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Yousef EH, El Gayar AM, El-Magd NFA. Insights into Sorafenib resistance in hepatocellular carcinoma: Mechanisms and therapeutic aspects. Crit Rev Oncol Hematol 2025; 212:104765. [PMID: 40389183 DOI: 10.1016/j.critrevonc.2025.104765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 05/07/2025] [Accepted: 05/11/2025] [Indexed: 05/21/2025] Open
Abstract
The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.
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Affiliation(s)
- Eman H Yousef
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Pharmacology and Biochemistry department, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34511, Egypt.
| | - Amal M El Gayar
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Nada F Abo El-Magd
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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2
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Bhowmick K, Yang X, Mohammad T, Xiang X, Molmenti CL, Mishra B, Dasarathy S, Krainer AR, Hassan MI, Crandall KA, Mishra L. Microbial metabolite ammonia disrupts TGF-β signaling to promote colon cancer. J Biol Chem 2025:108559. [PMID: 40311681 DOI: 10.1016/j.jbc.2025.108559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 04/19/2025] [Accepted: 04/24/2025] [Indexed: 05/03/2025] Open
Abstract
Colorectal cancer (CRC) is rising alarmingly in younger populations, potentially arising from factors such as obesity, pro-inflammatory gut microbiome and the accumulation of toxic metabolites. However, how metabolites such as ammonia impact key signaling pathways to promote CRC remains unclear. Our study investigates a critical link between gut microbiome alterations, ammonia, and their toxic effects on the TGF-β signaling pathway, driving CRC progression. We observe altered microbial populations in an obesity-induced mouse model of cancer, where ammonia promotes caspase-3-mediated cleavage of the SMAD3 adaptor βII-spectrin (SPTBN1). Cleaved SPTBN1 fragments form adducts with ammonia that induce pro-inflammatory cytokine expression and disrupt TGF-β signaling. Extending from AlphaFold docking simulations, we identified that ammonia interacts with N-terminal SPTBN1 potentially through residues D81, Y556, S663, Y666, N986, and D1177 to form hydrogen bonds that disrupt downstream SMAD3 signaling, altering TGF-β signaling to a protumorigenic phenotype. Blocking SPTBN1, through an SPTBN1-specific siRNA blocks ammonia toxicity and restores normal SMAD3/TGF-β signaling by reducing the abundance of SPTBN1 cleaved fragments in SW480 and Caco-2 (CRC) cell lines. In addition, our research establishes crosstalk between TGF-β signaling and a microbial sensor, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is significantly overexpressed in CRC patients. We identified CEACAM1-SPTBN1 interactions at specific residues (E517 and Y520) within the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 cytoplasmic domain, identifying distinguishing a potential axis that is harnessed by the altered microbiome. Our study identifies mechanistic insights into how microbial metabolites target TGF-β as a major signaling pathway to promote CRC.
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Affiliation(s)
- Krishanu Bhowmick
- Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research; Divisions of Gastroenterology and Hepatology, Department of Medicine, Northwell Health, Manhasset, NY, USA; Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, USA.
| | - Xiaochun Yang
- Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research; Divisions of Gastroenterology and Hepatology, Department of Medicine, Northwell Health, Manhasset, NY, USA; Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, USA
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, India
| | - Xiyan Xiang
- Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research; Divisions of Gastroenterology and Hepatology, Department of Medicine, Northwell Health, Manhasset, NY, USA; Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, USA
| | - Christine L Molmenti
- Department of Occupational Medicine, Epidemiology and Prevention, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; Feinstein Institutes for Medical Research, Institute of Cancer Research, Manhasset, NY, USA; Department of Surgery, Northwell Health, Manhasset, NY, USA
| | - Bibhuti Mishra
- Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research; Divisions of Gastroenterology and Hepatology, Department of Medicine, Northwell Health, Manhasset, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Department of Neurology, Hempstead, NY, USA
| | - Srinivasan Dasarathy
- Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
| | | | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, India
| | - Keith A Crandall
- Computational Biology Institute and Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Washington DC, USA
| | - Lopa Mishra
- Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research; Divisions of Gastroenterology and Hepatology, Department of Medicine, Northwell Health, Manhasset, NY, USA; Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, USA; Department of Surgery, George Washington University, Washington DC, USA.
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3
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Eun JR. Overview of hepatocarcinogenesis focusing on cellular origins of liver cancer stem cells: a narrative review. JOURNAL OF YEUNGNAM MEDICAL SCIENCE 2024; 42:3. [PMID: 39523770 PMCID: PMC11812091 DOI: 10.12701/jyms.2024.01088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 09/26/2024] [Accepted: 10/02/2024] [Indexed: 11/16/2024]
Abstract
Hepatocellular carcinoma (HCC) accounts for 85% to 90% of primary liver cancers and generally has a poor prognosis. The hierarchical model, which posits that HCC originates from liver cancer stem cells (CSCs), is now widely accepted, as it is for other cancer types. As CSCs typically reside in the G0 phase of the cell cycle, they are resistant to conventional chemotherapy. Therefore, to effectively treat HCC, developing therapeutic strategies that target liver CSCs is essential. Clinically, HCCs exhibit a broad spectrum of pathological and clinical characteristics, ranging from well-differentiated to poorly differentiated forms, and from slow-growing tumors to aggressive ones with significant metastatic potential. Some patients with HCC also show features of cholangiocarcinoma. This HCC heterogeneity may arise from the diverse cellular origins of liver CSCs. This review explores the normal physiology of liver regeneration and provides a comprehensive overview of hepatocarcinogenesis, including cancer initiation, isolation of liver CSCs, molecular signaling pathways, and microRNAs. Additionally, the cellular origins of liver CSCs are reviewed, emphasizing hematopoietic and mesenchymal stem cells, along with the well-known hepatocytes and hepatic progenitor cells.
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Affiliation(s)
- Jong Ryeol Eun
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Ilsan, Korea
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4
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Devan AR, Nair B, Pradeep GK, Alexander R, Vinod BS, Nath LR, Calina D, Sharifi-Rad J. The role of glypican-3 in hepatocellular carcinoma: Insights into diagnosis and therapeutic potential. Eur J Med Res 2024; 29:490. [PMID: 39369212 PMCID: PMC11453014 DOI: 10.1186/s40001-024-02073-2] [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] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 09/22/2024] [Indexed: 10/07/2024] Open
Abstract
Glypican-3 (GPC-3) is predominantly found in the placenta and fetal liver, with limited expression in adult tissues. Its re-expression in hepatocellular carcinoma (HCC) and secretion into the serum highlights its potential as a diagnostic marker. GPC-3 is involved in important cellular processes such as proliferation, metastasis, apoptosis, and epithelial-mesenchymal transition through various signaling pathways including Wnt, IGF, YAP, and Hedgehog. To review the structure, biosynthesis, and post-translational modifications of GPC-3, and to elucidate its signaling mechanisms and role as a pro-proliferative protein in HCC, emphasizing its diagnostic and therapeutic potential. A comprehensive literature review was conducted, focusing on the expression of GPC-3 in various tumors, with a special emphasis on HCC. The review synthesized findings from experimental studies and clinical trials, analyzing the overexpression of GPC-3 in HCC, its differentiation from other liver diseases, and its potential as a diagnostic and therapeutic target. GPC-3 overexpression in HCC is linked to aggressive tumor behavior and poor prognosis, including shorter overall and disease-free survival. Additionally, GPC-3 has emerged as a promising therapeutic target. Ongoing investigations, including immunotherapies such as monoclonal antibodies and CAR-T cell therapies, demonstrate potential in inhibiting tumor growth and improving clinical outcomes. The review details the multifaceted roles of GPC-3 in tumorigenesis, including its impact on tumor-associated macrophages, glucose metabolism, and epithelial-mesenchymal transition, all contributing to HCC progression. GPC-3's re-expression in HCC and its involvement in key tumorigenic processes underscore its value as a biomarker for early diagnosis and a target for therapeutic intervention. Further research is warranted to fully exploit GPC-3's diagnostic and therapeutic potential in HCC management.
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Affiliation(s)
- Aswathy R Devan
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala, 682041, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala, 682041, India
| | - Govind K Pradeep
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala, 682041, India
| | - Roshini Alexander
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala, 682041, India
| | - Balachandran S Vinod
- Department of Biochemistry, Sree Narayana College, Kollam, Kerala, 691001, India
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala, 682041, India.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
| | - Javad Sharifi-Rad
- Universidad Espíritu Santo, Samborondón, 092301, Ecuador.
- Department of Medicine, College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
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Abstract
All cancers arise from normal cells whose progeny acquire the cancer-initiating mutations and epigenetic modifications leading to frank tumorigenesis. The identity of those "cells-of-origin" has historically been a source of controversy across tumor types, as it has not been possible to witness the dynamic events giving rise to human tumors. Genetically engineered mouse models (GEMMs) of cancer provide an invaluable substitute, enabling researchers to interrogate the competence of various naive cellular compartments to initiate tumors in vivo. Researchers using these models have relied on lineage-specific promoters, knowledge of preneoplastic disease states in humans, and technical advances allowing more precise manipulations of the mouse germline. These approaches have given rise to the emerging view that multiple lineages within a given organ may generate tumors with similar histopathology. Here, we review some of the key studies leading to this conclusion in solid tumors and highlight the biological and clinical ramifications.
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Affiliation(s)
- Jason R Pitarresi
- Division of Hematology and Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01655, USA
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01655, USA
| | - Ben Z Stanger
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
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Ma Y, Lv H, Xing F, Xiang W, Wu Z, Feng Q, Wang H, Yang W. Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression. Front Med 2024; 18:430-445. [PMID: 38600350 DOI: 10.1007/s11684-023-1049-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/15/2023] [Indexed: 04/12/2024]
Abstract
Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.
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Affiliation(s)
- Yue Ma
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongwei Lv
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China
| | - Fuxue Xing
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Wei Xiang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Zixin Wu
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Qiyu Feng
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongyang Wang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
| | - Wen Yang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
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7
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Zhang M, Ding Y, Gao M, Lu X, Tan J, Yu F, Gu C, Gu L, Ren X, Hao C, Ming L, Xu K, Mao W, Jin Y, Zhang M, You L, Wang Z, Sun Y, Jiang J, Yang Y, Zhang D, Tang X. Discovery of Novel N-(Anthracen-9-ylmethyl) Benzamide Derivatives as ZNF207 Inhibitors Promising in Treating Glioma. J Med Chem 2024; 67:3909-3934. [PMID: 38377560 DOI: 10.1021/acs.jmedchem.3c02241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2024]
Abstract
Targeting tumor stemness is an innovative approach to cancer treatment. Zinc Finger Protein 207 (ZNF207) is a promising target for weakening the stemness of glioma cells. Here, a series of novel N-(anthracen-9-ylmethyl) benzamide derivatives against ZNF207 were rationally designed and synthesized. The inhibitory activity was evaluated, and their structure-activity relationships were summarized. Among them, C16 exhibited the most potent inhibitory activity, as evidenced by its IC50 values ranging from 0.5-2.5 μM for inhibiting sphere formation and 0.5-15 μM for cytotoxicity. Furthermore, we found that C16 could hinder tumorigenesis and migration and promote apoptosis in vitro. These effects were attributed to the downregulation of stem-related genes. The in vivo evaluation demonstrated that C16 exhibited efficient permeability across the blood-brain barrier and potent efficacy in both subcutaneous and orthotopic glioma tumor models. Hence, C16 may serve as a potential lead compound targeting ZNF207 and has promising therapeutic potential for glioma.
