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Yang C, Li Y, Wang Z, Shan H, Zhang G, Meng X, Wang G, Hou Z, Zhao X, Zhang X, Liu A, Bing Y, Lei G, Jin Y, Luo J, Guo L, Yin Y. Identification of a cancer stem cell-like subpopulation that promotes HCC metastasis. JHEP Rep 2025; 7:101302. [PMID: 40242316 PMCID: PMC11999271 DOI: 10.1016/j.jhepr.2024.101302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 04/18/2025] Open
Abstract
Background & Aims Cancer stem cells (CSCs) are well-established drivers of tumorigenesis, but their role in regulating tumor metastasis remains poorly understood. Here, we report the identification and characterization of a cluster of metastasis-promoting CSC-like cells in hepatocellular carcinoma (HCC). Methods CSC-like cells in HCC were identified through the analysis of single cell RNA-sequencing data from 19 HCC samples. The stemness and invasive characteristics of these cells were evaluated using bioinformatical analyses of nine clinical cohorts and experimental validations. Spatial transcriptomics sequencing of 12 HCC samples revealed the cellular interactions between the CSC-like cells and tumor microenvironments, which were validated through gene co-expression analyses and immunohistochemistry. Finally, signaling pathway blockade was used to assess the potential clinical application of CSC-like cells. Results Through comprehensive analyses of single cell RNA-sequencing data from 19 patients with HCC and spatial transcriptomics data from 12 patients with HCC, a metastasis-promoting CSC-like subpopulation was identified. These CSC-like cells expressed high levels of epithelial-mesenchymal transition genes and were associated with poor prognosis of HCC. Histologically, CSC-like cells were enriched in highly aggressive tumors, especially in intrahepatic disseminated foci, where they interacted with immune cells. Functionally, CSC-like cells induced macrophage M2 polarization and T cell exhaustion through the ICAM1 signaling pathway, forming immunosuppressive microenvironments. Downregulation of ICAM1 expression in CSC-like cells suppressed macrophage M2-polarization and T cell exhaustion, thereby reversing antitumor immune effects. Conclusions Our study identified a metastasis-promoting CSC subpopulation, providing a potential perspective for CSC-targeted therapies in HCC. Impact and implications The heterogeneity of CSCs in HCC has been identified, yet the identification and characterization of metastasis-promoting CSC subpopulations remain unexplored. Here, we identified a CSC-like tumor cell subpopulation that promotes HCC metastasis by increasing cell invasiveness and suppressing antitumor immune responses via the ICAM1 signaling pathway. Our study uncovers novel mechanisms of HCC metastasis from the perspective of CSCs, and proposes potential tumor therapeutic strategies by inhibiting cellular interactions between CSC-like cells and immune cells.
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Affiliation(s)
- Chunyuan Yang
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
| | - Yang Li
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
- Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Zhaohai Wang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Hui Shan
- Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Guangze Zhang
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
| | - Xiangyan Meng
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
| | - Guangxi Wang
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
| | - Zhiyuan Hou
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
| | - Xuyang Zhao
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
| | - Xin Zhang
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
| | - Anhang Liu
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
| | - Yuntao Bing
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
| | - Guanglin Lei
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, 100039 Beijing, China
| | - Yan Jin
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
| | - Jianyuan Luo
- Department of Medical Genetics, School of Basic Medical Sciences Peking University, Beijing 100191, China
| | - Limei Guo
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
| | - Yuxin Yin
- Institute of Systems Biomedicine, Department of Pathology, Center of Basic Medical Research, Institute of Medical Innovation and Research, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China
- Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen 518036, China
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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [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: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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3
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Wang C, Xia W. Proanthocyanidin Regulates NETosis and Inhibits the Growth and Proliferation of Liver Cancer Cells - In Vivo, In Vitro and In Silico Investigation. Cell Biochem Biophys 2025; 83:1223-1235. [PMID: 39382828 DOI: 10.1007/s12013-024-01557-6] [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] [Accepted: 09/17/2024] [Indexed: 10/10/2024]
Abstract
Liver cancer ranks third in global cancer-related mortality, with about 700,000 deaths recorded yearly, making it one of the most common cancers worldwide. Even though prognoses differ according to the severity of the diseases, many patients now exhibit an increased life cycle since the implementation of chemotherapy. In the current study, we investigated the effect of proanthocyanidin ‒a polyphenol molecule found in many plants‒ on the proliferation and invasion of liver cancer cells. In particular, we determined the effect of proanthocyanidin on the serum levels of four strategic liver cancer target, TNFα, IL-6, cfDNA, and IL-1β. Further molecular insight on the inhibitory mechanism of proanthocyanidin against TNFα, IL-6, and IL-1β was obtained via molecular docking, molecular dynamics simulations and binding free energy calculations. Results showed that proanthocyanidin inhibited the growth of HepG2 and HEP3B cells, and effectively reduced clonogenic survival and invasion potential when compared to control cells. Proanthocyanidin was also found to suppress the expression of Bcl-2 (26 kDa) protein in HepG2 cells, while increasing the expression of Bax (21 kDa). Molecular dynamics (MD) and thermodynamic binding free energy calculations showed that proanthocyanidin maintained stable binding within the active site of target proteins across the entire 100 ns MD simulation period, and its binding affinity outscored respective control molecules.In conclusion, the multifaceted analysis showcased in this study demonstrated promising anti-cancer effect of proanthocyanidin on HepG2 and HEP3B cancer cells, highlighting its potential as a viable liver cancer therapeutic alternative.
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Affiliation(s)
- Chenhui Wang
- Department of Pharmaceutical, Brain Hospital of Hunan Province, The Second People's Hospital of Hunan Province, No. 427, Section 3, Furong Middle Road, Changsha, 410007, China
| | - Wu Xia
- Department of Pharmaceutical, Brain Hospital of Hunan Province, The Second People's Hospital of Hunan Province, No. 427, Section 3, Furong Middle Road, Changsha, 410007, China.
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Ji P, Chen T, Li C, Zhang J, Li X, Zhu H. Comprehensive review of signaling pathways and therapeutic targets in gastrointestinal cancers. Crit Rev Oncol Hematol 2025; 206:104586. [PMID: 39653094 DOI: 10.1016/j.critrevonc.2024.104586] [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: 05/31/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024] Open
Abstract
Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.
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Affiliation(s)
- Pengfei Ji
- Department of Thoracic Surgery, West China Hospital, Sichuan University, No. 37 GuoXue Xiang, Chengdu, Sichuan 610041, China
| | - Tingting Chen
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Chao Li
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Jinyuan Zhang
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Xiao Li
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 GuoXue Xiang, Chengdu, Sichuan 610041, China.
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5
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Ye W, Zhao Y, Wang Y, Wang Y, Zhang H, Wang F, Chen W. Farnesoid X Receptor Attenuates the Tumorigenicity of Liver Cancer Stem Cells by Inhibiting STAT3 Phosphorylation. Int J Mol Sci 2025; 26:1122. [PMID: 39940889 PMCID: PMC11817294 DOI: 10.3390/ijms26031122] [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: 12/12/2024] [Revised: 01/16/2025] [Accepted: 01/20/2025] [Indexed: 02/16/2025] Open
Abstract
The Farnesoid X receptor (FXR) has recently been identified as being closely associated with the progression of primary hepatocellular carcinoma. Cancer stem cells (CSCs) play a crucial role in tumor initiation, progression, invasion, metastasis, recurrence, and drug resistance. The elucidation of the role and regulatory mechanism of FXR in CSCs is therefore deemed significant. Here, bioinformatics analysis has revealed a downregulation of FXR in hepatocellular carcinoma (HCC), which showed a negative correlation with HCC malignancy. This result was further confirmed through clinical sample analysis. Subsequently, CSCs were isolated from HCC cell lines and exhibited a significant decrease in the expression of FXR. The activation of FXR resulted in a remarkable inhibition of the proliferation, invasion, and tumorigenicity of CSCs. Furthermore, activated FXR prominently upregulated the expression of SOCS3 while suppressing STAT3 phosphorylation in CSCs. To further investigate this discovery, we established a DEN-induced HCC model in mice and observed that FXR-deficient mice exhibited heightened susceptibility to HCC. This was accompanied by decreased expression levels of SOCS3 and elevated expression and phosphorylation levels of STAT3, as well as significantly enhanced HCC CSCs markers and stemness-related genes expression in DEN-induced HCC tissues of FXR-deficient mice. Additionally, we also found a significant upregulation of CSCs markers and stemness-related genes within HCC clinical samples. Based on these findings, we postulated that targeted regulation of SOCS3 by FXR inhibits STAT3 phosphorylation, thereby exerting an inhibitory effect on CSCs.
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Affiliation(s)
- Wenling Ye
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010110, China
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Kaifeng 475001, China
| | - Yang Zhao
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Kaifeng 475001, China
| | - Yibo Wang
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Kaifeng 475001, China
| | - Yahan Wang
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Kaifeng 475001, China
| | - Huan Zhang
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Kaifeng 475001, China
| | - Fengling Wang
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010110, China
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Kaifeng 475001, China
| | - Weidong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010110, China
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Kaifeng 475001, China
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Jin X, Dong H, Wang J, Ou G, Lai X, Tian X, Wang L, Zhuang H, Li T, Xiang K. HBx Facilitates Drug Resistance in Hepatocellular Carcinoma via CD133-regulated Self-renewal of Liver Cancer Stem Cells. J Clin Transl Hepatol 2025; 13:15-24. [PMID: 39801781 PMCID: PMC11712087 DOI: 10.14218/jcth.2024.00259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 11/02/2024] [Accepted: 11/04/2024] [Indexed: 01/16/2025] Open
Abstract
Background and Aims Hepatitis B virus (HBV) infection contributes to hepatocellular carcinoma (HCC) tumorigenesis, drug resistance, and recurrence, although the underlying molecular mechanisms remain unclear. Recent studies suggest that HBV infection may be associated with liver cancer stem cells (LCSCs), but the exact mechanisms are yet to be resolved. In this study, we aimed to analyze the role of HBV infection in regulating the stemness of HCCs, which is closely linked to drug resistance. Methods Sphere formation assay and real-time Polymerase Chain Reaction quantification were used to isolate and confirm liver cancer stem cells. The inhibitory concentration values of sorafenib and regorafenib were calculated and compared using the Cell Counting Kit-8 assay. HBV infection was used to assess the effect of HBV replication on LCSC markers. Co-immunoprecipitation assay was performed to detect the interaction between CD133 and SRC. Furthermore, we utilized the CRISPR-Cas9 system to knockout CD133 expression in HepG2.2.15 cells. Results LCSCs derived from HCCs exhibited high expression of stem cell markers and demonstrated reduced sensitivity to sorafenib and regorafenib. HBV replication promoted both drug resistance and stemness in hepatoma cells and clinical samples. Overexpression of HBx protein in HepG2 cells upregulated the expression of CD133, EpCAM, and CD24, enhancing resistance to sorafenib and regorafenib. Knockout of CD133 expression using the CRISPR-Cas9 system significantly inhibited drug resistance to both sorafenib and regorafenib in HepG2.2.15 cells. Mechanistically, HBV replication promoted CD133 expression, which in turn interacted with the SRC/STAT3 signaling pathway. Conclusions Our data suggest that HBV replication enhances the stemness and drug resistance of HCC, providing a strong theoretical foundation for the development of targeted and efficient treatments for HBV-infected HCCs.
