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Liu P, Zhang Q, Liu F. Biological roles and clinical applications of EpCAM in HCC. Discov Oncol 2025; 16:319. [PMID: 40087210 PMCID: PMC11909382 DOI: 10.1007/s12672-025-02095-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 03/07/2025] [Indexed: 03/17/2025] Open
Abstract
Epithelial cell adhesion molecule (EpCAM) is an important biomarker in tumors. In hepatocellular carcinoma (HCC), EpCAM + cells exhibit high invasiveness, tumorigenic ability, therapeutic resistance, and self-renewal ability, often identified as liver cancer stem cells (CSCs). Detecting EpCAM + cells in tumor lesions and circulation is valuable for predicting patient prognosis and monitoring therapeutic outcomes, emphasizing its clinical significance. Given its broad expression in HCC, especially in CSCs and circulating tumor cells (CTCs), EpCAM-targeting agents have garnered substantial research interest. However, the role of EpCAM in HCC progression and its regulatory mechanisms remains poorly understood. Furthermore, clinical applications of EpCAM, such as liquid biopsy and targeted therapies, are still controversial. This review summarizes the biological properties of EpCAM + HCC cells, explores the regulatory mechanisms governing EpCAM expression, and discusses its clinical significance of using EpCAM as a prognostic marker and therapeutic target.
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Affiliation(s)
- Peng Liu
- Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qun Zhang
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Fengchao Liu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
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2
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Jiang H, Qian C, Deng Y, Lv X, Liu Y, Li A, Li X. Novel Multimode Assay Based on Asymmetrically Competitive CRISPR and Raman Barcode Spectra for Multiple Hepatocellular Carcinoma Biomarkers Detection. Anal Chem 2024; 96:20004-20014. [PMID: 39641617 DOI: 10.1021/acs.analchem.4c04593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
Commercial pregnancy test strips (PTS) possess the advantages of lower price, higher stability, and better repeatability and have been popularized to integrate with novel sensing strategies to detect other disease biomarkers, which accelerates the commercialization process of those novel sensing strategies. However, the current integration of novel sensing strategies into commercial PTS still faced the problems of insufficient quantification, low sensitivity, and lack of multiple detection capabilities. Hence, we proposed the concept of "visual classification recognition, spectral signal subdivision" for multiple hepatocellular carcinoma biomarkers (miRNA122 and miRNA233) detection with dual signals based on asymmetric competitive CRISPR (acCRISPR) and surface-enhanced Raman spectroscopy coupling with PTS, named the acCRISPR-PTS-SERS assay. In this assay, acCRISPR was used as a nonamplified cascaded signal amplification method to improve the sensitivity of detection. Two AuNPs-based core-shell Raman tags, each corresponding to different miRNA biomarkers, were used to achieve both visual recognition and spectral segmentation to enhance the quantification of PTS detection and the capability for multiple detection. Under the optimal conditions, the LOD for miRNA122 and miRNA223 were 10.36 and 4.65 fM, respectively. The sensitivity was enhanced by nearly 2 orders of magnitude. In the future, simultaneous hand-held detection for fingerprint barcodes of different cancers can be achieved with the assistance of a microfluidic chip and smartphone.
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Affiliation(s)
- Hao Jiang
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China
| | - Cheng Qian
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China
| | - Yulin Deng
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China
| | - Xuefei Lv
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China
| | - Ying Liu
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China
| | - Anyi Li
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China
| | - Xiaoqiong Li
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China
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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: 7] [Impact Index Per Article: 7.0] [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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Gholamzad A, Khakpour N, Khosroshahi EM, Asadi S, Koohpar ZK, Matinahmadi A, Jebali A, Rashidi M, Hashemi M, Sadi FH, Gholamzad M. Cancer stem cells: The important role of CD markers, Signaling pathways, and MicroRNAs. Pathol Res Pract 2024; 256:155227. [PMID: 38490099 DOI: 10.1016/j.prp.2024.155227] [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: 11/28/2023] [Revised: 02/23/2024] [Accepted: 02/25/2024] [Indexed: 03/17/2024]
Abstract
For the first time, a subset of small cancer cells identified in acute myeloid leukemia has been termed Cancer Stem Cells (CSCs). These cells are notorious for their robust proliferation, self-renewal abilities, significant tumor-forming potential, spread, and resistance to treatments. CSCs are a global concern, as it found in numerous types of cancer, posing a real-world challenge today. Our review encompasses research on key CSC markers, signaling pathways, and MicroRNA in three types of cancer: breast, colon, and liver. These factors play a critical role in either promoting or inhibiting cancer cell growth. The reviewed studies have shown that as cells undergo malignant transformation, there can be an increase or decrease in the expression of different Cluster of Differentiation (CD) markers on their surface. Furthermore, alterations in essential signaling pathways, such as Wnt and Notch1, may impact CSC proliferation, survival, and movement, while also providing potential targets for cancer therapies. Additionally, some research has focused on MicroRNAs due to their dual role as potential therapeutic biomarkers and their ability to enhance CSCs' response to anti-cancer drugs. MicroRNAs also regulate a wide array of cellular processes, including the self-renewal and pluripotency of CSCs, and influence gene transcription. Thus, these studies indicate that MicroRNAs play a significant role in the malignancy of various tumors. Although the gathered information suggests that specific CSC markers, signaling pathways, and MicroRNAs are influential in determining the destiny of cancer cells and could be advantageous for therapeutic strategies, their precise roles and impacts remain incompletely defined, necessitating further investigation.