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Affiliation(s)
- Menghan Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China 211112
| | - Yushi Ding
- Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China 211112
| | - Mengkang Gao
- School of Pharmacy, China Pharmaceutical University, Nanjing, China 211112
| | - Xiaolin Lu
- School of Science, China Pharmaceutical University, Nanjing, China 211112
| | - Jun Tan
- School of Science, China Pharmaceutical University, Nanjing, China 211112
| | - Fei Yu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China 211112
| | - Congying Gu
- School of Science, China Pharmaceutical University, Nanjing, China 211112
| | - Lujun Gu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China 211112
| | - Xiameng Ren
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China 211112
| | - Chenyan Hao
- School of Science, China Pharmaceutical University, Nanjing, China 211112
| | - Liqin Ming
- School of Science, China Pharmaceutical University, Nanjing, China 211112
| | - Kang Xu
- School of Science, China Pharmaceutical University, Nanjing, China 211112
| | - Wenhao Mao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China 211112
| | - Yuqing Jin
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China 211112
| | - Min Zhang
- Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China 211112
| | - Linjun You
- Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China 211112
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China 211112
| | - Zhanbo Wang
- Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China 211112
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China 211112
| | - Yuanyuan Sun
- Shuangyun BioMed Sci & Tech (Suzhou) Co., Ltd, Suzhou, China 215000
| | - Jingwei Jiang
- Shuangyun BioMed Sci & Tech (Suzhou) Co., Ltd, Suzhou, China 215000
| | - Yong Yang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China 211112
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China 211112
- School of Pharmacy, Xuzhou Medical University, Xuzhou, China 221004
| | - Dayong Zhang
- School of Science, China Pharmaceutical University, Nanjing, China 211112
| | - Xinying Tang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China 211112
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8
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Xiang X, Bhowmick K, Shetty K, Ohshiro K, Yang X, Wong LL, Yu H, Latham PS, Satapathy SK, Brennan C, Dima RJ, Chambwe N, Sharifova G, Cacaj F, John S, Crawford JM, Huang H, Dasarathy S, Krainer AR, He AR, Amdur RL, Mishra L. Mechanistically based blood proteomic markers in the TGF-β pathway stratify risk of hepatocellular cancer in patients with cirrhosis. Genes Cancer 2024; 15:1-14. [PMID: 38323119 PMCID: PMC10843195 DOI: 10.18632/genesandcancer.234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 12/05/2023] [Indexed: 02/08/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer worldwide but is often diagnosed at an advanced incurable stage. Yet, despite the urgent need for blood-based biomarkers for early detection, few studies capture ongoing biology to identify risk-stratifying biomarkers. We address this gap using the TGF-β pathway because of its biological role in liver disease and cancer, established through rigorous animal models and human studies. Using machine learning methods with blood levels of 108 proteomic markers in the TGF-β family, we found a pattern that differentiates HCC from non-HCC in a cohort of 216 patients with cirrhosis, which we refer to as TGF-β based Protein Markers for Early Detection of HCC (TPEARLE) comprising 31 markers. Notably, 20 of the patients with cirrhosis alone presented an HCC-like pattern, suggesting that they may be a group with as yet undetected HCC or at high risk for developing HCC. In addition, we found two other biologically relevant markers, Myostatin and Pyruvate Kinase M2 (PKM2), which were significantly associated with HCC. We tested these for risk stratification of HCC in multivariable models adjusted for demographic and clinical variables, as well as batch and site. These markers reflect ongoing biology in the liver. They potentially indicate the presence of HCC early in its evolution and before it is manifest as a detectable lesion, thereby providing a set of markers that may be able to stratify risk for HCC.
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Affiliation(s)
- Xiyan Xiang
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
- These authors contributed equally to this work
| | - Krishanu Bhowmick
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
- These authors contributed equally to this work
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, University of Maryland, Baltimore, MD 21201, USA
| | - Kazufumi Ohshiro
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
| | - Xiaochun Yang
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
| | - Linda L. Wong
- Department of Surgery, University of Hawaii, Honolulu, HI 96813, USA
| | - Herbert Yu
- Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Patricia S. Latham
- Department of Pathology, The George Washington University, Washington, DC 20037, USA
| | - Sanjaya K. Satapathy
- Department of Medicine, Sandra Atlas Bass Center for Liver Diseases and Transplantation, North Shore University Hospital/Northwell Health, Manhasset, NY 11030, USA
| | - Christina Brennan
- Office of Clinical Research, Northwell Health, Lake Success, NY 11042, USA
- The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
| | - Richard J. Dima
- Office of Clinical Research, Northwell Health, Lake Success, NY 11042, USA
| | - Nyasha Chambwe
- Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
| | - Gulru Sharifova
- Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Fellanza Cacaj
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
| | - Sahara John
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
| | | | - Hai Huang
- The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
| | - Srinivasan Dasarathy
- Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44106, USA
| | | | - Aiwu R. He
- Georgetown Lombardi Comprehensive Cancer Center, Washington, DC 20007, USA
| | - Richard L. Amdur
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
- Quantitative Intelligence, The Institutes for Health Systems Science, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
- Department of Surgery, The George Washington University, Washington, DC 20037, USA
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9
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Nenu I, Toadere TM, Topor I, Țichindeleanu A, Bondor DA, Trella ȘE, Sparchez Z, Filip GA. Interleukin-6 in Hepatocellular Carcinoma: A Dualistic Point of View. Biomedicines 2023; 11:2623. [PMID: 37892997 PMCID: PMC10603956 DOI: 10.3390/biomedicines11102623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/14/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023] Open
Abstract
Hepatocellular Carcinoma (HCC) is a pressing health concern, demanding a deep understanding of various mediators' roles in its development for therapeutic progress. Notably, interleukin-6 (IL-6) has taken center stage in investigations due to its intricate and context-dependent functions. This review delves into the dual nature of IL-6 in HCC, exploring its seemingly contradictory roles as both a promoter and an inhibitor of disease progression. We dissect the pro-tumorigenic effects of IL-6, including its impact on tumor growth, angiogenesis, and metastasis. Concurrently, we examine its anti-tumorigenic attributes, such as its role in immune response activation, cellular senescence induction, and tumor surveillance. Through a comprehensive exploration of the intricate interactions between IL-6 and the tumor microenvironment, this review highlights the need for a nuanced comprehension of IL-6 signaling in HCC. It underscores the importance of tailored therapeutic strategies that consider the dynamic stages and diverse surroundings within the tumor microenvironment. Future research directions aimed at unraveling the multifaceted mechanisms of IL-6 in HCC hold promise for developing more effective treatment strategies and improving patient outcomes.
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Affiliation(s)
- Iuliana Nenu
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania;
| | - Teodora Maria Toadere
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Ioan Topor
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Andra Țichindeleanu
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Daniela Andreea Bondor
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Șerban Ellias Trella
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Zeno Sparchez
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania;
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Gabriela Adriana Filip
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
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10
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Nakagawa C, Kadlera Nagaraj M, Hernandez JC, Uthay Kumar DB, Shukla V, Machida R, Schüttrumpf J, Sher L, Farci P, Mishra L, Tahara SM, Ou JHJ, Machida K. β-CATENIN stabilizes HIF2 through lncRNA and inhibits intravenous immunoglobulin immunotherapy. Front Immunol 2023; 14:1204907. [PMID: 37744383 PMCID: PMC10516572 DOI: 10.3389/fimmu.2023.1204907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 08/03/2023] [Indexed: 09/26/2023] Open
Abstract
Introduction Tumor-initiating cells (TICs) are rare, stem-like, and highly malignant. Although intravenous hepatitis B and C immunoglobulins have been used for HBV and HCV neutralization in patients, their tumor-inhibitory effects have not yet been examined. Hepatitis B immunoglobulin (HBIG) therapy is employed to reduce hepatocellular carcinoma (HCC) recurrence in patients after living donor liver transplantations (LDLT). Hypothesis We hypothesized that patient-derived intravenous immunoglobulin (IVIG) binding to HCC associated TICs will reduce self-renewal and cell viability driven by β-CATENIN-downstream pathways. β-CATENIN activity protected TICs from IVIG effects. Methods The effects of HBIG and HCIG binding to TICs were evaluated for cell viability and self-renewal. Results Inhibition of β-CATENIN pathway(s) augmented TIC susceptibility to HBIG- and HCIG-immunotherapy. HBV X protein (HBx) upregulates both β-CATENIN and NANOG expression. The co-expression of constitutively active β-CATENIN with NANOG promotes self-renewal ability and tumor-initiating ability of hepatoblasts. HBIG bound to HBV+ cells led to growth inhibition in a TIC subset that expressed hepatitis B surface antigen. The HBx protein transformed cells through β-CATENIN-inducible lncRNAs EGLN3-AS1 and lnc-β-CatM. Co-expression of constitutively active β-CATENIN with NANOG promoted self-renewal ability of TICs through EGLN3 induction. β-CATENIN-induced lncRNAs stabilized HIF2 to maintain self-renewal of TICs. Targeting of EGLN3-AS1 resulted in destabilization of EZH2-dependent β-CATENIN activity and synergized cell-killing of TICs by HBIG or HCIG immunotherapy. Discussion Taken together, WNT and stemness pathways induced HIF2 of TICs via cooperating lncRNAs resulting in resistance to cancer immunotherapy. Therefore, therapeutic use of IVIG may suppress tumor recurrence through inhibition of TICs.
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Affiliation(s)
- Chad Nakagawa
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Manjunatha Kadlera Nagaraj
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Juan Carlos Hernandez
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Dinesh Babu Uthay Kumar
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Vivek Shukla
- University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Risa Machida
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | | | - Linda Sher
- Department of Surgery, University of Southern California, Los Angeles, CA, United States
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Lopa Mishra
- University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Stanley M. Tahara
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Keigo Machida
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
- Southern California Research Center for Alcoholic Liver Disease and Pancreatic Disease (ALPD) and Cirrhosis, Los Angeles, CA, United States
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11
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Lominadze Z, Shaik MR, Choi D, Zaffar D, Mishra L, Shetty K. Hepatocellular Carcinoma Genetic Classification. Cancer J 2023; 29:249-258. [PMID: 37796642 PMCID: PMC10686192 DOI: 10.1097/ppo.0000000000000682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
ABSTRACT Hepatocellular carcinoma (HCC) represents a significant global burden, with management complicated by its heterogeneity, varying presentation, and relative resistance to therapy. Recent advances in the understanding of the genetic, molecular, and immunological underpinnings of HCC have allowed a detailed classification of these tumors, with resultant implications for diagnosis, prognostication, and selection of appropriate treatments. Through the correlation of genomic features with histopathology and clinical outcomes, we are moving toward a comprehensive and unifying framework to guide our diagnostic and therapeutic approach to HCC.