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Affiliation(s)
- Xiangshu Jin
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Department of Obstetrics and Gynecology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Huijun Dong
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University–YHLO Joint Laboratory for Molecular Diagnostics of Infectious Diseases, Peking University, Beijing, China
| | - Juan Wang
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Guomin Ou
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University–YHLO Joint Laboratory for Molecular Diagnostics of Infectious Diseases, Peking University, Beijing, China
| | - Xinyuan Lai
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University–YHLO Joint Laboratory for Molecular Diagnostics of Infectious Diseases, Peking University, Beijing, China
| | - Xing Tian
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Department of Physiology, Shenyang Medical College, Shenyang, Liaoning, China
| | - Lei Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Hui Zhuang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University–YHLO Joint Laboratory for Molecular Diagnostics of Infectious Diseases, Peking University, Beijing, China
| | - Tong Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University–YHLO Joint Laboratory for Molecular Diagnostics of Infectious Diseases, Peking University, Beijing, China
| | - Kuanhui Xiang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Peking University–YHLO Joint Laboratory for Molecular Diagnostics of Infectious Diseases, Peking University, Beijing, China
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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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Bae SDW, Nguyen R, Yuen L, Lam V, George J, Qiao L. Constitutive androstane receptor (CAR) functions as a tumor suppressor via regulating stemness in liver cancer. Sci Rep 2024; 14:30926. [PMID: 39730609 DOI: 10.1038/s41598-024-81571-z] [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: 09/09/2024] [Accepted: 11/27/2024] [Indexed: 12/29/2024] Open
Abstract
Constitutive androstane receptor (CAR) is a xenosensor that is almost exclusively expressed in the liver. Studies in rodents suggest an oncogenic role for CAR in liver cancer, but its role in human liver cancer is unclear. We aimed to investigate the functional roles of CAR in human liver cancer with a focus on the liver cancer stem cells. We used bioinformatics to increase our understanding of CAR in human liver cancer and associated stem cell markers. We studied the functional roles of CAR in human liver cancer with a focus on the liver cancer stem cell using siRNA, modulation of CAR activity, and tumorsphere formation assays. We have revealed significant associations between CAR and a wide variety of signalling pathways including stemness signalling. Further in vitro studies have shown that activation of CAR significantly reduces cancer cell stemness and represses proliferation, migration, invasion, and the tumorsphere-forming abilities of liver cancer cells (p < 0.05). Our data demonstrates the unequivocal tumor-suppressive role of CAR in liver cancer. While more detailed mechanistic studies are warranted, the efficacy of CAR xeno-activators in the treatment of advanced hepatocellular carcinoma (HCC) may potentially open a new avenue for liver cancer therapy.
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Affiliation(s)
- Sarah Da Won Bae
- Storr Liver Centre, Westmead Institute for Medical Research, Department of Medicine, the University of Sydney at Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Romario Nguyen
- Storr Liver Centre, Westmead Institute for Medical Research, Department of Medicine, the University of Sydney at Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Lawrence Yuen
- Department of Surgery, Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Department of Medicine, the University of Sydney at Westmead Hospital, Westmead, NSW, 2145, Australia.
- School of Medicine, University of Sydney, Sydney, Australia.
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, Department of Medicine, the University of Sydney at Westmead Hospital, Westmead, NSW, 2145, Australia.
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Kim B. MicroRNA Profiling of PRELI-Modulated Exosomes and Effects on Hepatic Cancer Stem Cells. Int J Mol Sci 2024; 25:13299. [PMID: 39769068 PMCID: PMC11678812 DOI: 10.3390/ijms252413299] [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: 11/04/2024] [Revised: 12/08/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
The increasing incidence and mortality rates of liver cancer have heightened the demand for the development of effective anticancer drugs with minimal side effects. In this study, the roles of exosomes derived from liver cancer stem cells (LCSCs) with PRELI (Protein of Relevant Evolutionary and Lymphoid Interest) modulation and their miRNAs were investigated to explore their therapeutic properties for liver cancer. Various techniques, such as miRNA profiling, microRNA transfection, overexpression, flow cytometry, Western blotting, and immunocytochemistry, were used to evaluate the effects of exosomes under PRELI up- and downregulation. Downregulated PRELI cellular exosomes (DPEs) reduced the levels of five markers-CD133, CD90, CD24, CD13, and EpCAM-in LCSCs, with the exception of OV-6. Conversely, upregulated PRELI cellular exosomes (UPEs) significantly increased the expression of CD90, CD24, and CD133 in NHs, with the maximum increase in CD24. PRELI upregulation altered expression levels of miRNAs, including hsa-miR-378a-3p (involved in stem-like properties), hsa-miR-25-3p (contributing to cell proliferation), and hsa-miR-423-3p (driving invasiveness). Exosomes with downregulated PRELI inhibited the AKT/mTORC1 signaling pathway, whereas LCSCs transfected with the candidate miRNAs activated it. Additionally, under PRELI upregulation, exosomes showed increased surface marker expression, promoting cancer progression. The modulation of PRELI in LCSCs affected miRNA expression significantly, revealing candidate miRNA targets for liver cancer treatment. Exosomes with PRELI downregulation show potential as a novel therapeutic strategy. Consequently, this study proposes the potential of PRELI-induced exosomes and the three miRNAs as a liver anticancer therapeutic candidate.
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Affiliation(s)
- Boyong Kim
- EVERBIO, 131, Jukhyeon-gil, Gwanghyewon-myeon, Jincheon-gun 27809, Republic of Korea
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Guo T, Zhang S, Zeng W, Liang Y, Xie J, Liu S, Qiu Y, Fu Y, Ou Y, Ma K, Wang B, Gu W, Duan Y. Isolation and identification of patient-derived liver cancer stem cells and development of personalized treatment strategies. J Transl Med 2024; 22:1036. [PMID: 39558364 PMCID: PMC11575129 DOI: 10.1186/s12967-024-05870-9] [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: 08/24/2024] [Accepted: 11/10/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND Liver cancer stem cells (LCSCs) are thought to drive the metastasis and recurrence, however, the heterogeneity of molecular markers of LCSCs has hindered the development of effective methods to isolate them. METHODS This study introduced an effective approach to isolate and culture LCSCs from human primary liver cancer (HPLC), leveraging mouse embryonic fibroblasts (MEFs) as feeder cells in conjunction with using defined medium. Isolated LCSCs were further characterized by multiple approaches. Transcriptome sequencing data analysis was conducted to identify highly expressed genes in LCSCs and classify different subtypes of liver cancers. RESULTS Total sixteen cell strains were directly isolated from 24 tissues of three types of HPLC without sorting, seven of which could be maintained long-term culture as colony growth on MEFs, which is unique characteristics of stem cells. Even 10 of cloned cells formed the tumors in immunodeficient mice, indicating that those cloned cells were tumorgenic. The histologies and gene expression pattern of human xenografts were very similar to those of HPLC where these cloned cells were isolated. Moreover, putative markers of LCSCs were further verified to all express in cloned cells, confirming that these cells were LCSCs. These cloned LCSCs could be cryopreserved, and still maintained the feature of colony growth on MEFs after the recovery. Compared to suspension culture as conventional approach to culture LCSCs, our approach much better maintained stemness of LCSCs for a long time. To date, these cloned cells could be cultured on MEFs over 12 passages. Moreover, bioinformatics analysis of sequencing data revealed the gene expression profiles in LCSCs, and liver cancers were classified into two subtypes C1 and C2 based on genes associated with the prognosis of LCSCs. Patients of the C2 subtype, which is closely related to the extracellular matrix, were found to be sensitive to treatments such as Cisplatin, Axitinib, JAK1 inhibitors, WNT-c59, Sorafenib, and RO-3306. CONCLUSION In summary, this effective approach offers new insights into the molecular landscape of human liver cancers, and the identification of the C2 subtype and its unique response to the treatment pave the way for the creation of more effective, personalized therapeutic strategies.
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Affiliation(s)
- Tingting Guo
- Laboratory of Stem Cells and Translational Medicine, Institute for Medical Research, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Shuai Zhang
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, 510180, P.R. China
| | - Weiping Zeng
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Yan Liang
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Jinghe Xie
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, P.R. China
| | - ShouPei Liu
- Laboratory of Stem Cells and Translational Medicine, Institute for Medical Research, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Yaqi Qiu
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Yingjie Fu
- Laboratory of Stem Cells and Translational Medicine, Institute for Medical Research, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China
| | - Yimeng Ou
- Department of General Surgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510699, P.R. China
| | - Keqiang Ma
- Department of Hepatobiliary Pancreatic Surgery, Huadu District People's Hospital of Guangzhou, Guangzhou, 510800, P.R. China
| | - Bailin Wang
- Department of General Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, P.R. China
| | - Weili Gu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, 510180, P.R. China.
- Department of Gastroenterology and Hepatology Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, No.1 Panfu Road, Guangzhou, 510180, P.R. China.
| | - Yuyou Duan
- Laboratory of Stem Cells and Translational Medicine, Institute for Medical Research, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China.
- Laboratory of Stem cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, 510006, P.R. China.
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China.
- The Innovation Centre of Ministry of Education for Development and Diseases, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China.
- Laboratory of Stem Cells and Translational Medicine, Institute for Clinical Medicine, The Second Affiliation Hospital, School of Medicine, South China University of Technology, No.10 Huanyu Erlu, 9th Floor, Guangzhou, 510180, P.R. China.
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11
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Yang X, Zhang Q, Li D, Hu L, Wang Y, Yan X, Li Y, Wang Y, Zhang F, Shen J. A Multifunctional Nanodrug Increases the Therapeutic Sensitivity of Lenvatinib to Hepatocellular Carcinoma by Inhibiting the Stemness of Hepatic Cancer Stem Cells. Adv Healthc Mater 2024; 13:e2401398. [PMID: 39359011 DOI: 10.1002/adhm.202401398] [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: 04/18/2024] [Revised: 08/17/2024] [Indexed: 10/04/2024]
Abstract
Drug resistance resulting from diverse mechanisms including the presence of cancer stem cells (CSCs) is the main obstacle for improving therapeutic efficacy of lenvatinib in hepatocellular carcinoma (HCC). Herein, a nanomedicine (siCD24-Len-MnO@PLAP) is developed by incorporating manganese oxide (MnO), lenvatinib (Len), and siRNA against CD24 (siCD24) into micelles composed of methoxypolyethylene glycol (mPEG), poly-L-lysine (PLLys), and polyasparagyl(N-(2-Aminoethyl)piperidine) (PAsp(PIP)) triblock copolymer. The nanomedicine can respond to the tumor microenvironment (TME) to release lenvatinib, and produce Mn2+ and O2, accompanied by changes in nanoparticle charge, which facilitates cellular endocytosis of siCD24-loaded nanoparticles. The released siCD24 and lenvatinib synergistically reduces CD24 expression, resulting in a more pronounced inhibition of stemness of CSCs. In the mouse models of HCC using Huh7-derived CSCs and Hepa1-6-derived CSCs, the nanomedicine shows remarkable anti-cancer effect by enhancing the therapeutic effects of lenvatinib against HCC via reducing the expression level of CD24 and decreasing the expression of hypoxia inducible factor-1α (HIF-1α). Moreover, in situ production of paramagnetic Mn2+ from the nanomedicine serves as an excellent contrast agent for magnetic resonance imaging (MRI) to monitor the therapeutic process. This study demonstrates that this multifunctional MRI-visible siCD24- and lenvatinib-loaded nanodrug holds great potential in enhancing therapeutic sensitivity for HCC lenvatinib therapy.
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Affiliation(s)
- Xieqing Yang
- Department of Radiology, Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Qiaoyun Zhang
- College of Chemistry and Materials Science, Jinan University, No.855 Xingye Road East, Guangzhou, Guangdong, 510632, China
| | - Dongye Li
- Department of Radiology, Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Lanxin Hu
- Department of Radiology, Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yu Wang
- Department of Radiology, Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Xinyu Yan
- Department of Radiology, Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yunhua Li
- Department of Radiology, Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yong Wang
- College of Chemistry and Materials Science, Jinan University, No.855 Xingye Road East, Guangzhou, Guangdong, 510632, China
| | - Fang Zhang
- Department of Radiology, Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jun Shen
- Department of Radiology, Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
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12
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Wu J, Zhou Z, Huang Y, Deng X, Zheng S, He S, Huang G, Hu B, Shi M, Liao W, Huang N. Radiofrequency ablation: mechanisms and clinical applications. MedComm (Beijing) 2024; 5:e746. [PMID: 39359691 PMCID: PMC11445673 DOI: 10.1002/mco2.746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 08/31/2024] [Accepted: 09/02/2024] [Indexed: 10/04/2024] Open
Abstract
Radiofrequency ablation (RFA), a form of thermal ablation, employs localized heat to induce protein denaturation in tissue cells, resulting in cell death. It has emerged as a viable treatment option for patients who are ineligible for surgery in various diseases, particularly liver cancer and other tumor-related conditions. In addition to directly eliminating tumor cells, RFA also induces alterations in the infiltrating cells within the tumor microenvironment (TME), which can significantly impact treatment outcomes. Moreover, incomplete RFA (iRFA) may lead to tumor recurrence and metastasis. The current challenge is to enhance the efficacy of RFA by elucidating its underlying mechanisms. This review discusses the clinical applications of RFA in treating various diseases and the mechanisms that contribute to the survival and invasion of tumor cells following iRFA, including the roles of heat shock proteins, hypoxia, and autophagy. Additionally, we analyze the changes occurring in infiltrating cells within the TME after iRFA. Finally, we provide a comprehensive summary of clinical trials involving RFA in conjunction with other treatment modalities in the field of cancer therapy, aiming to offer novel insights and references for improving the effectiveness of RFA.