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Affiliation(s)
- Amir Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Niloofar Khakpour
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences,Tonekabon Branch,Islamic Azad University, Tonekabon, Iran
| | - Arash Matinahmadi
- Department of Cellular and Molecular Biology, Nicolaus Copernicus,Torun,Poland
| | - Ali Jebali
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Deprtment of Medical Nanotechnology,Faculty of Advanced Sciences and Technology,Tehran Medical Sciences,Islamic Azad University, Tehran, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran.
| | | | - Mehrdad Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Fu Y, Mackowiak B, Feng D, Lu H, Guan Y, Lehner T, Pan H, Wang XW, He Y, Gao B. MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression. Gut 2023; 72:1942-1958. [PMID: 36593103 PMCID: PMC11283862 DOI: 10.1136/gutjnl-2022-327924] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2023]
Abstract
OBJECTIVE The current treatment for hepatocellular carcinoma (HCC) to block angiogenesis and immunosuppression provides some benefits only for a subset of patients with HCC, thus optimised therapeutic regimens are unmet needs, which require a thorough understanding of the underlying mechanisms by which tumour cells orchestrate an inflamed tumour microenvironment with significant myeloid cell infiltration. MicroRNA-223 (miR-223) is highly expressed in myeloid cells but its role in regulating tumour microenvironment remains unknown. DESIGN Wild-type and miR-223 knockout mice were subjected to two mouse models of inflammation-associated HCC induced by injection of diethylnitrosamine (DEN) or orthotopic HCC cell implantation in chronic carbon tetrachloride (CCl4)-treated mice. RESULTS Genetic deletion of miR-223 markedly exacerbated tumourigenesis in inflammation-associated HCC. Compared with wild-type mice, miR-223 knockout mice had more infiltrated programmed cell death 1 (PD-1+) T cells and programmed cell death ligand 1 (PD-L1+) macrophages after DEN+CCl4 administration. Bioinformatic analyses of RNA sequencing data revealed a strong correlation between miR-223 levels and tumour hypoxia, a condition that is well-documented to regulate PD-1/PD-L1. In vivo and in vitro mechanistic studies demonstrated that miR-223 did not directly target PD-1 and PD-L1 in immune cells rather than indirectly downregulated them by modulating tumour microenvironment via the suppression of hypoxia-inducible factor 1α-driven CD39/CD73-adenosine pathway in HCC. Moreover, gene delivery of miR-223 via adenovirus inhibited angiogenesis and hypoxia-mediated PD-1/PD-L1 activation in both HCC models, thereby hindering HCC progression. CONCLUSION The miR-223 plays a critical role in modulating hypoxia-induced tumour immunosuppression and angiogenesis, which may serve as a novel therapeutic target for HCC.
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Affiliation(s)
- Yaojie Fu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Hongkun Lu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Yukun Guan
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Taylor Lehner
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Hongna Pan
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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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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7
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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: 5] [Impact Index Per Article: 1.7] [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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8
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Panoramic view of microRNAs in regulating cancer stem cells. Essays Biochem 2022; 66:345-358. [PMID: 35996948 DOI: 10.1042/ebc20220007] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 12/17/2022]
Abstract
Cancer stem cells (CSCs) are a subgroup of tumor cells, possessing the abilities of self-renewal and generation of heterogeneous tumor cell lineages. They are believed to be responsible for tumor initiation, metastasis, as well as chemoresistance in human malignancies. MicroRNAs (miRNAs) are small noncoding RNAs that play essential roles in various cellular activities including CSC initiation and CSC-related properties. Mature miRNAs with ∼22 nucleotides in length are generated from primary miRNAs via its precursors by miRNA-processing machinery. Extensive studies have demonstrated that mature miRNAs modulate CSC initiation and stemness features by regulating multiple pathways and targeting stemness-related factors. Meanwhile, both miRNA precursors and miRNA-processing machinery can also affect CSC properties, unveiling a new insight into miRNA function. The present review summarizes the roles of mature miRNAs, miRNA precursors, and miRNA-processing machinery in regulating CSC properties with a specific focus on the related molecular mechanisms, and also outlines the potential application of miRNAs in cancer diagnosis, predicting prognosis, as well as clinical therapy.