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Affiliation(s)
- Zurabi Lominadze
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
| | | | - Dabin Choi
- Department of Medicine, University of Maryland Medical Center
| | - Duha Zaffar
- Department of Medicine, University of Maryland Midtown Medical Center
| | - Lopa Mishra
- Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory; Divisions of Gastroenterology and Hepatology, Northwell Health
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
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12
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Hernandez JC, Chen CL, Machida T, Uthaya Kumar DB, Tahara SM, Montana J, Sher L, Liang J, Jung JU, Tsukamoto H, Machida K. LIN28 and histone H3K4 methylase induce TLR4 to generate tumor-initiating stem-like cells. iScience 2023; 26:106254. [PMID: 36949755 PMCID: PMC10025994 DOI: 10.1016/j.isci.2023.106254] [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: 01/03/2020] [Revised: 01/09/2022] [Accepted: 02/16/2023] [Indexed: 02/24/2023] Open
Abstract
Chemoresistance and plasticity of tumor-initiating stem-like cells (TICs) promote tumor recurrence and metastasis. The gut-originating endotoxin-TLR4-NANOG oncogenic axis is responsible for the genesis of TICs. This study investigated mechanisms as to how TICs arise through transcriptional, epigenetic, and post-transcriptional activation of oncogenic TLR4 pathways. Here, we expressed constitutively active TLR4 (caTLR4) in mice carrying pLAP-tTA or pAlb-tTA, under a tetracycline withdrawal-inducible system. Liver progenitor cell induction accelerated liver tumor development in caTLR4-expressing mice. Lentiviral shRNA library screening identified histone H3K4 methylase SETD7 as central to activation of TLR4. SETD7 combined with hypoxia induced TLR4 through HIF2 and NOTCH. LIN28 post-transcriptionally stabilized TLR4 mRNA via de-repression of let-7 microRNA. These results supported a LIN28-TLR4 pathway for the development of HCCs in a hypoxic microenvironment. These findings not only advance our understanding of molecular mechanisms responsible for TIC generation in HCC, but also represent new therapeutic targets for the treatment of HCC.
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Affiliation(s)
- Juan Carlos Hernandez
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- MS Biotechnology Program, California State University Channel Islands, Camarillo, CA 93012, USA
| | - Chia-Lin Chen
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- Department of Life Sciences & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 110, Taiwan
| | - Tatsuya Machida
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Dinesh Babu Uthaya Kumar
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Stanley M. Tahara
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Jared Montana
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Linda Sher
- Department of Surgery, University of Southern California, Los Angeles, CA 90033, USA
| | | | - Jae U. Jung
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Hidekazu Tsukamoto
- Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA
- Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Keigo Machida
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA
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13
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Yan ZJ, Chen L, Wang HY. To be or not to be: The double-edged sword roles of liver progenitor cells. Biochim Biophys Acta Rev Cancer 2023; 1878:188870. [PMID: 36842766 DOI: 10.1016/j.bbcan.2023.188870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/11/2023] [Accepted: 01/28/2023] [Indexed: 02/28/2023]
Abstract
Given the liver's remarkable and unique regenerative capacity, researchers have long focused on liver progenitor cells (LPCs) and liver cancer stem cells (LCSCs). LPCs can differentiate into both hepatocytes and cholangiocytes. However, the mechanism underlying cell conversion and its distinct contribution to liver homeostasis and tumorigenesis remain unclear. In this review, we discuss the complicated conversions involving LPCs and LCSCs. As the critical intermediate state in malignant transformation, LPCs play double-edged sword roles. LPCs are not only involved in hepatic wound-healing responses by supplementing liver cells and bile duct cells in the damaged liver but may transform into LCSCs under dysregulation of key signaling pathways, resulting in refractory malignant liver tumors. Because LPC lineages are temporally and spatially dynamic, we discuss crucial LPC subgroups and summarize regulatory factors correlating with the trajectories of LPCs and LCSCs in the liver tumor microenvironment. This review elaborates on the double-edged sword roles of LPCs to help understand the liver's regenerative potential and tumor heterogeneity. Understanding the sources and transformations of LPCs is essential in determining how to exploit their regenerative capacity in the future.
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Affiliation(s)
- Zi-Jun Yan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China
| | - Lei Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China.
| | - Hong-Yang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China.
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14
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Huang H, Tsui YM, Ng IOL. Fueling HCC Dynamics: Interplay Between Tumor Microenvironment and Tumor Initiating Cells. Cell Mol Gastroenterol Hepatol 2023; 15:1105-1116. [PMID: 36736664 PMCID: PMC10036749 DOI: 10.1016/j.jcmgh.2023.01.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 02/05/2023]
Abstract
Liver cancer (hepatocellular carcinoma) is a common cancer worldwide. It is an aggressive cancer, with high rates of tumor relapse and metastasis, high chemoresistance, and poor prognosis. Liver tumor-initiating cells (LTICs) are a distinctive subset of liver cancer cells with self-renewal and differentiation capacities that contribute to intratumoral heterogeneity, tumor recurrence, metastasis, and chemo-drug resistance. LTICs, marked by different TIC markers, have high plasticity and use diverse signaling pathways to promote tumorigenesis and tumor progression. LTICs are nurtured in the tumor microenvironment (TME), where noncellular and cellular components participate to build an immunosuppressive and tumor-promoting niche. As a result, the TME has emerged as a promising anticancer therapeutic target, as exemplified by some successful applications of tumor immunotherapy. In this review, we discuss the plasticity of LTICs in terms of cellular differentiation, epithelial-mesenchymal transition, and cellular metabolism. We also discuss the various components of the TME, including its noncellular and cellular components. Thereafter, we discuss the mutual interactions between TME and LTICs, including recently reported molecular mechanisms. Lastly, we summarize and describe new ideas concerning novel approaches and strategies for liver cancer therapy.
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Affiliation(s)
- Hongyang Huang
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Yu-Man Tsui
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.
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15
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Yang Z, Wan W, Zhang P, Wang S, Zhao Z, Xue J, Yao M, Zhao Y, Zheng W, Niu B, Wang M, Li H, Guo W, Ren Z, Hu Y. Crosstalk between heat shock factor 1 and signal transducer and activator of transcription 3 mediated by interleukin-8 autocrine signaling maintains the cancer stem cell phenotype in liver cancer. J Gastroenterol Hepatol 2023; 38:138-152. [PMID: 36300571 DOI: 10.1111/jgh.16040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 05/10/2022] [Accepted: 10/15/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIM Liver cancer stem cells (LCSCs) cause therapeutic refractoriness and relapse in hepatocellular carcinoma. Heat shock factor 1 (HSF1) plays versatile roles in multiple cancers. However, the role of HSF1 in LCSCs is not well understood. This study investigated the function and signal mechanisms of HSF1 in maintaining LCSC phenotypes. METHODS We established two LCSC lines, HepG2-R and HuH-7-R. Constitutive activation of HSF1 was observed in these LCSCs. Specific short hairpin RNAs (shRNAs) and chemical inhibitors were used to identify the relationship between HSF1 expression and LCSCs phenotypes. RESULTS We revealed a concomitant activation modality involving HSF1 and STAT3 in LCSCs and liver cancer tissues. We also found that liver cancer patients whose HSF1 and STAT3 mRNA expression levels were high presented with unfavorable clinicopathological characteristics. Moreover, the secretion of interleukin-8 (IL-8) was elevated in the LCSC medium and was directly regulated by HSF1 at the transcriptional level. In turn, IL-8 activated HSF1 and STAT3 signaling, and a neutralizing IL-8 antibody inhibited HSF1 and STAT3 activity, reduced cancer stem cell marker expression, and decreased LCSC microsphere formation. Simultaneous intervention with HSF1 and STAT3 led to synergistically suppressed stemness acquisition and growth suppression in the LCSCs in vivo and in vitro. CONCLUSIONS Our study indicates that IL-8 mediates the crosstalk between the HSF1 and Stat3 signaling pathways in LCSCs and that the combined targeting of HSF1 and STAT3 is a promising treatment strategy for patients with advanced liver cancer.
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Affiliation(s)
- Zhengyan Yang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
| | - Wenjuan Wan
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
| | - Pai Zhang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
| | - Shuangfeng Wang
- Shenzhen Key Laboratory of Prevention and Treatment of Severe Infections, Department of Critical Care Medicine, Shenzhen People's Hospital, Shenzhen, China
| | - Zhi Zhao
- Henan University-Affiliated Zhengzhou Yihe Hospital, Zhengzhou, China
| | - Jingrui Xue
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
| | - Mengzhuo Yao
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
| | - Yiwei Zhao
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
| | - Weifeng Zheng
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
| | - Baohua Niu
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
| | - Mingli Wang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
| | - Hui Li
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
| | - Weikai Guo
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
| | - Zhiguang Ren
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China.,Institute of Traditional Chinese Medicine, Henan University, Kaifeng, China
| | - Yanzhong Hu
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Basic Medicine, Henan University, Kaifeng, China
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16
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Zhang G, Zhang K, Zhao Y, Yang Q, Lv X. A novel stemness-hypoxia-related signature for prognostic stratification and immunotherapy response in hepatocellular carcinoma. BMC Cancer 2022; 22:1103. [DOI: 10.1186/s12885-022-10195-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/18/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The specific differentiation potential, unlimited proliferation, and self-renewal capacity of cancer stem cells (CSCs) are closely related to the occurrence, recurrence, and drug resistance of hepatocellular carcinoma (HCC), as well as hypoxia. Therefore, an in-depth analysis of the relationship between HCC stemness, oxygenation status, and the effectiveness of immunotherapy is necessary to improve the poor prognosis of HCC patients.
Methods
The weighted gene co-expression network analysis (WGCNA) was utilized to find hypoxia-related genes, and the stemness index (mRNAsi) was evaluated using the one-class logistic regression (OCLR) technique. Based on stemness-hypoxia-related genes (SHRGs), population subgroup categorization using NMF cluster analysis was carried out. The relationship between SHRGs and survival outcomes was determined using univariate Cox regression. The LASSO-Cox regression strategy was performed to investigate the quality and establish the classifier associated with prognosis. The main effect of risk scores on the tumor microenvironment (TME) and its response to immune checkpoint drugs was also examined. Finally, qRT-PCR was performed to explore the expression and prognostic value of the signature in clinical samples.
Results
After identifying tumor stemness- and hypoxia-related genes through a series of bioinformatics analyses, we constructed a prognostic stratification model based on these SHRGs, which can be effectively applied to the prognostic classification of HCC patients and the prediction of immune checkpoint inhibitors (ICIs) efficacy. Independent validation of the model in the ICGC cohort yielded good results. In addition, we also constructed hypoxic cell models in Herp3B and Huh7 cells to verify the expression of genes in the prognostic model and found that C7, CLEC1B, and CXCL6 were not only related to the tumor stemness but also related to hypoxia. Finally, we found that the constructed signature had a good prognostic value in the clinical sample.
Conclusions
We constructed and validated a stemness-hypoxia-related prognostic signature that can be used to predict the efficacy of ICIs therapy. We also verified that C7, CLEC1B, and CXCL6 are indeed associated with stemness and hypoxia through a hypoxic cell model, which may provide new ideas for individualized immunotherapy.
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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18
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Machida K, Tahara SM. Immunotherapy and Microbiota for Targeting of Liver Tumor-Initiating Stem-like Cells. Cancers (Basel) 2022; 14:2381. [PMID: 35625986 PMCID: PMC9139909 DOI: 10.3390/cancers14102381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/04/2022] [Accepted: 05/06/2022] [Indexed: 02/08/2023] Open
Abstract
Cancer contains tumor-initiating stem-like cells (TICs) that are resistant to therapies. Hepatocellular carcinoma (HCC) incidence has increased twice over the past few decades, while the incidence of other cancer types has trended downward globally. Therefore, an understanding of HCC development and therapy resistance mechanisms is needed for this incurable malignancy. This review article describes links between immunotherapies and microbiota in tumor-initiating stem-like cells (TICs), which have stem cell characteristics with self-renewal ability and express pluripotency transcription factors such as NANOG, SOX2, and OCT4. This review discusses (1) how immunotherapies fail and (2) how gut dysbiosis inhibits immunotherapy efficacy. Gut dysbiosis promotes resistance to immunotherapies by breaking gut immune tolerance and activating suppressor immune cells. Unfortunately, this leads to incurable recurrence/metastasis development. Personalized medicine approaches targeting these mechanisms of TIC/metastasis-initiating cells are emerging targets for HCC immunotherapy and microbiota modulation therapy.