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Affiliation(s)
- Jianhua Wu
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Zhiyuan Zhou
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Yuanwen Huang
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Xinyue Deng
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Siting Zheng
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Shangwen He
- Department of Respiratory and Critical Care MedicineChronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical UniversityGuangzhouGuangdongChina
| | - Genjie Huang
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Binghui Hu
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Min Shi
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Wangjun Liao
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
| | - Na Huang
- Department of Oncology, Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina
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13
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Tinajero-Rodríguez JM, Ramírez-Vidal L, Becerril-Rico J, Alvarado-Ortiz E, Romero-Rodríguez DP, López-Casillas F, Hernández-Sotelo D, Fernández-Ramírez F, Contreras-Paredes A, Ortiz-Sánchez E. ICAM1 (CD54) Contributes to the Metastatic Capacity of Gastric Cancer Stem Cells. Int J Mol Sci 2024; 25:8865. [PMID: 39201551 PMCID: PMC11354656 DOI: 10.3390/ijms25168865] [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: 07/10/2024] [Revised: 08/08/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Gastric cancer is the fourth leading cause of cancer deaths worldwide. The presence of chemoresistant cells has been used to explain this high mortality rate. These higher tumorigenic and chemoresistant cells involve cancer stem cells (CSCs), which have the potential for self-renewal, a cell differentiation capacity, and a greater tumorigenic capacity. Our research group identified gastric cancer stem cells (GCSCs) with the CD24+CD44+CD326+ICAM1+ immunophenotype isolated from gastric cancer patients. Interestingly, this GCSC immunophenotype was absent in cells isolated from healthy people, who presented a cell population with a CD24+CD44+CD326+ immunophenotype, lacking ICAM1. We aimed to explore the role of ICAM1 in these GCSCs; for this purpose, we isolated GCSCs from the AGS cell line and generated a GCSC line knockout for ICAM1 using CRISPR/iCas9, which we named GCSC-ICAM1KO. To assess the role of ICAM1 in the GCSCs, we analyzed the migration, invasion, and chemoresistance capabilities of the GCSCs using in vitro assays and evaluated the migratory, invasive, and tumorigenic properties in a zebrafish model. The in vitro analysis showed that ICAM1 regulated STAT3 activation (pSTAT3-ser727) in the GCSCs, which could contribute to the ability of GCSCs to migrate, invade, and metastasize. Interestingly, we demonstrated that the GCSC-ICAM1KO cells lost their capacity to migrate, invade, and metastasize, but they exhibited an increased resistance to a cisplatin treatment compared to their parental GCSCs; the GCSC-ICAM1KO cells also exhibited an increased tumorigenic capability in vivo.
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Affiliation(s)
- José Manuel Tinajero-Rodríguez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Mexico City 14080, Mexico; (J.M.T.-R.); (A.C.-P.)
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico;
| | - Lizbeth Ramírez-Vidal
- Posgrado de Ciencias Biomédicas, Facultad de Medicina, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Mexico City 04510, Mexico;
| | - Jared Becerril-Rico
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (J.B.-R.); (E.A.-O.)
| | - Eduardo Alvarado-Ortiz
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; (J.B.-R.); (E.A.-O.)
| | - Dámaris P. Romero-Rodríguez
- Laboratorio Nacional Conahcyt de Investigación y Diagnóstico por Inmunocitofluorometría (LANCIDI), INER, Mexico City 14080, Mexico;
| | - Fernando López-Casillas
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Mexico City 04510, Mexico;
| | - Daniel Hernández-Sotelo
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico;
| | | | - Adriana Contreras-Paredes
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Mexico City 14080, Mexico; (J.M.T.-R.); (A.C.-P.)
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Mexico City 14080, Mexico; (J.M.T.-R.); (A.C.-P.)
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14
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Tsui YM, Tian L, Lu J, Ma H, Ng IOL. Interplay among extracellular vesicles, cancer stemness and immune regulation in driving hepatocellular carcinoma progression. Cancer Lett 2024; 597:217084. [PMID: 38925362 DOI: 10.1016/j.canlet.2024.217084] [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: 03/27/2024] [Revised: 06/20/2024] [Accepted: 06/23/2024] [Indexed: 06/28/2024]
Abstract
The intricate interplay among extracellular vesicles, cancer stemness properties, and the immune system significantly impacts hepatocellular carcinoma (HCC) progression, treatment response, and patient prognosis. Extracellular vesicles (EVs), which are membrane-bound structures, play a pivotal role in conveying proteins, lipids, and nucleic acids between cells, thereby serving as essential mediators of intercellular communication. Since a lot of current research focuses on small extracellular vesicles (sEVs), with diameters ranging from 30 nm to 200 nm, this review emphasizes the role of sEVs in the context of interactions between HCC stemness-bearing cells and the immune cells. sEVs offer promising opportunities for the clinical application of innovative diagnostic and prognostic biomarkers in HCC. By specifically targeting sEVs, novel therapeutics aimed at cancer stemness can be developed. Ongoing investigations into the roles of sEVs in cancer stemness and immune regulation in HCC will broaden our understanding and ultimately pave the way for groundbreaking therapeutic interventions.
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Affiliation(s)
- Yu-Man Tsui
- Department of Pathology, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Lu Tian
- Department of Pathology, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Jingyi Lu
- Department of Pathology, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Huanhuan Ma
- Department of Pathology, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.
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15
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Lin J, Zou B, Li H, Wang J, Li S, Cao J, Xie D, Wang F. Collagen XVII promotes dormancy of colorectal cancer cells by activating mTORC2 signaling. Cell Signal 2024; 120:111234. [PMID: 38795810 DOI: 10.1016/j.cellsig.2024.111234] [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: 02/09/2024] [Revised: 05/06/2024] [Accepted: 05/22/2024] [Indexed: 05/28/2024]
Abstract
Tumor dormancy is the underpinning for cancer relapse and chemoresistance, leading to massive cancer-related death in colorectal cancer (CRC). However, our comprehension of the mechanisms dictating tumor dormancy and strategies for eliminating dormant tumor cells remains restricted. In this study, we identified that collagen XVII (COL17A1), a hemidesmosomal transmembrane protein, can promote the dormancy of CRC cells. The upregulation of COL17A1 was observed to prolong quiescence periods and diminish drug susceptibility of CRC cells. Mechanistically, COL17A1 acts as a scaffold, enhancing the crosstalk between mTORC2 and Akt, thereby instigating the mTORC2-mediated dormant signaling. Notably, the activation of mTORC2 is contingent upon the intracellular domain of COL17A1, regardless of its ectodomain shedding. Our findings underscore a pivotal role of the COL17A1-mTORC2 axis in CRC dormancy, suggesting that mTORC2-specific inhibitors may hold therapeutic prospects for the eradication of dormant tumor cells.
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Affiliation(s)
- Jinlong Lin
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Bingxu Zou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Hongbo Li
- Department of Musculoskeletal Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Jing Wang
- Department of Anesthesiology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Shuman Li
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, China
| | - Jinghua Cao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Dan Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
| | - Fengwei Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
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16
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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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Zhao K, Wu C, Li X, Niu M, Wu D, Cui X, Zhao H. From mechanism to therapy: the journey of CD24 in cancer. Front Immunol 2024; 15:1401528. [PMID: 38881902 PMCID: PMC11176514 DOI: 10.3389/fimmu.2024.1401528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 04/25/2024] [Indexed: 06/18/2024] Open
Abstract
CD24 is a glycosylphosphatidylinositol-anchored protein that is expressed in a wide range of tissues and cell types. It is involved in a variety of physiological and pathological processes, including cell adhesion, migration, differentiation, and apoptosis. Additionally, CD24 has been studied extensively in the context of cancer, where it has been found to play a role in tumor growth, invasion, and metastasis. In recent years, there has been growing interest in CD24 as a potential therapeutic target for cancer treatment. This review summarizes the current knowledge of CD24, including its structure, function, and its role in cancer. Finally, we provide insights into potential clinical application of CD24 and discuss possible approaches for the development of targeted cancer therapies.
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Affiliation(s)
- Kai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Caifeng Wu
- Department of Hand and Foot, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiangjun Li
- Department of Breast Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Mengchao Niu
- Department of Operation Room, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Dan Wu
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaofeng Cui
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
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Li T, Liu L, Li L, Yao X, Hu X, Cheng J, Chen Z, Guo J, Li R, Ge C, Lin MCM, Yao H. HGFK1 Enhances the Anti-Tumor Effects of Angiogenesis Inhibitors via Inhibition of CD90+ CSCs in Hepatocellular Carcinoma. Pharmaceuticals (Basel) 2024; 17:645. [PMID: 38794215 PMCID: PMC11125149 DOI: 10.3390/ph17050645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/04/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
The combination of anti-angiogenesis agents with immune-checkpoint inhibitors is a promising treatment for patients with advanced hepatocellular carcinoma (HCC); however, therapeutic resistance caused by cancer stem cells present in tumor microenvironments remains to be overcome. In this study, we report for the first time that the Kringle 1 domain of human hepatocyte growth-factor α chain (HGFK1), a previously described anti-angiogenesis peptide, repressed the sub-population of CD90+ cancer stem cells (CSCs) and promoted their differentiation and chemotherapy sensitivity mainly through downregulation of pre-Met protein expression and inhibition of Wnt/β-catenin and Notch pathways. Furthermore, we showed that the i.p. injection of PH1 (a tumor-targeted and biodegradable co-polymer), medicated plasmids encoding Endostatin (pEndo), HGFK1 genes (pEndo), and a combination of 50% pEndo + 50% pHGFK1 all significantly suppressed tumor growth and prolonged the survival of the HCC-bearing mice. Importantly, the combined treatment produced a potent synergistic effect, with 25% of the mice showing the complete clearance of the tumor via a reduction in the microvessel density (MVD) and the number of CD90+ CSCs in the tumor tissues. These results suggest for the first time that HGFK1 inhibits the CSCs of HCC. Furthermore, the combination of two broad-spectrum anti-angiogenic factors, Endo and HGFK1, is the optimal strategy for the development of effective anti-HCC drugs.
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Affiliation(s)
- Tao Li
- Cancer Biotherapy Center & Cancer Research Institute, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China; (T.L.)
| | - Ling Liu
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, China
| | - Li Li
- Cancer Biotherapy Center & Cancer Research Institute, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China; (T.L.)
| | - Xiaoxuan Yao
- Cancer Biotherapy Center & Cancer Research Institute, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China; (T.L.)
| | - Xiaoyuan Hu
- Cancer Biotherapy Center & Cancer Research Institute, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China; (T.L.)
| | - Jiaxing Cheng
- Cancer Biotherapy Center & Cancer Research Institute, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China; (T.L.)
| | - Zhenpu Chen
- Cancer Biotherapy Center & Cancer Research Institute, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China; (T.L.)
| | - Jiyin Guo
- Cancer Biotherapy Center & Cancer Research Institute, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China; (T.L.)
| | - Ruilei Li
- Cancer Biotherapy Center & Cancer Research Institute, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China; (T.L.)
| | - Chunlei Ge
- Cancer Biotherapy Center & Cancer Research Institute, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China; (T.L.)
| | - Marie Chia-Mi Lin
- Cancer Biotherapy Center & Cancer Research Institute, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China; (T.L.)
| | - Hong Yao
- Cancer Biotherapy Center & Cancer Research Institute, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China; (T.L.)
