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Zhang S, Dong H, Jin X, Sun J, Li Y. The multifaceted roles of macrophages in the transition from hepatitis to hepatocellular carcinoma: From mechanisms to therapeutic strategies. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167676. [PMID: 39828046 DOI: 10.1016/j.bbadis.2025.167676] [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: 11/28/2024] [Revised: 01/06/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
Macrophages are central to the progression from hepatitis to hepatocellular carcinoma (HCC), with their remarkable plasticity and ability to adapt to the changing liver microenvironment. Chronic inflammation, fibrosis, and ultimately tumorigenesis are driven by macrophage activation, making them key regulators of liver disease progression. This review explores the diverse roles of macrophages in the transition from hepatitis to HCC. In the early stages of hepatitis, macrophages are essential for pathogen clearance and tissue repair. However, chronic activation leads to prolonged inflammation, which exacerbates liver damage and promotes fibrosis. As the disease progresses to liver fibrosis, macrophages interact with hepatic stellate cells, fostering a pro-tumorigenic microenvironment that supports HCC development. In hepatocarcinogenesis, macrophages contribute to tumor initiation, growth, metastasis, immune evasion, cancer stem cell maintenance, and angiogenesis. Their functional plasticity enables them to adapt to the tumor microenvironment, thereby promoting tumor progression and resistance to therapy. Targeting macrophages represents a promising strategy for preventing and treating HCC. Therapeutic approaches, including reprogramming macrophage phenotypes to enhance anti-tumor immunity, blocking macrophage recruitment and activation, and utilizing nanoparticle-based drug delivery systems, may provide new avenues for combating HCC by modulating macrophage functions and tumor microenvironment dynamics.
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Affiliation(s)
- Shuairan Zhang
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China
| | - Hang Dong
- Phase I Clinical Trials Center, The People's Hospital of China Medical University, Shenyang, PR China
| | - Xiuli Jin
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China
| | - Jing Sun
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China
| | - Yiling Li
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China.
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2
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Tu T, McQuaid TJ, Jacobson IM. HBV-Induced Carcinogenesis: Mechanisms, Correlation With Viral Suppression, and Implications for Treatment. Liver Int 2025; 45:e16202. [PMID: 39720865 DOI: 10.1111/liv.16202] [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: 02/05/2024] [Revised: 10/29/2024] [Accepted: 11/26/2024] [Indexed: 12/26/2024]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is a common but underdiagnosed and undertreated health condition and is the leading cause of hepatocellular carcinoma (HCC) worldwide. HBV (rated a Grade 1 carcinogen by the International Agency for Research on Cancer) drives the transformation of hepatocytes in multiple ways by inducing viral DNA integrations, genetic dysregulation, chromosomal translocations, chronic inflammation, and oncogenic pathways facilitated by some HBV proteins. Importantly, these mechanisms are active throughout all phases of HBV infection. Nevertheless, most clinical guidelines for antiviral therapy recommend treatment based on a complex combination of HBV DNA levels, transaminasemia, liver histology, and demographic factors, rather than prompt treatment for all people with infection. AIMS To determine if current frameworks for antiviral treatment address the impacts of chronic HBV infection particularly preventing cancer development. MATERIALS AND METHODS We reviewed the recent data demonstrating pro-oncogenic factors acting throughout a chronic HBV infection can be inhibited by antiviral therapy. RESULTS We extensively reviewed Hepatitis B virology data and correlating clinical outcome data. From thi, we suggest that new findings support simplifying and expanding treatment initiation to reduce the incidence ofnew infections, progressive liver disease, and risk of hepatocellular carcinoma. We also consider lessons learned from other blood-borne pathogens, including the benefits of antiviral treatment in preventing transmission, reducing stigma, and reframing treatment as cancer prevention. CONCLUSION Incorporating these practice changes into treatment is likely to reduce the overall burden of chronic HBV infections and HCC. Through this, we may better achieve the World Health Organization's goal of eliminating viral hepatitis as a public health threat and minimise its impact on people's lives.
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Affiliation(s)
- Thomas Tu
- Storr Liver Centre, Westmead Clinical School, Centre for Infectious Diseases and Microbiology and Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
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Xia Q, Liu G, Lin W, Zhang J. microRNA-2117 Negatively Regulates Liver Cancer Stem Cells Expansion and Chemoresistance Via Targeting SOX2. Mol Carcinog 2025; 64:33-43. [PMID: 39400383 PMCID: PMC11636587 DOI: 10.1002/mc.23824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 09/11/2024] [Accepted: 09/18/2024] [Indexed: 10/15/2024]
Abstract
Cancer stem cells (CSCs) are involved in the regulation of tumor initiation, progression, recurrence, and chemoresistance. However, the role of microRNAs (miRNAs) in liver CSCs has not been fully understood. Here we show that miR-2117 is downregulated in liver CSCs and predicts the poor prognosis of hepatocellular carcinoma (HCC) patients. Biofunction studies found that knockdown miR-2117 facilitates liver CSCs self-renewal and tumorigenesis. Conversely, forced miR-2117 expression suppresses liver CSCs self-renewal and tumorigenesis. Mechanistically, we find that transcription factor SOX2 is required for miR-2117-mediated liver CSCs expansion. The correlation between miR-2117 and SOX2 was confirmed in human HCC tissues. More importantly, miR-2117 overexpression HCC cells are more sensitive to CDDP treatment. Analysis of patients' cohort further demonstrates that miR-2117 may predict transcatheter arterial chemoembolization benefits in HCC patients. Our findings revealed the crucial role of miR-2117 in liver CSCs expansion, rendering miR-2117 as an optimal therapeutic target for HCC.
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Affiliation(s)
- Qing Xia
- Department of General Surgery, Hwa Mei Hospital (Ningbo No.2 Hospital)University of Chinese Academy of SciencesNingboChina
- Ningbo Institute of Life and Health IndustryUniversity of Chinese Academy of SciencesNingboChina
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang ProvinceNingboChina
| | - Guanghua Liu
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Department of Interventional RadiologyXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Wenbo Lin
- Department of Orthopedic Surgery, Changzheng HospitalNavy Medical UniversityShanghaiChina
| | - Jin Zhang
- Department of General SurgeryThird Affiliated Hospital of Second Military Medical UniversityShanghaiChina
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Zhang K, Tian L, Sun Q, Lv J, Ding R, Yu Y, Li Y, Duan J. Constructing an adverse outcome pathway framework for the impact of maternal exposure to PM 2.5 on liver development and injury in offspring. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2024; 112:104585. [PMID: 39489199 DOI: 10.1016/j.etap.2024.104585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/24/2024] [Accepted: 10/29/2024] [Indexed: 11/05/2024]
Abstract
Ambient fine particulate matter (PM2.5) is a significant contributor to air pollution. PM2.5 exposure poses a substantial hazard to public health. In recent years, the adverse effects of maternal PM2.5 exposure on fetal health have gradually gained public attention. As the largest organ in the body, the liver has many metabolic and secretory functions. Liver development, as well as factors that interfere with its growth and function, are of concern. This review utilized the adverse outcome pathway (AOP) framework as the analytical approach to demonstrate the link between maternal PM2.5 exposure and potential neonatal liver injury from the molecular to the population level. The excessive generation of reactive oxygen species (ROS), subsequent endoplasmic reticulum (ER) stress, and oxidative stress were regarded as the essential components in this framework, as they could trigger adverse developmental outcomes in the offspring through DNA damage, autophagy dysfunction, mitochondrial injury, and other pathways. To the best of our knowledge, this is the first article based on an AOP framework that elaborates on the influence of maternal exposure to PM2.5 on liver injury occurrence and adverse effects on liver development in offspring. Therefore, this review offered mechanistic insights into the developmental toxicity of PM2.5 in the liver, which provided a valuable basis for future studies and prevention strategies.
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Affiliation(s)
- Kexin Zhang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
| | - Li Tian
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
| | - Qinglin Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
| | - Jianong Lv
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
| | - Ruiyang Ding
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
| | - Yang Yu
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
| | - Yang Li
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China.
| | - Junchao Duan
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China.
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Zhang Y, Rao Y, Lu J, Wang J, Ker DFE, Zhou J, Wang DM. The influence of biophysical niche on tumor-associated macrophages in liver cancer. Hepatol Commun 2024; 8:e0569. [PMID: 39470328 PMCID: PMC11524744 DOI: 10.1097/hc9.0000000000000569] [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: 03/04/2024] [Accepted: 08/30/2024] [Indexed: 10/30/2024] Open
Abstract
HCC, the most common type of primary liver cancer, is a leading cause of cancer-related mortality worldwide. Although the advancement of immunotherapies by immune checkpoint inhibitors (ICIs) that target programmed cell death 1 or programmed cell death 1-ligand 1 has revolutionized the treatment for HCC, the majority is still not beneficial. Accumulating evidence has pointed out that the potent immunosuppressive tumor microenvironment in HCC poses a great challenge to ICI therapeutic efficacy. As a key component in tumor microenvironment, tumor-associated macrophages (TAMs) play vital roles in HCC development, progression, and ICI low responsiveness. Mechanistically, TAM can promote cancer invasion and metastasis, angiogenesis, epithelial-mesenchymal transition, maintenance of stemness, and most importantly, immunosuppression. Targeting TAMs, therefore, represents an opportunity to enhance the ICI therapeutic efficacy in patients with HCC. While previous research has primarily focused on biochemical cues influencing macrophages, emerging evidence highlights the critical role of biophysical signals, such as substrate stiffness, topography, and external forces. In this review, we summarize the influence of biophysical characteristics within the tumor microenvironment that regulate the phenotype and function of TAMs in HCC pathogenesis and progression. We also explore the possible mechanisms and discuss the potential of manipulating biophysical cues in regulating TAM for HCC therapy. By gaining a deeper understanding of how macrophages sense and respond to mechanical forces, we may potentially usher in a path toward a curative approach for combinatory cancer immunotherapies.
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Affiliation(s)
- Ying Zhang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
- Institute of Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
- Institute of Precision Medicine, Jining Medical University, Jining, China
| | - Ying Rao
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
- Institute of Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
| | - Jiahuan Lu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
| | - Jiyu Wang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
- Institute of Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
| | - Dai Fei Elmer Ker
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Sha Tin, Hong Kong, SAR, China
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, SAR, China
| | - Jingying Zhou
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
| | - Dan Michelle Wang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
- Institute of Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Sha Tin, Hong Kong, SAR, China
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China
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Le Y, Geng C, Gao X, Zhang P. The risk of thyroid cancer and sex differences in Hashimoto's thyroiditis, a meta-analysis. BMC Endocr Disord 2024; 24:151. [PMID: 39135006 PMCID: PMC11321178 DOI: 10.1186/s12902-024-01670-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 07/24/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND AND OBJECTIVE The prevalence of thyroid cancer (TC) has exhibited an upward trajectory in recent years. An accelerating amount of evidence shows a significant association between Hashimoto's thyroiditis (HT) and TC. The present study encompasses a meticulously designed systematic review and meta-analysis with the aim of scrutinizing the risk of TC and clarifying sex disparities in HT. METHODS A comprehensive search was conducted across reputable online databases, including PubMed, Cochrane Library, EMBASE, and Web of Science. English-language publications on the correlation between HT and TC were examined without temporal restrictions. Two authors independently screened the articles and extracted pertinent data. The collected data underwent statistical analysis using the STATA software, enabling the calculation of the pooled Odds Ratio (OR) and 95% confidence intervals (CI). Additionally, a supplementary analysis was conducted on studies incorporating sex-specific data to determine the OR (female vs. male) and the sex-based prevalence of TC in HT. RESULTS A total of 2,845 records were obtained, and 26 retrospective studies were included in this meta-analysis. The results indicated a significant role for HT in TC (OR: 2.22, 95% CI: 1.85-2.67). Supplementary analysis indicated that the prevalence of TC in HT patients was lower in women (0.31, 95% CI: 0.17-0.45) than in men (0.37, 95% CI: 0.21-0.53). However, the result was not statistically significant. CONCLUSION This systematic review and meta-analysis provide evidence that HT is associated with increasing odds of TC. Regular review of HT patients holds positive clinical significance.