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Pandrangi SL, Chittineedi P, Chalumuri SS, Meena AS, Neira Mosquera JA, Sánchez Llaguno SN, Pamuru RR, Mohiddin GJ, Mohammad A. Role of Intracellular Iron in Switching Apoptosis to Ferroptosis to Target Therapy-Resistant Cancer Stem Cells. Molecules 2022; 27:3011. [PMID: 35566360 PMCID: PMC9100132 DOI: 10.3390/molecules27093011] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/30/2022] [Accepted: 05/02/2022] [Indexed: 02/07/2023] Open
Abstract
Iron is a crucial element required for the proper functioning of the body. For instance, hemoglobin is the vital component in the blood that delivers oxygen to various parts of the body. The heme protein present in hemoglobin comprises iron in the form of a ferrous state which regulates oxygen delivery. Excess iron in the body is stored as ferritin and would be utilized under iron-deficient conditions. Surprisingly, cancer cells as well as cancer stem cells have elevated ferritin levels suggesting that iron plays a vital role in protecting these cells. However, apart from the cytoprotective role iron also has the potential to induce cell death via ferroptosis which is a non-apoptotic cell death dependent on iron reserves. Apoptosis a caspase-dependent cell death mechanism is effective on cancer cells however little is known about its impact on cancer stem cell death. This paper focuses on the molecular characteristics of apoptosis and ferroptosis and the importance of switching to ferroptosis to target cancer stem cells death thereby preventing cancer relapse. To the best of our knowledge, this is the first review to demonstrate the importance of intracellular iron in regulating the switching of tumor cells and therapy resistant CSCs from apoptosis to ferroptosis.
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Affiliation(s)
- Santhi Latha Pandrangi
- Onco-Stem Cell Research Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM Deemed to be University, Visakhapatnam 530045, India; (P.C.); (S.S.C.)
| | - Prasanthi Chittineedi
- Onco-Stem Cell Research Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM Deemed to be University, Visakhapatnam 530045, India; (P.C.); (S.S.C.)
| | - Sphoorthi Shree Chalumuri
- Onco-Stem Cell Research Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM Deemed to be University, Visakhapatnam 530045, India; (P.C.); (S.S.C.)
| | - Avtar Singh Meena
- CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500007, India;
| | - Juan Alejandro Neira Mosquera
- Department of Life Sciences and Agriculture, Armed Forces University-ESPE, Santo Domingo 230101, Ecuador; (J.A.N.M.); (S.N.S.L.)
- Faculty of Industry and Production Sciences, Quevedo State Technical University, km 11/2 via Santo Domingo, Quevedo 120301, Ecuador
| | - Sungey Naynee Sánchez Llaguno
- Department of Life Sciences and Agriculture, Armed Forces University-ESPE, Santo Domingo 230101, Ecuador; (J.A.N.M.); (S.N.S.L.)
| | | | - Gooty Jaffer Mohiddin
- Department of Life Sciences and Agriculture, Armed Forces University-ESPE, Santo Domingo 230101, Ecuador; (J.A.N.M.); (S.N.S.L.)
| | - Arifullah Mohammad
- Department of Agriculture Science, Faculty of Agro-Based Industry, Universiti Malaysia Kelantan, Jeli 17600, Malaysia
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Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications. Nat Rev Gastroenterol Hepatol 2022; 19:26-44. [PMID: 34504325 DOI: 10.1038/s41575-021-00508-3] [Citation(s) in RCA: 280] [Impact Index Per Article: 93.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. The cancer stem cell (CSC) model states that tumour growth is powered by a subset of tumour stem cells within cancers. This model explains several clinical observations in HCC (as well as in other cancers), including the almost inevitable recurrence of tumours after initial successful chemotherapy and/or radiotherapy, as well as the phenomena of tumour dormancy and treatment resistance. The past two decades have seen a marked increase in research on the identification and characterization of liver CSCs, which has encouraged the design of novel diagnostic and treatment strategies for HCC. These studies revealed novel aspects of liver CSCs, including their heterogeneity and unique immunobiology, which are suggestive of opportunities for new research directions and potential therapies. In this Review, we summarize the present knowledge of liver CSC markers and the regulators of stemness in HCC. We also comprehensively describe developments in the liver CSC field with emphasis on experiments utilizing single-cell transcriptomics to understand liver CSC heterogeneity, lineage-tracing and cell-ablation studies of liver CSCs, and the influence of the CSC niche and tumour microenvironment on liver cancer stemness, including interactions between CSCs and the immune system. We also discuss the potential application of liver CSC-based therapies for treatment of HCC.
