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Dai Q, Zhu J, Yang J, Zhang CY, Yang WJ, Pan BS, Yang XR, Guo W, Wang BL. Construction of a Cancer Stem Cell related Histone Acetylation Regulatory Genes Prognostic Model for Hepatocellular Carcinoma via Bioinformatics Analysis: Implications for Tumor Chemotherapy and Immunity. Curr Stem Cell Res Ther 2025; 20:103-122. [PMID: 38561604 DOI: 10.2174/011574888x305642240327041753] [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: 01/20/2024] [Revised: 03/10/2024] [Accepted: 03/13/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND Cancer stem cells (CSC) play an important role in the development of Liver Hepatocellular Carcinoma (LIHC). However, the regulatory mechanisms between acetylation- associated genes (HAGs) and liver cancer stem cells remain unclear. OBJECTIVE To identify a set of histone acetylation genes (HAGs) with close associations to liver cancer stem cells (LCSCs), and to construct a prognostic model that facilitates more accurate prognosis assessments for LIHC patients. METHODS LIHC expression data were downloaded from the public databases. Using mRNA expression- based stemness indices (mRNAsi) inferred by One-Class Logistic Regression (OCLR), Differentially Expressed Genes (DEGs) (mRNAsi-High VS. mRNAsi-Low groups) were intersected with DEGs (LIHC VS. normal samples), as well as histone acetylation-associated genes (HAGs), to obtain mRNAsi-HAGs. A risk model was constructed employing the prognostic genes, which were acquired through univariate Cox and Least Shrinkage and Selection Operator (LASSO) regression analyses. Subsequently, independent prognostic factors were identified via univariate and multivariate Cox regression analyses and then a nomogram for prediction of LIHC survival was developed. Additionally, immune infiltration and drug sensitivity analysis were performed to explore the relationships between prognostic genes and immune cells. Finally, the expressions of selected mRNAsi-HAGs were validated in the LIHC tumor sphere by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) assay and western blot analysis. RESULTS Among 13 identified mRNAsi-HAGs, 3 prognostic genes (HDAC1, HDAC11, and HAT1) were selected to construct a risk model (mRNAsi-HAGs risk score = 0.02 * HDAC1 + 0.09 * HAT1 + 0.05 * HDAC11). T-stage, mRNAsi, and mRNAsi-HAGs risk scores were identified as independent prognostic factors to construct the nomogram, which was proved to predict the survival probability of LIHC patients effectively. We subsequently observed strongly positive correlations between mRNAsi-HAGs risk score and tumor-infiltrating T cells, B cells and macrophages/monocytes. Moreover, we found 8 drugs (Mitomycin C, IPA 3, FTI 277, Bleomycin, Tipifarnib, GSK 650394, AICAR and EHT 1864) had significant correlations with mRNAsi-HAGs risk scores. The expression of HDAC1 and HDAC11 was higher in CSC-like cells in the tumor sphere. CONCLUSION This study constructed a mRNAsi and HAGs-related prognostic model, which has implications for potential immunotherapy and drug treatment of LIHC.
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Grants
- 81772263, 81972000, 81872355, 82072715, 82172348 National Natural Science Foundation of China
- 82202608, 81902139 National Natural Science Foundation of China Youth Fund
- 2018ZSLC05, 2020ZSLC54, 2020ZSLC31 Specialized Fund for the clinical research of Zhongshan Hospital affiliated Fudan University
- 2021ZSCX28 Science Foundation of Zhongshan Hospital, Fudan University
- 2021ZSGG08 Excellent backbone of Zhongshan Hospital, Fudan University
- shslczdzk03302 construction project of clinical key disciplines in Shanghai
- YDZX20193502000002 Key medical and health projects of Xiamen
- BSZK-2023-A18 Shanghai Baoshan Medical Key Specialty
- 2019YFC1315800, 2019YFC1315802 National Key R&D Program of China
- 81830102 State Key Program of National Natural Science of China
- 2019CXJQ02 Shanghai Municipal Health Commission Collaborative Innovation Cluster Project
- 19441905000, 21140900300 Shanghai Science and Technology Commission
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Affiliation(s)
- Qian Dai
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Zhu
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Yang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chun-Yan Zhang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Shanghai Geriatric Medical Center, Shanghai, China
| | - Wen-Jing Yang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bai-Shen Pan
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
- Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin-Rong Yang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
- Cancer Center, Shanghai Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Guo
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
- Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bei-Li Wang
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Shanghai Geriatric Medical Center, Shanghai, China
- Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
- Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, Shanghai, China
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Li H, An S, Li J, Cui X, Wang M, Yuan F, Zhang J, Guo W, Hu Y. Coptisine acts as a nucleolus fluorescent probe in vitro. Biochem Biophys Res Commun 2025; 744:151194. [PMID: 39706054 DOI: 10.1016/j.bbrc.2024.151194] [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: 08/30/2024] [Revised: 11/27/2024] [Accepted: 12/14/2024] [Indexed: 12/23/2024]
Abstract
Coptisine (COP) is a natural protoberberine isoquinoline alkaloid that is isolated from Coptis chinensis and exhibits a variety of pharmacological activities, such as the inhibition of tumor growth, bacterial infection, inflammation and oxidative stress. In this study, COP penetrated and produced fluorescent signals in living tumor cell lines, primary MEF cells and polyformaldehyde-fixed cells. The fluorescent signal was detected at a wavelength of 488 nm. The fluorescent signal of COP was observed predominantly in the nucleoli and colocalized with nucleolus fibrillarin and B23. The fluorescence intensity of COP was associated with tumor malignancy. Compared with cells with high fluorescent signals, cells with low fluorescent signals were highly malignant. Taken together, these data suggest that COP can function as a nucleolus probe and a probe candidate for distinguishing tumor cell malignancy.
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Affiliation(s)
- Hui Li
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Shuangshuang An
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Jing Li
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Xiukun Cui
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Mingli Wang
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Fengling Yuan
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Jing Zhang
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Weikai Guo
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Yanzhong Hu
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China; Kaifeng Key Lab for Cataract and Myopia, Institute of Eye Disease, Kaifeng Central Hospital, Kaifeng, China.