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Affiliation(s)
- Keigo Machida
- Southern California Research Center for ALPD and Cirrhosis, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, 2011 Zonal Ave., 503C-HMR, Los Angeles, CA 90033, USA;
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Raissa R, Riawan W, Safitri A, Masruri M, Beltran MAG, Aulanniam A. In vitro and in vivo study: Ethanolic extract leaves of Azadirachta indica Juss. variant of Indonesia and Philippines suppresses tumor growth of hepatocellular carcinoma by inhibiting IL-6/STAT3 signaling. F1000Res 2022; 11:477. [PMID: 37829248 PMCID: PMC10565427 DOI: 10.12688/f1000research.109557.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/30/2022] [Indexed: 10/14/2023] Open
Abstract
Background: Azadirachta indica Juss. has been shown to suppress cancer progression through a variety of mechanisms. In order to treat cancer progression, cancer immunotherapy is used to stimulate the immune system where immunosuppression is present in tumor microenvironments. Many cancer cells produce a lot of interleukin-6 (IL-6) and signal transducer activator of transcription 3 (STAT3). STAT3 plays a key role in suppressing the expression of critical immune activation regulators. IL-6-mediated STAT3 activation is common in the tumor microenvironment. Inhibiting the IL-6/STAT3 signaling pathway has become a therapeutic option for cancer progression. As vimentin is also expressed in hepatic stellate cells boosting cancer survival. We focused on the precise effect of extract from leaves of Azadirachta indica Juss, on inhibiting the IL-6/STAT3 signaling cascade on hepatocellular carcinoma by in vitro and in vivo study. Methods: In the in vitro study, the effect of Azadirachta indica Juss. variant Indonesia and Philippines against the expression of IL-6 and STAT3 was examined in liver cancer cell line. In the in vivo study, 24 male rats ( Rattus norvegicus) strain Wistar were induced by diethylnitrosamine and carbon tetrachloride (CCl 4). Based on the therapy given, the groups were divided into negative control, positive control, Indonesia extract, and Philippine extract. Expression of IL-6, STAT3, and vimentin were tested using immunohistochemistry staining. The data were analyzed using analysis of variance, which was then followed by the Tukey test. Results: Statistically significant difference in IL-6 and STAT3 was observed between the treatment groups and positive control group by in vitro study and in vivo study. Generally, there is no significant difference between treatment using Indonesian and Philippine leaves. Conclusion: Both therapy doses of Azadirachta indica variant in Indonesia and Philippines were able to reduce IL-6, STAT3 and vimentin expression of hepatocellular carcinoma cell by in vitro and in vivo experiment.
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Affiliation(s)
- Ricadonna Raissa
- Doctoral Program of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
| | - Wibi Riawan
- Department of Biochemistry, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, Indonesia
| | - Anna Safitri
- Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
- Research Center for Smart Molecules of Natural Genetic Resources (SMONAGENES), Universitas Brawijaya, Malang, East Java, Indonesia
| | - Masruri Masruri
- Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
| | | | - Aulanniam Aulanniam
- Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, East Java, Indonesia
- Department of Biochemistry, Faculty of Veterinary Medicine, Universitas Brawijaya, Malang, East Java, Indonesia
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20
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Song J, Zhou H, Gu D, Xu Y. Hepatocellular Carcinoma Differentiation: Research Progress in Mechanism and Treatment. Front Oncol 2022; 11:790358. [PMID: 35096588 PMCID: PMC8790246 DOI: 10.3389/fonc.2021.790358] [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: 10/06/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Although progress has been made in diagnosis and treatment, morbidity and mortality continue to rise. Chronic liver disease and liver cirrhosis are still the most important risk factors for liver cancer. Although there are many treatments, it can only be cured by orthotopic liver transplantation (OLT) or surgical resection. And the worse the degree of differentiation, the worse the prognosis of patients with liver cancer. Then it can be considered that restoring a better state of differentiation may improve the prognosis. The differentiation treatment of liver cancer is to reverse the dedifferentiation process of hepatocytes to liver cancer cells by means of drugs, improve the differentiation state of the tumor, and restore the normal liver characteristics, so as to improve the prognosis. Understanding the mechanism of dedifferentiation of liver cancer can provide ideas for drug design. Liver enrichment of transcription factors, imbalance of signal pathway and changes of tumor microenvironment can promote the occurrence and development of liver cancer, and restoring its normal level can inhibit the malignant behavior of tumor. At present, some drugs have been proved to be effective, but more clinical data are needed to support the effectiveness and reliability of drugs. The differentiation treatment of liver cancer is expected to become an important part of the treatment of liver cancer in the future.
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Affiliation(s)
- Jianning Song
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China.,Guangzhou Medical University, Shenzhen, China
| | - Hongzhong Zhou
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China.,Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Dayong Gu
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China
| | - Yong Xu
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China.,Guangzhou Medical University, Shenzhen, China
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21
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Zaidi S, Gough NR, Mishra L. Mechanisms and clinical significance of TGF-β in hepatocellular cancer progression. Adv Cancer Res 2022; 156:227-248. [DOI: 10.1016/bs.acr.2022.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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22
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Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment. Int J Mol Sci 2021; 22:ijms222111765. [PMID: 34769191 PMCID: PMC8583957 DOI: 10.3390/ijms222111765] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/15/2021] [Accepted: 10/20/2021] [Indexed: 12/28/2022] Open
Abstract
The balance between anti-tumor and tumor-promoting immune cells, such as CD4+ Th1 and regulatory T cells (Tregs), respectively, is assumed to dictate the progression of hepatocellular carcinoma (HCC). The transforming growth factor beta (TGFβ) markedly shapes the HCC microenvironment, regulating the activation state of multiple leukocyte subsets and driving the differentiation of cancer associated fibroblasts (CAFs). The fibrotic (desmoplastic) reaction in HCC tissue strongly depends on CAFs activity. In this study, we attempted to assess the role of TGFβ on transendothelial migration of Th1-oriented and Treg-oriented CD4+ T cells via a direct or indirect, CAF-mediated mechanisms, respectively. We found that the blockage of TGFβ receptor I-dependent signaling in Tregs resulted in impaired transendothelial migration (TEM) of these cells. Interestingly, the secretome of TGFβ-treated CAFs inhibited the TEM of Tregs but not Th1 cells, in comparison to the secretome of untreated CAFs. In addition, we found a significant inverse correlation between alpha-SMA and FoxP3 (marker of Tregs) mRNA expression in a microarray analysis involving 78 HCCs, thus suggesting that TGFβ-activated stromal cells may counteract the trafficking of Tregs into the tumor. The apparent dual behavior of TGFβ as both pro- and anti-tumorigenic cytokines may add a further level of complexity to the mechanisms that regulate the interactions among cancerous, stromal, and immune cells within HCC, as well as other solid tumors, and contribute to better manipulation of the TGFβ signaling as a therapeutic target in HCC patients.
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23
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Gough NR, Xiang X, Mishra L. TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer. Gastroenterology 2021; 161:434-452.e15. [PMID: 33940008 PMCID: PMC8841117 DOI: 10.1053/j.gastro.2021.04.064] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/05/2021] [Accepted: 04/25/2021] [Indexed: 02/06/2023]
Abstract
Genetic alterations affecting transforming growth factor-β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-β signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination. Here, we review the involvement of the TGF-β pathway mediated by the transcriptional regulators SMADs in disease progression to cancer in the digestive system. The review integrates human genomic studies with animal models that provide clues toward understanding and managing the complexity of the pathway in disease and cancer.
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Affiliation(s)
- Nancy R. Gough
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York
| | - Xiyan Xiang
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York; Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, District of Columbia.
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24
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Lv D, Chen L, Du L, Zhou L, Tang H. Emerging Regulatory Mechanisms Involved in Liver Cancer Stem Cell Properties in Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:691410. [PMID: 34368140 PMCID: PMC8339910 DOI: 10.3389/fcell.2021.691410] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/01/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and one of the leading causes of cancer-related deaths worldwide. A growing body of evidence supports the hypothesis that HCC is driven by a population of cells called liver cancer stem cells (LCSCs). LCSCs have been proposed to contribute to malignant HCC progression, including promoting tumor occurrence and growth, mediating tumor metastasis, and treatment resistance, but the regulatory mechanism of LCSCs in HCC remains unclear. Understanding the signaling pathways responsible for LCSC maintenance and survival may provide opportunities to improve patient outcomes. Here, we review the current literature about the origin of LCSCs and the niche composition, describe the current evidence of signaling pathways that mediate LCSC stemness, then highlight several mechanisms that modulate LCSC properties in HCC progression, and finally, summarize the new developments in therapeutic strategies targeting LCSCs markers and regulatory pathways.
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Affiliation(s)
- Duoduo Lv
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Liyu Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lingyun Zhou
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy and Center of Infectious Diseases, Division of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
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25
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Aashaq S, Batool A, Mir SA, Beigh MA, Andrabi KI, Shah ZA. TGF-β signaling: A recap of SMAD-independent and SMAD-dependent pathways. J Cell Physiol 2021; 237:59-85. [PMID: 34286853 DOI: 10.1002/jcp.30529] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 06/06/2021] [Accepted: 07/06/2021] [Indexed: 12/20/2022]
Abstract
Transforming growth factor-β (TGF-β) is a proinflammatory cytokine known to control a diverse array of pathological and physiological conditions during normal development and tumorigenesis. TGF-β-mediated physiological effects are heterogeneous and vary among different types of cells and environmental conditions. TGF-β serves as an antiproliferative agent and inhibits tumor development during primary stages of tumor progression; however, during the later stages, it encourages tumor development and mediates metastatic progression and chemoresistance. The fundamental elements of TGF-β signaling have been divulged more than a decade ago; however, the process by which the signals are relayed from cell surface to nucleus is very complex with additional layers added in tumor cell niches. Although the intricate understanding of TGF-β-mediated signaling pathways and their regulation are still evolving, we tried to make an attempt to summarize the TGF-β-mediated SMAD-dependent andSMAD-independent pathways. This manuscript emphasizes the functions of TGF-β as a metastatic promoter and tumor suppressor during the later and initial phases of tumor progression respectively.