- Cancer Institute, Xuzhou Medical University, Xuzhou 221002, China
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20
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Tsui YM, Ho DWH, Sze KMF, Lee JMF, Lee E, Zhang Q, Cheung GCH, Tang CN, Tang VWL, Cheung ETY, Lo ILO, Chan ACY, Cheung TT, Ng IOL. Sorted-Cell Sequencing on HCC Specimens Reveals EPS8L3 as a Key Player in CD24/CD13/EpCAM-Triple Positive, Stemness-Related HCC Cells. Cell Mol Gastroenterol Hepatol 2024; 18:101358. [PMID: 38750898 PMCID: PMC11238133 DOI: 10.1016/j.jcmgh.2024.05.006] [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: 10/10/2023] [Revised: 05/07/2024] [Accepted: 05/07/2024] [Indexed: 06/02/2024]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a heterogeneous cancer with varying levels of liver tumor initiating or cancer stem cells in the tumors. We aimed to investigate the expression of different liver cancer stem cell (LCSC) markers in human HCCs and identify their regulatory mechanisms in stemness-related cells. METHODS We used an unbiased, single-marker sorting approach by flow cytometry, fluorescence-activated cell sorting, and transcriptomic analyses on HCC patients' resected specimens. Knockdown approach was used, and relevant functional assays were conducted on the identified targets of interest. RESULTS Flow cytometry on a total of 60 HCC resected specimens showed significant heterogeneity in the expression of LCSC markers, with CD24, CD13, and EpCAM mainly contributing to this heterogeneity. Concomitant expression of CD24, CD13, and EpCAM was detected in 32 HCC samples, and this was associated with advanced tumor stages. Transcriptomic sequencing on the HCC cells sorted for these individual markers identified epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3) as a common gene associated with the 3 markers and was functionally validated in HCC cells. Knocking down EPS8L3 suppressed the expression of all 3 markers. To search for the upstream regulation of EPS8L3, we found SP1 bound to EPS8L3 promoter to drive EPS8L3 expression. Furthermore, using Akt inhibitor MK2206, we showed that Akt signaling-driven SP1 drove the expression of the 3 LCSC markers. CONCLUSIONS Our findings suggest that Akt signaling-driven SP1 promotes EPS8L3 expression, which is critical in maintaining the downstream expression of CD24, CD13, and EpCAM. The findings provide insight into potential LCSC-targeting therapeutic strategies.
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Affiliation(s)
- Yu-Man Tsui
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Daniel Wai-Hung Ho
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Karen Man-Fong Sze
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Joyce Man-Fong Lee
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Eva Lee
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Qingyang Zhang
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Gary Cheuk-Hang Cheung
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | | | | | | | | | - Albert Chi-Yan Chan
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong; Department of Surgery, The University of Hong Kong, Hong Kong
| | - Tan-To Cheung
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong; Department of Surgery, The University of Hong Kong, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.
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21
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Zhao H, Ling Y, He J, Dong J, Mo Q, Wang Y, Zhang Y, Yu H, Tang C. Potential targets and therapeutics for cancer stem cell-based therapy against drug resistance in hepatocellular carcinoma. Drug Resist Updat 2024; 74:101084. [PMID: 38640592 DOI: 10.1016/j.drup.2024.101084] [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: 02/26/2024] [Revised: 03/22/2024] [Accepted: 04/06/2024] [Indexed: 04/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common digestive malignancyin the world, which is frequently diagnosed at late stage with a poor prognosis. For most patients with advanced HCC, the therapeutic options arelimiteddue to cancer occurrence of drug resistance. Hepatic cancer stem cells (CSCs) account for a small subset of tumor cells with the ability of self-renewal and differentiationin HCC. It is widely recognized that the presence of CSCs contributes to primary and acquired drug resistance. Therefore, hepatic CSCs-targeted therapy is considered as a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. In this article, we review drug resistance in HCC and provide a summary of potential targets for CSCs-based therapy. In addition, the development of CSCs-targeted therapeuticsagainst drug resistance in HCC is summarized in both preclinical and clinical trials. The in-depth understanding of CSCs-related drug resistance in HCC will favor optimization of the current therapeutic strategies and gain encouraging therapeutic outcomes.
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Affiliation(s)
- Hongxing Zhao
- Department of Radiology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yuhang Ling
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jie He
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jinling Dong
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Qinliang Mo
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yao Wang
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Ying Zhang
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Hongbin Yu
- Department of General Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Chengwu Tang
- Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China.
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22
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He X, Zhang Y, Fang Q, Sun Y, Zheng X, Fu Y, Fan W, Yang L, Hong Y, Du Y, Wang Z, Chen L. Unraveling the role of CD24 in Hepatocellular carcinoma: Involvement of inactivated Hippo signaling and SOX4-mediated regulation. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167117. [PMID: 38462024 DOI: 10.1016/j.bbadis.2024.167117] [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: 07/12/2023] [Revised: 03/03/2024] [Accepted: 03/05/2024] [Indexed: 03/12/2024]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent type of liver cancer, and CD24 gene is reportedly involved in HCC progression. However, the precise regulatory mechanisms of CD24 in HCC remain unclear. In this study, we established a primary HCC mouse model and observed that CD24, induced by inactivation of the Hippo pathway, was highly expressed in HCC. Using a systematic molecular and genomic approach, we identified the Hippo-YAP1-SOX4 pathway as the mechanism through which YAP1 induces CD24 upregulation in HCC cells. CD24 knockdown significantly attenuated YAP1 activation-induced HCC. These findings shed light on the link between CD24 and HCC progression, particularly in the Hippo-inactivated subclass of HCC. Therefore, CD24 may serve as a potential target for specific treatment of this HCC subclass.
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Affiliation(s)
- Xiaobai He
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China; Zhejiang Provincial Engineering Research Centre for Key Technology of Diagnostic Testing, Hangzhou, China; Zhejiang Provincial Key Laboratory of Biomarkers and In Vitro Diagnostics Translation, Hangzhou, China
| | - Yangyang Zhang
- Department of Clinical Laboratory, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Quan Fang
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Yue Sun
- Blood Transfusion Department, Grand Hospital of Shuozhou, Shuozhou, China
| | - Xiaoguang Zheng
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Yu Fu
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Weijiao Fan
- Institute of Clinical Medicine Research, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Leixiang Yang
- Department of Genetic and Genomic Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Yeting Hong
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Yaoqiang Du
- Allergy Center, Department of Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
| | - Zhen Wang
- Zhejiang Provincial Engineering Research Centre for Key Technology of Diagnostic Testing, Hangzhou, China; Allergy Center, Department of Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
| | - Linjie Chen
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China; Zhejiang Provincial Engineering Research Centre for Key Technology of Diagnostic Testing, Hangzhou, China; Zhejiang Provincial Key Laboratory of Biomarkers and In Vitro Diagnostics Translation, Hangzhou, China.
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23
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Jang Y, Kang S, Han HH, Kim BG, Cho NH. CD24 induced cellular quiescence-like state and chemoresistance in ovarian cancer cells via miR-130a/301a-dependent CDK19 downregulation. Cell Death Discov 2024; 10:81. [PMID: 38360723 PMCID: PMC10869724 DOI: 10.1038/s41420-024-01858-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 02/02/2024] [Accepted: 02/07/2024] [Indexed: 02/17/2024] Open
Abstract
Cancer stem-like cell (CSC) is thought to be responsible for ovarian cancer recurrence. CD24 serves as a CSC marker for ovarian cancer and regulates the expression of miRNAs, which are regulators of CSC phenotypes. Therefore, CD24-regulated miRNAs may play roles in manifesting the CSC phenotypes in ovarian cancer cells. Our miRNA transcriptome analysis showed that 94 miRNAs were up or down-regulated in a CD24-high clone from an ovarian cancer patient compared to a CD24-low one. The CD24-dependent expression trend of the top 7 upregulated miRNAs (miR-199a-3p, 34c, 199a-5p, 130a, 301a, 214, 34b*) was confirmed in other 8 clones (4 clones for each group). CD24 overexpression upregulated the expression of miR-199a-3p, 34c, 199a-5p, 130a, 301a, 214, and 34b* in TOV112D (CD24-low) cells compared to the control, while CD24 knockdown downregulated the expression of miR-199a-3p, 199a-5p, 130a, 301a, and 34b* in OV90 (CD24-high) cells. miR-130a and 301a targeted CDK19, which induced a cellular quiescence-like state (increased G0/G1 phase cell population, decreased cell proliferation, decreased colony formation, and decreased RNA synthesis) and resistance to platinum-based chemotherapeutic agents. CD24 regulated the expression of miR-130a and 301a via STAT4 and YY1 phosphorylation mediated by Src and FAK. miR-130a and 301a were positively correlated in expression with CD24 in ovarian cancer patient tissues and negatively correlated with CDK19. Our results showed that CD24 expression may induce a cellular quiescence-like state and resistance to platinum-based chemotherapeutic agents in ovarian cancer via miR-130a and 301a upregulation. CD24-miR-130a/301a-CDK19 signaling axis could be a prognostic marker for or a potential therapeutic target against ovarian cancer recurrence.
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Affiliation(s)
- Yeonsue Jang
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Suki Kang
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyun Ho Han
- Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Baek Gil Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Nam Hoon Cho
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Severance Biomedical Science Institute (SBSI), Yonsei University College of Medicine, Seoul, Republic of Korea.
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24
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Salah RA, El-Derby AM, El-Gammal Z, Wadie B, Ahmed SM, Elshenawy SE, Magdy S, Salah A, Gabr M, Mohamed I, El-Badri N. Hepatocellular carcinoma patients serum modulates the regenerative capacities of adipose mesenchymal stromal cells. Heliyon 2024; 10:e24794. [PMID: 38333871 PMCID: PMC10850426 DOI: 10.1016/j.heliyon.2024.e24794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 02/10/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers causing the highest mortality rate worldwide. Treatment options of surgery, radiation, cytotoxic drugs and liver transplantation suffer significant side effects and a high frequency of relapse. Stem cell therapy has been proposed as a new effective therapy, however, controversial reports are emerging on the role of mesenchymal stem cells in cancer. In this work, we aimed to assess the regenerative capacities of adipose mesenchymal stem cells when exposed to serum from HCC patients, by assessing the effect of the sera on modulating the regenerative capacities of h-AMSCs and the cancer properties in HCC cells. This will pave the way for maximizing the efficacy of MSCs in cancer therapy. Our data show that HCC serum-treated hA-MSCs suffered oncogene-induced senescence as shown by their altered morphology and ameliorated proliferation and differentiation. The cells were enlarged with small irregular nuclei, swollen rough endoplasmic reticulum cisternae, and aging lysosomes typified by dark residual bodies. HCC serum-treated Huh-7 cancer cells on the other hand displayed higher tumor aggressiveness as depicted by altered morphology, increased cellular proliferation and migration, and decreased percentage of early and late apoptotic cells. Our findings provide evidence that exposure of hA-MSCs to the serum of HCC patients decreases their regenerative capacities and should be considered when employed as a potential therapy in HCC patients.
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Affiliation(s)
- Radwa Ayman Salah
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Azza M. El-Derby
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Zaynab El-Gammal
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Stem Cells and Regenerative Medicine Department, Egypt Center for Research and Regenerative Medicine (ECRRM), Giza, 12578, Egypt
| | - Bishoy Wadie
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Sara M. Ahmed
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Shimaa E. Elshenawy
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Stem Cells and Regenerative Medicine Department, Egypt Center for Research and Regenerative Medicine (ECRRM), Giza, 12578, Egypt
| | - Shireen Magdy
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Ayman Salah
- Department of Hepatogastroenterology, Kasr El-Aini Cairo University, Cairo, Egypt
| | - Mahmoud Gabr
- Urology and Nephrology Center, Mansoura, 35516, Egypt
| | - Ihab Mohamed
- Department of Zoology, Faculty of Science, Ain Shams University, Cairo, 11566, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
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25
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Yang CL, Song R, Hu JW, Huang JT, Li NN, Ni HH, Li YK, Zhang J, Lu Z, Zhou M, Wang JD, Li MJ, Zhan GH, Peng T, Yu HP, Qi LN, Wang QY, Xiang BD. Integrating single-cell and bulk RNA sequencing reveals CK19 + cancer stem cells and their specific SPP1 + tumor-associated macrophage niche in HBV-related hepatocellular carcinoma. Hepatol Int 2024; 18:73-90. [PMID: 38159218 DOI: 10.1007/s12072-023-10615-9] [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: 05/17/2023] [Accepted: 11/05/2023] [Indexed: 01/03/2024]
Abstract
PURPOSE Cytokeratin 19-positive cancer stem cells (CK19 + CSCs) and their tumor-associated macrophages (TAMs) have not been fully explored yet in the hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN Single-cell RNA sequencing was performed on the viable cells obtained from 11 treatment-naïve HBV-associated HCC patients, including 8 CK19 + patients, to elucidate their transcriptomic landscape, CK19 + CSC heterogeneity, and immune microenvironment. Two in-house primary HCC cohorts (96 cases-related HBV and 89 cases with recurrence), TCGA external cohort, and in vitro and in vivo experiments were used to validate the results. RESULTS A total of 64,581 single cells derived from the human HCC and adjacent normal tissues were sequenced, and 11 cell types were identified. The result showed that CK19 + CSCs were phenotypically and transcriptionally heterogeneous, co-expressed multiple hepatics CSC markers, and were positively correlated with worse prognosis. Moreover, the SPP1 + TAMs (TAM_SPP1) with strong M2-like features and worse prognosis were specifically enriched in the CK19 + HCC and promoted tumor invasion and metastasis by activating angiogenesis. Importantly, matrix metalloproteinase 9 (MMP9) derived from TAM_SPP1, as the hub gene of CK19 + HCC, was activated by the VEGFA signal. CONCLUSIONS This study revealed the heterogeneity and stemness characteristics of CK19 + CSCs and specific immunosuppressive TAM_SPP1 in CK19 + HCC. The VEGFA signal can activate TAM_SPP1-derived MMP9 to promote the invasion and metastasis of CK19 + HCC tumors. This might provide novel insights into the clinical treatment of HCC patients.