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3
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Sherif O, Khelwatty SA, Bagwan I, Seddon AM, Dalgleish A, Mudan S, Modjtahedi H. Expression of EGFRvIII and its co‑expression with wild‑type EGFR, or putative cancer stem cell biomarkers CD44 or EpCAM are associated with poorer prognosis in patients with hepatocellular carcinoma. Oncol Rep 2024; 52:172. [PMID: 39450530 PMCID: PMC11526438 DOI: 10.3892/or.2024.8831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 08/30/2024] [Indexed: 10/26/2024] Open
Abstract
The aberrant expression of HER family members and cancer stem cells (CSCs) have been associated with tumour progression and resistance to therapy. At present, several HER inhibitors have been approved for the treatment of patients with a range of cancers but not for the treatment of patients with hepatocellular carcinoma (HCC). The present study investigated the co‑expression and prognostic significance of HER family members, type‑III deletion mutant EGFR (EGFRvIII), and the putative CSC biomarkers CD44 and epithelial cell adhesion molecule (EpCAM) in 43 patients with HCC. The relative expression of these biomarkers was determined using immunohistochemistry. At a cut off value of >5% of tumour cells stained for these biomarkers, 35% [wild‑type (wt)EGFR], 58% (HER‑2), 0% (HER‑3), 19% (HER‑4), 26% (EGFRvIII), 40% (CD44) and 33% (EpCAM) of patients were positive. In 23, 14 and 9% of the patients, wtEGFR expression was accompanied by co‑expression with HER‑2, EGFRvIII and HER‑2/EGFRvIII, respectively. EGFRvIII expression, membranous expression of CD44 and co‑expression of wtEGFR/EGFRvIII were associated with poor overall survival (OS). By contrast, cytoplasmic CD44 expression was associated with a longer OS time. The present study also investigated the effect of several agents targeting one or more members of the HER family, other growth factor receptors and cell signalling proteins on the proliferation of HCC cell lines. Among agents targeting one or more members of the HER family, the pan‑HER family blocker afatinib was the most effective, inhibiting the proliferation of three out of seven human liver cancer cell lines (LCCLs), while the CDK inhibitor dinacicilib was the most effective agent, inhibiting the proliferation of all human LCCLs tested. Taken together, the present results suggested that EGFRvIII expression and its co‑expression with wtEGFR or CD44 was of prognostic significance. These results also support further investigations of the therapeutic potential of drugs targeting EGFRvIII and other members of the HER family in patients with HCC.
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MESH Headings
- Humans
- Epithelial Cell Adhesion Molecule/metabolism
- Epithelial Cell Adhesion Molecule/genetics
- Hyaluronan Receptors/metabolism
- Hyaluronan Receptors/genetics
- ErbB Receptors/metabolism
- ErbB Receptors/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/drug therapy
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms/genetics
- Liver Neoplasms/mortality
- Female
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Prognosis
- Middle Aged
- Biomarkers, Tumor/metabolism
- Biomarkers, Tumor/genetics
- Male
- Aged
- Adult
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Aged, 80 and over
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Affiliation(s)
- Ozlem Sherif
- Department of Biomolecular Sciences, School of Life Science, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston upon Thames KT1 2EE, UK
| | - Said A. Khelwatty
- Department of Biomolecular Sciences, School of Life Science, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston upon Thames KT1 2EE, UK
| | - Izhar Bagwan
- Department of Biomolecular Sciences, School of Life Science, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston upon Thames KT1 2EE, UK
- Berkshire Surrey Pathology Services, Royal Surrey Hospital, Guildford GU2 7XX, UK
| | - Alan M. Seddon
- Department of Biomolecular Sciences, School of Life Science, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston upon Thames KT1 2EE, UK
| | - Angus Dalgleish
- Infection and Immunity Research Institute, St George's, University of London, London SW17 0RE, UK
| | | | - Helmout Modjtahedi
- Department of Biomolecular Sciences, School of Life Science, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston upon Thames KT1 2EE, UK
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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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5
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Kim S, Yeop Baek S, Cha C. Bioactive Microgels with Tunable Microenvironment as a 3D Platform to Guide the Complex Physiology of Hepatocellular Carcinoma Spheroids. Chembiochem 2024:e202400482. [PMID: 39226234 DOI: 10.1002/cbic.202400482] [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: 06/07/2024] [Revised: 08/08/2024] [Accepted: 09/03/2024] [Indexed: 09/05/2024]
Abstract
Miniaturized three-dimensional tissue models, such as spheroids, have become a highly useful and efficient platform to investigate tumor physiology and explore the effect of chemotherapeutic efficacy over traditional two-dimensional monolayer culture, since they can provide more in-depth analysis, especially in regards to intercellular interactions and diffusion. The development of most tumor spheroids relies on the high proliferative capacity and self-aggregation behavior of tumor cells. However, it often disregards the effect of microenvironmental factors mediated by extracellular matrix, which are indispensable components of tissue structure. In this study, hepatocellular carcinoma (HCC) cells are encapsulated in bioactive microgels consisting of gelatin and hyaluronic acid designed to emulate tumor microenvironment in order to induce hepatic tumor spheroid formation. Two different subtypes of HCC's, HepG2 and Hep3B cell lines, are explored. The physicomechanical and biochemical properties of the microgels, controlled by changing the crosslinking density and polymer composition, are clearly shown to have substantial influence over the formation and spheroid formation. Moreover, the spheroids made from different cells and microgel properties display highly variable chemoresistance effects, further highlighting the importance of microenvironmental factors guiding tumor spheroid physiology.
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Affiliation(s)
- Suntae Kim
- Department of Materials Science and Engineering, Ulsan National Institute of Science and Technology (UNIST), 50 UNIST-gil, Ulju-gun, Ulsan, 44919, Republic of Korea
| | - Seung Yeop Baek
- Department of Materials Science and Engineering, Ulsan National Institute of Science and Technology (UNIST), 50 UNIST-gil, Ulju-gun, Ulsan, 44919, Republic of Korea
| | - Chaenyung Cha
- Department of Materials Science and Engineering, Ulsan National Institute of Science and Technology (UNIST), 50 UNIST-gil, Ulju-gun, Ulsan, 44919, Republic of Korea
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6
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Jeng KS, Chang CF, Tsang YM, Sheen IS, Jeng CJ. Reappraisal of the Roles of the Sonic Hedgehog Signaling Pathway in Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1739. [PMID: 38730691 PMCID: PMC11083695 DOI: 10.3390/cancers16091739] [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: 04/05/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
HCC remains one of the leading causes of cancer-related death globally. The main challenges in treatments of hepatocellular carcinoma (HCC) primarily arise from high rates of postoperative recurrence and the limited efficacy in treating advanced-stage patients. Various signaling pathways involved in HCC have been reported. Among them, the Sonic hedgehog (SHH) signaling pathway is crucial. The presence of SHH ligands is identified in approximately 60% of HCC tumor tissues, including tumor nests. PTCH-1 and GLI-1 are detected in more than half of HCC tissues, while GLI-2 is found in over 84% of HCC tissues. The SHH signaling pathway (including canonical and non-canonical) is involved in different aspects of HCC, including hepatocarcinogenesis, tumor growth, tumor invasiveness, progression, and migration. The SHH signaling pathway also contributes to recurrence, metastasis, modulation of the cancer microenvironment, and sustaining cancer stem cells. It also affects the resistance of HCC cells to chemotherapy, target therapy, and radiotherapy. Reappraisal of the roles of the SHH signaling pathway in HCC may trigger some novel therapies for HCC.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