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Affiliation(s)
- Sabreena Aashaq
- Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, JK, India
| | - Asiya Batool
- Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, Srinagar, JK, India
| | | | | | | | - Zaffar Amin Shah
- Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, JK, India
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26
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Li C, Qiu Q, Gao X, Yan X, Fan C, Luo X, Liu X, Wang S, Lai X, Song Y, Deng Y. Sialic acid conjugate-modified liposomal platform modulates immunosuppressive tumor microenvironment in multiple ways for improved immune checkpoint blockade therapy. J Control Release 2021; 337:393-406. [PMID: 34171446 DOI: 10.1016/j.jconrel.2021.06.027] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 06/08/2021] [Accepted: 06/20/2021] [Indexed: 12/22/2022]
Abstract
Immune checkpoint blockade (ICB) treatment is promising for the clinical therapy of numerous malignancies. However, most cancer patients rarely benefit from such single-agent immunotherapies because of the complexity of both the tumor and tumor microenvironment. A tumor-specific liposomal vehicle (DOX-SAL) modified with a sialic acid-cholesterol conjugate (SA-CH) and remotely loaded with doxorubicin (DOX) is herein reported for improving chemoimmunotherapy. The intravenous administration of DOX-SAL dramatically downregulates tumor-associated macrophage (TAM)-mediated immunosuppression, inhibits immunoregulatory functions, and promotes intratumoral infiltration of CD8+ T cells. Compared to conventional liposomes, DOX-SAL-mediated combination therapy with a PD-1-blocking monoclonal antibody (aPD-1 mAb) almost completely eliminates B16F10 tumors and efficiently inhibits 4T1 tumors. Moreover, cancer stem cells exhibit efficient tumor-initiating, tumor-propagating, and immunosuppressive tumor microenvironment-shaping capabilities. To further improve the treatment efficacy of an immunologically "cold" tumor, metformin (MET), which selectively eradicates breast cancer tumor stem cells, is co-encapsulated with DOX into liposomes to develop DOX/MET-SAL. The combination therapy with DOX/MET-SAL and aPD-1 mAb in a 4T1 orthotopic mouse model indicates their synergetic benefit on primary tumor inhibition, metastasis suppression, and survival rate improvement. Thus, the multifunctional liposomal platform has potential value for ICB combination immunotherapy.
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Affiliation(s)
- Cong Li
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Qiujun Qiu
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Xin Gao
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Xinyang Yan
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Chuizhong Fan
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Xiang Luo
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Xinrong Liu
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Shuo Wang
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Xiaoxue Lai
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Yanzhi Song
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
| | - Yihui Deng
- College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
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27
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Tsai IJ, Su ECY, Tsai IL, Lin CY. Clinical Assay for the Early Detection of Colorectal Cancer Using Mass Spectrometric Wheat Germ Agglutinin Multiple Reaction Monitoring. Cancers (Basel) 2021; 13:cancers13092190. [PMID: 34063271 PMCID: PMC8124906 DOI: 10.3390/cancers13092190] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/26/2021] [Accepted: 04/29/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is currently the third leading cause of cancer death worldwide. Early diagnosis of CRC is important for increasing the opportunity for treatment and receiving a good prognosis. The aim of our study was to develop a detection method that combined wheat germ agglutinin (WGA) chromatography with mass spectrometry (MS) for early detection of CRC. Further, machine learning algorithms and logistic regression were applied to combine multiple biomarkers we discovered. We validated in a population of 286 plasma samples the diagnostic performance of peptides corresponding to WGA-captured protein and its combination, which received a sensitivity of 84.5% and a specificity of 97.5% in the diagnoses of CRC. Proteomic biomarkers combined with algorithms can provide a powerful tool for discriminating patients with CRC and health controls (HCs). Measurements of WGA-captured PF4, ITIH4, and APOE with MS are then useful for early detection of CRC. Additionally, our study revealed the potential of applying lectin chromatography with MS for disease diagnosis. Abstract Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality in the world. U.S. Food and Drug Administration-approved circulating tumor markers, including carcinoembryonic antigen, carbohydrate antigen (CA) 19-9 and CA125 were used as prognostic biomarkers of CRC that attributed to low sensitivity in diagnosis of CRC. Therefore, our purpose is to develop a novel strategy for novel clinical biomarkers for early CRC diagnosis. We used mass spectrometry (MS) methods such as nanoLC-MS/MS, targeted LC-MS/MS, and stable isotope-labeled multiple reaction monitoring (MRM) MS coupled to test machine learning algorithms and logistic regression to analyze plasma samples from patients with early-stage CRC, late-stage CRC, and healthy controls (HCs). On the basis of our methods, 356 peptides were identified, 6 differential expressed peptides were verified, and finally three peptides corresponding wheat germ agglutinin (WGA)-captured proteins were semi-quantitated in 286 plasma samples (80 HCs and 206 CRCs). The novel peptide biomarkers combination of PF454–62, ITIH4429–438, and APOE198–207 achieved sensitivity 84.5%, specificity 97.5% and an AUC of 0.96 in CRC diagnosis. In conclusion, our study demonstrated that WGA-captured plasma PF454–62, ITIH4429–438, and APOE198–207 levels in combination may serve as highly effective early diagnostic biomarkers for patients with CRC.
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Affiliation(s)
- I-Jung Tsai
- Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
| | - Emily Chia-Yu Su
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
- Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - I-Lin Tsai
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Ching-Yu Lin
- Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: ; Tel.: +886-2-2736-1661 (ext. 3326)
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28
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Interplay of autophagy and cancer stem cells in hepatocellular carcinoma. Mol Biol Rep 2021; 48:3695-3717. [PMID: 33893928 DOI: 10.1007/s11033-021-06334-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 04/02/2021] [Indexed: 12/22/2022]
Abstract
Liver cancer is the sixth most common cancer and the fourth leading cause of cancer deaths in the world. The most common type of liver cancers is hepatocellular carcinoma (HCC). Autophagy is the cellular digestion of harmful components by sequestering the waste products into autophagosomes followed by lysosomal degradation for the maintenance of cellular homeostasis. The impairment of autophagy is highly associated with the development and progression of HCC although autophagy may be involved in tumour-suppressing cellular events. In regards to its protecting role, autophagy also shelters the cells from anoikis- a programmed cell death in anchorage-dependent cells detached from the surrounding extracellular matrix which facilitates metastasis in HCC. Liver cancer stem cells (LCSCs) have the ability for self-renewal and differentiation and are associated with the development and progression of HCC by regulating stemness, resistance and angiogenesis. Interestingly, autophagy is also known to regulate normal stem cells by promoting cellular survival and differentiation and maintaining cellular homeostasis. In this review, we discuss the basal autophagic mechanisms and double-faceted roles of autophagy as both tumour suppressor and tumour promoter in HCC, as well as its association with and contribution to self-renewal and differentiation of LCSCs.
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29
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Wang X, Wang J, Tsui YM, Shi C, Wang Y, Zhang X, Yan Q, Chen M, Jiang C, Yuan YF, Wong CM, Liu M, Feng ZY, Chen H, Ng IOL, Jiang L, Guan XY. RALYL increases hepatocellular carcinoma stemness by sustaining the mRNA stability of TGF-β2. Nat Commun 2021; 12:1518. [PMID: 33750796 PMCID: PMC7943813 DOI: 10.1038/s41467-021-21828-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 02/10/2021] [Indexed: 12/18/2022] Open
Abstract
Growing evidences suggest that cancer stem cells exhibit many molecular characteristics and phenotypes similar to their ancestral progenitor cells. In the present study, human embryonic stem cells are induced to differentiate into hepatocytes along hepatic lineages to mimic liver development in vitro. A liver progenitor specific gene, RALY RNA binding protein like (RALYL), is identified. RALYL expression is associated with poor prognosis, poor differentiation, and metastasis in clinical HCC patients. Functional studies reveal that RALYL could promote HCC tumorigenicity, self-renewal, chemoresistance, and metastasis. Moreover, molecular mechanism studies show that RALYL could upregulate TGF-β2 mRNA stability by decreasing N6-methyladenosine (m6A) modification. TGF-β signaling and the subsequent PI3K/AKT and STAT3 pathways, upregulated by RALYL, contribute to the enhancement of HCC stemness. Collectively, RALYL is a liver progenitor specific gene and regulates HCC stemness by sustaining TGF-β2 mRNA stability. These findings may inspire precise therapeutic strategies for HCC. RALYL is a liver progenitor cell-specific gene but its role in hepatocellular carcinoma (HCC) remains unknown. Here, the authors demonstrate that RALYL regulates HCC stemness through upregulation of TGF-β2 mRNA stability by decreasing N6-methyladenosine modification.
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Affiliation(s)
- Xia Wang
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.,Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - Jin Wang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yu-Man Tsui
- State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.,Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - Chaoran Shi
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Ying Wang
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.,Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xin Zhang
- State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.,Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - Qian Yan
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Miao Chen
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Chen Jiang
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.,Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yun-Fei Yuan
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Chun-Ming Wong
- State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.,Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - Ming Liu
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.,Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Zeng-Yu Feng
- Department of General Surgery, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Honglin Chen
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Irene Oi Lin Ng
- State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.,Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - Lingxi Jiang
- State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China. .,Department of General Surgery, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
| | - Xin-Yuan Guan
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China. .,State key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
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30
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Abstract
IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.
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Affiliation(s)
- Toshio Hirano
- National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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31
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Soler L, Szczubiał M, Dąbrowski R, Płusa A, Bochniarz M, Brodzki P, Lampreave F, Piñeiro M. Measurement of ITIH4 and Hp levels in bitches with pyometra using newly developed ELISA methods. Vet Immunol Immunopathol 2021; 235:110221. [PMID: 33730638 DOI: 10.1016/j.vetimm.2021.110221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 02/22/2021] [Accepted: 02/27/2021] [Indexed: 12/01/2022]
Abstract
Measurement of acute phase proteins (APPs) as biomarkers in canine medicine is in increasing demand. In the present study, the development and validation of two ELISA methods for the quantification of canine inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) and haptoglobin (Hp) are shown. The adequate imprecision and accuracy and wide analytical range make the developed methods appropriate to quantify ITIH4 and Hp in serum samples. The inter- and intra-assay CVs were lower than 10 %, and the assays maintained linearity under dilution and showed analytical equivalence with the method of radial immunodiffusion. The measurement of CRP, Hp and ITIH4 in sera from bitches affected by pyometra allowed us to determine that ITIH4 behaves as a moderate APP in dogs. The group of bitches affected by pyometra showed very high levels of CRP (147 ± 91 mg/L), corresponding to a strong inflammatory process, which resulted in a moderate increase in the concentrations of Hp (7 times) and ITIH4 (3 times) compared to the control group.