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Affiliation(s)
- Cheng-Lei Yang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
| | - Rui Song
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
| | - Jun-Wen Hu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
| | - Jun-Tao Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
| | - Nan-Nan Li
- Department of Ultrasound, Guangxi Zhuang Autonomous Region Workers' Hospital, Nanning, 530021, Guangxi Province, China
| | - Hang-Hang Ni
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
| | - Yuan-Kuan Li
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
| | - Jie Zhang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
| | - Zhan Lu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
| | - Min Zhou
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
| | - Jun-Duo Wang
- The First Clinical Medical School, Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Min-Jun Li
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
| | - Guo-Hua Zhan
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
| | - Tao Peng
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Hong-Ping Yu
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China
- Research Department, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Province, China
| | - Lu-Nan Qi
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China.
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China.
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China.
| | - Qiu-Yan Wang
- Department of Biochemistry and Molecular Biology, Guangxi Medical University, Nanning, 530021, Guangxi Province, China.
- Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuang Yong Road, Nanning, 530021, Guangxi Province, China.
| | - Bang-De Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China.
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China.
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China.
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Huang H, Tsui YM, Ho DWH, Chung CYS, Sze KMF, Lee E, Cheung GCH, Zhang VX, Wang X, Lyu X, Ng IOL. LANCL1, a cell surface protein, promotes liver tumor initiation through FAM49B-Rac1 axis to suppress oxidative stress. Hepatology 2024; 79:323-340. [PMID: 37540188 PMCID: PMC10789379 DOI: 10.1097/hep.0000000000000523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/25/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND AND AIMS HCC is an aggressive cancer with a poor clinical outcome. Understanding the mechanisms that drive tumor initiation is important for improving treatment strategy. This study aimed to identify functional cell membrane proteins that promote HCC tumor initiation. APPROACH AND RESULTS Tailor-made siRNA library screening was performed for all membrane protein-encoding genes that are upregulated in human HCC (n = 134), with sphere formation as a surrogate readout for tumor initiation. Upon confirmation of membranous localization by immunofluorescence and tumor initiation ability by limiting dilution assay in vivo, LanC-like protein-1 (LANCL1) was selected for further characterization. LANCL1 suppressed intracellular reactive oxygen species (ROS) and promoted tumorigenicity both in vitro and in vivo. Mechanistically, with mass spectrometry, FAM49B was identified as a downstream binding partner of LANCL1. LANCL1 stabilized FAM49B by blocking the interaction of FAM49B with the specific E3 ubiquitin ligase TRIM21, thus protecting FAM49B from ubiquitin-proteasome degradation. The LANCL1-FAM49B axis suppressed the Rac1-NADPH oxidase-driven ROS production, but this suppression of ROS was independent of the glutathione transferase function of LANCL1. Clinically, HCCs with high co-expression of LANCL1 and FAM49B were associated with more advanced tumor stage, poorer overall survival, and disease-free survival. In addition, anti-LANCL1 antibodies targeting the extracellular N-terminal domain were able to suppress the self-renewal ability, as demonstrated by the sphere formation ability of HCC cells. CONCLUSIONS Our data showed that LANCL1 is a cell surface protein and a key contributor to HCC initiation. Targeting the LANCL1-FAM49B-Rac1-NADPH oxidase-ROS signaling axis may be a promising therapeutic strategy for HCC.
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Affiliation(s)
- Hongyang Huang
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Yu-Man Tsui
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Daniel Wai-Hung Ho
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Clive Yik-Sham Chung
- Department of Pathology, The University of Hong Kong, Hong Kong
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Karen Man-Fong Sze
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Eva Lee
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Gary Cheuk-Hang Cheung
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Vanilla Xin Zhang
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Xia Wang
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Xueying Lyu
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
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Hu Y, Dong Z, Liu K. Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery. J Exp Clin Cancer Res 2024; 43:23. [PMID: 38245798 PMCID: PMC10799433 DOI: 10.1186/s13046-024-02949-5] [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: 11/08/2023] [Accepted: 01/08/2024] [Indexed: 01/22/2024] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcriptional factor involved in almost all cancer hallmark features including tumor proliferation, metastasis, angiogenesis, immunosuppression, tumor inflammation, metabolism reprogramming, drug resistance, cancer stemness. Therefore, STAT3 has become a promising therapeutic target in a wide range of cancers. This review focuses on the up-to-date knowledge of STAT3 signaling in cancer. We summarize both the positive and negative modulators of STAT3 together with the cancer hallmarks involving activities regulated by STAT3 and highlight its extremely sophisticated regulation on immunosuppression in tumor microenvironment and metabolic reprogramming. Direct and indirect inhibitors of STAT3 in preclinical and clinical studies also have been summarized and discussed. Additionally, we highlight and propose new strategies of targeting STAT3 and STAT3-based combinations with established chemotherapy, targeted therapy, immunotherapy and combination therapy. These efforts may provide new perspectives for STAT3-based target therapy in cancer.
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Affiliation(s)
- Yamei Hu
- Tianjian Laboratory for Advanced Biomedical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
- Medical Research Center, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Zigang Dong
- Tianjian Laboratory for Advanced Biomedical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450008, Henan, China.
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China.
| | - Kangdong Liu
- Tianjian Laboratory for Advanced Biomedical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450008, Henan, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China.
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou, Henan, China.
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China.
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Wang H, Shi P, Shi X, Lv Y, Xie H, Zhao H. Surprising magic of CD24 beyond cancer. Front Immunol 2024; 14:1334922. [PMID: 38313430 PMCID: PMC10834733 DOI: 10.3389/fimmu.2023.1334922] [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: 11/08/2023] [Accepted: 12/28/2023] [Indexed: 02/06/2024] Open
Abstract
CD24 has emerged as a molecule of significant interest beyond the oncological arena. Recent studies have unveiled its surprising and diverse roles in various biological processes and diseases. This review encapsulates the expanding spectrum of CD24 functions, delving into its involvement in immune regulation, cancer immune microenvironment, and its potential as a therapeutic target in autoimmune diseases and beyond. The 'magic' of CD24, once solely attributed to cancer, now inspires a new paradigm in understanding its multifunctionality in human health and disease, offering exciting prospects for medical advancements.
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Affiliation(s)
- He Wang
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Peng Shi
- Department of Emergency Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xinyu Shi
- Department of Radiology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yaqing Lv
- Department of Outpatient, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongwei Xie
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
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Frąszczak K, Barczyński B. The Role of Cancer Stem Cell Markers in Ovarian Cancer. Cancers (Basel) 2023; 16:40. [PMID: 38201468 PMCID: PMC10778113 DOI: 10.3390/cancers16010040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/15/2023] [Accepted: 12/17/2023] [Indexed: 01/12/2024] Open
Abstract
Ovarian cancer is the most lethal gynaecological cancer and the eighth most common female cancer. The early diagnosis of ovarian cancer remains a clinical problem despite the significant development of technology. Nearly 70% of patients with ovarian cancer are diagnosed with stages III-IV metastatic disease. Reliable diagnostic and prognostic biomarkers are currently lacking. Ovarian cancer recurrence and resistance to chemotherapy pose vital problems and translate into poor outcomes. Cancer stem cells appear to be responsible for tumour recurrence resulting from chemotherapeutic resistance. These cells are also crucial for tumour initiation due to the ability to self-renew, differentiate, avoid immune destruction, and promote inflammation and angiogenesis. Studies have confirmed an association between CSC occurrence and resistance to chemotherapy, subsequent metastases, and cancer relapses. Therefore, the elimination of CSCs appears important for overcoming drug resistance and improving prognoses. This review focuses on the expression of selected ovarian CSC markers, including CD133, CD44, CD24, CD117, and aldehyde dehydrogenase 1, which show potential prognostic significance. Some markers expressed on the surface of CSCs correlate with clinical features and can be used for the diagnosis and prognosis of ovarian cancer. However, due to the heterogeneity and plasticity of CSCs, the determination of specific CSC phenotypes is difficult.
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Affiliation(s)
| | - Bartłomiej Barczyński
- 1st Chair and Department of Oncological Gynaecology and Gynaecology, Medical University in Lublin, 20-081 Lublin, Poland;
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Yang S, Ruan X, Hu B, Tu J, Cai H. lncRNA SNHG9 enhances liver cancer stem cell self-renewal and tumorigenicity by negatively regulating PTEN expression via recruiting EZH2. Cell Tissue Res 2023; 394:441-453. [PMID: 37851112 DOI: 10.1007/s00441-023-03834-x] [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: 02/07/2023] [Accepted: 09/28/2023] [Indexed: 10/19/2023]
Abstract
Liver cancer stem cell (CSC) self-renewal and tumorigenesis are important causes of hepatocellular carcinoma (HCC) recurrence. We purposed to investigate the function of long noncoding RNA small nucleolar RNA host gene 9 (SNHG9) in liver CSC self-renewal and tumorigenesis in this study. Flow cytometry was carried out to separate CD133+ Populations and CD133- Populations from HCC cell lines. A combination of CD133+ cells and Matrigel matrix was subcutaneously injected to create the NOD-SCID mouse xenograft tumor model. Colony formation test and spheroids formation assay were carried out to clarify the impact of SNHG9 on the self-renewal of liver CSCs. RNA immunoprecipitation, RNA-pull down, and chromatin immunoprecipitation were performed on CD133+ cells to elucidate the mechanism of SNHG9 regulating PTEN expression. We found that SNHG9 was highly expressed in HCC clinical samples, HCC cells, and CD133+ cells. In vitro, interference with SNHG9 prevented the formation of colonies and spheroids in liver CSC cells and primary HCC cells. In vivo, interference with SNHG9 reduced the tumor volume and weight. SNHG9 could bind to EZH2, and SNHG9 interference suppressed EZH2 recruitment and H3K27me3 levels in the PTEN promoter region. In addition, SNHG9 inhibition promoted PTEN expression while having little impact on EZH2 levels. Interference with SNHG9 inhibited liver CSC self-renewal and tumorigenesis by up-regulating PTEN levels. In conclusion, by binding to EZH2, SNHG9 down-regulated PTEN levels, promoting liver CSC self-renewal and tumor formation, and exacerbating HCC progression.
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Affiliation(s)
- Shouzhang Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, China
| | - Xiaojiao Ruan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Bingren Hu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, China
| | - Jinfu Tu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, China
| | - Huajie Cai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, China.