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Affiliation(s)
- Yali Le
- Health Management Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266035, Shandong, PR China
| | - Chenchen Geng
- Department of Ultrasound, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266035, Shandong, PR China
| | - Xiaoqian Gao
- Department of Ultrasound, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266035, Shandong, PR China
| | - Ping Zhang
- Health Management Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266035, Shandong, PR China.
- Department of Ultrasound, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266035, Shandong, PR China.
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Yang D, Zhang P, Yang Z, Hou G, Yang Z. miR-4461 inhibits liver cancer stem cells expansion and chemoresistance via regulating SIRT1. Carcinogenesis 2024; 45:463-474. [PMID: 36437743 DOI: 10.1093/carcin/bgac093] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 10/11/2022] [Accepted: 11/27/2022] [Indexed: 02/17/2024] Open
Abstract
MicroRNAs (miRNAs) were involved in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. We show here that miR-4461 expression is reduced in liver cancer stem cells (CSCs) and predicts the poor prognosis of HCC patients. Knockdown of miR-4461 enhances the self-renewal and tumorigenicity of liver CSCs. Conversely, forced miR-4461 expression inhibits liver CSCs self-renewal and tumorigenesis. Mechanically, miR-4461 directly targets sirtuin 1 (SIRT1) via binding to its 3' untranslated region in liver CSCs. The correlation of miR-4461 and SIRT1 was confirmed in human HCC patients' tissues. Additionally, we found that miR-4461 overexpression hepatoma cells are more sensitive to cisplatin treatment. Patient-derived xenografts also showed that miR-4461 high HCC xenografts are sensitive to cisplatin treatment. Clinical cohort analysis further confirmed that HCC patients with high miR-4461 benefited more from transcatheter arterial chemoembolization treatment. In conclusion, our findings revealed the crucial role of miR-4461 in liver CSCs expansion and cisplatin response, rendering miR-4461 as an optimal target for the prevention and intervention of HCC.
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Affiliation(s)
- Daji Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Xinmin Street, Changchun 130021, China
| | - Ping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Xinmin Street, Changchun 130021, China
| | - Ziting Yang
- Department of Emergency, The 964th Hospital of the Chinese People's Liberation Army, Changchun, China
| | - Guojun Hou
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai 200438, China
| | - Ziyu Yang
- Department of Integrative Medicine, Third Affiliated Hospital of Second Military Medical University, Shanghai 200438, China
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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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Xiang Z, Chen H, Xu B, Wang H, Zhang T, Guan X, Ma Z, Liang K, Shi Q. Gelatin/heparin coated bio-inspired polyurethane composite fibers to construct small-caliber artificial blood vessel grafts. Int J Biol Macromol 2024; 269:131849. [PMID: 38670202 DOI: 10.1016/j.ijbiomac.2024.131849] [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: 02/01/2024] [Revised: 04/21/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024]
Abstract
Long-term patency and ability for revascularization remain challenges for small-caliber blood vessel grafts to treat cardiovascular diseases clinically. Here, a gelatin/heparin coated bio-inspired polyurethane composite fibers-based artificial blood vessel with continuous release of NO and biopeptides to regulate vascular tissue repair and maintain long-term patency is fabricated. A biodegradable polyurethane elastomer that can catalyze S-nitrosothiols in the blood to release NO is synthesized (NPU). Then, the NPU core-shell structured nanofiber grafts with requisite mechanical properties and biopeptide release for inflammation manipulation are fabricated by electrospinning and lyophilization. Finally, the surface of tubular NPU nanofiber grafts is coated with heparin/gelatin and crosslinked with glutaraldehyde to obtain small-caliber artificial blood vessels (ABVs) with the ability of vascular revascularization. We demonstrate that artificial blood vessel grafts promote the growth of endothelial cells but inhibit the growth of smooth muscle cells by the continuous release of NO; vascular grafts can regulate inflammatory balance for vascular tissue remodel without excessive collagen deposition through the release of biological peptides. Vascular grafts prevent thrombus and vascular stenosis to obtain long-term patency. Hence, our work paves a new way to develop small-caliber artificial blood vessel grafts that can maintain long-term patency in vivo and remodel vascular tissue successfully.
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Affiliation(s)
- Zehong Xiang
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; University of Science and Technology of China, Hefei, Anhui 230026, China; Zhuhai Institute of Advanced Technology, Chinese Academy of Sciences, Zhuhai, Guangdong 519000, China
| | - Honghong Chen
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Baofeng Xu
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Chang Chun 130021, China; Hunan Provincial Key Laboratory of the R&D of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China.
| | - Haozheng Wang
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; University of Science and Technology of China, Hefei, Anhui 230026, China.
| | - Tianci Zhang
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Xinghua Guan
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Zhifang Ma
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China
| | - Kuntang Liang
- Zhuhai Institute of Advanced Technology, Chinese Academy of Sciences, Zhuhai, Guangdong 519000, China
| | - Qiang Shi
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; University of Science and Technology of China, Hefei, Anhui 230026, China.
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10
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Wang H, Wang X, Zhang X, Xu W. The promising role of tumor-associated macrophages in the treatment of cancer. Drug Resist Updat 2024; 73:101041. [PMID: 38198845 DOI: 10.1016/j.drup.2023.101041] [Citation(s) in RCA: 36] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 12/16/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024]
Abstract
Macrophages are important components of the immune system. Mature macrophages can be recruited to tumor microenvironment that affect tumor cell proliferation, invasion and metastasis, extracellular matrix remodeling, immune suppression, as well as chemotherapy resistance. Classically activated type I macrophages (M1) exhibited marked tumor killing and phagocytosis. Therefore, using macrophages for adoptive cell therapy has attracted attention and become one of the most effective strategies for cancer treatment. Through cytokines and/or chemokines, macrophage can inhibit myeloid cells recruitment, and activate anti-tumor and immune killing functions. Applying macrophages for anti-tumor delivery is one of the most promising approaches for cancer therapy. This review article introduces the role of macrophages in tumor development and drug resistance, and the possible clinical application of targeting macrophages for overcoming drug resistance and enhancing cancer therapeutics, as well as its challenges.
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Affiliation(s)
- Hongbin Wang
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, PR China; Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin Medical University, PR China; Department of Surgical Oncology, Harbin Medical University Cancer Hospital, PR China.
| | - Xueying Wang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, PR China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, PR China
| | - Xin Zhang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, PR China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, PR China
| | - Wanhai Xu
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, PR China; Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin Medical University, PR China; Department of Urology, Harbin Medical University Cancer Hospital, PR China.
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Liu YM, Li XQ, Zhang XR, Chen YY, Liu YP, Zhang HQ, Chen Y. Uncovering the key pharmacodynamic material basis and possible molecular mechanism of extract of Epimedium against liver cancer through a comprehensive investigation. JOURNAL OF ETHNOPHARMACOLOGY 2023; 317:116765. [PMID: 37328080 DOI: 10.1016/j.jep.2023.116765] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Liver cancer is a worldwide malignant tumor, and currently lacks effective treatments. Clinical studies have shown that epimedium (YYH) has therapeutic effects on liver cancer, and some of its prenylflavonoids have demonstrated anti-liver cancer activity through multiple mechanisms. However, there is still a need for systematic research to uncover the key pharmacodynamic material basis and mechanism of YYH. AIM OF THE STUDY This study aimed to screen the anti-cancer material basis of YYH via integrating spectrum-effect analysis with serum pharmacochemistry, and explore the multi-target mechanisms of YYH against liver cancer by combining network pharmacology with metabolomics. MATERIALS AND METHODS The anti-cancer effect of the extract of YYH (E-YYH) was first evaluated in mice with xenotransplantation H22 tumor cells burden and cultured hepatic cells. Then, the interaction between E-YYH compounds and the cytotoxic effects was revealed through spectrum-effect relationship analysis. And the cytotoxic effects of screened compounds were verified in hepatic cells. Next, UHPLC-Q-TOF-MS/MS was employed to identify the absorbed components of E-YYH in rat plasma to distinguish anti-cancer components. Subsequently, network pharmacology based on anti-cancer materials and metabolomics were used to discover the potential anti-tumor mechanisms of YYH. Key targets and biomarkers were identified and pathway enrichment analysis was performed. RESULTS The anti-cancer effect of E-YYH was verified through in vitro and in vivo experiments. Six anti-cancer compounds in plasma (icariin, baohuoside Ⅰ, epimedin C, 2″-O-rhamnosyl icariside Ⅱ, epimedin B and sagittatoside B) were screened out by spectrum-effect analysis. Forty-five liver-cancer-related targets were connected with these compounds. Among these targets, PTGS2, TNF, NOS3 and PPARG were considered to be the potential key targets preliminarily verified by molecular docking. Meanwhile, PI3K/AKT signaling pathway and arachidonic acid metabolism were found to be associated with E-YYH's efficacy in network pharmacology and metabolomics analysis. CONCLUSIONS Our research revealed the characteristics of multi-component, multi-target and multi-pathway mechanism of E-YYH. This study also provided an experimental basis and scientific evidence for the clinical application and rational development of YYH.
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Affiliation(s)
- Yi-Min Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Multi-component of Traditional Chinese Medicine and Microecology Research Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
| | - Xiao-Qi Li
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Multi-component of Traditional Chinese Medicine and Microecology Research Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
| | - Xiao-Ran Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Multi-component of Traditional Chinese Medicine and Microecology Research Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
| | - Yuan-Yuan Chen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Multi-component of Traditional Chinese Medicine and Microecology Research Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
| | - Yu-Ping Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Multi-component of Traditional Chinese Medicine and Microecology Research Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
| | - Huang-Qin Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Multi-component of Traditional Chinese Medicine and Microecology Research Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
| | - Yan Chen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Multi-component of Traditional Chinese Medicine and Microecology Research Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
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12
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Qi D, Lu M, Xu P, Yao X, Chen Y, Gan L, Li Y, Cui Y, Tong X, Liu S, Zhao J, Liu N, Ye X. Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF-α signaling. Cancer Commun (Lond) 2023; 43:1354-1372. [PMID: 37670477 PMCID: PMC10693303 DOI: 10.1002/cac2.12482] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/26/2023] [Accepted: 08/29/2023] [Indexed: 09/07/2023] Open
Abstract
BACKGROUND Hepatic inflammation is the major risk factor of hepatocellular carcinoma (HCC). However, the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood. This study was designed to investigate the role of ETS translocation variant 4 (ETV4) in linking hepatic inflammation to HCC. METHODS Quantitative real-time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines. RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4. Hepatocyte-specific ETV4-knockout (ETV4fl/fl, alb-cre ) and transgenic (ETV4Hep-TG ) mice and diethylnitrosamine-carbon tetrachloride (DEN-CCL4 ) treatment experiments were applied to investigate the function of ETV4 in vivo. The Cancer Genome Atlas (TCGA) database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor-alpha (TNF-α) and mitogen-activated protein kinase 11 (MAPK11). RESULTS We revealed that ETV4 was highly expressed in HCC. High levels of ETV4 predicted a poor survival rate of HCC patients. Then we identified ETV4 as a transcription activator of TNF-α and MAPK11. ETV4 was positively correlated with TNF-α and MAPK11 in HCC patients. As expected, an increase in hepatic TNF-α secretion and macrophage accumulation were observed in the livers of ETV4Hep-TG mice. The protein levels of TNF-α, MAPK11, and CD68 were significantly higher in the livers of ETV4Hep-TG mice compared with wild type mice but lower in ETV4fl/fl, alb-cre mice compared with ETV4fl/fl mice as treated with DEN-CCL4 , indicating that ETV4 functioned as a driver of TNF-α/MAPK11 expression and macrophage accumulation during hepatic inflammation. Hepatocyte-specific knockout of ETV4 significantly prevented development of DEN-CCL4 -induced HCC, while transgenic expression of ETV4 promoted growth of HCC. CONCLUSIONS ETV4 promoted hepatic inflammation and HCC by activating transcription of TNF-α and MAPK11. Both the ETV4/TNF-α and ETV4/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC. ETV4+TNF-α were potential prognostic markers for HCC patients.