| | - Chiung-Fang Chang
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan;
| | - Yuk-Ming Tsang
- Department of Imaging Medicine, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan;
| | - I-Shyan Sheen
- Department of Gastroenterology & Hepatology, Linkou Chang Memorial Hospital, Chang Gung Medical Foundation, Taoyuan City 333, Taiwan;
| | - Chi-Juei Jeng
- Graduate Institude of Clinical Medicine, National Taiwan University, College of Medicine, Taipei City 10617, Taiwan;
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Cruz SM, Iranpur KR, Judge SJ, Ames E, Sturgill IR, Farley LE, Darrow MA, Crowley JS, Monjazeb AM, Murphy WJ, Canter RJ. Low-Dose Sorafenib Promotes Cancer Stem Cell Expansion and Accelerated Tumor Progression in Soft Tissue Sarcomas. Int J Mol Sci 2024; 25:3351. [PMID: 38542325 PMCID: PMC10969893 DOI: 10.3390/ijms25063351] [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: 02/04/2024] [Revised: 03/14/2024] [Accepted: 03/14/2024] [Indexed: 08/03/2024] Open
Abstract
The cancer stem cell (CSC) hypothesis postulates that heterogeneous human cancers harbor a population of stem-like cells which are resistant to cytotoxic therapies, thus providing a reservoir of relapse following conventional therapies like chemotherapy and radiation (RT). CSCs have been observed in multiple human cancers, and their presence has been correlated with worse clinical outcomes. Here, we sought to evaluate the impact of drug dosing of the multi-tyrosine kinase inhibitor, sorafenib, on CSC and non-CSCs in soft tissue sarcoma (STS) models, hypothesizing differential effects of sorafenib based on dose and target cell population. In vitro, human cancer cell lines and primary STS from surgical specimens were exposed to escalating doses of sorafenib to determine cell viability and expression of CSC marker aldehyde dehydrogenase (ALDH). In vivo, ALDHbright CSCs were isolated, exposed to sorafenib, and xenograft growth and survival analyses were performed. We observed that sarcoma CSCs appear to paradoxically respond to the tyrosine kinase inhibitor sorafenib at low doses with increased proliferation and stem-like function of CSCs, whereas anti-viability effects dominated at higher doses. Importantly, STS patients receiving neoadjuvant sorafenib and RT on a clinical trial (NCT00864032) showed increased CSCs post therapy, and higher ALDH scores post therapy were associated with worse metastasis-free survival. These data suggest that low-dose sorafenib may promote the CSC phenotype in STS with clinically significant effects, including increased tumor growth and higher rates of metastasis formation in sarcoma patients.
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Affiliation(s)
- Sylvia M. Cruz
- Division of Surgical Oncology, Department of Surgery, University of California Davis, Sacramento, CA 95817, USA
| | - Khurshid R. Iranpur
- Division of Surgical Oncology, Department of Surgery, University of California Davis, Sacramento, CA 95817, USA
| | - Sean J. Judge
- Division of Surgical Oncology, Department of Surgery, University of California Davis, Sacramento, CA 95817, USA
| | - Erik Ames
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Ian R. Sturgill
- Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lauren E. Farley
- Division of Surgical Oncology, Department of Surgery, University of California Davis, Sacramento, CA 95817, USA
| | - Morgan A. Darrow
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA 95817, USA
| | - Jiwon Sarah Crowley
- Division of Surgical Oncology, Department of Surgery, University of California Davis, Sacramento, CA 95817, USA
| | - Arta M. Monjazeb
- Department of Radiation Oncology, University of California Davis, Sacramento, CA 95817, USA
| | - William J. Murphy
- Department of Dermatology, University of California Davis, Sacramento, CA 95817, USA;
| | - Robert J. Canter
- Division of Surgical Oncology, Department of Surgery, University of California Davis, Sacramento, CA 95817, USA
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Afsar S, Syed RU, Bin Break MK, Alsukaybi RH, Alanzi RA, Alshobrmi AM, Alshagdali NM, Alshammari AD, Alharbi FM, Alshammari AM, Algharbi WF, Albrykan KM, Alshammari FN. The dual role of MiR-210 in the aetiology of cancer: A focus on hypoxia-inducible factor signalling. Pathol Res Pract 2024; 253:155018. [PMID: 38070222 DOI: 10.1016/j.prp.2023.155018] [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: 10/19/2023] [Revised: 12/02/2023] [Accepted: 12/04/2023] [Indexed: 01/24/2024]
Abstract
Tumorigenesis exemplifies the complex process of neoplasm origination, which is characterised by somatic genetic alterations and abnormal cellular growth. This multidimensional phenomenon transforms previously dormant cells into malignant equivalents, resulting in uncontrollable proliferation and clonal expansion. Various elements, including random mutations, harmful environmental substances, and genetic predispositions, influence tumorigenesis's aetiology. MicroRNAs (miRNAs) are now recognised as crucial determinants of gene expression and key players in several biological methods, including oncogenesis. A well-known hypoxia-inducible miRNA is MiR-210, which is of particular interest because of its complicated role in the aetiology of cancer and a variation of physiological and pathological situations. MiR-210 significantly impacts cancer by controlling the hypoxia-inducible factor (HIF) signalling pathway. By supporting angiogenesis, metabolic reprogramming, and cellular survival in hypoxic microenvironments, HIF signalling orchestrates adaptive responses, accelerating the unstoppable development of tumorous growth. Targeting several components of this cascade, including HIF-1, HIF-3, and FIH-1, MiR-210 plays a vital role in modifying HIF signalling and carefully controlling the HIF-mediated response and cellular fates in hypoxic environments. To understand the complexities of this relationship, careful investigation is required at the intersection of MiR-210 and HIF signalling. Understanding this relationship is crucial for uncovering the mechanisms underlying cancer aetiology and developing cutting-edge therapeutic approaches. The current review emphasises MiR-210's significance as a vital regulator of the HIF signalling cascade, with substantial implications spanning a range of tumor pathogenesis.
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Affiliation(s)
- S Afsar
- Department of Virology, Sri Venkateswara University, Tirupathi, Andhra Pradesh 517502, India
| | - Rahamat Unissa Syed
- Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia.
| | - Mohammed Khaled Bin Break
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia; Medical and Diagnostic Research Centre, University of Hail, Hail 55473, Saudi Arabia
| | | | - Reem A Alanzi
- College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia
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Sukowati CH, El-Khobar K, Jasirwan COM, Kurniawan J, Gani RA. Stemness markers in hepatocellular carcinoma of Eastern vs. Western population: Etiology matters? Ann Hepatol 2024; 29:101153. [PMID: 37734662 DOI: 10.1016/j.aohep.2023.101153] [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: 08/08/2023] [Accepted: 08/22/2023] [Indexed: 09/23/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. HCC development is associated with its underlying etiologies, mostly caused by infection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol, non-alcoholic fatty liver disease, and exposure to aflatoxins. These variables, together with human genetic susceptibility, contribute to HCC molecular heterogeneity, including at the cellular level. HCC initiation, tumor recurrence, and drug resistance rates have been attributed to the presence of liver cancer stem cells (CSC). This review summarizes available data regarding whether various HCC etiologies may be associated to the appearance of CSC biomarkers. It also described the genetic variations of tumoral tissues obtained from Western and Eastern populations, in particular to the oncogenic effect of HBV in the human genome.