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31
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Wada H, Otsuka R, Germeraad WTV, Murata T, Kondo T, Seino KI. Tumor cell-induced macrophage senescence plays a pivotal role in tumor initiation followed by stable growth in immunocompetent condition. J Immunother Cancer 2023; 11:e006677. [PMID: 37963635 PMCID: PMC10649871 DOI: 10.1136/jitc-2023-006677] [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] [Accepted: 10/06/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND The cancer stem cell theory proposes that tumor formation in vivo is driven only by specific tumor-initiating cells having stemness; however, clinical trials conducted to test drugs that target the tumor stemness provided unsatisfactory results thus far. Recent studies showed clear involvement of immunity in tumors; however, the requirements of tumor-initiation followed by stable growth in immunocompetent individuals remain largely unknown. METHODS To clarify this, we used two similarly induced glioblastoma lines, 8B and 9G. They were both established by overexpression of an oncogenic H-RasL61 in p53-deficient neural stem cells. In immunocompromised animals in an orthotopic transplantation model using 1000 cells, both show tumor-forming potential. On the other hand, although in immunocompetent animals, 8B shows similar tumor-forming potential but that of 9G's are very poor. This suggests that 8B cells are tumor-initiating cells in immunocompetent animals. Therefore, we hypothesized that the differences in the interaction properties of 8B and 9G with immune cells could be used to identify the factors responsible for its tumor forming potential in immunocompetent animals and performed analysis. RESULTS Different from 9G, 8B cells induced senescence-like state of macrophages around tumors. We investigated the senescence-inducing factor of macrophages by 8B cells and found that it was interleukin 6. Such senescence-like macrophages produced Arginase-1, an immunosuppressive molecule known to contribute to T-cell hyporesponsiveness. The senescence-like macrophages highly expressed CD38, a nicotinamide adenine dinucleotide (NAD) glycohydrolase associated with NAD shortage in senescent cells. The addition of nicotinamide mononucleotide (NMN), an NAD precursor, in vitro inhibited to the induction of macrophage senescence-like phenotype and inhibited Arginase-1 expression resulting in retaining T-cell function. Moreover, exogenous in vivo administration of NMN after tumor inoculation inhibited tumor-initiation followed by stable growth in the immunocompetent mouse tumor model. CONCLUSIONS We identified one of the requirements for tumor-initiating cells in immunocompetent animals. In addition, we have shown that tumor growth can be inhibited by externally administered NMN against macrophage senescence-like state that occurs in the very early stages of tumor-initiating cell development. This therapy targeting the immunosuppressive environment formed by macrophage senescence-like state is expected to be a novel promising cancer therapeutic strategy.
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Affiliation(s)
- Haruka Wada
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Ryo Otsuka
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Wilfred T V Germeraad
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, Limburg, The Netherlands
- Department of Internal Medicine, Division of Hematology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Tomoki Murata
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Toru Kondo
- Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Ken-Ichiro Seino
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
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32
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Wei Y, Fu J, Zhang H, Ling Y, Tang X, Liu S, Yu M, Liu F, Zhuang G, Qian H, Zhang K, Yang P, Yang X, Yang Q, Ge S, Zhang B, Tan Y, Li L, Wang H. N6-methyladenosine modification promotes hepatocarcinogenesis through circ-CDYL-enriched and EpCAM-positive liver tumor-initiating exosomes. iScience 2023; 26:108022. [PMID: 37954137 PMCID: PMC10638478 DOI: 10.1016/j.isci.2023.108022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 07/13/2023] [Accepted: 09/19/2023] [Indexed: 11/14/2023] Open
Abstract
CircRNAs play multiple roles in a variety of cellular processes. We found that Circ-CDYL is highly enriched in early HCC plasma exosomes. Moreover, EpCAM+ HCC cells and exosomes had significant Circ-CDYL levels. We postulated that Circ-CDYL-enriched and EpCAM-positive exosomes would function as liver tumor-initiating exosomes (LTi-Exos). As predicted, intercellular transfer of LTi-Exos activates the HDGF-PI3K-AKT-mTOR and HIF1AN-NOTCH2 axes in recipient cells, promoting malignancy. Upstream, we found that the N6-methyladenosine (m6A) modification of Circ-CDYL exerted its action in HCC cells through a dual mechanism. First, it stimulated back-splicing processes via YTHDC1 to promote Circ-CDYL biogenesis. Second, it facilitates the active sorting of Circ-CDYL into exosomes via hnRNPA2/B1. Clinically, the combination of LTi-Exos and plasma alpha-fetoprotein (AFP) provides a promising early diagnostic biomarker for HCC with an AUC of 0.896. This study highlights the effect and mechanism by which m6A modification promotes hepatocarcinogenesis via modulation of the tumor microenvironment by LTi-Exos.
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Affiliation(s)
- Yanping Wei
- International Cooperation 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 Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Hailing Zhang
- Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yan Ling
- Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xuewu Tang
- National Center for Liver Cancer, Shanghai, China
- Hepato-pancreato-biliary Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Shuowu Liu
- International Cooperation 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 Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Fuyan Liu
- International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Guokun Zhuang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Haihua Qian
- International Cooperation 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
| | - Pinhua 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
| | - Qi Yang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Shennian Ge
- International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Baohua Zhang
- Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yexiong Tan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Liang Li
- International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Hongyang Wang
- International Cooperation 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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Aguilar-Chaparro MA, Rivera-Pineda SA, Hernández-Galdámez HV, Piña-Vázquez C, Villa-Treviño S. The CD44std and CD44v9 subpopulations in non-tumorigenic invasive SNU-423 cells present different features of cancer stem cells. Stem Cell Res 2023; 72:103222. [PMID: 37844417 DOI: 10.1016/j.scr.2023.103222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/11/2023] [Accepted: 10/10/2023] [Indexed: 10/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of liver cancer, in which CD44 isoforms have been proposed as markers to identify cancer stem cells (CSCs). However, it is unclear what characteristics are associated with CSCs that exclusively express CD44 isoforms. The objective of the present study was to determine the expression of CD44 isoforms and their properties in CSCs. Analysis of transcriptomic data from HCC patient samples identified CD44v8-10 as a potential marker in HCC. In SNU-423 cells, CD44 expression was detected in over 99% of cells, and two CD44 isoforms, namely, CD44std and CD44v9, were identified in this cell line. CD44 subpopulations, including both CD44v9+ (CD44v9) and CD44v9- (CD44std) cells, were obtained by purification using a magnetic cell separation kit for human CD44v9+ cancer stem cells. CD44v9 cells showed greater potential for colony and spheroid formation, whereas CD44std cells demonstrated significant migration and invasion capabilities. These findings suggested that CD44std and CD44v9 may be used to identify features in CSC populations and provide insights into their roles in HCC.
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Affiliation(s)
- Mario Alejandro Aguilar-Chaparro
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV), Av. IPN No. 2508 Col. San Pedro Zacatenco, México City CP 07360, Mexico
| | - Sonia Andrea Rivera-Pineda
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV), Av. IPN No. 2508 Col. San Pedro Zacatenco, México City CP 07360, Mexico
| | - Hury Viridiana Hernández-Galdámez
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV), Av. IPN No. 2508 Col. San Pedro Zacatenco, México City CP 07360, Mexico
| | - Carolina Piña-Vázquez
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV), Av. IPN No. 2508 Col. San Pedro Zacatenco, México City CP 07360, Mexico
| | - Saúl Villa-Treviño
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV), Av. IPN No. 2508 Col. San Pedro Zacatenco, México City CP 07360, Mexico.
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Wang Q, Liang N, Liu C, Li J, Bai Y, Lei S, Huang Q, Sun L, Tang L, Zeng C, Tang Y, He X, Yang T, Wang G. BEX1 supports the stemness of hepatoblastoma by facilitating Warburg effect in a PPARγ/PDK1 dependent manner. Br J Cancer 2023; 129:1477-1489. [PMID: 37715024 PMCID: PMC10628275 DOI: 10.1038/s41416-023-02418-4] [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: 02/10/2023] [Revised: 08/15/2023] [Accepted: 08/29/2023] [Indexed: 09/17/2023] Open
Abstract
BACKGROUND Hepatoblastoma (HB) is a highly aggressive paediatric malignancy that exhibits a high presence of cancer stem cells (CSCs), which related to tumour recurrence and chemotherapy resistance. Brain expressed X-linked protein 1 (BEX1) plays a pivotal role in ciliogenesis, axon regeneration and differentiation of neural stem cells. However, the role of BEX1 in metabolic and stemness programs in HB remains unclear. METHODS BEX1 expression in human and mouse HB was analyzed using gene expression profile data from NCBI GEO and immunohistochemical validation. Seahorse extracellular flux analyzer, ultra-high-performance liquid-chromatography mass spectrometry (LC-MS), flow cytometry, qRT-PCR, Western Blot, sphere formation assay, and diluted xenograft tumour formation assay were used to analyze metabolic and stemness features. RESULTS Our results indicated that overexpression of BEX1 significantly enhanced the Warburg effect in HB cells. Furthermore, glycolysis inhibition largely attenuated the effects of BEX1 on HB cell growth and self-renewal, suggesting that BEX1 promotes stemness maintenance of HB cells by regulating the Warburg effect. Mechanistically, BEX1 enhances Warburg effect through the downregulation of peroxisome proliferator-activated receptor-gamma (PPARγ). Furthermore, pyruvate dehydrogenase kinase isozyme 1 (PDK1) is required for PPARγ-induced inhibition of Warburg effect in HB. In addition, BEX1 supports the stemness of HB by enhancing Warburg effect in a PPARγ/PDK1 dependent manner. CONCLUSIONS HB patients with high BEX1 and PDK1 expression had a poor prognosis. BEX1 promotes the stemness maintenance of HB cells via modulating the Warburg effect, which depends on PPARγ/PDK1 axis. Pioglitazone could be used to target BEX1-mediated stemness properties in HB by upregulating PPARγ.
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Affiliation(s)
- Qian Wang
- Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, China.
- Department of General Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
| | - Ning Liang
- Department of General Surgery, The 75th Group Army Hospital, Dali, 671000, China
| | - Chaoxu Liu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, 310006, China
| | - Jing Li
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, China
- Department of Stomatology, Shaanxi Province People's Hospital, Xi'an, 710068, China
| | - Yaxing Bai
- Department of Dermatology, XiJing Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Shuanghong Lei
- Anorectal Department, The First People's Hospital of Longnan, Longnan, 742500, China
| | - Qian Huang
- Department of Obstetrics and Gynecology, The 75th Group Army Hospital, Dali, Yunnan, 671000, China
| | - Ligang Sun
- Department of General Surgery, The 75th Group Army Hospital, Dali, 671000, China
| | - Liangke Tang
- Department of General Surgery, Hospital of Integrated Chinese and Western Medicine, Southern Medical University, Guangzhou, 510315, China
| | - Chao Zeng
- Department of Neurology, The 74th Group Army Hospital, Guangzhou, 510318, China
| | - Yuqun Tang
- Minimally Invasive tumour Comprehensive Therapy Center, Second People's Hospital of Guangdong Province, Guangzhou, 510310, China
| | - Xianli He
- Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, China.
| | - Tao Yang
- Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710038, China.
| | - Gang Wang
- Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, China.
- Department of General Surgery, Affiliated Jiangmen Hospital, Southern Medical University, Jiangmen, 529000, China.
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Wang F, Gao Y, Xue S, Zhao L, Jiang H, Zhang T, Li Y, Zhao C, Wu F, Siqin T, Liu Y, Wu J, Yan Y, Yuan J, Jiang JD, Li K. SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity. Nat Commun 2023; 14:5917. [PMID: 37739936 PMCID: PMC10517016 DOI: 10.1038/s41467-023-41593-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 09/11/2023] [Indexed: 09/24/2023] Open
Abstract
CSCs (Cancer stem cells) with distinct metabolic features are considered to cause HCC (hepatocellular carcinoma) initiation, metastasis and therapeutic resistance. Here, we perform a metabolic gene CRISPR/Cas9 knockout library screen in tumorspheres derived from HCC cells and find that deletion of SCARB2 suppresses the cancer stem cell-like properties of HCC cells. Knockout of Scarb2 in hepatocytes attenuates HCC initiation and progression in both MYC-driven and DEN (diethylnitrosamine)-induced HCC mouse models. Mechanistically, binding of SCARB2 with MYC promotes MYC acetylation by interfering with HDCA3-mediated MYC deacetylation on lysine 148 and subsequently enhances MYC transcriptional activity. Screening of a database of FDA (Food and Drug Administration)-approved drugs shows Polymyxin B displays high binding affinity for SCARB2 protein, disrupts the SCARB2-MYC interaction, decreases MYC activity, and reduces the tumor burden. Our study identifies SCARB2 as a functional driver of HCC and suggests Polymyxin B-based treatment as a targeted therapeutic option for HCC.