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Affiliation(s)
- Dandan Qi
- Key Laboratory of Pathogenic Microbiology and ImmunologyInstitute of Microbiology, Chinese Academy of SciencesBeijingP. R. China
| | - Min Lu
- Key Laboratory of Pathogenic Microbiology and ImmunologyInstitute of Microbiology, Chinese Academy of SciencesBeijingP. R. China
- Savaid Medical SchoolUniversity of Chinese Academy of SciencesBeijingP. R. China
| | - Pengfei Xu
- The Fifth Medical Center of Chinese People's Liberation Army General HospitalBeijingP. R. China
| | - Xinli Yao
- Key Laboratory of Pathogenic Microbiology and ImmunologyInstitute of Microbiology, Chinese Academy of SciencesBeijingP. R. China
- Savaid Medical SchoolUniversity of Chinese Academy of SciencesBeijingP. R. China
| | - Yongchen Chen
- Key Laboratory of Pathogenic Microbiology and ImmunologyInstitute of Microbiology, Chinese Academy of SciencesBeijingP. R. China
- Savaid Medical SchoolUniversity of Chinese Academy of SciencesBeijingP. R. China
| | - Lipeng Gan
- Key Laboratory of Pathogenic Microbiology and ImmunologyInstitute of Microbiology, Chinese Academy of SciencesBeijingP. R. China
- Savaid Medical SchoolUniversity of Chinese Academy of SciencesBeijingP. R. China
| | - Yong Li
- Key Laboratory of Pathogenic Microbiology and ImmunologyInstitute of Microbiology, Chinese Academy of SciencesBeijingP. R. China
- Savaid Medical SchoolUniversity of Chinese Academy of SciencesBeijingP. R. China
| | - Yahua Cui
- School of Life SciencesUniversity of Science and Technology of ChinaHefeiAnhuiP. R. China
| | - Xiaomei Tong
- Key Laboratory of Pathogenic Microbiology and ImmunologyInstitute of Microbiology, Chinese Academy of SciencesBeijingP. R. China
| | - Shuhong Liu
- The Fifth Medical Center of Chinese People's Liberation Army General HospitalBeijingP. R. China
| | - Jingmin Zhao
- The Fifth Medical Center of Chinese People's Liberation Army General HospitalBeijingP. R. China
| | - Ningning Liu
- Key Laboratory of Pathogenic Microbiology and ImmunologyInstitute of Microbiology, Chinese Academy of SciencesBeijingP. R. China
| | - Xin Ye
- Key Laboratory of Pathogenic Microbiology and ImmunologyInstitute of Microbiology, Chinese Academy of SciencesBeijingP. R. China
- Savaid Medical SchoolUniversity of Chinese Academy of SciencesBeijingP. R. China
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13
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Zeng Z, Fu M, Hu Y, Wei Y, Wei X, Luo M. Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer. Mol Cancer 2023; 22:172. [PMID: 37853437 PMCID: PMC10583419 DOI: 10.1186/s12943-023-01877-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/05/2023] [Indexed: 10/20/2023] Open
Abstract
Cancer stem cells (CSCs), initially identified in leukemia in 1994, constitute a distinct subset of tumor cells characterized by surface markers such as CD133, CD44, and ALDH. Their behavior is regulated through a complex interplay of networks, including transcriptional, post-transcriptional, epigenetic, tumor microenvironment (TME), and epithelial-mesenchymal transition (EMT) factors. Numerous signaling pathways were found to be involved in the regulatory network of CSCs. The maintenance of CSC characteristics plays a pivotal role in driving CSC-associated tumor metastasis and conferring resistance to therapy. Consequently, CSCs have emerged as promising targets in cancer treatment. To date, researchers have developed several anticancer agents tailored to specifically target CSCs, with some of these treatment strategies currently undergoing preclinical or clinical trials. In this review, we outline the origin and biological characteristics of CSCs, explore the regulatory networks governing CSCs, discuss the signaling pathways implicated in these networks, and investigate the influential factors contributing to therapy resistance in CSCs. Finally, we offer insights into preclinical and clinical agents designed to eliminate CSCs.
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Affiliation(s)
- Zhen Zeng
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Minyang Fu
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuan Hu
- Department of Pediatric Nephrology Nursing, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Min Luo
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China.
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Li Y, Tuerxun H, Liu X, Zhao Y, Wen S, Li Y, Cao J, Zhao Y. Nrf2--a hidden bridge linking cancer stem cells to ferroptosis. Crit Rev Oncol Hematol 2023; 190:104105. [PMID: 37598896 DOI: 10.1016/j.critrevonc.2023.104105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 08/01/2023] [Accepted: 08/15/2023] [Indexed: 08/22/2023] Open
Abstract
Cancer stem cells (CSCs), a small population of stem cells existing in cancer cells, are considered as the "culprits" of tumor recurrence, metastasis, and drug resistance. Ferroptosis is a promising new lead in anti-cancer therapy. Because of unique metabolic characteristics, CSCs' growth is more dependent on the iron and lipid than ordinary cancer cells. When the metabolism of iron/lipid is disordered, that is, imbalanced redox homeostasis, CSCs are more susceptible to ferroptosis. The expression of Nuclear factor E2-related factor 2 (Nrf2), a molecule playing a major regulatory role in redox homeostasis, determines whether the cells are under oxidative stress and ferroptosis occurs. Nrf2 expression level is higher in CSCs, indicating stronger dependence on Nrf2. Here we expound the unique biological and metabolic characteristics of CSCs, explore the mechanism of inducing ferroptosis by targeting Nrf2, thus providing promising new targets for eliminating aggressive tumors and achieving the goal of curing tumors.
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Affiliation(s)
- Yawen Li
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Halahati Tuerxun
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Xingyu Liu
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yixin Zhao
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Shuhui Wen
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yaping Li
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Jingjing Cao
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yuguang Zhao
- Cancer Center, the First Hospital of Jilin University, Changchun, Jilin 130021, China.
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Song M, Liang J, Wang L, Li W, Jiang S, Xu S, Tang L, Du Q, Liu G, Meng H, Zhai D, Shi S, Yang Y, Zhang L, Zhang B. IL-17A functions and the therapeutic use of IL-17A and IL-17RA targeted antibodies for cancer treatment. Int Immunopharmacol 2023; 123:110757. [PMID: 37579542 DOI: 10.1016/j.intimp.2023.110757] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/31/2023] [Accepted: 08/01/2023] [Indexed: 08/16/2023]
Abstract
Interleukin 17A (IL-17A) is a major member of the IL-17 cytokine family and is produced mainly by T helper 17 (Th17) cells. Other cells such as CD8+ T cells, γδ T cells, natural killer T cells and innate lymphoid-like cells can also produce IL-17A. In healthy individuals, IL-17A has a host-protective capacity, but excessive elevation of IL-17A is associated with the development of autoimmune diseases and cancer. Monoclonal antibodies (mAbs) targeting IL-17A (e.g., ixekizumab and secukinumab) or IL-17A receptor (IL-17RA) (e.g., brodalumab) would be investigated as potential treatments for these diseases. Currently, the application of IL-17A-targeted drugs in autoimmune diseases will provide new ideas for the treatment of tumors, and its combined application with immune checkpoint inhibitors has become a research hotspot. This article reviews the mechanism of action of IL-17A and the application of anti-IL-17A antibodies, focusing on the research progress on the mechanism of action and therapeutic blockade of IL-17A in various tumors such as colorectal cancer (CRC), lung cancer, gastric cancer and breast cancer. Moreover, we also include the results of therapeutic blockade in the field of cancer as well as recent advances in the regulation of IL-17A signaling.
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Affiliation(s)
- Meiying Song
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Jie Liang
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Luoyang Wang
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Wei Li
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Suli Jiang
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Shuo Xu
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Lei Tang
- Department of Special Medicine, School of Basic Medical College, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Qiaochu Du
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Guixian Liu
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Haining Meng
- School of Emergency Medicine, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Dongchang Zhai
- Department of Special Medicine, School of Basic Medical College, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Shangheng Shi
- Department of Liver Transplantation, School of Clinical Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Yanyan Yang
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Li Zhang
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Bei Zhang
- Department of Immunology, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China.
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16
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Lam KH, Ma S. Noncellular components in the liver cancer stem cell niche: Biology and potential clinical implications. Hepatology 2023; 78:991-1005. [PMID: 35727189 DOI: 10.1002/hep.32629] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/16/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023]
Abstract
Cancer stem cells (CSCs) are now recognized as one of the major root causes of therapy failure and tumor recurrence in hepatocellular carcinoma (HCC). Early studies in the field focused primarily on the intrinsic regulators of CSC maintenance, but in recent years, mounting evidence has demonstrated the presence and role of extrinsic regulators in the tumor microenvironment (TME) in the control of liver CSCs. In addition to direct interaction with cellular components, noncellular components, including the extracellular matrix, hypoxia, nutrient deprivation, and secreted molecules within the tumor stroma and hepatitis viruses, also play a critical role in shaping the CSC niche. In this review, we highlight how various noncellular components in the TME play a role in regulating CSCs and how CSCs secrete components to interact with the TME to generate their own niche, working hand in hand to drive tumor physiology in HCC. In addition, we describe the potential clinical applications of these findings and propose perspectives on future research of noncellular components in the liver CSC niche.
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Affiliation(s)
- Ka-Hei Lam
- School of Biomedical Sciences , Li Ka Shing Faculty of Medicine , The University of Hong Kong , Hong Kong , Hong Kong
| | - Stephanie Ma
- School of Biomedical Sciences , Li Ka Shing Faculty of Medicine , The University of Hong Kong , Hong Kong , Hong Kong
- The University of Hong Kong , Shenzhen Hospital , Hong Kong , Hong Kong
- State Key Laboratory of Liver Research , The University of Hong Kong , Hong Kong , Hong Kong
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Liang Q, Liu S, Yin F, Liu M, Wang L, Guo E, Lei L, Wu L, Yang Y, Zhang D, Zeng X. Low expression of GOT2 promotes tumor progress and predicts poor prognosis in hepatocellular carcinoma. Biomark Med 2023; 17:755-765. [PMID: 38095985 DOI: 10.2217/bmm-2023-0236] [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: 01/12/2024] Open
Abstract
Background: To explore the biological function and the underlying mechanisms of GOT2 in hepatocellular carcinoma (HCC). Materials & methods: The expression level and prognostic value of GOT2 were examined using International Cancer Genome Consortium and International Cancer Proteogenome Consortium databases. The cell counting kit-8 method, clone formation, Transwell® assays and western blotting were used to evaluate the effects of GOT2 on the biological function and autophagy of HCC cells. Results: The expression of GOT2 was downregulated in HCC tissues and correlated with poor prognosis of HCC patients. Knockdown of GOT2 promoted proliferation, migration and invasion of HCC cells and promoted cells' proliferation by inducing autophagy. Conclusion: GOT2 plays a tumor-inhibitory role in HCC and may be a potential therapeutic target for HCC.
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Affiliation(s)
- Qiuli Liang
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Nanning Center for Disease Control & Prevention, Nanning, Guangxi, 530002, China
| | - Shun Liu
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Fuqiang Yin
- Life Sciences Institute Guangxi Medical University, Nanning, Guangxi, 530021, China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China
| | - Meiliang Liu
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Lijun Wang
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Erna Guo
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
- School of International Education, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Lei Lei
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Liuyu Wu
- Department of Hospital Infection Control, Liuzhou People's Hospital, Liuzhou, Guangxi, 545026, China
| | - Yu Yang
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Di Zhang
- Department of Scientific Research, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, China
| | - Xiaoyun Zeng
- School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China
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Zong C, Meng Y, Ye F, Yang X, Li R, Jiang J, Zhao Q, Gao L, Han Z, Wei L. AIF1 + CSF1R + MSCs, induced by TNF-α, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis. Hepatology 2023; 78:434-451. [PMID: 35989499 PMCID: PMC10344441 DOI: 10.1002/hep.32738] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 08/12/2022] [Accepted: 08/12/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Increasing evidence suggests that mesenchymal stem cells (MSCs) home to injured local tissues and the tumor microenvironment in the liver. Chronic inflammation is regarded as the major trait of primary liver cancer. However, the characteristics of endogenous MSCs in the inflammatory environment and their role in the occurrence of liver cancer remain obscure. APPROACH AND RESULTS Using single-cell RNA sequencing, we identified a distinct inflammation-associated subset of MSCs, namely AIF1 + CSF1R + MSCs, which existed in the microenvironment before the occurrence of liver cancer. Furthermore, we found that this MSC subgroup is likely to be induced by TNF-α stimulation through the TNFR1/SIRT1 (sirtuin 1) pathway. In a rat primary liver cancer model, we showed that MSCs with high SIRT1 expression (Ad-Sirt1-MSCs) promoted macrophage recruitment and synergistically facilitated liver cancer occurrence by secreting C-C motif chemokine ligand (CCL) 5. Interestingly, depletion of macrophages or knockdown of CCL5 expression in Ad-Sirt1-MSCs attenuated the promotive effect of Ad-Sirt1-MSCs on liver inflammation and hepatocarcinogenesis (HCG). Finally, we demonstrated that SIRT1 up-regulated CCL5 expression through activation of the AKT/HIF1α signaling axis in MSCs. CONCLUSIONS Together, our results show that MSCs, which are mobilized to the injured site, can be educated by macrophages. In turn, the educated MSCs are involved in generating a chronic inflammatory microenvironment and promoting HCG.