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Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
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Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Espejo-Cruz ML, González-Rubio S, Zamora-Olaya J, Amado-Torres V, Alejandre R, Sánchez-Frías M, Ciria R, De la Mata M, Rodríguez-Perálvarez M, Ferrín G. Circulating Tumor Cells in Hepatocellular Carcinoma: A Comprehensive Review and Critical Appraisal. Int J Mol Sci 2021; 22:13073. [PMID: 34884878 PMCID: PMC8657934 DOI: 10.3390/ijms222313073] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/27/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and a major cause of cancer-related death worldwide. There is no ideal biomarker allowing early diagnosis of HCC and tumor surveillance in patients receiving therapy. Liquid biopsy, and particularly circulating tumor cells (CTCs), have emerged as a useful tool for diagnosis and monitoring therapeutic responses in different tumors. In the present manuscript, we evaluate the current evidence supporting the quantitative and qualitative assessment of CTCs as potential biomarkers of HCC, as well as technical aspects related to isolation, identification, and classification of CTCs. Although the dynamic assessment of CTCs in patients with HCC may aid the decision-making process, there are still many uncertainties and technical caveats to be solved before this methodology has a true impact on clinical practice guidelines. More studies are needed to identify the optimal combination of surface markers, to increase the efficiency of ex-vivo expansion of CTCs, or even to target CTCs as a potential therapeutic strategy to prevent HCC recurrence after surgery or to hamper tumor progression and extrahepatic spreading.
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Affiliation(s)
- María Lola Espejo-Cruz
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
| | - Sandra González-Rubio
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
| | - Javier Zamora-Olaya
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
| | - Víctor Amado-Torres
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
| | - Rafael Alejandre
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
| | - Marina Sánchez-Frías
- Department of Pathology, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain;
| | - Rubén Ciria
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, 14004 Córdoba, Spain
| | - Manuel De la Mata
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - Manuel Rodríguez-Perálvarez
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - Gustavo Ferrín
- Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; (M.L.E.-C.); (S.G.-R.); (J.Z.-O.); (V.A.-T.); (R.A.); (R.C.); (M.D.l.M.); (G.F.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
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13
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Cable J, Pei D, Reid LM, Wang XW, Bhatia S, Karras P, Melenhorst JJ, Grompe M, Lathia JD, Song E, Kuo CJ, Zhang N, White RM, Ma SK, Ma L, Chin YR, Shen MM, Ng IOL, Kaestner KH, Zhou L, Sikandar S, Schmitt CA, Guo W, Wong CCL, Ji J, Tang DG, Dubrovska A, Yang C, Wiedemeyer WR, Weissman IL. Cancer stem cells: advances in biology and clinical translation-a Keystone Symposia report. Ann N Y Acad Sci 2021; 1506:142-163. [PMID: 34850398 PMCID: PMC9153245 DOI: 10.1111/nyas.14719] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 12/16/2022]
Abstract
The test for the cancer stem cell (CSC) hypothesis is to find a target expressed on all, and only CSCs in a patient tumor, then eliminate all cells with that target that eliminates the cancer. That test has not yet been achieved, but CSC diagnostics and targets found on CSCs and some other cells have resulted in a few clinically relevant therapies. However, it has become apparent that eliminating the subset of tumor cells characterized by self-renewal properties is essential for long-term tumor control. CSCs are able to regenerate and initiate tumor growth, recapitulating the heterogeneity present in the tumor before treatment. As great progress has been made in identifying and elucidating the biology of CSCs as well as their interactions with the tumor microenvironment, the time seems ripe for novel therapeutic strategies that target CSCs to find clinical applicability. On May 19-21, 2021, researchers in cancer stem cells met virtually for the Keystone eSymposium "Cancer Stem Cells: Advances in Biology and Clinical Translation" to discuss recent advances in the understanding of CSCs as well as clinical efforts to target these populations.