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Affiliation(s)
- Caecilia Hc Sukowati
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park campus Basovizza, SS14 km 163.5, Trieste 34149, Italy; Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), B.J. Habibie Building, Jl. M.H. Thamrin No. 8, Jakarta Pusat 10340, Indonesia.
| | - Korri El-Khobar
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), B.J. Habibie Building, Jl. M.H. Thamrin No. 8, Jakarta Pusat 10340, Indonesia
| | - Chyntia Olivia Maurine Jasirwan
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
| | - Juferdy Kurniawan
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
| | - Rino Alvani Gani
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
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10
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Wang Y, Wan X, Du S. Integrated analysis revealing a novel stemness-metabolism-related gene signature for predicting prognosis and immunotherapy response in hepatocellular carcinoma. Front Immunol 2023; 14:1100100. [PMID: 37622118 PMCID: PMC10445950 DOI: 10.3389/fimmu.2023.1100100] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 07/10/2023] [Indexed: 08/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant lethal tumor and both cancer stem cells (CSCs) and metabolism reprogramming have been proven to play indispensable roles in HCC. This study aimed to reveal the connection between metabolism reprogramming and the stemness characteristics of HCC, established a new gene signature related to stemness and metabolism and utilized it to assess HCC prognosis and immunotherapy response. The clinical information and gene expression profiles (GEPs) of 478 HCC patients came from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). The one-class logistic regression (OCLR) algorithm was employed to calculate the messenger ribonucleic acid expression-based stemness index (mRNAsi), a new stemness index quantifying stemness features. Differentially expressed analyses were done between high- and low-mRNAsi groups and 74 differentially expressed metabolism-related genes (DEMRGs) were identified with the help of metabolism-related gene sets from Molecular Signatures Database (MSigDB). After integrated analysis, a risk score model based on the three most efficient prognostic DEMRGs, including Recombinant Phosphofructokinase Platelet (PFKP), phosphodiesterase 2A (PDE2A) and UDP-glucuronosyltransferase 1A5 (UGT1A5) was constructed and HCC patients were divided into high-risk and low-risk groups. Significant differences were found in pathway enrichment, immune cell infiltration patterns, and gene alterations between the two groups. High-risk group patients tended to have worse clinical outcomes and were more likely to respond to immunotherapy. A stemness-metabolism-related model composed of gender, age, the risk score model and tumor-node-metastasis (TNM) staging was generated and showed great discrimination and strong ability in predicting HCC prognosis and immunotherapy response.
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Affiliation(s)
| | | | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
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11
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Jeng KS, Chang CF, Sheen IS, Jeng CJ, Wang CH. Cellular and Molecular Biology of Cancer Stem Cells of Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:1417. [PMID: 36674932 PMCID: PMC9861908 DOI: 10.3390/ijms24021417] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death globally. The cancer stem cells (CSCs) of HCC are responsible for tumor growth, invasion, metastasis, recurrence, chemoresistance, target therapy resistance and radioresistance. The reported main surface markers used to identify liver CSCs include epithelial cell adhesion/activating molecule (EpCAM), cluster differentiation 90 (CD90), CD44 and CD133. The main molecular signaling pathways include the Wnt/β-catenin, transforming growth factors-β (TGF-β), sonic hedgehog (SHH), PI3K/Akt/mTOR and Notch. Patients with EpCAM-positive alpha-fetoprotein (AFP)-positive HCC are usually young but have advanced tumor-node-metastasis (TNM) stages. CD90-positive HCCs are usually poorly differentiated with worse prognosis. Those with CD44-positive HCC cells develop early metastases. Those with CD133 expression have a higher recurrence rate and a shorter overall survival. The Wnt/β-catenin signaling pathway triggers angiogenesis, tumor infiltration and metastasis through the enhancement of angiogenic factors. All CD133+ liver CSCs, CD133+/EpCAM+ liver CSCs and CD44+ liver CSCs contribute to sorafenib resistance. SHH signaling could protect HCC cells against ionizing radiation in an autocrine manner. Reducing the CSC population of HCC is crucial for the improvement of the therapy of advanced HCC. However, targeting CSCs of HCC is still challenging.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
| | - Chiung-Fang Chang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
| | - I-Shyang Sheen
- Department of Hepato Gastroenterology, Linkou Medical Center, Chang-Gung University, Taoyuan City 33305, Taiwan
| | - Chi-Juei Jeng
- Postgraduate of Institute of Medicine, National Taiwan University, Taipei 10617, Taiwan
| | - Chih-Hsuan Wang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
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12
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Li L, Xun C, Yu CH. Role of microRNA-regulated cancer stem cells in recurrent hepatocellular carcinoma. World J Hepatol 2022; 14:1985-1996. [PMID: 36618329 PMCID: PMC9813843 DOI: 10.4254/wjh.v14.i12.1985] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/24/2022] [Accepted: 11/22/2022] [Indexed: 12/23/2022] Open
Abstract
Among the most common cancers, hepatocellular carcinoma (HCC) has a high rate of tumor recurrence, tumor dormancy, and drug resistance after initial successful chemotherapy or radiotherapy. A small subset of cancer cells, cancer stem cells (CSCs), exhibit stem cell characteristics and are present in various cancers, including HCC. The dysregulation of microRNAs (miRNAs) often accompanies the occurrence and development of HCC. miRNAs can influence tumorigenesis, progression, recurrence, and drug resistance by regulating CSCs properties, which supports their clinical utility in managing and treating HCC. This review summarizes the regulatory effects of miRNAs on CSCs in HCC with a special focus on their impact on HCC recurrence.
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Affiliation(s)
- Lei Li
- Department of Pathology, University of Otago, Dunedin 9016, New Zealand
| | - Chen Xun
- Department of Hepatobiliary Surgery, Zhuzhou Central Hospital, Zhuzhou 412000, Hunan Province, China
| | - Chun-Hong Yu
- School of Engineering Medicine, Beihang University, Beijing 100191, China.