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Affiliation(s)
- Chen Zong
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Yan Meng
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Fei Ye
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Xue Yang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Lu Gao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
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Gu Z, Wang L, Dong Q, Xu K, Ye J, Shao X, Yang S, Lu C, Chang C, Hou Y, Zhai Y, Wang X, He F, Sun A. Aberrant LYZ expression in tumor cells serves as the potential biomarker and target for HCC and promotes tumor progression via csGRP78. Proc Natl Acad Sci U S A 2023; 120:e2215744120. [PMID: 37428911 PMCID: PMC10629575 DOI: 10.1073/pnas.2215744120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 05/02/2023] [Indexed: 07/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) takes the predominant malignancy of hepatocytes with bleak outcomes owing to high heterogeneity among patients. Personalized treatments based on molecular profiles will better improve patients' prognosis. Lysozyme (LYZ), a secretory protein with antibacterial function generally expressed in monocytes/macrophages, has been observed for the prognostic implications in different types of tumors. However, studies about the explicit applicative scenarios and mechanisms for tumor progression are still quite limited, especially for HCC. Here, based on the proteomic molecular classification data of early-stage HCC, we revealed that the LYZ level was elevated significantly in the most malignant HCC subtype and could serve as an independent prognostic predictor for HCC patients. Molecular profiles of LYZ-high HCCs were typical of those for the most malignant HCC subtype, with impaired metabolism, along with promoted proliferation and metastasis characteristics. Further studies demonstrated that LYZ tended to be aberrantly expressed in poorly differentiated HCC cells, which was regulated by STAT3 activation. LYZ promoted HCC proliferation and migration in both autocrine and paracrine manners independent of the muramidase activity through the activation of downstream protumoral signaling pathways via cell surface GRP78. Subcutaneous and orthotopic xenograft tumor models indicated that targeting LYZ inhibited HCC growth markedly in NOD/SCID mice. These results propose LYZ as a prognostic biomarker and therapeutic target for the subclass of HCC with an aggressive phenotype.
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Affiliation(s)
- Zhiwen Gu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
- Research Unit of Proteomics-driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing102206, China
| | - Lei Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
- Faculty of Environment and Life, Beijing University of Technology, Beijing100124, China
| | - Qian Dong
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
| | - Kaikun Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
| | - Jingnan Ye
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
| | - Xianfeng Shao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
| | - Songpeng Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
| | - Cuixiu Lu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
| | - Cheng Chang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
- Research Unit of Proteomics-driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing102206, China
| | - Yushan Hou
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
| | - Yuanjun Zhai
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
- Research Unit of Proteomics-driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing102206, China
| | - Xinxin Wang
- Department of Pathology, Beijing You’an Hospital, Capital Medical University, Beijing100069, China
| | - Fuchu He
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
- Research Unit of Proteomics-driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing102206, China
| | - Aihua Sun
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing102206, China
- Research Unit of Proteomics-driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing102206, China
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20
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Luo Y, Xiao JH. Inflammatory auxo-action in the stem cell division theory of cancer. PeerJ 2023; 11:e15444. [PMID: 37309372 PMCID: PMC10257902 DOI: 10.7717/peerj.15444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 05/01/2023] [Indexed: 06/14/2023] Open
Abstract
Acute inflammation is a beneficial response to the changes caused by pathogens or injuries that can eliminate the source of damage and restore homeostasis in damaged tissues. However, chronic inflammation causes malignant transformation and carcinogenic effects of cells through continuous exposure to pro-inflammatory cytokines and activation of inflammatory signaling pathways. According to the theory of stem cell division, the essential properties of stem cells, including long life span and self-renewal, make them vulnerable to accumulating genetic changes that can lead to cancer. Inflammation drives quiescent stem cells to enter the cell cycle and perform tissue repair functions. However, as cancer likely originates from DNA mutations that accumulate over time via normal stem cell division, inflammation may promote cancer development, even before the stem cells become cancerous. Numerous studies have reported that the mechanisms of inflammation in cancer formation and metastasis are diverse and complex; however, few studies have reviewed how inflammation affects cancer formation from the stem cell source. Based on the stem cell division theory of cancer, this review summarizes how inflammation affects normal stem cells, cancer stem cells, and cancer cells. We conclude that chronic inflammation leads to persistent stem cells activation, which can accumulate DNA damage and ultimately promote cancer. Additionally, inflammation not only facilitates the progression of stem cells into cancer cells, but also plays a positive role in cancer metastasis.
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Affiliation(s)
- Yi Luo
- Institute of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology & Guizhou Provincial Research Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jian-Hui Xiao
- Institute of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology & Guizhou Provincial Research Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Gynaecology and Obstetrics, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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21
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Yan X, Liu Y, Li C, Mao X, Xu T, Hu Z, Zhang C, Lin N, Lin Y, Zhang Y. Pien-Tze-Huang prevents hepatocellular carcinoma by inducing ferroptosis via inhibiting SLC7A11-GSH-GPX4 axis. Cancer Cell Int 2023; 23:109. [PMID: 37280673 PMCID: PMC10246043 DOI: 10.1186/s12935-023-02946-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 05/15/2023] [Indexed: 06/08/2023] Open
Abstract
BACKGROUND Malignant transformation from hepatic fibrosis to carcinogenesis may be a therapeutic target for hepatocellular carcinoma (HCC). The aim of this study was to evaluate anti-cancer efficacy of Pien-Tze-Huang (PZH), and to investigate the underlying mechanisms by integrating transcriptional regulatory network analysis and experimental validation. METHODS A diethylnitrosamine (DEN)-induced HCC model in rats was established and used to evaluate the anti-cancer efficacy of PZH. After detecting a transcriptomic profiling, the "disease-related gene-drug effective target" interaction network was constructed, and the candidate targets of PZH against malignant transformation from hepatic fibrosis to HCC were identified and verified in vitro. RESULTS PZH effectively alleviated the pathological changes of hepatic fibrosis and cirrhosis, and inhibited tumor formation and growth in DEN-induced HCC rats. Additionally, the administration of PZH reduced the levels of various hepatic function-related serological indicators significantly. Mechanically, a ferroptosis-related SLC7A11-GSH-GPX4 axis might be one of potential targets of PZH against malignant transformation from hepatic fibrosis to HCC. Especially, high SLC7A11 expression may be associated with poor prognosis of HCC patients. Experimentally, the administration of PZH markedly increased the trivalent iron and ferrous ion, suppressed the expression levels of SLC7A11 and GPX4 proteins, and reduced the GSH/GSSG ratio in the liver tissues of DEN-induced HCC rats. CONCLUSIONS Our data offer an evidence that PZH may effectively improve the hepatic fibrosis microenvironment and prevent the occurrence of HCC through promoting ferroptosis in tumor cells via inhibiting the SLC7A11-GSH-GPX4 axis, implying that PZH may be a potential candidate drug for prevention and treatment of HCC at an early stage.
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Affiliation(s)
- Xiangying Yan
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Yudong Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China
| | - Congchong Li
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Xia Mao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China
| | - Tengteng Xu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China
| | - Zhixing Hu
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Chu Zhang
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Na Lin
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China
| | - Ya Lin
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China.
| | - Yanqiong Zhang
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China.
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China.
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22
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Tao Q, Ji H, Zhou Y, Shu Y, Chen Y, Shao M, Wu Z, Chen M, Lv T, Shi Y. HDAC3 Controls Liver Homeostasis More by Facilitating Deoxyribonucleic Acid Damage Repair than by Regulating Transcription in Hepatocytes. J Transl Med 2023; 103:100120. [PMID: 36801398 DOI: 10.1016/j.labinv.2023.100120] [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: 09/20/2022] [Revised: 01/18/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023] Open
Abstract
By controlling DNA damage repair and regulating gene transcription, the critical epigenetic regulator histone deacetylase 3 (HDAC3) plays pivotal roles in liver cancer and liver regeneration; however, the role of HDAC3 in liver homeostasis has not been fully elucidated. In this study, we found that HDAC3-deficient livers developed a defective morphology and metabolism with an increasing degree of DNA damage in the hepatocytes along the portal-central axis of the lobule. Most strikingly, in the Alb-CreERT:Hdac3-/- mice, it was demonstrated that HDAC3 ablation did not impair liver homeostasis in terms of histologic characteristics, function, proliferation, or gene profiles prior to the profound accumulation of DNA damage. Next, we identified that the hepatocytes in the portal area, which carried less DNA damage than those in the central area, repopulated the hepatic lobule by active regeneration and movement toward the center. As a result, the liver became more viable after each surgery. Furthermore, in vivo tracing of keratin-19-expressing hepatic progenitor cells, which lacked HDAC3, showed that the hepatic progenitor cells gave rise to newly generated periportal hepatocytes. In hepatocellular carcinoma, HDAC3 deficiency impaired DNA damage response and enhanced radiotherapy sensitivity in vitro and in vivo. Taken together, we demonstrated that HDAC3 deficiency interferes with liver homeostasis, which is more dependent on the accumulation of DNA damage in hepatocytes than on transcriptional dysregulation. Our findings support the hypothesis that selective HDAC3 inhibition has the potential to augment the effect of chemoradiotherapy aimed at inducing DNA damage in cancer therapy.
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Affiliation(s)
- Qing Tao
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Hongjie Ji
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China; School of Bioscience and Technology, Weifang Medical University, Weifang, China
| | - Yongjie Zhou
- Laboratory of Liver Transplantation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yuke Shu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Yuwei Chen
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Mingyang Shao
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenru Wu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Menglin Chen
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Lv
- Laboratory of Liver Transplantation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China; Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
| | - Yujun Shi
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Liver Transplantation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
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23
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Ait-Ahmed Y, Lafdil F. Novel insights into the impact of liver inflammatory responses on primary liver cancer development. LIVER RESEARCH 2023; 7:26-34. [PMID: 39959704 PMCID: PMC11791919 DOI: 10.1016/j.livres.2023.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/05/2022] [Accepted: 01/27/2023] [Indexed: 03/10/2023]
Abstract
Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context. This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process (initiation steps) and the impact of the immune response favoring tumor cell expansion (progression steps). Several cytokines, namely interleukin (IL)-6, IL-17, IL-1beta, and tumor necrosis factor-alpha, have been described to play a prominent role in the initiation of liver cancers. Additionally, inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response, angiogenesis, and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation. These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation. These strategies are based on the use of anti-inflammatory agents, antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors, metastasis key factors, and microRNAs involved in tumor development. This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development.
