa, FL, USA
| | - Barbara A Centeno
- 1 Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA.,2 Department of Oncologic Sciences, Morsani College of Medicine at University of South Florida, Tampa, FL, USA
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Morgillo F, Dallio M, Della Corte CM, Gravina AG, Viscardi G, Loguercio C, Ciardiello F, Federico A. Carcinogenesis as a Result of Multiple Inflammatory and Oxidative Hits: a Comprehensive Review from Tumor Microenvironment to Gut Microbiota. Neoplasia 2018; 20:721-733. [PMID: 29859426 PMCID: PMC6014569 DOI: 10.1016/j.neo.2018.05.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/30/2018] [Accepted: 05/01/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Floriana Morgillo
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy.
| | - Marcello Dallio
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Carminia Maria Della Corte
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Antonietta Gerarda Gravina
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Viscardi
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Carmelina Loguercio
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Fortunato Ciardiello
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Alessandro Federico
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
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O'Rourke CJ, Munoz-Garrido P, Aguayo EL, Andersen JB. Epigenome dysregulation in cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis 2018. [DOI: 10.1016/j.bbadis.2017.06.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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46
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Yang XW, Li L, Hou GJ, Yan XZ, Xu QG, Chen L, Zhang BH, Shen F. STAT3 overexpression promotes metastasis in intrahepatic cholangiocarcinoma and correlates negatively with surgical outcome. Oncotarget 2018; 8:7710-7721. [PMID: 28032598 PMCID: PMC5352354 DOI: 10.18632/oncotarget.13846] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 11/30/2016] [Indexed: 12/21/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) promotes tumor progression in many types of cancer. In this study, we analyzed the prognostic value of this marker in human intrahepatic cholangiocarcinoma (ICC). Using real-time PCR, western blot and immunohistochemistry assays, we found that STAT3 is overexpressed in ICC patients. STAT3 expression correlated with several clinicopathological features, including tumor size, pathological satellite, vascular invasion, undifferentiated-type histology, lymph node metastasis and TNM stage in two independent cohorts of ICC patients. Patients with high STAT3 levels had a poor prognosis in terms of overall survival (OS) and disease-free survival (DFS). Multivariate survival analysis indicated that STAT3 is an independent prognostic factor for OS and DFS. Furthermore, we observed that STAT3 overexpression promotes the invasion, metastasis and proliferation of ICC cells in vitro and in vivo, and also promotes STAT3 phosphorylation. These findings suggest that STAT3 expression correlated negatively with surgical outcome and inhibition of STAT3 expression may constitute a novel target for the treatment of ICC patients.
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Affiliation(s)
- Xin-Wei Yang
- Department of Laparoscopy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Liang Li
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China
| | - Guo-Jun Hou
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Xin-Zhou Yan
- Department of Laparoscopy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Qin-Guo Xu
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Lei Chen
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China
| | - Bao-Hua Zhang
- Department of Laparoscopy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Feng Shen
- Department of Comprehensive Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
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Florea ID, Karaoulani C. Epigenetic Changes of the Immune System with Role in Tumor Development. Methods Mol Biol 2018; 1856:203-218. [PMID: 30178253 DOI: 10.1007/978-1-4939-8751-1_11] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Tumor development is closely related to chronic inflammation and to evasion of immune defense mechanisms by neoplastic cells. The mediators of the inflammatory process as well as proteins involved in immune response or immune response evasion can be subject to various epigenetic changes such as methylation, acetylation, or phosphorylation. Some of these, such as cytokine suppressors, are undergoing repression through epigenetic changes, and others such as cytokines or chemokines are undergoing activation through epigenetic changes, both modifications having as a result tumor progression. The activating changes can affect the receptor molecules involved in immune response and these promote inflammation and subsequently tumor development while the inactivating changes seem to be related to the tumor regression process. The proteins involved in antigen presentation, and, therefore in immune response escape, such as classical HLA proteins and related APM (antigen presentation machinery) with their epigenetic changes contribute to the tumor development process, either to tumor progression or regression, depending on the immune effector cells that are in play.
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48
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-like Lesions of the Liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:780-879. [DOI: 10.1016/b978-0-7020-6697-9.00013-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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49
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Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases? Int J Mol Sci 2017; 19:ijms19010007. [PMID: 29267211 PMCID: PMC5795959 DOI: 10.3390/ijms19010007] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 12/15/2022] Open
Abstract
Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed.
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50
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Jiang M, Chen J, Zhang W, Zhang R, Ye Y, Liu P, Yu W, Wei F, Ren X, Yu J. Interleukin-6 Trans-Signaling Pathway Promotes Immunosuppressive Myeloid-Derived Suppressor Cells via Suppression of Suppressor of Cytokine Signaling 3 in Breast Cancer. Front Immunol 2017; 8:1840. [PMID: 29326716 PMCID: PMC5736866 DOI: 10.3389/fimmu.2017.01840] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 12/05/2017] [Indexed: 12/28/2022] Open
Abstract
Interleukin-6 (IL-6) has been reported to stimulate myeloid-derived suppressor cells (MDSCs) in multiple cancers, but the molecular events involved in this process are not completely understood. We previously found that cancer-derived IL-6 induces T cell suppression of MDSCs in vitro via the activation of STAT3/IDO signaling pathway. In this study, we aimed to elucidate the underlying mechanisms. We found that in primary breast cancer tissues, cancer-derived IL-6 was positively correlated with infiltration of MDSCs in situ, which was accompanied by more aggressive tumor phenotypes and worse clinical outcomes. In vitro IL-6 stimulated the amplification of MDSCs and promoted their T cell suppression ability, which were fully inhibited by an IL-6-specific blocking antibody. Our results demonstrate that IL-6-dependent suppressor of cytokine signaling 3 (SOCS3) suppression in MDSCs induced phosphorylation of the JAK1, JAK2, TYK2, STAT1, and STAT3 proteins, which was correlated with T cell suppression of MDSCs in vitro. Therefore, dysfunction in the SOCS feedback loop promoted long-term activation of the JAK/STAT signaling pathway and predominantly contributed to IL-6-mediated effects on MDSCs. Furthermore, IL-6-induced inhibition of SOCS3 and activation of the JAK/STAT pathway was correlated with an elevated expression of IL-6 receptor α (CD126), in which the soluble CD126-mediated IL-6 trans-signaling pathway significantly regulated IL-6-mediated effects on MDSCs. Finally, IL-6-induced SOCS3 dysfunction and sustained activation of the JAK/STAT signaling pathway promoted the amplification and immunosuppressive function of breast cancer MDSCs in vitro and in vivo, and thus blocking the IL-6 signaling pathway is a promising therapeutic strategy for eliminating and inhibiting MDSCs to improve prognosis.
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Affiliation(s)
- Mengmeng Jiang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jieying Chen
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Wenwen Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Rui Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yingnan Ye
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Pengpeng Liu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Wenwen Yu
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Feng Wei
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xiubao Ren
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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