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13
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Li J, Tang M, Wu J, Qu H, Tu M, Pan Z, Gao C, Yang Y, Qu C, Huang W, Hong J. NUSAP1, a novel stemness-related protein, promotes early recurrence of hepatocellular carcinoma. Cancer Sci 2022; 113:4165-4180. [PMID: 36106345 DOI: 10.1111/cas.15585] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 08/15/2022] [Accepted: 09/07/2022] [Indexed: 01/27/2023] Open
Abstract
Early recurrence (within 2 years after resection) is the primary cause of poor outcomes among hepatocellular carcinoma (HCC) patients, and liver cancer stem cells are the main contributors to postsurgical HCC recurrence. Nucleolar and spindle-associated protein 1 (NUSAP1) has been reported to be involved in tumor progression. We investigated the function and clinical value of NUSAP1 in early recurrence of HCC. Data from public datasets and our cohort were used to assess the association between NUSAP1 expression and early HCC recurrence. Gain- and loss-of-function experiments were carried out in vivo and in vitro. The predictive effect of NUSAP1 on early HCC recurrence was further evaluated by a validation cohort. We found that elevated NUSAP1 expression in HCC specimens was correlated with poor outcome, especially in cases with postoperative early recurrence. Functional studies indicated that NUSAP1 significantly promotes HCC progression. A postsurgical recurrence murine model further revealed that upregulated NUSAP1 dramatically increased the likelihood of HCC early recurrence. RNA sequencing data revealed that the gene sets of cancer stemness and the signal transducer and activator of transcription 3 (STAT3) pathway were enriched by NUSAP1 overexpression. Mechanistically, NUSAP1 enhanced cancer stemness through stimulating STAT3 nuclear translocation and activation through receptor of activated protein C kinase 1 (RACK1). In a validation cohort with 112 HCC patients, NUSAP1 effectively predicted HCC early recurrence. Our results indicated that NUSAP1 promotes early recurrence of HCC by sustaining cancer stemness and could serve as a valuable predictive indicator for postsurgical intervention in HCC patients.
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Affiliation(s)
- Jinying Li
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China.,Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
| | - Ming Tang
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China.,Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
| | - Junru Wu
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
| | - Hengdong Qu
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
| | - Mengxian Tu
- The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhaojie Pan
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Chongqing Gao
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
| | - Yuping Yang
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Chen Qu
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China
| | - Wei Huang
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Jian Hong
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China.,Department of Hepatological Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, China
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14
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Cabral LKD, Reyes PAC, Crocè LS, Tiribelli C, Sukowati CHC. The Relevance of SOCS1 Methylation and Epigenetic Therapy in Diverse Cell Populations of Hepatocellular Carcinoma. Diagnostics (Basel) 2021; 11:1825. [PMID: 34679523 PMCID: PMC8534387 DOI: 10.3390/diagnostics11101825] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/27/2021] [Accepted: 09/29/2021] [Indexed: 12/11/2022] Open
Abstract
The suppressor of cytokine signaling 1 (SOCS1) is a tumor suppressor gene found to be hypermethylated in cancers. It is involved in the oncogenic transformation of cirrhotic liver tissues. Here, we investigated the clinical relevance of SOCS1 methylation and modulation upon epigenetic therapy in diverse cellular populations of hepatocellular carcinoma (HCC). HCC clinical specimens were evaluated for SOCS1 methylation and mRNA expression. The effect of 5-Azacytidine (5-AZA), a demethylation agent, was assessed in different subtypes of HCC cells. We demonstrated that the presence of SOCS1 methylation was significantly higher in HCC compared to peri-HCC and non-tumoral tissues (52% vs. 13% vs. 14%, respectively, p < 0.001). In vitro treatment with a non-toxic concentration of 5-AZA significantly reduced DNMT1 protein expression for stromal subtype lines (83%, 73%, and 79%, for HLE, HLF, and JHH6, respectively, p < 0.01) compared to cancer stem cell (CSC) lines (17% and 10%, for HepG2 and Huh7, respectively), with the strongest reduction in non-tumoral IHH cells (93%, p < 0.001). 5-AZA modulated the SOCS1 expression in different extents among the cells. It was restored in CSC HCC HepG2 and Huh7 more efficiently than sorafenib. This study indicated the relevance of SOCS1 methylation in HCC and how cellular heterogeneity influences the response to epigenetic therapy.
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Affiliation(s)
- Loraine Kay D. Cabral
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (C.T.)
- Doctoral School in Molecular Biomedicine, University of Trieste, 34127 Trieste, Italy
| | | | - Lory S. Crocè
- Liver Unit, Clinical Department of Medical, Surgical and Health Sciences, Trieste University, 34127 Trieste, Italy;
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (C.T.)
| | - Caecilia H. C. Sukowati
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (C.T.)
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15
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Bondoc A, Glaser K, Jin K, Lake C, Cairo S, Geller J, Tiao G, Aronow B. Identification of distinct tumor cell populations and key genetic mechanisms through single cell sequencing in hepatoblastoma. Commun Biol 2021; 4:1049. [PMID: 34497364 PMCID: PMC8426487 DOI: 10.1038/s42003-021-02562-8] [Citation(s) in RCA: 22] [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: 10/19/2020] [Accepted: 08/16/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatoblastoma (HB) is the most common primary liver malignancy of childhood, and molecular investigations are limited and effective treatment options for chemoresistant disease are lacking. There is a knowledge gap in the investigation of key driver cells of HB in tumor. Here we show single cell ribonucleic acid sequencing (scRNAseq) analysis of human tumor, background liver, and patient derived xenograft (PDX) to demonstrate gene expression patterns within tumor and to identify intratumor cell subtype heterogeneity to define differing roles in pathogenesis based on intracellular signaling in pediatric HB. We have identified a driver tumor cell cluster in HB by genetic expression which can be examined to define disease mechanism and treatments. Identification of both critical mechanistic pathways combined with unique cell populations provide the basis for discovery and investigation of novel treatment strategies in vitro and in vivo.
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Affiliation(s)
- Alexander Bondoc
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital, Medical Center, Cincinnati, OH, USA.
| | - Kathryn Glaser
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital, Medical Center, Cincinnati, OH, USA
| | - Kang Jin
- Division of Biomedical Informatics, Developmental Biology, and Pediatrics, Cincinnati, Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Biomedical Informatics, University of Cincinnati, Cincinnati, OH, USA
| | - Charissa Lake
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital, Medical Center, Cincinnati, OH, USA
| | - Stefano Cairo
- Research and Development Unit, XenTech, Genopole-Campus 3, Fontaine, France
- Istituto di Ricerca Pediatrica (IRP), Corso Stati Uniti, Padua, Italy
| | - James Geller
- Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Gregory Tiao
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital, Medical Center, Cincinnati, OH, USA
| | - Bruce Aronow
- Division of Biomedical Informatics, Developmental Biology, and Pediatrics, Cincinnati, Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Biomedical Informatics, University of Cincinnati, Cincinnati, OH, USA
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16
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Sukowati CHC, El-Khobar KE, Tiribelli C. Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells. World J Stem Cells 2021; 13:795-824. [PMID: 34367478 PMCID: PMC8316870 DOI: 10.4252/wjsc.v13.i7.795] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/25/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy related to diverse etiological factors. Different oncogenic mechanisms and genetic variations lead to multiple HCC molecular classifications. Recently, an immune-based strategy using immune checkpoint inhibitors (ICIs) was presented in HCC therapy, especially with ICIs against the programmed death-1 (PD-1) and its ligand PD-L1. However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. In this review, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells (CSCs). Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to cancer. PD-L1 expression in tumoral tissues is differentially expressed in CSCs, particularly in those with a close association with the tumor microenvironment. This information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.