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Affiliation(s)
| | - Duanqing Pei
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou, China
| | - Lola M Reid
- Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, and Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sonam Bhatia
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | - Panagiotis Karras
- Laboratory for Molecular Cancer Biology, Center for Cancer Biology and Laboratory for Molecular Cancer Biology, Department of Oncology, Leuven, Belgium
| | - Jan Joseph Melenhorst
- Glioblastoma Translational Center of Excellence, The Abramson Cancer Center and Department of Pathology & Laboratory Medicine, Perelman School of Medicine and Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Markus Grompe
- Department of Molecular and Medical Genetics, Department of Pediatrics, and Oregon Stem Cell Center, Oregon Health & Science University, Portland, Oregon
| | - Justin D Lathia
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Erwei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center and Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Bioland Laboratory; Program of Molecular Medicine, Zhongshan School of Medicine, Sun Yat-Sen University; and Fountain-Valley Institute for Life Sciences, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Calvin J Kuo
- Division of Hematology, Department of Medicine, Stanford University, Stanford, California
| | - Ning Zhang
- Translational Cancer Research Center, Peking University First Hospital, Beijing, China
| | - Richard M White
- Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Stephanie Ky Ma
- School of Biomedical Sciences and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Lichun Ma
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Y Rebecca Chin
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Michael M Shen
- Departments of Medicine, Genetics and Development, Urology, and Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York
| | - Irene Oi Lin Ng
- Department of Pathology and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Klaus H Kaestner
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lei Zhou
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, Hong Kong
| | - Shaheen Sikandar
- Institute for the Biology of Stem Cells, University of California, Santa Cruz, Santa Cruz, California
| | - Clemens A Schmitt
- Charité - Universitätsmedizin Berlin, Hematology/Oncology, and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany, and Johannes Kepler University, Kepler Universitätsklinikum, Hematology/Oncology, Linz, Austria
| | - Wei Guo
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Carmen Chak-Lui Wong
- Department of Pathology and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Junfang Ji
- MOE Key Laboratory of Biosystems Homeostasis & Protection, and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Dean G Tang
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, and Experimental Therapeutics (ET) Graduate Program, University at Buffalo, Buffalo, New York
| | - Anna Dubrovska
- OncoRay National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, Heidelberg, Germany
| | - Chunzhang Yang
- Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland
| | | | - Irving L Weissman
- Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, California
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14
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Wu J, Zhou X, Li P, Lin X, Wang J, Hu Z, Zhang P, Chen D, Cai H, Niessner R, Haisch C, Sun P, Zheng Y, Jiang Z, Zhou H. Ultrasensitive and Simultaneous SERS Detection of Multiplex MicroRNA Using Fractal Gold Nanotags for Early Diagnosis and Prognosis of Hepatocellular Carcinoma. Anal Chem 2021; 93:8799-8809. [PMID: 34076420 DOI: 10.1021/acs.analchem.1c00478] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Sensitive and simultaneous detection of multiple cancer-related biomarkers in serum is essential for diagnosis, therapy, prognosis, and staging of cancer. Herein, we proposed a magnetically assisted sandwich-type surface-enhanced Raman scattering (SERS)-based biosensor for ultrasensitive and multiplex detection of three hepatocellular carcinoma-related microRNA (miRNA) biomarkers. The biosensor consists of an SERS tag (probe DNA-conjugated DNA-engineered fractal gold nanoparticles, F-AuNPs) and a magnetic capture substrate (capture DNA-conjugated Ag-coated magnetic nanoparticles, AgMNPs). The proposed strategy achieved simultaneous and sensitive detection of three miRNAs (miRNA-122, miRNA-223, and miRNA-21), and the limits of detection of the three miRNAs in human serum are 349 aM for miRNA-122, 374 aM for miRNA-223, and 311 aM for miRNA-21. High selectivity and accuracy of the SERS biosensor were proved by practical analysis in human serum. Moreover, the biosensor exhibited good practicability in multiplex detection of three miRNAs in 92 clinical sera from AFP-negative patients, patients before and after hepatectomy, recurred and relapse-free patients after hepatectomy, and hepatocellular carcinoma patients at distinct Barcelona clinic liver cancer stages. The experiment results demonstrate that our SERS-based assay is a promising candidate in clinical application and exhibited potential for the prediction, diagnosis, monitoring, and staging of cancers.
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Affiliation(s)
- Jiamin Wu
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
| | - Xia Zhou
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
| | - Ping Li
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
| | - Xiaoling Lin
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
| | - Jinhua Wang
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
| | - Ziwei Hu
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
| | - Pengcheng Zhang
- College of Chemistry and Chemical Engineering, Zhoukou Normal University, Zhoukou, Henan 466000, China
| | - Dong Chen
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Huaihong Cai
- College of Chemistry and Materials Science, Jinan University, Guangzhou, Guangdong 510632, China
| | - Reinhard Niessner
- Institute of Hydrochemistry and Chair for Analytical Chemistry, Technical University of Munich, Marchioninistr. 17, Munich D-81377, Germany
| | - Christoph Haisch
- Institute of Hydrochemistry and Chair for Analytical Chemistry, Technical University of Munich, Marchioninistr. 17, Munich D-81377, Germany
| | - Pinghua Sun
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
| | - Yun Zheng
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Zhengjin Jiang
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
| | - Haibo Zhou
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
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15
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Emam AA, Abo-Elkhair SM, Sobh M, El-Sokkary AMA. Role of exopolysaccharides (EPSs) as anti-Mir-155 in cancer cells. Heliyon 2021; 7:e06698. [PMID: 33869874 PMCID: PMC8045046 DOI: 10.1016/j.heliyon.2021.e06698] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 02/25/2021] [Accepted: 03/31/2021] [Indexed: 11/29/2022] Open
Abstract
Micro-RNAs (MiRNAs) are a class of small non-coding RNAs that regulate cellular gene expression. MiR-155 overexpression has been implicated in many types of cancer. Besides, miR-155 appears to help tumor invasion and migration and works as a moderator of epithelial-to-mesenchymal transition (EMT). Exopolysaccharides (EPSs) are a large group of natural heterogeneous polymers of sugars with a biologically antitumor effect. Herein, we test a hypothesis that EPS might promote its anti-tumorigenic effect via regulating miR-155 expression and its target pathways. Expression of miR-155 and a panel of targeted genes were investigated by real-time PCR. In our study, we have succeeded in the extraction, purification of exopolysaccharide with great cytotoxicity to different cancer cell lines, HepG II, Caco-2, and MCF-7. We reported that EPSs have a suppression effect on the oncogenic miR-155. In conclusion, this work clarifies a new possible mechanism for the anti-tumorigenic effect of EPSs in cancer cells and provides insights into the biological pathways through which EPSs act. Moreover, it paves the way for new prospective cancer therapeutics as anti-miRNA.