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Affiliation(s)
- Yeni Ait-Ahmed
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
| | - Fouad Lafdil
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
- Institut Universitaire de France (IUF), Paris, France
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24
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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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25
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Razi Soofiyani S, Minaei Beirami S, Hosseini K, Mohammadi Nasr M, Ranjbar M, Forouhandeh H, Tarhriz V, Sadeghi M. Revisiting Inhibition Effects of miR-28 as a Metastasis Suppressor in Gastrointestinal Cancers. Microrna 2023; 12:131-142. [PMID: 37073155 DOI: 10.2174/2211536612666230413125126] [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: 05/11/2022] [Revised: 11/09/2022] [Accepted: 01/20/2023] [Indexed: 04/20/2023]
Abstract
MicroRNAs are critical epigenetic regulators that can be used as diagnostic, prognostic, and therapeutic biomarkers for the treatment of various diseases, including gastrointestinal cancers, among a variety of cellular and molecular biomarkers. MiRNAs have also shown oncogenic or tumor suppressor roles in tumor tissue and other cell types. Studies showed that the dysregulation of miR-28 is involved in cell growth and metastasis of gastrointestinal cancers. MiR-28 plays a key role in controlling the physiological processes of cancer cells including growth and proliferation, migration, invasion, apoptosis, and metastasis. Therefore, miR-28 expression patterns can be used to distinguish patient subgroups. Based on the previous studies, miR-28 expression can be a suitable biomarker to detect tumor size and predict histological grade metastasis. In this review, we summarize the inhibitory effects of miR-28 as a metastasis suppressor in gastrointestinal cancers. miR-28 plays a role as a tumor suppressor in gastrointestinal cancers by regulating cancer cell growth, cell differentiation, angiogenesis, and metastasis. As a result, using it as a prognostic, diagnostic, and therapeutic biomarker in the treatment of gastrointestinal cancers can be a way to solve the problems in this field.
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Affiliation(s)
- Saiedeh Razi Soofiyani
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Clinical Research Development Unit, Sina Educational, Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sohrab Minaei Beirami
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kamran Hosseini
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Faculty of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mina Mohammadi Nasr
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences. Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Ranjbar
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Haleh Forouhandeh
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammadreza Sadeghi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences. Tabriz University of Medical Sciences, Tabriz, Iran
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26
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Zhu M, Li S, Cao X, Rashid K, Liu T. The STAT family: Key transcription factors mediating crosstalk between cancer stem cells and tumor immune microenvironment. Semin Cancer Biol 2023; 88:18-31. [PMID: 36410636 DOI: 10.1016/j.semcancer.2022.11.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 11/14/2022] [Accepted: 11/16/2022] [Indexed: 11/21/2022]
Abstract
Signal transducer and activator of transcription (STAT) proteins compose a family of transcription factors critical for cancer stem cells (CSCs), and they are involved in maintaining stemness properties, enhancing cell proliferation, and promoting metastasis. Recent studies suggest that STAT proteins engage in reciprocal communication between CSCs and infiltrate immune cell populations in the tumor microenvironment (TME). Emerging evidence has substantiated the influence of immune cells, including macrophages, myeloid-derived suppressor cells, and T cells, on CSC survival through the regulation of STAT signaling. Conversely, dysregulation of STATs in CSCs or immune cells contributes to the establishment of an immunosuppressive TME. Thus, STAT proteins are promising therapeutic targets for cancer treatment, especially when used in combination with immunotherapy. From this perspective, we discuss the complex roles of STATs in CSCs and highlight their functions in the crosstalk between CSCs and the immune microenvironment. Finally, cutting-edge clinical trial progress with STAT signaling inhibitors is summarized.
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Affiliation(s)
- Mengxuan Zhu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; Center of Evidence-based Medicine, Fudan University, Shanghai, China
| | - Suyao Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; Center of Evidence-based Medicine, Fudan University, Shanghai, China
| | - Xin Cao
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Khalid Rashid
- Department of Cancer Biology, Faculty of Medicine, University of Cincinnati, OH, USA.
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; Center of Evidence-based Medicine, Fudan University, Shanghai, China.
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27
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Zhang H, Sheng D, Han Z, Zhang L, Sun G, Yang X, Wang X, Wei L, Lu Y, Hou X, Zhang L. Doxorubicin-liposome combined with clodronate-liposome inhibits hepatocellular carcinoma through the depletion of macrophages and tumor cells. Int J Pharm 2022; 629:122346. [DOI: 10.1016/j.ijpharm.2022.122346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 10/17/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022]
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28
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Cancer Stem Cells in Hepatocellular Carcinoma: Intrinsic and Extrinsic Molecular Mechanisms in Stemness Regulation. Int J Mol Sci 2022; 23:ijms232012327. [PMID: 36293184 PMCID: PMC9604119 DOI: 10.3390/ijms232012327] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/18/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains the most predominant type of liver cancer with an extremely poor prognosis due to its late diagnosis and high recurrence rate. One of the culprits for HCC recurrence and metastasis is the existence of cancer stem cells (CSCs), which are a small subset of cancer cells possessing robust stem cell properties within tumors. CSCs play crucial roles in tumor heterogeneity constitution, tumorigenesis, tumor relapse, metastasis, and resistance to anti-cancer therapies. Elucidation of how these CSCs maintain their stemness features is essential for the development of CSCs-based therapy. In this review, we summarize the present knowledge of intrinsic molecules and signaling pathways involved in hepatic CSCs, especially the CSC surface markers and associated signaling in regulating the stemness characteristics and the heterogeneous subpopulations within the CSC pool. In addition, we recapitulate the effects of crucial extrinsic cellular components in the tumor microenvironment, including stromal cells and immune cells, on the modulation of hepatic CSCs. Finally, we synopsize the currently valuable CSCs-targeted therapy strategies based on intervention in these intrinsic and extrinsic molecular mechanisms, in the hope of shedding light on better clinical management of HCC patients.
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29
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Tu T, Alba MM, Datta AA, Hong H, Hua B, Jia Y, Khan J, Nguyen P, Niu X, Pammidimukkala P, Slarve I, Tang Q, Xu C, Zhou Y, Stiles BL. Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis. Front Oncol 2022; 12:958696. [PMID: 36276076 PMCID: PMC9581256 DOI: 10.3389/fonc.2022.958696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/17/2022] [Indexed: 12/02/2022] Open
Abstract
Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.
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Affiliation(s)
- Taojian Tu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Mario M. Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Aditi A. Datta
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Handan Hong
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yunyi Jia
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Jared Khan
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Phillip Nguyen
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Xiatoeng Niu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Pranav Pammidimukkala
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Qi Tang
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Chenxi Xu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Bangyan L. Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Bangyan L. Stiles,
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Makino Y, Hikita H, Fukumoto K, Sung JH, Sakano Y, Murai K, Sakane S, Kodama T, Sakamori R, Kondo J, Kobayashi S, Tatsumi T, Takehara T. Constitutive Activation of the Tumor Suppressor p53 in Hepatocytes Paradoxically Promotes Non-Cell Autonomous Liver Carcinogenesis. Cancer Res 2022; 82:2860-2873. [PMID: 35696550 PMCID: PMC9379366 DOI: 10.1158/0008-5472.can-21-4390] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 04/27/2022] [Accepted: 06/08/2022] [Indexed: 01/07/2023]
Abstract
In chronic liver diseases (CLD), p53 is constitutively activated in hepatocytes due to various etiologies as viral infection, ethanol exposure, or lipid accumulation. This study was aimed to clarify the significance of p53 activation on the pathophysiology of CLDs. In Kras-mutant liver cancer model, murine double minute 2 (Mdm2), a negative regulator of p53, was specifically deleted in hepatocytes [Alb-Cre KrasLSL-G12D Mdm2fl/fl (LiKM; KrasG12D mutation and Mdm2 loss in the liver)]. Accumulation of p53 and upregulation of its downstream genes were observed in hepatocytes in LiKM mice. LiKM mice showed liver inflammation accompanied by hepatocyte apoptosis, senescence-associated secretory phenotype (SASP), and the emergence of hepatic progenitor cells (HPC). More importantly, Mdm2 deletion promoted non-cell autonomous development of liver tumors. Organoids generated from HPCs harbored tumor-formation ability when subcutaneously inoculated into NOD/Shi-scid/IL2Rγ (null) mice. Treatment with acyclic retinoid suppressed growth of HPCs in vitro and inhibited tumorigenesis in LiKM mice. All of the phenotypes in LiKM mice, including accelerated liver tumorigenesis, were negated by further deletion of p53 in hepatocytes (Alb-Cre KrasLSL-G12D Mdm2fl/fl p53fl/fl). Activation of hepatic p53 was noted in liver biopsy samples obtained from 182 patients with CLD, in comparison with 23 normal liver samples without background liver diseases. In patients with CLD, activity of hepatic p53 was positively correlated with the expression of apoptosis, SASP, HPC-associated genes and tumor incidence in the liver after biopsy. In conclusion, activation of hepatocyte p53 creates a microenvironment prone to tumor formation from HPCs. Optimization of p53 activity in hepatocytes is important to prevent patients with CLD from hepatocarcinogenesis. SIGNIFICANCE This study reveals that activation of p53 in hepatocytes promotes liver carcinogenesis derived from HPCs, which elucidates a paradoxical aspect of a tumor suppressor p53 and novel mechanism of liver carcinogenesis. See related commentary by Barton and Lozano, p. 2824.
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Affiliation(s)
- Yuki Makino
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kenji Fukumoto
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ji Hyun Sung
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshihiro Sakano
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kazuhiro Murai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Sadatsugu Sakane
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Jumpei Kondo
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.,Corresponding Author: Tetsuo Takehara, Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Phone: 816-6879-3621; Fax: 816-6879-3629; E-mail:
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31
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Yan X, Yang P, Liu H, Zhao Y, Wu Z, Zhang B. miR-4461 inhibits the progression of Gallbladder carcinoma via regulating EGFR/AKT signaling. Cell Cycle 2022; 21:1166-1177. [PMID: 35196196 PMCID: PMC9103642 DOI: 10.1080/15384101.2022.2042775] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Increasing evidence has demonstrated that microRNAs (miRNAs) participated in the tumorigenesis, progression and recurrence of various malignancies including Gallbladder carcinoma (GBC). miR-4461 was reported to work as a tumor suppressor gene in renal cell carcinoma. However, the role of miR-4461 in GBC remains unknown. Herein, we show that miR-4461 is downregulated in gallbladder cancer stem cells (CSCs). Forced miR-4461 expression attenuates the self-renewal, tumorigenicity of gallbladder CSCs, and inhibits proliferation and metastasis of GBC cells. Conversely, miR-4461 knockdown promotes the self-renewal of gallbladder CSCs, and facilities proliferation and metastasis of GBC cells. Mechanistically, miR-4461 inhibits GBC progression via downregulating EGFR/AKT pathway. Special EGFR siRNA or AKT overexpression virus abolishes the discrepancy of self-renewal, tumorigenesis, growth, and metastasis between miR-4461 overexpression GBC cells and their control cells. In conclusion, miR-4461 suppresses GBC cells self-renewal, tumorigenicity, proliferation, and metastasis by inactivating EGFR/AKT signaling, and may therefore prove to be a potential therapeutic target for GBC patients.
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Affiliation(s)
- Xingzhou Yan
- Department of Biliary Tract Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Pinghua Yang
- Department of Biliary Tract Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, China,Zhixiong Wu Department of Critical Care Medicine, Huadong Hospital, Shanghai, 200040, China
| | - Hu Liu
- Department of Biliary Tract Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, China,CONTACT Baohua Zhang Department of Biliary Surgery, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, 200438 Shanghai, China
| | - Yongyang Zhao
- Department of Biliary Tract Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, China,Zhixiong Wu Department of Critical Care Medicine, Huadong Hospital, Shanghai, 200040, China
| | - Zhixiong Wu
- Department of Critical Care Medicine, Huadong Hospital, Shanghai, China
| | - Baohua Zhang
- Department of Biliary Tract Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, China,CONTACT Baohua Zhang Department of Biliary Surgery, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, 200438 Shanghai, China
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Troglitazone inhibits hepatic oval cell proliferation by inducing cell cycle arrest through Hippo/YAP pathway regulation. Dig Liver Dis 2022; 54:791-799. [PMID: 34531129 DOI: 10.1016/j.dld.2021.08.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 08/21/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022]
Abstract
Hepatic oval cells have strong proliferation and differentiation capabilities and are activated when chronic liver injury occurs or when liver function is severely impaired. Peroxisome proliferation-activated receptors (PPARs) are ligand-dependent, sequence-specific nuclear transcription factors. PPARγ is closely related to liver diseases (such as liver cancer, liver fibrosis and non-alcoholic fatty liver disease). As the main effector downstream of the Hippo signaling pathway, YAP can activate the hepatic progenitor cell program, and different expression or activity levels of YAP can determine different liver cell fates. We found that troglitazone (TRO), a classic PPARγ activator, can inhibit the growth of hepatic oval cells, and flow cytometry results showed that TRO inhibited the growth of WB-F344 cells by arresting the cells in the G0/1 phase. Western blot results also confirmed changes in G0/1 phase-related protein expression. Further experiments showed that PPARγ agonists induced hepatic oval cell proliferation inhibition and cell cycle G0/1 phase arrest through the Hippo/YAP pathway. Our experiment demonstrated, for the first time, the relationship between PPARγ and the Hippo/YAP pathway in liver oval cells and revealed that PPARγ acts as a negative regulator of liver regeneration by inhibiting the proliferation of oval cells.