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Affiliation(s)
| | | | - Claudio Tiribelli
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
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17
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Chmurska A, Matczak K, Marczak A. Two Faces of Autophagy in the Struggle against Cancer. Int J Mol Sci 2021; 22:2981. [PMID: 33804163 PMCID: PMC8000091 DOI: 10.3390/ijms22062981] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/10/2021] [Accepted: 03/12/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy can play a double role in cancerogenesis: it can either inhibit further development of the disease or protect cells, causing stimulation of tumour growth. This phenomenon is called "autophagy paradox", and is characterised by the features that the autophagy process provides the necessary substrates for biosynthesis to meet the cell's energy needs, and that the over-programmed activity of this process can lead to cell death through apoptosis. The fight against cancer is a difficult process due to high levels of resistance to chemotherapy and radiotherapy. More and more research is indicating that autophagy may play a very important role in the development of resistance by protecting cancer cells, which is why autophagy in cancer therapy can act as a "double-edged sword". This paper attempts to analyse the influence of autophagy and cancer stem cells on tumour development, and to compare new therapeutic strategies based on the modulation of these processes.
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Affiliation(s)
- Anna Chmurska
- Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland
| | - Karolina Matczak
- Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, Pomorska Street 141/143, 90-236 Lodz, Poland; (K.M.); (A.M.)
| | - Agnieszka Marczak
- Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, Pomorska Street 141/143, 90-236 Lodz, Poland; (K.M.); (A.M.)
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18
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19
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Dai X, Guo Y, Hu Y, Bao X, Zhu X, Fu Q, Zhang H, Tong Z, Liu L, Zheng Y, Zhao P, Fang W. Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma. Theranostics 2021; 11:3489-3501. [PMID: 33537099 PMCID: PMC7847682 DOI: 10.7150/thno.54648] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 12/21/2020] [Indexed: 02/06/2023] Open
Abstract
The rapid development and remarkable success of checkpoint inhibitors have provided significant breakthroughs in cancer treatment, including hepatocellular carcinoma (HCC). However, only 15-20% of HCC patients can benefit from checkpoint inhibitors. Cancer stem cells (CSCs) are responsible for recurrence, metastasis, and local and systemic therapy resistance in HCC. Accumulating evidence has suggested that HCC CSCs can create an immunosuppressive microenvironment through certain intrinsic and extrinsic mechanisms, resulting in immune evasion. Intrinsic evasion mechanisms mainly include activation of immune-related CSC signaling pathways, low-level expression of antigen presenting molecules, and high-level expression of immunosuppressive molecules. External evasion mechanisms are mainly related to HBV/HCV infection, alcoholic/nonalcoholic steatohepatitis, hypoxia stimulation, abnormal angiogenesis, and crosstalk between CSCs and immune cells. A better understanding of the complex mechanisms of CSCs involved in immune evasion will contribute to therapies for HCC. Here we will outline the detailed mechanisms of immune evasion for CSCs, and provide an overview of the current immunotherapies targeting CSCs in HCC.
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MESH Headings
- Antigen Presentation/drug effects
- Antineoplastic Agents, Immunological/therapeutic use
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Fatty Liver/genetics
- Fatty Liver/immunology
- Fatty Liver/pathology
- Fatty Liver/therapy
- Gene Expression Regulation, Neoplastic
- Hepatitis B/genetics
- Hepatitis B/immunology
- Hepatitis B/pathology
- Hepatitis B/therapy
- Hepatitis C/genetics
- Hepatitis C/immunology
- Hepatitis C/pathology
- Hepatitis C/therapy
- Humans
- Immunologic Factors/therapeutic use
- Immunotherapy/methods
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/genetics
- Neoplasm Proteins/immunology
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/therapy
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/pathology
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/immunology
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control
- Signal Transduction
- Tumor Escape/drug effects
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- Tumor Microenvironment/immunology
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Peng Zhao
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Weijia Fang
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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20
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Luong AB, Do HQ, Tarchi P, Bonazza D, Bottin C, Cabral LKD, Tran LDC, Doan TPT, Crocè LS, Pham HLT, Tiribelli C, Sukowati CHC. The mRNA Distribution of Cancer Stem Cell Marker CD90/Thy-1 Is Comparable in Hepatocellular Carcinoma of Eastern and Western Populations. Cells 2020; 9:2672. [PMID: 33322687 PMCID: PMC7764111 DOI: 10.3390/cells9122672] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 02/08/2023] Open
Abstract
Epidemiology of hepatocellular carcinoma (HCC) showed a correlation between incidence and geographical-relevant risk factors. This study aims to compare the distributions of cancer stem cells (CSC) in two distant populations in Asia and Europe. We analyzed 52 and 43 selected HCC patients undergoing hepatectomy in Ho Chi Minh City (Vietnam) and Trieste (Italy). Each patient sample consisted of HCC, peri-HCC, and non-tumoral (distal) tissue. Demographic data were recorded together with clinical findings. The protocol for the collection of tissue samples and RNA was standardized in both laboratories and gene expression analysis was performed in a single laboratory with identical PCR conditions. Baseline data showed comparable laboratory findings between the two cohorts. mRNA distribution showed a comparable pattern of all CSC markers analyzed with the expression of CD90 progressively increasing from distal and peri-HCC to be highest in HCC (p < 0.001), confirmed by immunofluorescence data. CD90 mRNA distribution was related to HBV-related HCC and a tumor diameter less than 5 cm. Patients with high tumoral CD90 mRNA had a shorter time (p < 0.05) to tumor recurrence compared to patients with lower CD90. This comparative study showed that CD90 mRNA expressions are comparable between Eastern and Western HCC cases.
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Affiliation(s)
- An B. Luong
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam
| | - Huy Q. Do
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Laboratory of Stem Cell Research and Application, VNUHCM-University of Science, Ho Chi Minh City 700000, Vietnam
| | - Paola Tarchi
- Clinical Surgery Unit, Azienda Sanitaria Universitaria Giuliana Isontina (ASUGI), 34148 Trieste, Italy;
| | - Deborah Bonazza
- Surgical Pathology Unit, Azienda Sanitaria Universitaria Giuliana Isontina (ASUGI), 34148 Trieste, Italy;
| | - Cristina Bottin
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy;
| | - Loraine Kay D. Cabral
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Doctoral School in Molecular Biomedicine, University of Trieste, 34127 Trieste, Italy
| | - Long D. C. Tran
- University Medical Center, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam; (L.D.C.T.); (H.L.T.P.)
| | - Thao P. T. Doan
- Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam;
| | - Lory S. Crocè
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy;
| | - Hoa L. T. Pham
- University Medical Center, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam; (L.D.C.T.); (H.L.T.P.)