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Affiliation(s)
- Ahmed A Emam
- Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Egypt
| | - Salwa M Abo-Elkhair
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Egypt
| | - Mohamed Sobh
- Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Egypt.,Urology and Nephrology Center, Faculty of Medicine, Mansoura University, Egypt
| | - Ahmed M A El-Sokkary
- Biochemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Egypt
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Wang X, He Y, Mackowiak B, Gao B. MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut 2021; 70:784-795. [PMID: 33127832 DOI: 10.1136/gutjnl-2020-322526] [Citation(s) in RCA: 291] [Impact Index Per Article: 72.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/01/2020] [Accepted: 10/09/2020] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression by binding to specific mRNA targets and promoting their degradation and/or translational inhibition. miRNAs regulate both physiological and pathological liver functions. Altered expression of miRNAs is associated with liver metabolism dysregulation, liver injury, liver fibrosis and tumour development, making miRNAs attractive therapeutic strategies for the diagnosis and treatment of liver diseases. Here, we review recent advances regarding the regulation and function of miRNAs in liver diseases with a major focus on miRNAs that are specifically expressed or enriched in hepatocytes (miR-122, miR-194/192), neutrophils (miR-223), hepatic stellate cells (miR-29), immune cells (miR-155) and in circulation (miR-21). The functions and target genes of these miRNAs are emphasised in alcohol-associated liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis and hepatocellular carcinoma, as well liver fibrosis and liver failure. We touch on the roles of miRNAs in intercellular communication between hepatocytes and other types of cells via extracellular vesicles in the pathogenesis of liver diseases. We provide perspective on the application of miRNAs as biomarkers for early diagnosis, prognosis and assessment of liver diseases and discuss the challenges in miRNA-based therapy for liver diseases. Further investigation of miRNAs in the liver will help us better understand the pathogeneses of liver diseases and may identify biomarkers and therapeutic targets for liver diseases in the future.
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Affiliation(s)
- Xiaolin Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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17
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Gu Y, Ji F, Liu N, Zhao Y, Wei X, Hu S, Jia W, Wang XW, Budhu A, Ji J, Zhao B, Roessler S, Zheng X, Ji J. Loss of miR-192-5p initiates a hyperglycolysis and stemness positive feedback in hepatocellular carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:268. [PMID: 33256802 PMCID: PMC7708108 DOI: 10.1186/s13046-020-01785-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 11/20/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Emerging studies revealed that cancer stem cells (CSCs) possessed peculiar metabolic properties, which however remained largely unknown in hepatocellular carcinoma (HCC). Genetic silencing of liver-abundant miR-192-5p was a key feature for multiple groups of CSC-positive HCCs. We thus aimed to investigate essential metabolic features of hepatic CSCs via using HCCs with miR-192-5p silencing as a model. METHODS Datasets from two independent HCC cohorts were used. Data integration analyses of miR-192-5p with metabolome and mRNA transcriptome data in HCC Cohort 1 were performed to investigate miR-192-5p related metabolic features, which was further validated in Cohort 2. Cellular and molecular assays were performed to examine whether and how miR-192-5p regulated the identified metabolic features. Co-culture systems consisting of HCC cells and LX2 (human hepatic stellate cell line) or THP1 (human monocyte cell line) were established to explore effects of the identified metabolic properties on stemness features of HCC cells via interacting with co-cultured non-tumor cells. RESULTS High levels of glycolysis-related metabolites and genes were present in HCCs with low miR-192-5p and CSC-positive HCCs in two independent HCC cohorts. miR-192-5p knockout cells displayed CSC features and miR-192-5p loss led to an enhanced glycolytic phenotype via upregulating three bona fide targets, GLUT1 and PFKFB3 (two glycolytic enzymes) and c-Myc (regulating glycolytic genes' expression). Meanwhile, c-Myc suppressed miR-192-5p transcription, ensuring a low-miR-192-5p/high-c-Myc loop to maintain hyperglycolysis. Moreover, over-produced lactic acid from hyperglycolytic HCC cells stimulated the ERK phosphorylation of co-cultured LX2 and THP1 non-tumor cells partially via NDRG3 and MCT1, which in turn promoted cell malignancy and stemness of HCC cells. Consistently, HCC patients with low level of miR-192-5p in their tumor tissues and high level of NDRG3 or MCT1 in their non-tumor tissues had the shortest overall survival. CONCLUSIONS In CSC-positive HCCs, miR-192-5p loss enhanced glycolysis and over produced lactate might further increase HCC malignant features via interacting with environmental non-tumor cells.