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Affiliation(s)
- Feng Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Yang Gao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Situ Xue
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Luyao Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Huimin Jiang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Tingting Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Yunxuan Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Chenxi Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Fan Wu
- Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 100021, Beijing, China
| | - Tana Siqin
- Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 100021, Beijing, China
| | - Ying Liu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Jie Wu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Yechao Yan
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Jian Yuan
- Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, 200120, China.
| | - Jian-Dong Jiang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China.
| | - Ke Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China.
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Park H, Lee S, Lee J, Moon H, Ro SW. Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications. Int J Mol Sci 2023; 24:13764. [PMID: 37762066 PMCID: PMC10531214 DOI: 10.3390/ijms241813764] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/04/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular Carcinoma (HCC) continues to pose a substantial global health challenge due to its high incidence and limited therapeutic options. In recent years, the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has emerged as a critical signaling cascade in HCC pathogenesis. The review commences with an overview of the JAK/STAT pathway, delving into the dynamic interplay between the JAK/STAT pathway and its numerous upstream activators, such as cytokines and growth factors enriched in pathogenic livers afflicted with chronic inflammation and cirrhosis. This paper also elucidates how the persistent activation of JAK/STAT signaling leads to diverse oncogenic processes during hepatocarcinogenesis, including uncontrolled cell proliferation, evasion of apoptosis, and immune escape. In the context of therapeutic implications, this review summarizes recent advancements in targeting the JAK/STAT pathway for HCC treatment. Preclinical and clinical studies investigating inhibitors and modulators of JAK/STAT signaling are discussed, highlighting their potential in suppressing the deadly disease. The insights presented herein underscore the necessity for continued research into targeting the JAK/STAT signaling pathway as a promising avenue for HCC therapy.
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Affiliation(s)
| | | | | | | | - Simon Weonsang Ro
- Department of Genetics and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si 17104, Republic of Korea; (H.P.); (S.L.); (J.L.); (H.M.)
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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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38
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Li Q, Tan G, Wu F. The functions and roles of C2H2 zinc finger proteins in hepatocellular carcinoma. Front Physiol 2023; 14:1129889. [PMID: 37457025 PMCID: PMC10339807 DOI: 10.3389/fphys.2023.1129889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 06/20/2023] [Indexed: 07/18/2023] Open
Abstract
C2H2 zinc finger (C2H2-ZF) proteins are the majority group of human transcription factors and they have many different molecular functions through different combinations of zinc finger domains. Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the main reason for cancer-related deaths worldwide. More and more findings support the abnormal expression of C2H2-ZF protein in the onset and progression of HCC. The C2H2-ZF proteins are involved in various biological functions in HCC, such as EMT, stemness maintenance, metabolic reprogramming, cell proliferation and growth, apoptosis, and genomic integrity. The study of anti-tumor drug resistance also highlights the pivotal roles of C2H2-ZF proteins at the intersection of biological functions (EMT, stemness maintenance, autophagy)and chemoresistance in HCC. The involvement of C2H2-ZF protein found recently in regulating different molecules, signal pathways and pathophysiological activities indicate these proteins as the possible therapeutic targets, and diagnostic or prognostic biomarkers for HCC.
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Wang Y, Yu H, Yu M, Liu H, Zhang B, Wang Y, Zhao S, Xia Q. CD24 blockade as a novel strategy for cancer treatment. Int Immunopharmacol 2023; 121:110557. [PMID: 37379708 DOI: 10.1016/j.intimp.2023.110557] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 05/22/2023] [Accepted: 06/21/2023] [Indexed: 06/30/2023]
Abstract
The CD24 protein is a heat-stable protein with a small core that undergoes extensive glycosylation. It is expressed on the surface of various normal cells, including lymphocytes, epithelial cells, and inflammatory cells. CD24 exerts its function by binding to different ligands. Numerous studies have demonstrated the close association of CD24 with tumor occurrence and progression. CD24 not only facilitates tumor cell proliferation, metastasis, and immune evasion but also plays a role in tumor initiation, thus, serving as a marker on the surface of cancer stem cells (CSCs). Additionally, CD24 induces drug resistance in various tumor cells following chemotherapy. To counteract the tumor-promoting effects of CD24, several treatment strategies targeting CD24 have been explored, such as the use of CD24 monoclonal antibodies (mAb) alone, the combination of CD24 and chemotoxic drugs, or the combination of these drugs with other targeted immunotherapeutic techniques. Regardless of the approach, targeting CD24 has demonstrated significant anti-tumor effects. Therefore, the present study focuses on anti-tumor therapy and provides a comprehensive review of the structure and fundamental physiological function of CD24 and its impact on tumor development, and suggests that targeting CD24 may represent an effective strategy for treating malignant tumors.
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Affiliation(s)
- Yawen Wang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China; Henan Engineering Research Center of Pathological Diagnostic Antibody, Zhengzhou 450008, China
| | - Haoran Yu
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China; Henan Engineering Research Center of Pathological Diagnostic Antibody, Zhengzhou 450008, China
| | - Mengyuan Yu
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China; Henan Engineering Research Center of Pathological Diagnostic Antibody, Zhengzhou 450008, China
| | - Hui Liu
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China
| | - Bing Zhang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China
| | - Yuanyuan Wang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China
| | - Simin Zhao
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China.
| | - Qingxin Xia
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China; Henan Medical Key Laboratory of Tumor Pathology and Artificial Intelligence Diagnosis, Zhengzhou 450008, China; Zhengzhou Key Laboratory of Accurate Pathological Diagnosis of Intractable Tumors, Zhengzhou 450008, China; Henan Engineering Research Center of Pathological Diagnostic Antibody, Zhengzhou 450008, China.
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Wang Y, Tong M. Protein Posttranslational Modification in Stemness Remodeling and Its Emerging Role as a Novel Therapeutic Target in Gastrointestinal Cancers. Int J Mol Sci 2023; 24:ijms24119173. [PMID: 37298124 DOI: 10.3390/ijms24119173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 05/16/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
The posttranslational modifications (PTMs) of proteins, as critical mechanisms for protein regulation, are well known to enhance the functional diversity of the proteome and dramatically participate in complicated biological processes. Recent efforts in the field of cancer biology have illustrated the extensive landscape of PTMs and their crosstalk with a wide range of pro-tumorigenic signaling pathways that decisively contribute to neoplastic transformation, tumor recurrence, and resistance to oncotherapy. Cancer stemness is an emerging concept that maintains the ability of tumor cells to self-renew and differentiate and has been recognized as the root of cancer development and therapy resistance. In recent years, the PTM profile for modulating the stemness of various tumor types has been identified. This breakthrough has shed light on the underlying mechanisms by which protein PTMs maintain cancer stemness, initiate tumor relapse, and confer resistance to oncotherapies. This review focuses on the latest knowledge of protein PTMs in reprogramming the stemness of gastrointestinal (GI) cancer. A deeper understanding of abnormal PTMs in specific proteins or signaling pathways provides an opportunity to specifically target cancer stem cells and highlights the clinical relevance of PTMs as potential biomarkers and therapeutic targets for patients with GI malignancies.
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Affiliation(s)
- Yifei Wang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Man Tong
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Warrier NM, Kelkar N, Johnson CT, Govindarajan T, Prabhu V, Kumar P. Understanding cancer stem cells and plasticity: Towards better therapeutics. Eur J Cell Biol 2023; 102:151321. [PMID: 37137199 DOI: 10.1016/j.ejcb.2023.151321] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/27/2023] [Accepted: 04/28/2023] [Indexed: 05/05/2023] Open
Abstract
The ability of cancer cells to finally overcome various lines of treatment in due course has always baffled the scientific community. Even with the most promising therapies, relapse is ultimately seen, and this resilience has proved to be a major hurdle in the management of cancer. Accumulating evidence now attributes this resilience to plasticity. Plasticity is the ability of cells to change their properties and is substantial as it helps in normal tissue regeneration or post-injury repair processes. It also helps in the overall maintenance of homeostasis. Unfortunately, this critical ability of cells, when activated incorrectly, can lead to numerous diseases, including cancer. Therefore, in this review, we focus on the plasticity aspect with an emphasis on cancer stem cells (CSCs). We discuss the various forms of plasticity that provide survival advantages to CSCs. Moreover, we explore various factors that affect plasticity. Furthermore, we provide the therapeutic implications of plasticity. Finally, we provide an insight into the future targeted therapies involving plasticity for better clinical outcomes.
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Affiliation(s)
- Neerada Meenakshi Warrier
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Nachiket Kelkar
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Carol Tresa Johnson
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | | | - Vijendra Prabhu
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
| | - Praveen Kumar
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
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Kim M, Jo KW, Kim H, Han ME, Oh SO. Genetic heterogeneity of liver cancer stem cells. Anat Cell Biol 2023; 56:94-108. [PMID: 36384888 PMCID: PMC9989795 DOI: 10.5115/acb.22.161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 11/19/2022] Open
Abstract
Cancer cell heterogeneity is a serious problem in the control of tumor progression because it can cause chemoresistance and metastasis. Heterogeneity can be generated by various mechanisms, including genetic evolution of cancer cells, cancer stem cells (CSCs), and niche heterogeneity. Because the genetic heterogeneity of CSCs has been poorly characterized, the genetic mutation status of CSCs was examined using Exome-Seq and RNA-Seq data of liver cancer. Here we show that different surface markers for liver cancer stem cells (LCSCs) showed a unique propensity for genetic mutations. Cluster of differentiation 133 (CD133)-positive cells showed frequent mutations in the IRF2, BAP1, and ERBB3 genes. However, leucine-rich repeat-containing G protein-coupled receptor 5-positive cells showed frequent mutations in the CTNNB1, RELN, and ROBO1 genes. In addition, some genetic mutations were frequently observed irrespective of the surface markers for LCSCs. BAP1 mutations was frequently observed in CD133-, CD24-, CD13-, CD90-, epithelial cell adhesion molecule-, or keratin 19-positive LCSCs. ASXL2, ERBB3, IRF2, TLX3, CPS1, and NFATC2 mutations were observed in more than three types of LCSCs, suggesting that common mechanisms for the development of these LCSCs. The present study provides genetic heterogeneity depending on the surface markers for LCSCs. The genetic heterogeneity of LCSCs should be considered in the development of LCSC-targeting therapeutics.
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Affiliation(s)
- Minjeong Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Kwang-Woo Jo
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Hyojin Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Myoung-Eun Han
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Sae-Ock Oh
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
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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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Wang J, Yu H, Dong W, Zhang C, Hu M, Ma W, Jiang X, Li H, Yang P, Xiang D. N6-Methyladenosine-Mediated Up-Regulation of FZD10 Regulates Liver Cancer Stem Cells' Properties and Lenvatinib Resistance Through WNT/β-Catenin and Hippo Signaling Pathways. Gastroenterology 2023; 164:990-1005. [PMID: 36764493 DOI: 10.1053/j.gastro.2023.01.041] [Citation(s) in RCA: 148] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 12/21/2022] [Accepted: 01/30/2023] [Indexed: 02/12/2023]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, but there is a deficiency of early diagnosis biomarkers and therapeutic targets. Drug resistance accounts for most HCC-related deaths, yet the mechanisms underlying drug resistance remain poorly understood. METHODS Expression of Frizzled-10 (FZD10) in liver cancer stem cells (CSCs) was identified by means of RNA sequencing and validated by means of real-time polymerase chain reaction and immunohistochemistry. In vitro and in vivo experiments were used to assess the effect of FZD10 on liver CSC expansion and lenvatinib resistance. RNA sequencing, RNA binding protein immunoprecipitation, and luciferase report assays were applied to explore the mechanism underlying FZD10-mediated liver CSCs expansion and lenvatinib resistance. RESULTS Activation of FZD10 in liver CSCs was mediated by METTL3-dependent N6-methyladenosine methylation of FZD10 messenger RNA. Functional studies revealed that FZD10 promotes self-renewal, tumorigenicity, and metastasis of liver CSCs via activating β-catenin and YAP1. The FZD10-β-catenin/YAP1 axis is activated in liver CSCs and predicts poor prognosis. Moreover, FZD10-β-catenin/c-Jun axis transcriptionally activates METTL3 expression, forming a positive feedback loop. Importantly, the FZD10/β-catenin/c-Jun/MEK/ERK axis determines the responses of hepatoma cells to lenvatinib treatment. Analysis of patient cohort, patient-derived tumor organoids, and patient-derived xenografts further suggest that FZD10 might predict lenvatinib clinical benefit in patients with HCC. Furthermore, treatment of lenvatinib-resistant HCC with adeno-associated virus targeting FZD10 or a β-catenin inhibitor restored lenvatinib response. CONCLUSIONS Elevated FZD10 expression promotes expansion of liver CSCs and lenvatinib resistance, indicating that FZD10 expression is a novel prognostic biomarker and therapeutic target for human HCC.