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33
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Shan L, Song P, Zhao Y, An N, Xia Y, Qi Y, Zhao H, Ge J. miR-600 promotes ovarian cancer cells stemness, proliferation and metastasis via targeting KLF9. J Ovarian Res 2022; 15:52. [PMID: 35501825 PMCID: PMC9063371 DOI: 10.1186/s13048-022-00981-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 04/11/2022] [Indexed: 11/10/2022] Open
Abstract
Previous studies have revealed that miRNAs participate in the pathogenesis of ovarian cancer; however, whether miR-600 is also involved remains unclear. In this study, we aimed to investigated the role of miR-600 in ovarian cancer progression. Here, miR-600 expression was significantly upregulated in ovarian cancer tissues and stem cells. Functional studies showed that miR-600 promoted ovarian cancer cell stemness, proliferation and metastasis. Mechanistic studies revealed that Kruppel like factor 9 (KLF9) was indicated as the target of miR-600. The luciferase reporter assay suggested that miR-600 directly bound to the 3'-untranslated region of KLF9. Additionally, miR-600 expression was negatively associated with KLF9 expression in human ovarian cancer tissues. Si-KLF9 partially abolished the discrepancy of self-renewal, growth and metastasis capacity between miR-600 knockdown ovarian cancer cells and control cells. In conclusion, our results suggest that miR-600 promotes ovarian cancer cell stemness, proliferation and metastasis via directly downregulating KLF9, and impairing miR-600 levels may be a new treatment strategy for ovarian cancer in the future.
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Affiliation(s)
- Lili Shan
- Department of Gynaecology and Obstetrics, the Veterans General Hospital of Liaoning Province, the Second Affiliated Hospital of Shenyang Medical College, Shenyang, 110002, Liaoning, China
| | - Pingping Song
- Department of Gynaecology and Obstetrics, the Veterans General Hospital of Liaoning Province, the Second Affiliated Hospital of Shenyang Medical College, Shenyang, 110002, Liaoning, China
| | - Yangyang Zhao
- Department of Gynaecology and Obstetrics, the Veterans General Hospital of Liaoning Province, the Second Affiliated Hospital of Shenyang Medical College, Shenyang, 110002, Liaoning, China
| | - Na An
- Department of Endoscopy, Northern Theater General Hospital, Shenyang, 110011, Liaoning, China
| | - Yanqiu Xia
- Department of Neonatology, Northern Theater General Hospital, Shenyang, 110011, Liaoning, China
| | - Yue Qi
- Department of Gynaecology and Obstetrics, the Veterans General Hospital of Liaoning Province, the Second Affiliated Hospital of Shenyang Medical College, Shenyang, 110002, Liaoning, China
| | - Hongyan Zhao
- Department of Endoscopy, Northern Theater General Hospital, Shenyang, 110011, Liaoning, China
| | - Jing Ge
- Department of Gynaecology and Obstetrics, the Veterans General Hospital of Liaoning Province, the Second Affiliated Hospital of Shenyang Medical College, Shenyang, 110002, Liaoning, China.
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Xu W, Cheng Y, Guo Y, Yao W, Qian H. Targeting tumor associated macrophages in hepatocellular carcinoma. Biochem Pharmacol 2022; 199:114990. [PMID: 35288152 DOI: 10.1016/j.bcp.2022.114990] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 03/02/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022]
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Wang YC, Wang ZJ, Zhang C, Ning BF. Cell reprogramming in liver with potential clinical correlations. J Dig Dis 2022; 23:13-21. [PMID: 34921720 DOI: 10.1111/1751-2980.13072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 12/11/2022]
Abstract
The theory of cell reprogramming has developed rapidly during the past decades. Cell reprogramming has been widely used in the construction of experimental models and cytotherapy for certain diseases. Hepatocyte-like cells that are important for the treatment of end-stage liver disease can now be obtained with a variety of reprogramming techniques. However, improving the differentiation status and physiological function of these cells remains challenging. Hepatocytes can transdifferentiate into other types of cells directly, whereas other types of cells can also transdifferentiate into hepatocyte-like cells both in vitro and in vivo. Moreover, cell reprogramming is to some extent similar to malignant cell transformation. During the initiation and progression of liver cancer, cell reprogramming is always associated with cancer metastasis and chemoresistance. In this review, we summarized the research related to cell reprogramming in liver and highlighted the potential effects of cell reprogramming in the pathogenesis and treatment of liver diseases.
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Affiliation(s)
- Yi Chuan Wang
- Clinical Cancer Institute, Center for Translational Medicine, Second Military Medical University, Shanghai, China
| | - Zhi Jie Wang
- Clinical Cancer Institute, Center for Translational Medicine, Second Military Medical University, Shanghai, China
| | - Cheng Zhang
- Department of Gastroenterology, Bethune International Peace Hospital, Shijiazhuang, Hebei Province, China
| | - Bei Fang Ning
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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36
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Li X, Lin J, Pan Y, Cui P, Xia J. Identification of a Liver Progenitor Cell-Related Genes Signature Predicting Overall Survival for Hepatocellular Carcinoma. Technol Cancer Res Treat 2021; 20:15330338211041425. [PMID: 34866477 PMCID: PMC8652186 DOI: 10.1177/15330338211041425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Liver progenitor cells (LPCs) play significant roles in the development and progression of hepatocellular carcinoma (HCC). However, no studies on the value of LPC-related genes for evaluating HCC prognosis exist. We developed a gene signature of LPC-related genes for prognostication in HCC. Methods: To identify LPC-related genes, we analyzed mRNA expression arrays from a dataset (GSE57812 & GSE 37071) containing LPCs, mature hepatocytes, and embryonic stem cell samples. HCC RNA-Seq data from The Cancer Genome Atlas (TCGA) were used to explore the differentially expressed genes (DEGs) related to prognosis through DEG analysis and univariate Cox regression analysis. Lasso and multivariate Cox regression analyses were performed to construct the LPC-related gene prognostic model in the TCGA training dataset. This model was validated in the TCGA testing set and an external dataset (International Cancer Genome Consortium [ICGC] dataset). Finally, we investigated the relationship between this prognostic model with tumor-node-metastasis stage, tumor grade, and vascular invasion of HCC. Results: Overall, 1770 genes were identified as LPC-related genes, of which 92 genes were identified as DEGs in HCC tissues compared with normal tissues. Furthermore, we randomly assigned patients from the TCGA dataset to the training and testing cohorts. Twenty-six DEGs correlated with overall survival (OS) in the univariate Cox regression analysis. Lasso and multivariate Cox regression analyses were performed in the TCGA training set, and a 3-gene signature was constructed to stratify patients into 2 risk groups: high-risk and low-risk. Patients in the high-risk group had significantly lower OS than those in the low-risk group. Receiver operating characteristic curve analysis confirmed the signature's predictive capacity. Moreover, the risk score was confirmed to be an independent predictor for patients with HCC. Conclusion: We demonstrated that the LPC-related gene signature can be used for prognostication in HCC. Thus, targeting LPCs may serve as a therapeutic alternative for HCC.
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Affiliation(s)
- Xiaoyong Li
- 26468Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiaqong Lin
- School of Basic Medical Sciences, 70570Southern Medical University, Guangzhou, China
| | - Yuguo Pan
- 26468Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Peng Cui
- 26468Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jintang Xia
- 26468Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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37
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Song F, Yang Z, Li L, Wei Y, Tang X, Liu S, Yu M, Chen J, Wang S, Fu J, Zhang K, Yang P, Yang X, Chen Z, Zhang B, Wang H. MiR-552-3p promotes malignant progression of gallbladder carcinoma by reactivating the Akt/β-catenin signaling pathway due to inhibition of the tumor suppressor gene RGMA. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1374. [PMID: 34733926 PMCID: PMC8506546 DOI: 10.21037/atm-21-2013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/23/2021] [Indexed: 11/06/2022]
Abstract
Background Gallbladder carcinoma (GBC) remains a highly lethal disease worldwide. MiR-552 family members promote the malignant progression of a variety of digestive system tumors, but the role of miR-552-3p in GBC has not been elucidated. miR-552-3p was predicted to target the 3'-untranslated region (3'UTR) of the mRNA for the tumor suppressor gene "repulsive guidance molecule BMP co-receptor a" (RGMA). The aim of the present study was to clarify the roles and mechanisms of miR-552-3p targeting RGMA in the malignant progression of GBC. Methods In vitro: expression of miR-552-3p was detected by real-time quantitative PCR (qRT-PCR) in tumor and non-tumor adjacent tissues (NATs). Lentivirus-miR-552-3p was employed to knockdown this miRNA in GBC cell lines. Stem cell-related transcription factors and markers were assessed by qRT-PCR. Cell Counting Kit-8 (CCK-8), sphere formation and transwell assays were used to determine the malignant phenotypes of GBC cells. Targeting the 3'UTR of RGMA by miR-552-3p was verified by integrated analysis including bioinformatics prediction, luciferase assays, measures of changes of gene expression and rescue experiments. In vivo: mouse models of subcutaneous tumors and lung metastases were established to observe the effect of miR-552-3p on tumorigenesis and organ metastasis, respectively. Results MiR-552-3p was abnormally highly expressed in GBC tissues and cancer stem cells. Interference with miR-552-3p in SGC-996 and GBC-SD cells significantly inhibited GBC stem cell expansion. Reciprocally, miR-552-3p promoted GBC cell proliferation, migration and invasion both in vitro and in vivo; hence, interference with this miRNA impeded the malignant progression of GBC. Furthermore, the important tumor suppressor gene RGMA was identified as a target of miR-552-3p. The effects of miR-552-3p on cell proliferation and metastasis were abrogated or enhanced by gain or loss of RGMA function, respectively. Mechanistically, miR-552-3p promoted GBC progression by reactivating the Akt/β-catenin pathway and epithelial-mesenchymal transformation (EMT). Clinically, miR-552-3p correlated with multi-malignant characteristics of GBC and acted as a prognostic marker for GBC outcome. Conclusions MiR-552-3p promotes the malignant progression of GBC by inhibiting the mRNA of the tumor suppressor gene RGMA, resulting in reactivation of the Akt/β-catenin signaling pathway.
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Affiliation(s)
- Fengliang Song
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, China
| | - Zhao Yang
- Department of Hepatic Surgery II, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Liang Li
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Yanping Wei
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Xuewu Tang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Shuowu Liu
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Miao Yu
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Jin Chen
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Suyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Jingbo Fu
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Kecheng Zhang
- Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Pinghua Yang
- Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xinwei Yang
- Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhong Chen
- Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, China
| | - Baohua Zhang
- Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hongyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China.,National Laboratory for Oncogenes and Related Genes, Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
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Abstract
Cellular heterogeneity and an immunosuppressive tumour microenvironment are independent yet synergistic drivers of tumour progression and underlie therapeutic resistance. Recent studies have highlighted the complex interaction between these cell-intrinsic and cell-extrinsic mechanisms. The reciprocal communication between cancer stem cells (CSCs) and infiltrating immune cell populations in the tumour microenvironment is a paradigm for these interactions. In this Perspective, we discuss the signalling programmes that simultaneously induce CSCs and reprogramme the immune response to facilitate tumour immune evasion, metastasis and recurrence. We further highlight biological factors that can impact the nature of CSC-immune cell communication. Finally, we discuss targeting opportunities for simultaneous regulation of the CSC niche and immunosurveillance.
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Affiliation(s)
- Defne Bayik
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Justin D Lathia
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Case Comprehensive Cancer Center, Cleveland, OH, USA.