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Affiliation(s)
- Lourdes Soler
- Acuvet Biotech, C/Bari 25 dpdo, Zaragoza, 50197, Spain.
| | - Marek Szczubiał
- Department and Clinic of Animal Reproduction, Faculty of Veterinary Medicine, University of Life Sciences, Gleboka 30, Lublin, 20-612, Poland
| | - Roman Dąbrowski
- Department and Clinic of Animal Reproduction, Faculty of Veterinary Medicine, University of Life Sciences, Gleboka 30, Lublin, 20-612, Poland
| | - Anna Płusa
- Department and Clinic of Animal Reproduction, Faculty of Veterinary Medicine, University of Life Sciences, Gleboka 30, Lublin, 20-612, Poland
| | - Mariola Bochniarz
- Department and Clinic of Animal Reproduction, Faculty of Veterinary Medicine, University of Life Sciences, Gleboka 30, Lublin, 20-612, Poland
| | - Piotr Brodzki
- Department and Clinic of Animal Reproduction, Faculty of Veterinary Medicine, University of Life Sciences, Gleboka 30, Lublin, 20-612, Poland
| | - Fermín Lampreave
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Pedro Cerbuna 12, Zaragoza, 50009, Spain
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Ning J, Ye Y, Bu D, Zhao G, Song T, Liu P, Yu W, Wang H, Li H, Ren X, Ying G, Zhao Y, Yu J. Imbalance of TGF-β1/BMP-7 pathways induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness. Mol Ther 2021; 29:2067-2087. [PMID: 33601054 DOI: 10.1016/j.ymthe.2021.02.016] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/27/2021] [Accepted: 02/10/2021] [Indexed: 12/27/2022] Open
Abstract
The transforming growth factor-beta (TGF-β) signaling pathway is the predominant cytokine signaling pathway in the development and progression of hepatocellular carcinoma (HCC). Bone morphogenetic protein (BMP), another member of the TGF-β superfamily, has been frequently found to participate in crosstalk with the TGF-β pathway. However, the complex interaction between the TGF-β and BMP pathways has not been fully elucidated in HCC. We found that the imbalance of TGF-β1/BMP-7 pathways was associated with aggressive pathological features and poor clinical outcomes in HCC. The induction of the imbalance of TGF-β1/BMP-7 pathways in HCC cells could significantly promote HCC cell invasion and stemness by increasing inhibitor of differentiation 1 (ID1) expression. We also found that the microRNA (miR)-17-92 cluster, originating from the extracellular vesicles (EVs) of M2-polarized tumor-associated macrophages (M2-TAMs), stimulated the imbalance of TGF-β1/BMP-7 pathways in HCC cells by inducing TGF-β type II receptor (TGFBR2) post-transcriptional silencing and inhibiting activin A receptor type 1 (ACVR1) post-translational ubiquitylation by targeting Smad ubiquitylation regulatory factor 1 (Smurf1). In vivo, short hairpin (sh)-MIR17HG and ACVR1 inhibitors profoundly attenuated HCC cell growth and metastasis by rectifying the imbalance of TGF-β1/BMP-7 pathways. Therefore, we proposed that the imbalance of TGF-β1/BMP-7 pathways is a feasible prognostic biomarker and recovering the imbalance of TGF-β1/BMP-7 pathways might be a potential therapeutic strategy for HCC.
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Affiliation(s)
- Junya Ning
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yingnan Ye
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Dechao Bu
- Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China
| | - Gang Zhao
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Tianqiang Song
- Department of Liver Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Pengpeng Liu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Wenwen Yu
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Hailong Wang
- Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Hui Li
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Xiubao Ren
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Guoguang Ying
- Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yi Zhao
- Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China; Ningbo Institute of Life and Health Industry, University of China Academy of Sciences, Zhejiang 315000, China.
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
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33
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Tang H, Fang H, Guo W, Cao S, Guo D, Zhang H, Gao J, Zhang S. Single nucleotide polymorphisms in interleukin-6 attenuates hepatocytes injury in hypoxia/re-oxygenation via STAT3 signal pathway mediated autophagy. Mol Biol Rep 2021; 48:1687-1695. [PMID: 33484391 PMCID: PMC7925450 DOI: 10.1007/s11033-020-06090-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 12/14/2020] [Indexed: 11/29/2022]
Abstract
Ischemia-reperfusion injury (IRI) is inevitable during liver surgery, and it is an important factor affecting the prognosis of patients. IL-6 rs1800796 single nucleotide polymorphisms (SNPs) can promote synthesis and secretion of IL-6 and protect hepatocytes from IRI. In this study, we investigated the mechanisms by which IL-6 alleviates hepatic IRI. We transfected lentivirus which carries IL-6 rs1800796 to L02 cells and constructed the cell line (L02-IL6) with a high expression of IL-6. The biological function of IL-6 SNPs was explored through a cell model of hypoxia-reoxygenation (H/R). Cell viability was evaluated by CCK8 and Real-Time Cell Analysis (RTCA), and found that the viability of the L02-IL6 cells was higher than that of the control group (P < 0.01). Flow cytometry assay showed that the rate of apoptosis was significantly decreased in L02-IL6 cells. Furthermore, in comparison with the control group, the level of cleaved-caspase3, which is an important marker of apoptosis, was dramatically decreased. These differences showed that the sequence variants at rs1800796 of the IL-6 gene could improve the resistance against H/R. Moreover, the levels of autophagy-related proteins, such as LC3 and Beclin-1, were upregulated in L02-IL6 group on H/R injury, which means IL-6 could alleviate apoptosis via activating the autophagy pathway. And we also found that the STAT3 signal pathway was activated. Next, we investigated whether the exogenous treatment with IL-6 affect hepatocytes and thus play a protective role. We pre-treated the L02 cells with recombinant human IL-6 for 12 h and then made H/R treatment. We found the treatment with 100 ng/ml IL-6 alleviated the damage of L02 cells and inhibited the apoptosis. And the further study revealed the pre-treatment with IL-6 activated the STAT3 signaling pathway in the L02 cells and then caused the activation of autophagy and apoptosis inhibition. IL-6 might play a critical role in alleviating hepatic IRI, through its modulation of the STAT3 signaling pathway, and activation of autophagy. Recombinant human IL-6 might be a potential therapeutic target in hepatic IRI.
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Affiliation(s)
- Hongwei Tang
- Open and Key laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, Henan, People's Republic of China.,ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, People's Republic of China
| | - Hongbo Fang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shengli Cao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danfeng Guo
- Open and Key laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, Henan, People's Republic of China.,ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, People's Republic of China
| | - Huapeng Zhang
- Open and Key laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, Henan, People's Republic of China.,ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, People's Republic of China
| | - Jie Gao
- Open and Key laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, Henan, People's Republic of China.,ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, People's Republic of China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. .,Open and Key laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, Henan, People's Republic of China. .,ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, People's Republic of China.
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34
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Dai X, Guo Y, Hu Y, Bao X, Zhu X, Fu Q, Zhang H, Tong Z, Liu L, Zheng Y, Zhao P, Fang W. Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma. Theranostics 2021; 11:3489-3501. [PMID: 33537099 PMCID: PMC7847682 DOI: 10.7150/thno.54648] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 12/21/2020] [Indexed: 02/06/2023] Open
Abstract
The rapid development and remarkable success of checkpoint inhibitors have provided significant breakthroughs in cancer treatment, including hepatocellular carcinoma (HCC). However, only 15-20% of HCC patients can benefit from checkpoint inhibitors. Cancer stem cells (CSCs) are responsible for recurrence, metastasis, and local and systemic therapy resistance in HCC. Accumulating evidence has suggested that HCC CSCs can create an immunosuppressive microenvironment through certain intrinsic and extrinsic mechanisms, resulting in immune evasion. Intrinsic evasion mechanisms mainly include activation of immune-related CSC signaling pathways, low-level expression of antigen presenting molecules, and high-level expression of immunosuppressive molecules. External evasion mechanisms are mainly related to HBV/HCV infection, alcoholic/nonalcoholic steatohepatitis, hypoxia stimulation, abnormal angiogenesis, and crosstalk between CSCs and immune cells. A better understanding of the complex mechanisms of CSCs involved in immune evasion will contribute to therapies for HCC. Here we will outline the detailed mechanisms of immune evasion for CSCs, and provide an overview of the current immunotherapies targeting CSCs in HCC.
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MESH Headings
- Antigen Presentation/drug effects
- Antineoplastic Agents, Immunological/therapeutic use
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Fatty Liver/genetics
- Fatty Liver/immunology
- Fatty Liver/pathology
- Fatty Liver/therapy
- Gene Expression Regulation, Neoplastic
- Hepatitis B/genetics
- Hepatitis B/immunology
- Hepatitis B/pathology
- Hepatitis B/therapy
- Hepatitis C/genetics
- Hepatitis C/immunology
- Hepatitis C/pathology
- Hepatitis C/therapy
- Humans
- Immunologic Factors/therapeutic use
- Immunotherapy/methods
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/genetics
- Neoplasm Proteins/immunology
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/therapy
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/pathology
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/immunology
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control
- Signal Transduction
- Tumor Escape/drug effects
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- Tumor Microenvironment/immunology
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Peng Zhao
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Weijia Fang
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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35
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Pihl R, Jensen RK, Poulsen EC, Jensen L, Hansen AG, Thøgersen IB, Dobó J, Gál P, Andersen GR, Enghild JJ, Thiel S. ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism. SCIENCE ADVANCES 2021; 7:7/2/eaba7381. [PMID: 33523981 PMCID: PMC7793589 DOI: 10.1126/sciadv.aba7381] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 11/16/2020] [Indexed: 05/02/2023]
Abstract
Inter-α-inhibitor heavy chain 4 (ITIH4) is a poorly characterized plasma protein that is proteolytically processed in multiple pathological conditions. However, no biological function of ITIH4 has been identified. Here, we show that ITIH4 is cleaved by several human proteases within a protease-susceptible region, enabling ITIH4 to function as a protease inhibitor. This is exemplified by its inhibition of mannan-binding lectin-associated serine protease-1 (MASP-1), MASP-2, and plasma kallikrein, which are key proteases for intravascular host defense. Mechanistically, ITIH4 acts as bait that, upon cleavage, forms a noncovalent, inhibitory complex with the executing protease that depends on the ITIH4 von Willebrand factor A domain. ITIH4 inhibits the MASPs by sterically preventing larger protein substrates from accessing their active sites, which remain accessible and fully functional toward small substrates. Thus, we demonstrate that ITIH4 functions as a protease inhibitor by a previously undescribed inhibitory mechanism.
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Affiliation(s)
- Rasmus Pihl
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Rasmus K Jensen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Emil C Poulsen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Lisbeth Jensen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | | | - Ida B Thøgersen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - József Dobó
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
| | - Péter Gál
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
| | - Gregers R Andersen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Jan J Enghild
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Steffen Thiel
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
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36
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Yang P, Yang Y, Sun P, Tian Y, Gao F, Wang C, Zong T, Li M, Zhang Y, Yu T, Jiang Z. βII spectrin (SPTBN1): biological function and clinical potential in cancer and other diseases. Int J Biol Sci 2021; 17:32-49. [PMID: 33390831 PMCID: PMC7757025 DOI: 10.7150/ijbs.52375] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 10/22/2020] [Indexed: 12/16/2022] Open
Abstract
βII spectrin, the most common isoform of non-erythrocyte spectrin, is a cytoskeleton protein present in all nucleated cells. Interestingly, βII spectrin is essential for the development of various organs such as nerve, epithelium, inner ear, liver and heart. The functions of βII spectrin include not only establishing and maintaining the cell structure but also regulating a variety of cellular functions, such as cell apoptosis, cell adhesion, cell spreading and cell cycle regulation. Notably, βII spectrin dysfunction is associated with embryonic lethality and the DNA damage response. More recently, the detection of altered βII spectrin expression in tumors indicated that βII spectrin might be involved in the development and progression of cancer. Its mutations and disorders could result in developmental disabilities and various diseases. The versatile roles of βII spectrin in disease have been examined in an increasing number of studies; nonetheless, the exact mechanisms of βII spectrin are still poorly understood. Thus, we summarize the structural features and biological roles of βII spectrin and discuss its molecular mechanisms and functions in development, homeostasis, regeneration and differentiation. This review highlight the potential effects of βII spectrin dysfunction in cancer and other diseases, outstanding questions for the future investigation of therapeutic targets. The investigation of the regulatory mechanism of βII spectrin signal inactivation and recovery may bring hope for future therapy of related diseases.