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Affiliation(s)
- Jinghan Wang
- Department of Hepatobiliary Surgery, East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hongming Yu
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, Shanghai, China
| | - Wei Dong
- Department of Pathology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, China
| | - Cheng Zhang
- Department of Gastroenterology, Bethune International Peace Hospital, Shijiazhuang, Hebei, China
| | - Mingtai Hu
- Department of Hepatobiliary Surgery, East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wencong Ma
- Department of Hepatobiliary Surgery, East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaoqing Jiang
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, Shanghai, China.
| | - Hengyu Li
- Department of Breast and Thyroid Surgery, Changhai Hospital, Naval Military Medical University, Shanghai, China.
| | - Pinghua Yang
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, Shanghai, China.
| | - Daimin Xiang
- Department of Hepatobiliary Surgery, East Hospital, School of Medicine, Tongji University, Shanghai, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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45
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Huang H, Tsui YM, Ng IOL. Fueling HCC Dynamics: Interplay Between Tumor Microenvironment and Tumor Initiating Cells. Cell Mol Gastroenterol Hepatol 2023; 15:1105-1116. [PMID: 36736664 PMCID: PMC10036749 DOI: 10.1016/j.jcmgh.2023.01.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 02/05/2023]
Abstract
Liver cancer (hepatocellular carcinoma) is a common cancer worldwide. It is an aggressive cancer, with high rates of tumor relapse and metastasis, high chemoresistance, and poor prognosis. Liver tumor-initiating cells (LTICs) are a distinctive subset of liver cancer cells with self-renewal and differentiation capacities that contribute to intratumoral heterogeneity, tumor recurrence, metastasis, and chemo-drug resistance. LTICs, marked by different TIC markers, have high plasticity and use diverse signaling pathways to promote tumorigenesis and tumor progression. LTICs are nurtured in the tumor microenvironment (TME), where noncellular and cellular components participate to build an immunosuppressive and tumor-promoting niche. As a result, the TME has emerged as a promising anticancer therapeutic target, as exemplified by some successful applications of tumor immunotherapy. In this review, we discuss the plasticity of LTICs in terms of cellular differentiation, epithelial-mesenchymal transition, and cellular metabolism. We also discuss the various components of the TME, including its noncellular and cellular components. Thereafter, we discuss the mutual interactions between TME and LTICs, including recently reported molecular mechanisms. Lastly, we summarize and describe new ideas concerning novel approaches and strategies for liver cancer therapy.
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Affiliation(s)
- Hongyang Huang
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Yu-Man Tsui
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.
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46
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Zhou XH, Li JR, Zheng TH, Chen H, Cai C, Ye SL, Gao B, Xue TC. Portal vein tumor thrombosis in hepatocellular carcinoma: molecular mechanism and therapy. Clin Exp Metastasis 2023; 40:5-32. [PMID: 36318440 DOI: 10.1007/s10585-022-10188-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/04/2022] [Indexed: 11/05/2022]
Abstract
Portal vein tumor thrombosis (PVTT), a common complication of advanced hepatocellular carcinoma (HCC), remains the bottleneck of the treatments. Liver cancer cells potentially experienced multi-steps during PVTT process, including cancer cells leave from cancer nest, migrate in extracellular matrix, invade the vascular barrier, and colonize in the portal vein. Accumulated evidences have revealed numerous of molecular mechanisms including genetic and epigenetic regulation, cancer stem cells, immunosuppressive microenvironment, hypoxia, et al. contributed to the PVTT formation. In this review, we discuss state-of-the-art PVTT research on the potential molecular mechanisms and experimental models. In addition, we summarize PVTT-associated clinical trials and current treatments for PVTT and suppose perspectives exploring the molecular mechanisms and improving PVTT-related treatment for the future.
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Affiliation(s)
- Xing-Hao Zhou
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Jing-Ru Li
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Tang-Hui Zheng
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Department of Hepatic Oncology, Xiamen Branch, Fudan University, Zhongshan Hospital, Xiamen, 361015, China
| | - Hong Chen
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Department of Hepatic Oncology, Xiamen Branch, Fudan University, Zhongshan Hospital, Xiamen, 361015, China
| | - Chen Cai
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Sheng-Long Ye
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Bo Gao
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai Medical College, Shanghai, 200032, China.
| | - Tong-Chun Xue
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China. .,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China. .,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China.
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47
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Whole-Transcriptome Sequencing Combined with High-Dimensional Proteomic Technologies Reveals the Potential Value of miR-135b-5p as a Biomarker for Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2023; 2023:6517963. [PMID: 36755690 PMCID: PMC9902149 DOI: 10.1155/2023/6517963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/26/2022] [Accepted: 11/29/2022] [Indexed: 01/31/2023]
Abstract
Purpose Hepatocellular carcinoma (HCC) is a disease with great heterogeneity and a high mortality rate. It is crucial to identify reliable biomarkers for diagnosis, prognosis, and treatment to improve clinical outcomes in patients with HCC. Alpha-fetoprotein (AFP) is not only a widely used biomarker in clinical practice but also plays a complicated role in HCC, and it has recently been considered to be related to immunotherapy. MicroRNAs (miRNAs) are regarded as key regulators and promising biomarkers of HCC. We investigated the role of an AFP-related miRNA, miR-135b-5p, in HCC progression. Methods Identification of miR-135b-5p was performed based on a cohort of 65 HCC cases and the liver hepatocellular carcinoma cohort of The Cancer Genome Atlas (Asian people only). A combination of whole-transcriptome sequencing and high-dimensional proteomic technologies was used to study the role of miR-135b-5p in HCC. Results Upregulation of miR-135b-5p was detected in patients with HCC with high serum AFP levels (AFP > 400 ng/ml). Elevated miR-135b-5p expression was associated with adverse prognosis. We also identified the relevance between high miR-135b-5p expression and tumor-related pathological characteristics, such as Edmondson grade and vascular invasion. We revealed tyrosine kinase nonreceptor 1 as a potential target of miR-135b-5p. Additionally, the transcriptional start site of miR-135b-5p had potential binding sites for SRY-box transcription factor 9, and the stemness properties of tumor cells were more remarkable in HCC with the upregulation of miR-135b-5p. The molecular characterization of the miR-135b-5p-high group was similar to that of the HCC subclasses containing moderately and poorly differentiated tumors. Finally, gene signatures associated with improved clinical outcomes in immune checkpoint inhibitor therapy were upregulated in the miR-135b-5p-high group. Conclusion miR-135b-5p could be a biomarker for predicting the prognosis and antiprogrammed cell death protein 1 monotherapy response in HCC.
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48
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Martin J, Islam F. Detection and Isolation of Cancer Stem Cells. CANCER STEM CELLS: BASIC CONCEPT AND THERAPEUTIC IMPLICATIONS 2023:45-69. [DOI: 10.1007/978-981-99-3185-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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49
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Swetha KL, Maravajjala KS, Li SD, Singh MS, Roy A. Breaking the niche: multidimensional nanotherapeutics for tumor microenvironment modulation. Drug Deliv Transl Res 2023; 13:105-134. [PMID: 35697894 DOI: 10.1007/s13346-022-01194-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2022] [Indexed: 12/13/2022]
Abstract
Most of the current antitumor therapeutics were developed targeting the cancer cells only. Unfortunately, in the majority of tumors, this single-dimensional therapy is found to be ineffective. Advanced research has shown that cancer is a multicellular disorder. The tumor microenvironment (TME), which is made by a complex network of the bulk tumor cells and other supporting cells, plays a crucial role in tumor progression. Understanding the importance of the TME in tumor growth, different treatment modalities have been developed targeting these supporting cells. Recent clinical results suggest that simultaneously targeting multiple components of the tumor ecosystem with drug combinations can be highly effective. This type of "multidimensional" therapy has a high potential for cancer treatment. However, tumor-specific delivery of such multi-drug combinations remains a challenge. Nanomedicine could be utilized for the tumor-targeted delivery of such multidimensional therapeutics. In this review, we first give a brief overview of the major components of TME. We then highlight the latest developments in nanoparticle-based combination therapies, where one drug targets cancer cells and other drug targets tumor-supporting components in the TME for a synergistic effect. We include the latest preclinical and clinical studies and discuss innovative nanoparticle-mediated targeting strategies.
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Affiliation(s)
- K Laxmi Swetha
- Department of Pharmacy, Birla Institute of Technology & Science, Vidya Vihar, Pilani, Rajasthan, 333031, India
| | - Kavya Sree Maravajjala
- Department of Pharmacy, Birla Institute of Technology & Science, Vidya Vihar, Pilani, Rajasthan, 333031, India
| | - Shyh-Dar Li
- Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Westbrook Mall, Vancouver, BC, Canada
| | - Manu Smriti Singh
- Department of Biotechnology, Bennett University, Greater Noida, Uttar Pradesh, 201310, India. .,Center of Excellence for Nanosensors and Nanomedicine, Bennett University, Greater Noida, Uttar Pradesh, 201310, India.
| | - Aniruddha Roy
- Department of Pharmacy, Birla Institute of Technology & Science, Vidya Vihar, Pilani, Rajasthan, 333031, India.
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50
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Xu L, Chen Z, Wang Y, Li Y, Wang Z, Li F, Xi X. Polyphyllin VII as a Potential Drug for Targeting Stemness in Hepatocellular Cancer via STAT3 Signaling. Curr Cancer Drug Targets 2023; 23:325-331. [PMID: 36284387 DOI: 10.2174/1568009623666221024103834] [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: 05/12/2022] [Revised: 09/07/2022] [Accepted: 09/13/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND At present, the treatment of hepatocellular carcinoma (HCC) is disturbed by the treatment failure and recurrence caused by the residual liver cancer stem cells (CSCs). Therefore, drugs targeting HCC CSCs should be able to effectively eliminate HCC and prevent its recurrence. In this study, we demonstrated the effect of Polyphyllin VII (PP7) on HCC CSCs and explored their potential mechanism. METHODS HepG2 and Huh7 cells were used to analyze the antitumor activity of PP7 by quantifying cell growth and metastasis as well as to study the effect on stemness. RESULTS Our results demonstrated that PP7 promoted apoptosis and significantly inhibited proliferation and migration of both HepG2 and Huh7 cells. PP7 also inhibited tumor spheroid formation and induced significant changes in the expression of stemness markers (CD133 and OCT-4). These effects of PP7 were mediated by STAT3 signaling. CONCLUSION PP7 can effectively suppress tumor initiation, growth, and metastasis and inhibit stemness through regulation of STAT3 signaling pathway in liver cancer cells. Our data would add more evidence to further clarify the therapeutic effect of PP7 against HCC.
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Affiliation(s)
- Liuhang Xu
- Department of Immunology, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, No. 30 Renmin Nanlu, Shiyan City, Hubei Province 442000, P.R. China
| | - Ziqi Chen
- Department of Immunology, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, No. 30 Renmin Nanlu, Shiyan City, Hubei Province 442000, P.R. China
| | - Yangbin Wang
- Department of Immunology, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, No. 30 Renmin Nanlu, Shiyan City, Hubei Province 442000, P.R. China
| | - Yulin Li
- Department of Immunology, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, No. 30 Renmin Nanlu, Shiyan City, Hubei Province 442000, P.R. China
| | - Zhongyu Wang
- Department of Immunology, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, No. 30 Renmin Nanlu, Shiyan City, Hubei Province 442000, P.R. China
| | - Fangzhou Li
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Shiyan, No. 30 Renmin Nanlu, Shiyan City, Hubei Province 442000, P.R. China
| | - Xueyan Xi
- Department of Immunology, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, No. 30 Renmin Nanlu, Shiyan City, Hubei Province 442000, P.R. China.,Renmin Hospital, Hubei University of Medicine, Shiyan, No. 30 Renmin Nanlu, Shiyan City, Hubei Province 442000, P.R. China.,Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, No. 30 Renmin Nanlu, Shiyan City, Hubei Province 442000, P.R. China
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