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Affiliation(s)
- Yuanzhuo Gu
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Fubo Ji
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Niya Liu
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Yongzhi Zhao
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Xiyang Wei
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Shiyuan Hu
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Wei Jia
- Hong Kong Baptist University, HongKong, China
| | - Xin Wei Wang
- Liver Carcinogenesis Section, The Lab of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Anuradha Budhu
- Liver Carcinogenesis Section, The Lab of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Juling Ji
- Department of Pathology, Medical School of Nantong University, Nantong, 226019, Jiangsu Province, China
| | - Bin Zhao
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Xin Zheng
- EZKIT L.L.C, Honolulu, HI, 96825, USA
| | - Junfang Ji
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China.
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18
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Li J, Zhu Y. Recent Advances in Liver Cancer Stem Cells: Non-coding RNAs, Oncogenes and Oncoproteins. Front Cell Dev Biol 2020; 8:548335. [PMID: 33117795 PMCID: PMC7575754 DOI: 10.3389/fcell.2020.548335] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 09/14/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide, with high morbidity, relapse, metastasis and mortality rates. Although liver surgical resection, transplantation, chemotherapy, radiotherapy and some molecular targeted therapeutics may prolong the survival of HCC patients to a certain degree, the curative effect is still poor, primarily because of tumor recurrence and the drug resistance of HCC cells. Liver cancer stem cells (LCSCs), also known as liver tumor-initiating cells, represent one small subset of cancer cells that are responsible for disease recurrence, drug resistance and death. Therefore, understanding the regulatory mechanism of LCSCs in HCC is of vital importance. Thus, new studies that present gene regulation strategies to control LCSC differentiation and replication are under development. In this review, we provide an update on the latest advances in experimental studies on non-coding RNAs (ncRNAs), oncogenes and oncoproteins. All the articles addressed the crosstalk between different ncRNAs, oncogenes and oncoproteins, as well as their upstream and downstream products targeting LCSCs. In this review, we summarize three pathways, the Wnt/β-catenin signaling pathway, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, and interleukin 6/Janus kinase 2/signal transducer and activator of transcription 3 (IL6/JAK2/STAT3) signaling pathway, and their targeting gene, c-Myc. Furthermore, we conclude that octamer 4 (OCT4) and Nanog are two important functional genes that play a pivotal role in LCSC regulation and HCC prognosis.
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Affiliation(s)
- Juan Li
- Department of Radiotherapy Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ying Zhu
- Department of Infectious Disease, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Liver Disease Center of Integrated Traditional and Western Medicine, Institute of Integrative Medicine, Dalian Medical University, Dalian, China
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miR-876 Inhibits EMT and Liver Fibrosis via POSTN to Suppress Metastasis in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1964219. [PMID: 33083453 PMCID: PMC7559219 DOI: 10.1155/2020/1964219] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 07/19/2020] [Accepted: 08/14/2020] [Indexed: 02/06/2023]
Abstract
Background The asymptomatic onset, frequent recurrence, and poor prognosis of hepatocellular carcinoma (HCC) prompted us to identify new therapeutic targets or predictive markers of HCC diagnosis or prognosis. Methods In this study, bioinformatics analysis was used to screen for target miRNAs from the open-access TCGA database. Transwell assays, Western blotting, and qRT-PCR analyses were used to detect cellular functions and gene expression in HCC cells and samples. A nude mouse tumorigenesis model was established to facilitate the observation of HCC progression. Other assays included luciferase reporter assays, IHC, and survival analysis. Results We found that the identified miR-876 from TCGA was expressed at low levels in HCC cell lines and that low miR-876 expression was corrected with liver cirrhosis, tumor thrombus, and TNM stage. Further research revealed that miR-876 regulated cell invasion, EMT, and collagen expression by targeting POSTN expression. miR-876 and POSTN were inversely correlated in HCC samples and associated with EMT status and liver fibrosis in clinical HCC tissues. miR-876 inhibited the liver cancer progression in in vivo animal assays. Finally, both miR-876 and POSTN were risk factors for HCC survival, and HCC patients with combined low miR-876 and high POSTN expression had worse prognosis. Conclusions miR-876 inhibited HCC EMT and fibrosis by targeting POSTN, thus affecting HCC progression and prognosis. miR-876 and POSTN may be useful therapeutic targets or prognostic markers of HCC.