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Affiliation(s)
- Panyu Yang
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Yanyan Yang
- Department of Immunology, Basic Medicine School, Qingdao University, No. 308 Ningxia Road, Qingdao 266071, People's Republic of China
| | - Pin Sun
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Yu Tian
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Fang Gao
- Department of Physical Medicine and Rehabiliation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Chen Wang
- Department of Physical Medicine and Rehabiliation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Tingyu Zong
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Min Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People's Republic of China
| | - Ying Zhang
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Tao Yu
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.,Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People's Republic of China
| | - Zhirong Jiang
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
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STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pathway. Oncogene 2020; 40:1091-1105. [PMID: 33323974 PMCID: PMC7116782 DOI: 10.1038/s41388-020-01584-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 10/30/2020] [Accepted: 11/24/2020] [Indexed: 12/22/2022]
Abstract
Metastatic melanoma is hallmarked by its ability of phenotype switching to more slowly proliferating, but highly invasive cells. Here, we tested the impact of signal transducer and activator of transcription 3 (STAT3) on melanoma progression in association with melanocyte inducing transcription factor (MITF) expression levels. We established a mouse melanoma model for deleting Stat3 in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a deficient background, two frequent driver mutations in human melanoma. Mice devoid of Stat3 showed early disease onset with higher proliferation in primary tumors, but displayed significantly diminished lung, brain and liver metastases. Whole genome expression profiling of tumor-derived cells also showed a reduced invasion phenotype, which was further corroborated by 3D melanoma model analysis. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3-induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that CEBPa/b binding to the MITF enhancer region silenced the MITF locus. Finally, by classification of patient-derived melanoma samples, we show that STAT3 and MITF act antagonistically and hence contribute differentially to melanoma progression. We conclude that STAT3 is a driver of the metastatic process in melanoma and able to antagonize MITF via direct induction of CEBP family member transcription.
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38
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Li Y, Chen G, Han Z, Cheng H, Qiao L, Li Y. IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells. Onco Targets Ther 2020; 13:9721-9730. [PMID: 33061451 PMCID: PMC7533247 DOI: 10.2147/ott.s262089] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 09/04/2020] [Indexed: 12/18/2022] Open
Abstract
Background Sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), even though acquired resistance to sorafenib has been found in many HCC patients, resulting in poor prognosis. Accumulating evidence demonstrates that liver cancer stem cells (LCSCs) contribute to sorafenib resistance in HCC. The inflammatory factor interleukin 6 (IL-6) plays a role in sorafenib resistance in HCC. However, the mechanism by which IL-6 in LCSCs is involved in the process of HCC sorafenib resistance remains elusive. Methods In this study, the sorafenib-resistant cell line PLC/PRF/5-R was generated by the concentration gradient method, and cell viability was determined by the CCK-8 assay. LCSCs were isolated from the PLC/PRF/5-R cell line by flow cytometry, and tumorigenesis was confirmed in nude mice. Blockade of IL-6 cells was achieved by lentiviral-mediated interference. The protein levels of stem cell markers (EpCAM, CD44), stemness markers (Oct3/4, β-catenin), and hepatocyte differentiation markers (glucose-6-phosphate, AFP) were measured by Western blotting analysis. Finally, a xenograft model was used to evaluate the function of IL-6 in the sorafenib resistance of HCC. Results The stable sorafenib-resistant HCC cell line PLC/PRF/5-R was established and showed significant epithelial–mesenchymal transition (EMT) characteristics; the isolated resistant LCSCs from PLC/PRF/5-R were more tumorigenic than the control LCSCs. We showed that IL-6, IL-6R, STAT3 and GP130 expression were dramatically increased in resistant LCSCs compared to control LCSCs. Downregulation of IL-6 expression with short hairpin RNA (shRNA) restored sorafenib sensitivity in resistant LCSCs, suggesting the critical roles of IL-6/STAT3 in inducing sorafenib resistance. Furthermore, a xenograft tumor model showed that IL-6 downregulation improved the antitumor effect of sorafenib. Conclusion LCSCs play an important role in sorafenib-resistant HCC, and inhibition of the IL-6/STAT3 signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo. These findings demonstrate that IL-6 in LCSCs may function as a novel target for combating sorafenib resistance in HCC.
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Affiliation(s)
- Yu Li
- General Surgery Department, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China
| | - Gang Chen
- General Surgery Department, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China
| | - Zhijian Han
- Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China
| | - Huijuan Cheng
- Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China
| | - Liang Qiao
- Storr Liver Unit at the Westmead Millennium Institute, The University of Sydney at Westmead Hospital, Sydney, NSW 2145, Australia
| | - Yumin Li
- General Surgery Department, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China
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39
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Lee HY, Hong IS. Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer. Cancers (Basel) 2020; 12:cancers12102746. [PMID: 32987767 PMCID: PMC7598600 DOI: 10.3390/cancers12102746] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.
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Affiliation(s)
- Hwa-Yong Lee
- Department of Biomedical Science, Jungwon University, 85 Goesan-eup, Munmu-ro, Goesan-gun, Chungcheongbuk-do 367700, Korea;
| | - In-Sun Hong
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea
- Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406840, Korea
- Correspondence: ; Tel.: +82-32-899-6315; Fax: +82-32-899-6350
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40
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Marin JJ, Macias RI, Monte MJ, Romero MR, Asensio M, Sanchez-Martin A, Cives-Losada C, Temprano AG, Espinosa-Escudero R, Reviejo M, Bohorquez LH, Briz O. Molecular Bases of Drug Resistance in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12061663. [PMID: 32585893 PMCID: PMC7352164 DOI: 10.3390/cancers12061663] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/19/2020] [Accepted: 06/20/2020] [Indexed: 12/11/2022] Open
Abstract
The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is mainly due to the high refractoriness of this aggressive tumor to classical chemotherapy. Novel pharmacological approaches based on the use of inhibitors of tyrosine kinases (TKIs), mainly sorafenib and regorafenib, have provided only a modest prolongation of the overall survival in these HCC patients. The present review is an update of the available information regarding our understanding of the molecular bases of mechanisms of chemoresistance (MOC) with a significant impact on the response of HCC to existing pharmacological tools, which include classical chemotherapeutic agents, TKIs and novel immune-sensitizing strategies. Many of the more than one hundred genes involved in seven MOC have been identified as potential biomarkers to predict the failure of treatment, as well as druggable targets to develop novel strategies aimed at increasing the sensitivity of HCC to pharmacological treatments.
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Affiliation(s)
- Jose J.G. Marin
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-923294674 (O.B.)
| | - Rocio I.R. Macias
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Maria J. Monte
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Marta R. Romero
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Anabel Sanchez-Martin
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Candela Cives-Losada
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Alvaro G. Temprano
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Ricardo Espinosa-Escudero
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Maria Reviejo
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Laura H. Bohorquez
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain; (R.I.R.M.); (M.J.M.); (M.R.R.); (M.A.); (A.S.-M.); (C.C.-L.); (A.G.T.); (R.E.-E.); (M.R.); (L.H.B.)
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Correspondence: (J.J.G.M.); (O.B.); Tel.: +34-663182872 (J.J.G.M.); +34-923294674 (O.B.)
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Son KH, Ahn CB, Kim HJ, Kim JS. Quantitative proteomic analysis of bile in extrahepatic cholangiocarcinoma patients. J Cancer 2020; 11:4073-4080. [PMID: 32368289 PMCID: PMC7196276 DOI: 10.7150/jca.40964] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 03/29/2020] [Indexed: 12/17/2022] Open
Abstract
Background and Aims: Extrahepatic cholangiocarcinoma (CCA) without liver-fluke is increasing. Multifactorial carcinogenesis makes it hard to find biomarkers related to CCA. Although there are a few studies of bile proteomics, these showed different protein profiles because of having heterogeneous groups of patients and different sampling methods. Our aim was to identify the specific bile proteins of extrahepatic CCA patients. Methods: We collected bile from 23 patients undergoing endoscopic nasobiliary drainage in Korea University Guro Hospital from May 2018 to January 2019. The CCA group included 18 patients diagnosed with extrahepatic CCA, and the control group included 5 patients with benign biliary conditions. We analyzed bile proteome using liquid chromatography mass spectrometry. We compared the relative abundance of various proteins in the CCA and control groups. Results: In all, we identified a total of 245 proteins in the bile of CCA and control patients. Increased top 14 proteins in CCA patients were immunoglobulin kappa light chain, apolipoprotein B, inter-alpha-trypsin inhibitor heavy chain H4, apolipoprotein E, Mucin 5B, inter-alpha-trypsin inhibitor heavy chain H1, apolipoprotein A-IV, intercellular adhesion molecule 1, complement C7, complement C5, apolipoprotein C-III, albumin, antithrombin-III, and apolipoprotein A-II. However, the significantly increased proteins in bile of CCA patients comparing with control patients were immunoglobulin kappa light chain, apolipoprotein E, albumin, apolipoprotein A-I, antithrombin-III, α1-antitrypsin, serotransferrin, immunoglobulin heavy constant mu, immunoglobulin J chain, complement C4-A, and complement C3 (p<0.05). Conclusions: In this study, we identified several proteins that were significantly increased in the bile of extrahepatic CCA. Further study is needed to validate them as potential tumor-associated proteins that may be potential biomarkers for CCA.
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Affiliation(s)
- Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon, 21565, Republic of Korea
| | - Chi Bum Ahn
- Center for information security technologies, Korea University
| | - Hyo Jung Kim
- Department of Internal Medicine, Korea University Guro Hospital
| | - Jae Seon Kim
- Department of Internal Medicine, Korea University Guro Hospital
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42
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The Cancer Stem Cell in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12030684. [PMID: 32183251 PMCID: PMC7140091 DOI: 10.3390/cancers12030684] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/11/2020] [Accepted: 03/12/2020] [Indexed: 12/11/2022] Open
Abstract
The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.
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Machida K. Cell fate, metabolic reprogramming and lncRNA of tumor-initiating stem-like cells induced by alcohol. Chem Biol Interact 2020; 323:109055. [PMID: 32171851 DOI: 10.1016/j.cbi.2020.109055] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 12/13/2019] [Accepted: 03/10/2020] [Indexed: 12/15/2022]
Abstract
Alcoholism synergizes the development of the hepatocellular carcinoma (HCC) in patients infected with hepatitis B or C virus (HBV or HCV). Tumor-initiating stem-like cells (TICs) are refractory to therapy and have expression of stemness transcription factors. Leaky-gut-derived endotoxin stimulates TLR4-NANOG pathway that skews asymmetric cell division and that metabolically reprograms hepatocytes/liver progenitor cells, leading to self-renewal. TICs isolated from mouse HCC models or human HCCs are tumorigenic and have p53 degradation via phosphorylation of the protective protein NUMB and its dissociation from p53 by the oncofetal protein TBC1D15. Furthermore, dysregulation of lncRNA promotes genesis of TICs, leading to HCC development. This review describes roles of cell fate decision, metabolic reprogramming and lncRNA for TIC genesis and liver oncogenesis. This project was supported by NIH grants 1R01AA018857-01, 5R21AA025470, P50AA11999 (Animal Core, Morphology Core, and Pilot Project Program), R24AA012885 (Non-Parenchymal Liver Cell Core) and pilot project funding (5P30DK048522-13).
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Affiliation(s)
- Keigo Machida
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA; Department of Molecular Microbiology and Immunology, Los Angeles, CA, USA.