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
| | - Caecilia H. C. Sukowati
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
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Jiang X, Xing L, Chen Y, Qin R, Song S, Lu Y, Xie S, Wang L, Pu H, Gui X, Li T, Xu J, Li J, Jia S, Lu D. CircMEG3 inhibits telomerase activity by reducing Cbf5 in human liver cancer stem cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 23:310-323. [PMID: 33425489 PMCID: PMC7779543 DOI: 10.1016/j.omtn.2020.11.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/10/2020] [Indexed: 12/13/2022]
Abstract
Circular RNA (CircRNA) is a newly identified special class of non-coding RNA (ncRNA) that plays an important regulatory role in the progression of certain diseases. Herein, our results indicate that CircMEG3 is downregulated expression and negatively correlated with the expression of telomerase-related gene Cbf5 in human liver cancer. Moreover, CircMEG3 inhibits the growth of human liver cancer stem cells in vivo and in vitro. CircMEG3 inhibits the expression of m6A methyltransferase METTL3 dependent on HULC. Moreover, CircMEG3 inhibits the expression of Cbf5, a component of telomere synthetase H/ACA ribonucleoprotein (RNP; catalyst RNA pseudouracil modification) through METTL3 dependent on HULC. Thereby, CircMEG3 inhibits telomerase activity and shortens telomere lifespan dependent on HULC and Cbf5 in human liver cancer stem cell. Strikingly, increased Cbf5 abrogates the ability of CircMEG3 to inhibit malignant differentiation of human liver cancer stem cells. In summary, these observations provide important basic information for finding effective liver cancer therapeutic targets.
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Affiliation(s)
- Xiaoxue Jiang
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Libo Xing
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Yingjie Chen
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Rushi Qin
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Shuting Song
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Yanan Lu
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Sijie Xie
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Liyan Wang
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Hu Pu
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Xin Gui
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Tianming Li
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Jie Xu
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Jiao Li
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Song Jia
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Dongdong Lu
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
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22
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Do HQ, Luong AB, Bonazza D, Bottin C, Doan TP, Tran LD, Truong NH, Tell G, Pham HL, Tiribelli C, Sukowati CH. Differential capacity of CD90+ cells in autophagy activation following chemotherapy in hepatocellular carcinoma. Ann Hepatol 2020; 19:645-652. [PMID: 32745631 DOI: 10.1016/j.aohep.2020.07.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/10/2020] [Accepted: 07/11/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Analysis of cancer biomarkers is an important tool in developing targeted-therapy and in modulating chemoresistance. Here, we analyze the relevance of CD90, a marker of cancer stem cells (CSC) in hepatocellular carcinoma (HCC) and its correlation with autophagy. MATERIALS AND METHODS For in vivo study, 86 specimens were collected from 43 patients undergoing liver resections. In each patient, HCC nodule (HCC) and surrounding non-tumor (SNT) were collected. For in vitro study, HCC cells JHH6 subpopulations expressing CD90+ and CD90- were isolated using magnetic-sorter and confirmed by flow-cytometry. Upon doxorubicin treatment, autophagy turn-over was analyzed by RTqPCR for mRNA expression, Western blot for protein expression, and autophagosome staining for autophagy-flux. Cytotoxicity test was performed by MTT assay. Gene and protein analysis were performed in clinical samples together with immunohistostaining. RESULTS CD90 mRNA expression was higher in HCC than in SNT for 8-fold (p < 0.001). LC3-II protein was up-regulated in the HCC in comparison with the SNT (p < 0.05). In vitro model showed that CD90+ and CD90- cells had diverse expressions of autophagy-related genes. Upon doxorubicin treatment, autophagy was activated in both cells by increasing LC3-II protein expression, autophagic vacuoles, and dysregulation of autophagy-related mRNAs. A differential autophagic capacity was noticed between two subpopulations and it was correlated with cellular toxicity assay. CONCLUSIONS We demonstrated the relevance of differential autophagy capacity of CD90+ cells in HCC. Autophagy was involved in cancer-defense mechanism against doxorubicin. Cancer promoting function of autophagy in CD90+ cells was also related to cancer environment.
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Affiliation(s)
- Huy Q Do
- Fondazione Italiana Fegato - ONLUS, AREA Science Park, Basovizza, Trieste, Italy; Laboratory of Stem Cell Research and Application, VNUHCM-University of Science, Ho Chi Minh, Vietnam
| | - An B Luong
- Fondazione Italiana Fegato - ONLUS, AREA Science Park, Basovizza, Trieste, Italy; Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh, Vietnam
| | - Deborah Bonazza
- Surgical Pathology Unit, Cattinara Hospital, Azienda Sanitaria Universitaria Giuliana Isontina (ASUGI), Trieste, Italy
| | - Cristina Bottin
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Thao Pt Doan
- Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh, Vietnam
| | - Long Dc Tran
- University Medical Center, University of Medicine and Pharmacy at Ho Chi Minh, Vietnam
| | - Nhung H Truong
- Laboratory of Stem Cell Research and Application, VNUHCM-University of Science, Ho Chi Minh, Vietnam
| | - Gianluca Tell
- Laboratory of Molecular Biology and DNA repair, Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Hoa Lt Pham
- University Medical Center, University of Medicine and Pharmacy at Ho Chi Minh, Vietnam
| | - Claudio Tiribelli
- Fondazione Italiana Fegato - ONLUS, AREA Science Park, Basovizza, Trieste, Italy
| | - Caecilia Hc Sukowati
- Fondazione Italiana Fegato - ONLUS, AREA Science Park, Basovizza, Trieste, Italy; Laboratory of Molecular Biology and DNA repair, Department of Medicine (DAME), University of Udine, Udine, Italy.
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23
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Walcher L, Kistenmacher AK, Suo H, Kitte R, Dluczek S, Strauß A, Blaudszun AR, Yevsa T, Fricke S, Kossatz-Boehlert U. Cancer Stem Cells-Origins and Biomarkers: Perspectives for Targeted Personalized Therapies. Front Immunol 2020; 11:1280. [PMID: 32849491 PMCID: PMC7426526 DOI: 10.3389/fimmu.2020.01280] [Citation(s) in RCA: 578] [Impact Index Per Article: 115.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023] Open
Abstract
The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.
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Affiliation(s)
- Lia Walcher
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Ann-Kathrin Kistenmacher
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Huizhen Suo
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Reni Kitte
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Sarah Dluczek
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Alexander Strauß
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - André-René Blaudszun
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Tetyana Yevsa
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Stephan Fricke
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Uta Kossatz-Boehlert
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
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Cabral LKD, Tiribelli C, Sukowati CHC. Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity. Cancers (Basel) 2020; 12:1576. [PMID: 32549224 PMCID: PMC7352671 DOI: 10.3390/cancers12061576] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/08/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Despite advances in biomedicine, the incidence and the mortality of hepatocellular carcinoma (HCC) remain high. The majority of HCC cases are diagnosed in later stages leading to the less than optimal outcome of the treatments. Molecular targeted therapy with sorafenib, a dual-target inhibitor targeting the serine-threonine kinase Raf and the tyrosine kinases VEGFR/PDGFR, is at present the main treatment for advanced-stage HCC, either in a single or combinatory regimen. However, it was observed in a large number of patients that its effectiveness is hampered by drug resistance. HCC is highly heterogeneous, within the tumor and among individuals, and this influences disease progression, classification, prognosis, and naturally cellular susceptibility to drug resistance. This review aims to provide an insight on how HCC heterogeneity influences the different primary mechanisms of chemoresistance against sorafenib including reduced drug intake, enhanced drug efflux, intracellular drug metabolism, alteration of molecular targets, activation/inactivation of signaling pathways, changes in the DNA repair machinery, and negative balance between apoptosis and survival of the cancer cells. The diverse variants, mutations, and polymorphisms in molecules and their association with drug response can be a helpful tool in treatment decision making. Accordingly, the existence of heterogeneous biomarkers in the tumor must be considered to strengthen multi-target strategies in patient-tailored treatment.