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Yang X, Shao C, Duan L, Hou X, Huang Y, Gao L, Zong C, Liu W, Jiang J, Ye F, Shi J, Zhao Q, Wu D, Wei L. Oncostatin M promotes hepatic progenitor cell activation and hepatocarcinogenesis via macrophage-derived tumor necrosis factor-α. Cancer Lett 2021; 517:46-54. [PMID: 34102284 DOI: 10.1016/j.canlet.2021.05.039] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/17/2021] [Accepted: 05/31/2021] [Indexed: 12/30/2022]
Abstract
Hepatocellular carcinoma (HCC) usually occurs at the late stage of chronic liver injury. Oncostatin M (OSM) is a tumor-associated cytokine highly expressed in cirrhosis and HCC patients; however, its role in hepatocarcinogenesis has not been clearly elucidated. In this study, we investigated the effect of OSM on HCC occurrence in a rat model of N-diethylnitrosamine-induced HCC. OSM overexpression significantly increased the number of tumor nodules and shortened the overall survival of the rats. Notably, OSM promoted HPC activation in vivo but did not directly regulate the proliferation of the HPC cell line in vitro. Further, OSM induced tumor necrosis factor-α (TNF-α) secretion and CD68+ macrophage accumulation, which were positively correlated with HPC activation. Additionally, TNF-α or macrophage depletion inhibited the promoting effect of OSM on hepatocarcinogenesis and HPC activation. Furthermore, OSM expression in the peritumoral tissues of HCC was positively correlated with poor overall survival of patients. In conclusion, OSM plays an important role in hepatocarcinogenesis by regulating the liver inflammation environment. Hence, OSM could be used as a potential target for HCC prevention and therapy or as an indicator of HCC prognosis.
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Affiliation(s)
- Xue Yang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Changchun Shao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Lixia Duan
- Department of Breast, Bone &Soft Tissue Oncology, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
| | - Xiaojuan Hou
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Yihua Huang
- Department of Pathology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350108, China
| | - Lu Gao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Chen Zong
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Wenting Liu
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Fei Ye
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Junxia Shi
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Dong Wu
- Department of Hepatic Surgery Ⅳ, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200444, China.
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China.
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40
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miR-93 regulates liver tumor initiating cells expansion and predicts chemotherapeutic response of patients. Arch Biochem Biophys 2021; 703:108871. [PMID: 33831356 DOI: 10.1016/j.abb.2021.108871] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 03/17/2021] [Accepted: 03/30/2021] [Indexed: 01/27/2023]
Abstract
Tumor initiating cells (T-ICs) play an important role in tumorigenesis, progression, metastasis, recurrence and drug resistance, but the underlying mechanism was not clearly elucidated. In our study, we found that miR-93 was highly expressed in liver T-ICs. Self-renewal and tumorigenesis ability of liver T-ICs were enhanced by miR-93 overexpression and attenuated by miR-93 interference. Mechanically, miR-93 regulated liver T-ICs by binding to 3'-UTR of myotubularin-related protein 3 (MTMR3). In addition, miR-93 was found highly expressed in cisplatin or sorafenib-resistant liver cancer tissues. Interference of miR-93 sensitizes hepatoma cells to cisplatin or sorafenib treatment. Clinical cohort analysis showed that Hepatocellular carcinoma (HCC) patients with low miR-93 were benefit more from TACE or sorafenib treatment. In conclusion, our study demonstrates a new regulation mechanism of liver T-ICs, a new target for HCC, and a biomarker for postoperative TACE or sorafenib.
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唐 淬, 胡 承, 周 宇, 宋 杨, 李 孟, 廖 敏, 孙 家, 钟 春, 周 琳, 林 志, 周 元. [Risk analysis for hepatocellular carcinoma in patients with chronic hepatitis B-associated cirrhosis complicated by type 2 diabetes mellitus: a 5-year prospective cohort study]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:313-318. [PMID: 33849820 PMCID: PMC8075784 DOI: 10.12122/j.issn.1673-4254.2021.03.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To elucidate the risk and synergistic factors of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B-associated cirrhosis (CHB-Cir) complicated by type 2 diabetes (T2DM). OBJECTIVE The patients with CHB-Cir who were followed up in Hepatology Center of Nanfang Hospital from June 2010 to June 2019 were divided based on their T2DM status into two cohorts matched for gender, age, HBeAg status and HBV DNA load: CHB-Cir with T2DM group (observation group) and CHB-Cir without T2DM group (control group). All the patients were followed up at a 6-month interval, and the cases with complete clinical data and follow-up data for more than 2 years were included in the analysis. Kaplan- Meier method was used to compare the cumulative incidence of HCC between the two groups. A Cox proportional hazard regression model was used to analyze the relationship between T2DM and the risk of HCC in these patients. OBJECTIVE A total of 467 patients with a mean follow-up time of 4.4±1.62 years were included in the analysis, including 203 in the observation group and 264 in the control group. Sixty-nine and forty-eight new HCC cases occurred in the observation group and control group, respectively, showing a significantly higher incidence rate of HCC in the observation group (P < 0.001). The cumulative incidence of HCC in the observation group was significantly higher than that in the control group (P < 0.001), with a relative risk of 2.096 (P < 0.01). After adjustment for age (≥40 years), family history of liver cancer, previous antiviral therapy, elevated cholesterol and elevated LDL cholesterol, T2DM remained an independent risk factor for HCC in CHB-Cir patients (P=0.000). OBJECTIVE T2DM is an independent risk factor for HCC, and the risk of HCC increases by more than two folds in CHB-Cir patients complicated by T2DM, suggesting the clinical significance of early interventions of diabetes to reduce the risk of HCC in CHB-Cir patients.
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Affiliation(s)
- 淬蓉 唐
- 南方医科大学南方医院消化内科，广东 广州 510515Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- 南方医科大学南方医院感染内科，广东 广州 510515Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 承光 胡
- 南方医科大学南方医院消化内科，广东 广州 510515Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- 南方医科大学南方医院感染内科，广东 广州 510515Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 宇辰 周
- 南方医科大学中西医结合医院肿瘤中心，广东 广州 510310Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510310, China
| | - 杨达 宋
- 南方医科大学南方医院消化内科，广东 广州 510515Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- 南方医科大学南方医院感染内科，广东 广州 510515Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 孟 李
- 南方医科大学南方医院消化内科，广东 广州 510515Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- 南方医科大学南方医院感染内科，广东 广州 510515Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 敏君 廖
- 南方医科大学南方医院消化内科，广东 广州 510515Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- 南方医科大学南方医院感染内科，广东 广州 510515Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 家润 孙
- 南方医科大学南方医院消化内科，广东 广州 510515Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- 南方医科大学南方医院感染内科，广东 广州 510515Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 春秀 钟
- 南方医科大学南方医院感染内科，广东 广州 510515Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 琳 周
- 南方医科大学南方医院内分泌科，广东 广州 510515Department of Endocrinology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 志昭 林
- 南方医科大学南方医院消化内科，广东 广州 510515Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 元平 周
- 南方医科大学南方医院消化内科，广东 广州 510515Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Dong Y, Li F, Wang J, Hu J, Li Z, Gu Y, Feng Y. miR-369 inhibits Liver Cancer progression by targeting ZEB1 pathway and predicts the prognosis of HCC patients. J Cancer 2021; 12:3067-3076. [PMID: 33854606 PMCID: PMC8040887 DOI: 10.7150/jca.54759] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Increasing evidences show that microRNAs (miRNAs) are involved in the regulation of tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). miR-369 works as a tumor suppressor in both lung cancer and thyroid cancer. However, the potential biological function of miR-369 in HCC is unknown. Herein, we for first found that miR-369 expression was downregulated in HCC tissues and predicted the poor prognosis of HCC patients. Forced miR-369 expression inhibited the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanically, bioinformatics and luciferase reporter analysis identified Zinc finger E-box binding homeobox 1 (ZEB1) as a direct target of miR-369 in HCC cells. miR-369 overexpressing downregulated the ZEB1 mRNA and protein expression in HCC cells. miR-369 expression was negatively associated with ZEB1 expression in human HCC tissues. More importantly, the ZEB1 siRNA diminished the discrepancy of growth and metastasis capacity between miR-369 overexpression HCC cells and control cells.
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Affiliation(s)
- Yuwei Dong
- Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University. Shanghai, 200080, China
| | - Fuxia Li
- Department of General Surgery, Cao County People's Hospital, Heze, Shandong province, 274400, China
| | - Junjun Wang
- Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University. Shanghai, 200080, China
| | - Jiangfeng Hu
- Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University. Shanghai, 200080, China
| | - Zhenghong Li
- Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University. Shanghai, 200080, China
| | - Yubei Gu
- Department of Gastroenterology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University. Shanghai, 200025, China
| | - Yun Feng
- Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University. Shanghai, 200080, China
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43
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Yao H, Yang Z, Lou Y, Huang J, Yang P, Jiang W, Chen S. miR-186 Inhibits Liver Cancer Stem Cells Expansion via Targeting PTPN11. Front Oncol 2021; 11:632976. [PMID: 33816273 PMCID: PMC8012905 DOI: 10.3389/fonc.2021.632976] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/29/2021] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) participated in the regulation of tumorigenesis, progression, metastasis, recurrence and chemo-resistance of cancers. However, the potential function of miRNAs in cancer stem cells (CSCs) or tumor-initiating cells (T-ICs) was not clearly elucidated. In the present study, we found that miR-186 expression was reduced in liver CSCs. Functional studies showed that miR-186 knockdown facilitated liver CSCs self-renewal and tumorigenesis. Conversely, forced miR-186 expression suppressed liver CSCs self-renewal and tumorigenesis. Mechanically, miR-186 downregulated PTPN11 via binding to its 3'-UTR in liver CSCs. The correlation of miR-186 and PTPN11 was confirmed in Hepatocellular carcinoma (HCC) patients' tissues. Further study showed that interference of PTPN11 can abolished the discrepancy between miR-186 mimic and control HCC cells in self-renewal and the proportion of CSCs. Additionally, we found that miR-186 overexpression HCC cells were more sensitive to cisplatin treatment. Clinical cohort analysis showed that HCC patients with high miR-186 were benefited more from transcatheter arterial chemoembolization (TACE) treatment. In conclusion, our study demonstrates a new regulation mechanism of liver CSCs, a new target for HCC, and a biomarker for postoperative TACE.
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Affiliation(s)
- Haochen Yao
- Department of Emergency Surgery, The First Hospital of Jilin University, Changchun, China
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medical Science, Jilin University, Changchun, China
| | - Ziting Yang
- Department of Emergency, The 964th Hospital of the Chinese People’s Liberation Army, Changchun, China
| | - Yan Lou
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Juanjuan Huang
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medical Science, Jilin University, Changchun, China
| | - Pinghua Yang
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Weiqi Jiang
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Shuai Chen
- Department of Emergency Surgery, The First Hospital of Jilin University, Changchun, China
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Meng Y, Zhao Q, An L, Jiao S, Li R, Sang Y, Liao J, Nie P, Wen F, Ju J, Zhou Z, Wei L. A TNFR2-hnRNPK Axis Promotes Primary Liver Cancer Development via Activation of YAP Signaling in Hepatic Progenitor Cells. Cancer Res 2021; 81:3036-3050. [PMID: 33619115 DOI: 10.1158/0008-5472.can-20-3175] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 01/13/2021] [Accepted: 02/17/2021] [Indexed: 11/16/2022]
Abstract
Most primary liver cancer (PLC) cases progress mainly due to underlying chronic liver inflammation, yet the underlying mechanisms of inflammation-mediated PLC remain unclear. Here we uncover a TNF receptor II (TNFR2)-hnRNPK-YAP signaling axis in hepatic progenitor cells (HPC) essential for PLC development. TNFR2, but not TNF receptor I (TNFR1), was required for TNFα-induced activation of YAP during malignant transformation of HPCs and liver tumorigenesis. Mechanistically, heterogeneous nuclear ribonuclear protein K (hnRNPK) acted downstream of TNFα-TNFR2 signaling to directly interact with and stabilize YAP on target gene promoters genome-wide, therefore coregulating the expression of YAP target genes. Single-cell RNA sequencing confirmed the association of TNFR2-hnRNPK with YAP expression and the pathologic importance of HPC. Accordingly, expressions of TNFR2, hnRNPK, and YAP were all upregulated in PLC tissues and were strongly associated with poor prognosis of PLC including patient survival. Collectively, this study clarifies the differential roles of TNFRs in HPC-mediated tumorigenesis, uncovering a TNFR2-hnRNPK-centered mechanistic link between the TNFα-mediated inflammatory milieu and YAP activation in HPCs during PLC development. SIGNIFICANCE: This work defines how hnRNPK links TNFα signaling and Hippo pathway transcription coactivator YAP in hepatic progenitor cells during primary liver tumorigenesis.