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44
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Stem Cell Therapy for Hepatocellular Carcinoma: Future Perspectives. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1237:97-119. [PMID: 31728916 DOI: 10.1007/5584_2019_441] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer and results in a high mortality rate worldwide. Unfortunately, most cases of HCC are diagnosed in an advanced stage, resulting in a poor prognosis and ineffective treatment. HCC is often resistant to both radiotherapy and chemotherapy, resulting in a high recurrence rate. Although the use of stem cells is evolving into a potentially effective approach for the treatment of cancer, few studies on stem cell therapy in HCC have been published. The administration of stem cells from bone marrow, adipose tissue, the amnion, and the umbilical cord to experimental animal models of HCC has not yielded consistent responses. However, it is possible to induce the apoptosis of cancer cells, repress angiogenesis, and cause tumor regression by administration of genetically modified stem cells. New alternative approaches to cancer therapy, such as the use of stem cell derivatives, exosomes or stem cell extracts, have been proposed. In this review, we highlight these experimental approaches for the use of stem cells as a vehicle for local drug delivery.
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Li J, Li R, Jiang W, Sun J, Li J, Guo Y, Zhu K, Zhang C, Kong G, Li Z. Splenic serum from portal hypertensive patients enhances liver stem cell proliferation and self-renewal via the IGF-II/ERK signaling pathway. Dig Liver Dis 2020; 52:205-213. [PMID: 31495600 DOI: 10.1016/j.dld.2019.07.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 07/19/2019] [Accepted: 07/22/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hypersplenism is a serious complication of portal hypertension (PH) and can affect the prognosis of liver disease. Liver stem cells (LSCs) are involved in liver regeneration and hepatocarcinogenesis after liver cirrhosis. AIM To explore the effects and mechanism of the spleen on the proliferation and differentiation of LSCs in PH due to liver cirrhosis. METHODS Fetal liver stem cells (FLSCs) were treated with splenic serum from liver cirrhosis patients with hypersplenism and control serum from healthy volunteers, and the proliferation, self-renewal, and IGF-II/ERK signaling pathway of FLSCs were then evaluated. RESULTS We found that splenic serum from PH patients promoted FLSC proliferation, colony formation, and Ki-67 expression in vitro. Splenic serum from PH also enhanced FLSC spheroid formation in vitro. Mechanistically, we determined that insulin-like growth factor (IGF)-II concentration was elevated in splenic serum from PH patients and could promote FLSC proliferation and self-renewal. Furthermore, both IGF-II and splenic serum from PH patients enhanced ERK signaling activation through IGF-I receptor (IGF-I R) in FLSCs. Consistently, blocking IGF-I R or ERK signaling could attenuate the effects of splenic serum from PH patients on FLSCs. CONCLUSIONS The spleen in PH patients promotes FLSC proliferation and self-renewal through the IGF-II/ERK signaling pathway.
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Affiliation(s)
- Jiangwei Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ren Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wei Jiang
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jin Sun
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jun Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ying Guo
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Kai Zhu
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Chen Zhang
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Guangyao Kong
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Zongfang Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Ko S, Russell JO, Molina LM, Monga SP. Liver Progenitors and Adult Cell Plasticity in Hepatic Injury and Repair: Knowns and Unknowns. ANNUAL REVIEW OF PATHOLOGY 2020; 15:23-50. [PMID: 31399003 PMCID: PMC7212705 DOI: 10.1146/annurev-pathmechdis-012419-032824] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The liver is a complex organ performing numerous vital physiological functions. For that reason, it possesses immense regenerative potential. The capacity for repair is largely attributable to the ability of its differentiated epithelial cells, hepatocytes and biliary epithelial cells, to proliferate after injury. However, in cases of extreme acute injury or prolonged chronic insult, the liver may fail to regenerate or do so suboptimally. This often results in life-threatening end-stage liver disease for which liver transplantation is the only effective treatment. In many forms of liver injury, bipotent liver progenitor cells are theorized to be activated as an additional tier of liver repair. However, the existence, origin, fate, activation, and contribution to regeneration of liver progenitor cells is hotly debated, especially since hepatocytes and biliary epithelial cells themselves may serve as facultative stem cells for one another during severe liver injury. Here, we discuss the evidence both supporting and refuting the existence of liver progenitor cells in a variety of experimental models. We also debate the validity of developing therapies harnessing the capabilities of these cells as potential treatments for patients with severe and chronic liver diseases.
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Affiliation(s)
- Sungjin Ko
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Jacquelyn O Russell
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Laura M Molina
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
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Farcas M, Gavrea AA, Gulei D, Ionescu C, Irimie A, Catana CS, Berindan-Neagoe I. SIRT1 in the Development and Treatment of Hepatocellular Carcinoma. Front Nutr 2019; 6:148. [PMID: 31608282 PMCID: PMC6773871 DOI: 10.3389/fnut.2019.00148] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 08/27/2019] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Current treatment options for inoperable HCCs have decreased therapeutic efficacy and are associated with systemic toxicity and chemoresistance. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide–dependent enzyme that is frequently overexpressed in HCC, where it promotes tumorigenicity, metastasis, and chemoresistance. SIRT1 also maintains the tumorigenic and self-renewal proprieties of liver cancer stem cells. Multiple tumor-suppressive microRNAs (miRNAs) are downregulated in HCC and, as a consequence, permit SIRT1-induced tumorigenicity. However, either directly targeting SIRT1, combining conventional chemotherapy with SIRT1 inhibitors, or upregulating tumor-suppressive miRNAs may improve therapeutic efficacy and patient outcomes. Here, we present the interaction between SIRT1, miRNAs, and liver cancer stem cells and discuss the consequences of their interplay for the development and treatment of HCC.
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Affiliation(s)
- Marius Farcas
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Andrei-Alexandru Gavrea
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Diana Gulei
- MEDFUTURE-Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Calin Ionescu
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,5th Surgical Department, Municipal Hospital, Cluj-Napoca, Romania
| | - Alexandru Irimie
- 11th Department of Oncological Surgery and Gynecological Oncology, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania.,Department of Surgery, The Oncology Institute "Prof. Dr. Ion Chiricuţǎ", Cluj-Napoca, Romania
| | - Cristina S Catana
- Department of Medical Biochemistry, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,MEDFUTURE-Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Functional Genomics and Experimental Pathology, The Oncology Institute "Prof Dr. Ion Chiricuţǎ", Cluj-Napoca, Romania
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Igelmann S, Neubauer HA, Ferbeyre G. STAT3 and STAT5 Activation in Solid Cancers. Cancers (Basel) 2019; 11:cancers11101428. [PMID: 31557897 PMCID: PMC6826753 DOI: 10.3390/cancers11101428] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/14/2019] [Accepted: 09/18/2019] [Indexed: 02/07/2023] Open
Abstract
The Signal Transducer and Activator of Transcription (STAT)3 and 5 proteins are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context-dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association with survival in cancer patients. The molecular mechanisms that underpin the oncogenic activity of STAT3/5 signaling include the regulation of genes that control cell cycle and cell death. However, recent advances also highlight the critical role of STAT3/5 target genes mediating inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling, including tyrosine phosphatases, the sumo ligase Protein Inhibitor of Activated STAT3 (PIAS3), the E3 ubiquitin ligase TATA Element Modulatory Factor/Androgen Receptor-Coactivator of 160 kDa (TMF/ARA160), the miRNAs miR-124 and miR-1181, the Protein of alternative reading frame 19 (p19ARF)/p53 pathway and the Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3) proteins. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated with STAT3/5 signaling, explaining their context-dependent association with tumor progression both in human cancers and animal models.
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Affiliation(s)
- Sebastian Igelmann
- Department of Biochemistry and Molecular Medicine, Université de Montréal, C.P. 6128, Succ. Centre-Ville, CRCHUM, Montréal, QC H3C 3J7, Canada.
- CRCHUM, 900 Saint-Denis St, Montréal, QC H2X 0A9, Canada.
| | - Heidi A Neubauer
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna 1210, Austria.
| | - Gerardo Ferbeyre
- Department of Biochemistry and Molecular Medicine, Université de Montréal, C.P. 6128, Succ. Centre-Ville, CRCHUM, Montréal, QC H3C 3J7, Canada.
- CRCHUM, 900 Saint-Denis St, Montréal, QC H2X 0A9, Canada.
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Czekaj P, Król M, Limanówka Ł, Michalik M, Lorek K, Gramignoli R. Assessment of animal experimental models of toxic liver injury in the context of their potential application as preclinical models for cell therapy. Eur J Pharmacol 2019; 861:172597. [PMID: 31408648 DOI: 10.1016/j.ejphar.2019.172597] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 08/04/2019] [Accepted: 08/08/2019] [Indexed: 02/06/2023]
Abstract
Preclinical animal models allow to study development and progression of several diseases, including liver disorders. These studies, for ethical reasons and medical limits, are impossible to carry out in human patients. At the same time, such experimental models constitute an important source of knowledge on pathomechanisms for drug- and virus-induced hepatotoxicity, both acute and chronic. Carbon tetrachloride, D-Galactosamine, and retrorsine are xenobiotics that can be used in immunocompetent animal models of hepatotoxicity, where chemical-intoxicated livers present histological features representative of human viruses-related infection. A prolonged derangement into liver architecture and functions commonly lead to cirrhosis, eventually resulting in hepatocellular carcinoma. In human, orthotopic liver transplantation commonly resolve most the problems related to cirrhosis. However, the shortage of donors does not allow all the patients in the waiting list to receive an organ on time. A promising alternative treatment for acute and chronic liver disease has been advised in liver cell transplantation, but the limited availability of hepatocytes for clinical approaches, in addition to the immunosuppressant regiment required to sustain cellular long-term engraftment have been encouraging the use of alternative cell sources. A recent effective source of stem cells have been recently identified in the human amnion membrane. Human amnion epithelial cells (hAEC) have been preclinically tested and proven sufficient to rescue immunocompetent rodents lethally intoxicated with drugs. The adoption of therapeutic procedures based on hAEC transplant in immunocompetent recipients affected by liver diseases, as well as patients with immune-related disorders, may constitute a successful new alternative therapy in regenerative medicine.
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Affiliation(s)
- Piotr Czekaj
- Department of Cytophysiology, Chair of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland, Medyków 18 str., 40-752, Katowice, Poland.
| | - Mateusz Król
- Students Scientific Society, Department of Cytophysiology, Chair of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland, Medyków 18 str., 40-752, Katowice, Poland.
| | - Łukasz Limanówka
- Students Scientific Society, Department of Cytophysiology, Chair of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland, Medyków 18 str., 40-752, Katowice, Poland
| | - Marcin Michalik
- Students Scientific Society, Department of Cytophysiology, Chair of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland, Medyków 18 str., 40-752, Katowice, Poland
| | - Katarzyna Lorek
- Students Scientific Society, Department of Cytophysiology, Chair of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland, Medyków 18 str., 40-752, Katowice, Poland
| | - Roberto Gramignoli
- Department of Laboratory Medicine (LABMED), H5, Division of Pathology, Karolinska Institutet, Alfred Nobels Allé 8, 14152, Huddinge, Sweden.
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50
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Luongo F, Colonna F, Calapà F, Vitale S, Fiori ME, De Maria R. PTEN Tumor-Suppressor: The Dam of Stemness in Cancer. Cancers (Basel) 2019; 11:E1076. [PMID: 31366089 PMCID: PMC6721423 DOI: 10.3390/cancers11081076] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 07/24/2019] [Accepted: 07/26/2019] [Indexed: 12/11/2022] Open
Abstract
PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.
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Affiliation(s)
- Francesca Luongo
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Francesca Colonna
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Federica Calapà
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Sara Vitale
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Micol E Fiori
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
| | - Ruggero De Maria
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy.
- Scientific Vice-Direction, Fondazione Policlinico Universitario "A. Gemelli"-I.R.C.C.S., Largo Francesco Vito 1-8, 00168 Rome, Italy.
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