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Affiliation(s)
| | | | - Caecilia H. C. Sukowati
- Fondazione Italiana Fegato (Italian Liver Foundation), AREA Science Park, Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (C.T.)
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25
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Sang X, Wu F, Wu D, Lin S, Li J, Zhao N, Chen X, Xu A. Human Hepatic Cancer Stem Cells (HCSCs) Markers Correlated With Immune Infiltrates Reveal Prognostic Significance of Hepatocellular Carcinoma. Front Genet 2020; 11:112. [PMID: 32184801 PMCID: PMC7058667 DOI: 10.3389/fgene.2020.00112] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 01/30/2020] [Indexed: 12/21/2022] Open
Abstract
Background Several markers have been reported to be specific for hepatic cancer stem cells (HCSCs), which is usually thought to be highly associated with poor clinical outcomes. Tumor-infiltrating immune cells act as an important factor for oncogenesis. Little is known about the correlation of HCSC markers to prognosis and immune infiltrates. Methods Expression of HCSC markers was analyzed through Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA) and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), respectively. The prognostic effect of HCSC markers was evaluated using Kaplan-Meier plotter in association with different tumor stages, risk factors, and gender. The correlation of HCSC markers to tumor-infiltrating immune cells was tested by Tumor Immune Estimation Resource (TIMER). HCSC markers related gene sets were investigated by GEPIA, with their biological functions being analyzed by Cytoscape software. Results The expression level of 10 HCSC markers in HCC was higher than that in normal tissues in at least one database. Among them, high expression of CD24, SOX9, and SOX12 was positively correlated with poor prognosis (CD24: OS P = 0.0012, PFS P = 7.9E–05. SOX9: OS P = 0.012. SOX12: OS P = 0.0004, PFS P = 0.0013, respectively). However, the expression of CD13, CD34 and ALDH1A1 was associated with prolonged OS and PFS. SOX12 was significantly upregulated in poor prognosis of HCC patients with different conditions. Besides, total nine HCSC markers were identified to be positively associated with immune infiltration, including SOX12. Furthermore, Toll-like receptor signaling pathway was found to be one major pathway of these HCSC markers related gene networks. Conclusion Our results suggest that seven upregulated HCSC markers (CD90, EpCAM, CD133, CD24, SOX9, CK19, and SOX12) are related with poor prognosis and immune infiltration in HCC. In addition, we find that high SOX12 expression remarkably affect prognosis in male HCC patients but not in female. HCC patients under viral infection or alcohol intake with increased SOX12 expression had poorer prognosis. Therefore, HCSCs markers likely play an important role in tumor related immune infiltration and SOX12 might be a potential therapeutic target in patients with HCC.
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Affiliation(s)
- Xiaopu Sang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Fenfang Wu
- Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Di Wu
- Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Shan Lin
- Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Jingyi Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Nan Zhao
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoni Chen
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Anlong Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.,Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
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26
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Models for Understanding Resistance to Chemotherapy in Liver Cancer. Cancers (Basel) 2019; 11:cancers11111677. [PMID: 31671735 PMCID: PMC6896032 DOI: 10.3390/cancers11111677] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/23/2019] [Accepted: 10/24/2019] [Indexed: 12/19/2022] Open
Abstract
The lack of response to pharmacological treatment constitutes a substantial limitation in the handling of patients with primary liver cancers (PLCs). The existence of active mechanisms of chemoresistance (MOCs) in hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma hampers the usefulness of chemotherapy. A better understanding of MOCs is needed to develop strategies able to overcome drug refractoriness in PLCs. With this aim, several experimental models are commonly used. These include in vitro cell-free assays using subcellular systems; studies with primary cell cultures; cancer cell lines or heterologous expression systems; multicellular models, such as spheroids and organoids; and a variety of in vivo models in rodents, such as subcutaneous and orthotopic tumor xenografts or chemically or genetically induced liver carcinogenesis. Novel methods to perform programmed genomic edition and more efficient techniques to isolate circulating microvesicles offer new opportunities for establishing useful experimental tools for understanding the resistance to chemotherapy in PLCs. In the present review, using three criteria for information organization: (1) level of research; (2) type of MOC; and (3) type of PLC, we have summarized the advantages and limitations of the armamentarium available in the field of pharmacological investigation of PLC chemoresistance.
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27
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Liu WT, Liu WB, Gao M, Zhang YY, Gu KS. Expression of ALDH1A1 and CD133 is associated with the prognosis and effect of different chemotherapeutic regimens in gastric cancer. Oncol Lett 2019; 18:4573-4582. [PMID: 31611965 PMCID: PMC6781782 DOI: 10.3892/ol.2019.10798] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 07/26/2019] [Indexed: 12/20/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors worldwide. Previous studies have reported that aldehyde dehydrogenase-1A1 (ALDH1A1) and cluster of differentiation (CD)-133 are considered to be cancer stem cell markers in GCs. The present study immunohistochemically examined the distribution and expression of two tumor stem cell markers, CD133 and ALDH1A1, in both primary tumors and para-tumor tissues. In 91 cases with stage III, 57 (62%) were positive for ALDH1A1 and 60 (66%) were positive for CD133. ALDH1A1 was detected in para-tumors and cancerous tissues of the stomach, and the immunoreactivity of the tumors was stronger than that in para-tumor tissues. CD133 was only detected in tumors. The expression of ALDH1A1 was significantly associated with advanced T/N stage (T stage, P=0.012; N stage, P=0.023) and poor differentiation (P=0.020), while CD133 was associated with advanced T stage (P=0.007). Univariate and multivariate Cox proportional hazards analysis revealed that tumor stage, CD133 expression, vascular invasion and sex were independent predictors of disease-free survival (DFS) time, and tumor size, vascular invasion and sex were independent predictors of overall survival (OS) time in patients with GC. Patients with CD133+ GC had poorer DFS (P=0.042), while ALDH1A1+ GC was not associated with poorer DFS. In regard to chemotherapy, improvements in survival were not observed after the addition of taxane compared with two-drug therapy. However, the subgroup analysis indicated that in the ALDH1A1− subgroup, and CD133+ and ALDH1A1− subgroups, an increased OS was observed in two-drug therapy (P=0.043). The results of the present study indicate that ALDH1A1 and CD133 may play an important role in tumor invasion, metastasis and prognosis, and ALDH1A1− expression does not benefit the taxane-based triple chemotherapeutic regimen in patients with GC.
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Affiliation(s)
- Wan-Ting Liu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Wen-Bo Liu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Min Gao
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Yi-Yin Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Kang-Sheng Gu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
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