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Affiliation(s)
- Yan Meng
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Liwei An
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Tongji University Cancer Center, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, Tongji University School of Medicine, Shanghai, China
| | - Shi Jiao
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yan Sang
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jianping Liao
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Pingping Nie
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Fuping Wen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Junyi Ju
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Tongji University Cancer Center, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, Tongji University School of Medicine, Shanghai, China
| | - Zhaocai Zhou
- Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Tongji University Cancer Center, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, Tongji University School of Medicine, Shanghai, China. .,State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
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45
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Jiang Y, Chen P, Hu K, Dai G, Li J, Zheng D, Yuan H, He L, Xie P, Tu M, Peng S, Qu C, Lin W, Chung RT, Hong J. Inflammatory microenvironment of fibrotic liver promotes hepatocellular carcinoma growth, metastasis and sorafenib resistance through STAT3 activation. J Cell Mol Med 2021; 25:1568-1582. [PMID: 33410581 PMCID: PMC7875922 DOI: 10.1111/jcmm.16256] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 10/14/2019] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
The pro-inflammatory and pro-fibrotic liver microenvironment facilitates hepatocarcinogenesis. However, the effects and mechanisms by which the hepatic fibroinflammatory microenvironment modulates intrahepatic hepatocellular carcinoma (HCC) progression and its response to systematic therapy remain largely unexplored. We established a syngeneic orthotopic HCC mouse model with a series of persistent liver injury induced by CCl4 gavage, which mimic the dynamic effect of hepatic pathology microenvironment on intrahepatic HCC growth and metastasis. Non-invasive bioluminescence imaging was applied to follow tumour progression over time. The effect of the liver microenvironment modulated by hepatic injury on sorafenib resistance was investigated in vivo and in vitro. We found that the persistent liver injury facilitated HCC growth and metastasis, which was positively correlated with the degree of liver inflammation rather than the extent of liver fibrosis. The inflammatory cytokines in liver tissue were clearly increased after liver injury. The two indicated cytokines, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), both promoted intrahepatic HCC progression via STAT3 activation. In addition, the hepatic inflammatory microenvironment contributed to sorafenib resistance through the anti-apoptotic protein mediated by STAT3, and STAT3 inhibitor S3I-201 significantly improved sorafenib efficacy impaired by liver inflammation. Clinically, the increased inflammation of liver tissues was accompanied with the up-regulated STAT3 activation in HCC. Above all, we concluded that the hepatic inflammatory microenvironment promotes intrahepatic HCC growth, metastasis and sorafenib resistance through activation of STAT3.
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Affiliation(s)
- Yuchuan Jiang
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Peng Chen
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Kaishun Hu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene RegulationMedical Research CenterSun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Guanqi Dai
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Jinying Li
- Department of GastroenterologyGuangzhou Overseas Chinese HospitalJinan UniversityGuangzhouChina
| | - Dandan Zheng
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Hui Yuan
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Lu He
- Department of RadiotherapyAffiliated Cancer Hospital & Institute of Guangzhou Medical UniversityGuangzhouChina
| | - Penghui Xie
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Mengxian Tu
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Shuang Peng
- Department of PathophysiologySchool of MedicineJinan UniversityGuangzhouChina
| | - Chen Qu
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Wenyu Lin
- Liver Center and Gastrointestinal DivisionMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Raymond T. Chung
- Liver Center and Gastrointestinal DivisionMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Jian Hong
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
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Jiang ZB, Ma BQ, Feng Z, Liu SG, Gao P, Yan HT. miR-365 inhibits the progression of gallbladder carcinoma and predicts the prognosis of Gallbladder carcinoma patients. Cell Cycle 2021; 20:308-319. [PMID: 33459111 DOI: 10.1080/15384101.2021.1874694] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Gallbladder carcinoma (GBC) is one of the most common fatal biliary tract tumors in the world. Its 3-year survival rate is 30% and the recurrence rate remains very high. miR-365 was downregulated in numerous tumors and worked as tumor suppressor gene. However, the role of miR-365 in GBC was unclear. In this study, our results found that the expression of miR-365 in GBC tissues was reduced rather than that in non-cancerous tissues. miR-365 overexpression inhibited the proliferation, metastasis and expansion of GBC CSCs. Mechanically, bioinformatic and luciferase reporter analysis identified Ras-related C3 botulinum toxin substrate 1 (RAC1) as a direct target of miR-365. Overexpression of miR-365 in GBC cells reduced the RAC1 mRNA and protein expression. The special RAC1 inhibitor EHop-106 abolished the discrepancy of growth, metastasis and self-renewal ability between miR-365-overexpression GBC cells and their control cells, which further demonstrated that RAC1 was involved in miR-365-disrupted GBC cells growth, metastasis and self-renewal. More importantly, reduced expression of miR-365 was a predictor of poor prognosis of GBC patients. In conclusion, miR-365 inhibited GBC cell growth, metastasis and self-renewal capacity by directly targeting RAC1, and may therefore prove to be a novel prognosis biomarker for GBC patients.
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Affiliation(s)
- Ze-Bin Jiang
- Department of General Surgery, Gansu Provincial Hospital , Gansu, China
| | - Bing-Qiang Ma
- Department of General Surgery, Gansu Provincial Hospital , Gansu, China
| | - Zongfeng Feng
- Department of General Surgery, Cao County People's Hospital , Heze, Shandong Province, China
| | - Shao-Guang Liu
- Department of Emergency Surgery, Gansu Provincial Hospital , Gansu, China
| | - Peng Gao
- Department of General Surgery, Gansu Provincial Hospital , Gansu, China
| | - Hui-Ting Yan
- Department of Nursing Department, Gansu Provincial Hospital , Gansu, China
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Chen P, Hsu WH, Han J, Xia Y, DePinho RA. Cancer Stemness Meets Immunity: From Mechanism to Therapy. Cell Rep 2021; 34:108597. [PMID: 33406434 PMCID: PMC7839836 DOI: 10.1016/j.celrep.2020.108597] [Citation(s) in RCA: 151] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/24/2020] [Accepted: 12/14/2020] [Indexed: 12/14/2022] Open
Abstract
Cancer stem cells (CSCs) are self-renewing cells that facilitate tumor initiation, promote metastasis, and enhance cancer therapy resistance. Transcriptomic analyses across many cancer types have revealed a prominent association between stemness and immune signatures, potentially implying a biological interaction between such hallmark features of cancer. Emerging experimental evidence has substantiated the influence of CSCs on immune cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and T cells, in the tumor microenvironment and, reciprocally, the importance of such immune cells in sustaining CSC stemness and its survival niche. This review covers the cellular and molecular mechanisms underlying the symbiotic interactions between CSCs and immune cells and how such heterotypic signaling maintains a tumor-promoting ecosystem and informs therapeutic strategies intercepting this co-dependency.
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Affiliation(s)
- Peiwen Chen
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Wen-Hao Hsu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jincheng Han
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yan Xia
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ronald A DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Qu S, Zhang X, Wu Y, Li H, Zhai J, Wu D. miR-361-3p Regulates Liver Tumor-initiating Cells Expansion and Chemo-resistance. J Cancer 2021; 12:1483-1492. [PMID: 33531993 PMCID: PMC7847642 DOI: 10.7150/jca.52395] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 12/15/2020] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence shows that liver tumor-initiating cells (T-ICs) closely associated with the progression, metastasis, recurrence and chemo-resistance of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver T-ICs remains unclear. Here we show that miR-361-3p is upregulated in liver T-ICs. Knockdown of miR-361-3p impairs the self-renewal and tumorigenicity liver T-ICs. Conversely, forced miR-361-3p expression enhances the self-renewal and tumorigenicity liver T-ICs. Mechanistically, miR-361-3p directly targets SOX1 via binding its 3'-UTR in liver T-ICs. Moreover, miR-361-3p knockdown hepatoma cells are more sensitive to cisplatin or sorafenib treatment. Clinical cohort analysis demonstrates that miR-361-3p low HCC patients are benefited from TACE (transcatheter arterial chemoembolization) or sorafenib treatment. In conclusion, our findings revealed the crucial role of the miR-361-3p in liver T-IC expansion and TACE or sorafenib response, rendering miR-361-3p an optimal target for the prevention and intervention in HCC.
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Affiliation(s)
- Shuping Qu
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Xiaobing Zhang
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Yue Wu
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - HengYu Li
- Department of General surgery, First Affiliated Hospital of Second Military Medical University, Shanghai, 200433, China
| | - Jian Zhai
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Dong Wu
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
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49
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He Y, Hwang S, Ahmed YA, Feng D, Li N, Ribeiro M, Lafdil F, Kisseleva T, Szabo G, Gao B. Immunopathobiology and therapeutic targets related to cytokines in liver diseases. Cell Mol Immunol 2021; 18:18-37. [PMID: 33203939 PMCID: PMC7853124 DOI: 10.1038/s41423-020-00580-w] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 10/15/2020] [Indexed: 02/07/2023] Open
Abstract
Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma. The progression of liver disease is controlled by a variety of factors, including liver injury, inflammatory cells, inflammatory mediators, cytokines, and the gut microbiome. In the current review, we discuss recent data on a large number of cytokines that play important roles in regulating liver injury, inflammation, fibrosis, and regeneration, with a focus on interferons and T helper (Th) 1, Th2, Th9, Th17, interleukin (IL)-1 family, IL-6 family, and IL-20 family cytokines. Hepatocytes can also produce certain cytokines (such as IL-7, IL-11, and IL-33), and the functions of these cytokines in the liver are briefly summarized. Several cytokines have great therapeutic potential, and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases, which are also described.
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Affiliation(s)
- Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Yeni Ait Ahmed
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
- Université Paris-Est, UMR-S955, UPEC, F-94000, Créteil, France
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Na Li
- Department of Medicine and Department of Surgery, School of Medicine, University of California, San Diego, CA, 92093, USA
| | - Marcelle Ribeiro
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Fouad Lafdil
- Université Paris-Est, UMR-S955, UPEC, F-94000, Créteil, France
- INSERM, U955, F-94000, Créteil, France
- Institut Universitaire de France (IUF), Paris, F-75231, Cedex 05, France
| | - Tatiana Kisseleva
- Department of Medicine and Department of Surgery, School of Medicine, University of California, San Diego, CA, 92093, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA.
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m6A RNA methylation-mediated HNF3γ reduction renders hepatocellular carcinoma dedifferentiation and sorafenib resistance. Signal Transduct Target Ther 2020; 5:296. [PMID: 33361765 PMCID: PMC7762754 DOI: 10.1038/s41392-020-00299-0] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 07/07/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocyte nuclear factor 3γ (HNF3γ) is a hepatocyte nuclear factor, but its role and clinical significance in hepatocellular carcinoma (HCC) remain unclear. Herein, we report that HNF3γ expression is downregulated in patient HCC and inversely correlated with HCC malignancy and patient survival. Moreover, our data suggested that the HNF3γ reduction in HCC could be mediated by METTL14-dependent m6A methylation of HNF3γ mRNA. HNF3γ expression was increased during hepatic differentiation and decreased in dedifferentiated HCC cells. Interestingly, HNF3γ delivery promoted differentiation of not only HCC cells but also liver CSCs, which led to suppression of HCC growth. Mechanistic analysis suggested an HNF3γ-centered regulatory network that includes essential liver differentiation-associated transcription factors and functional molecules, which could synergistically facilitate HCC cell differentiation. More importantly, enforced HNF3γ expression sensitized HCC cells to sorafenib-induced growth inhibition and cell apoptosis through transactivation of OATP1B1 and OATP1B3 expression, which are major membrane transporters for sorafenib uptake. Clinical investigation showed that patient-derived HCC xenografts with high HNF3γ expression exhibited a sorafenib response and patients with high HCC HNF3γ levels benefited from sorafenib therapy. Together, these results suggest that HNF3γ plays an essential role in HCC differentiation and may serve as a therapeutic target and predictor of sorafenib benefit in patients.
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