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Clinicopathological significance of miR-27b targeting Golgi protein 73 in patients with hepatocellular carcinoma. Anticancer Drugs 2020; 30:186-194. [PMID: 30418194 DOI: 10.1097/cad.0000000000000711] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Using five bioinformatics analysis software, we identified Golgi protein 73 (GP73) as a putative target of microRNA-27b (miR-27b), which is closely related to various biological processes or diseases such as bone metabolism disease, adipose cell and muscle cell development, pulmonary hypertension, cervical cancer, and breast cancer. However, the clinical significance of miR-27b in hepatocellular carcinoma (HCC) is still unclear. The differential expression of miR-27b in HCC and adjacent normal liver tissues was measured by quantitative reverse transcription PCR. Our results showed that the expression of miR-27b in tumor tissues is lower than that in adjacent nontumor tissues. The expression of miR-27b was significantly lower in HCC tissues with high expression of GP73, when compared with adjacent nontumor tissues. Moreover, down-regulated expression of miR-27b was closely correlated with serum GP73, tumor-node-metastasis stage, tumor size, and portal vein thrombosis. GP73 mRNA might be a target of miR-27b. The 5-year overall survival rate of the low miR-27b expression group was significantly lower than that of the high miR-27b expression group. Moreover, multivariate analysis of prognostic factors, with a Cox proportional hazards model, showed that low miR-27b expression was a significant and independent predictor of poor survival in HCC. Hence, the abnormal expression of miR-27b might be related to the occurrence and development of tumors. Similarly, a study in the Cancer Genome Atlas database demonstrated that the expression of miR-27b in 50 normal individuals was 1.6 times higher than that of 372 patients with liver cancer. The overall survival rate of the low GP73 expression group (275 liver cancer patients) was significantly longer than that of the high GP73 expression group (90 normal individuals). MiR-27b suppresses the expression of GP73 and is therefore a potential prognostic biomarker and therapy target in HCC.
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Xu J, An P, Winkler CA, Yu Y. Dysregulated microRNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Potential as Biomarkers and Therapeutic Targets. Front Oncol 2020; 10:1271. [PMID: 32850386 PMCID: PMC7399632 DOI: 10.3389/fonc.2020.01271] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/19/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are non-coding small RNAs that can function as gene regulators and are involved in tumorigenesis. We review the commonly dysregulated miRNAs in liver tumor tissues and plasma/serum of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. The frequently reported up-regulated miRNAs in liver tumor tissues include miR-18a, miR-21, miR-221, miR-222, and miR-224, whereas down-regulated miRNAs include miR-26a, miR-101, miR-122, miR-125b, miR-145, miR-199a, miR-199b, miR-200a, and miR-223. For a subset of these miRNAs (up-regulated miR-222 and miR-224, down-regulated miR-26a and miR-125b), the pattern of dysregulated circulating miRNAs in plasma/serum is mirrored in tumor tissue based on multiple independent studies. Dysregulated miRNAs target oncogenes or tumor suppressor genes involved in hepatocarcinogenesis. Normalization of dysregulated miRNAs by up- or down-regulation has been shown to inhibit HCC cell proliferation or sensitize liver cancer cells to chemotherapeutic treatment. miRNAs hold as yet unrealized potential as biomarkers for early detection of HCC and as precision therapeutic targets, but further studies in diverse populations and across all stages of HCC are needed.
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Affiliation(s)
- Jinghang Xu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking University, Beijing, China
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Ping An
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Cheryl A. Winkler
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Yanyan Yu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking University, Beijing, China
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Gu Y, Zheng X, Ji J. Liver cancer stem cells as a hierarchical society: yes or no? Acta Biochim Biophys Sin (Shanghai) 2020; 52:723-735. [PMID: 32490517 DOI: 10.1093/abbs/gmaa050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer stem cells (CSCs) are cells possessing abilities of self-renewal, differentiation, and tumorigenicity in NOD/SCID mice. Based on this definition, multiple cell surface markers (such as CD24, CD133, CD90, and EpCAM) as well as chemical methods are discovered to enrich liver CSCs in the recent decade. Accumulated studies have revealed molecular signatures and signaling pathways involved in regulating different liver CSCs. Among liver CSCs positive for different markers, some molecular features and regulatory pathways are commonly shared, while some are only unique in certain CSC populations. These studies imply that liver CSCs exhibit diverse heterogeneity, while a functional relationship also exists. The aim of this review is to revisit the society of liver CSCs and summarize the common or unique molecular features of known liver CSCs. We hope to call for attention of researchers on the relationship of the liver CSC subgroups and to provide clues on the hierarchical structure of the liver CSC society.
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Affiliation(s)
- Yuanzhuo Gu
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xin Zheng
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Junfang Ji
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
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Shao Z, Pan Q, Zhang Y. Hepatocellular carcinoma cell-derived extracellular vesicles encapsulated microRNA-584-5p facilitates angiogenesis through PCK1-mediated nuclear factor E2-related factor 2 signaling pathway. Int J Biochem Cell Biol 2020; 125:105789. [PMID: 32522621 DOI: 10.1016/j.biocel.2020.105789] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/22/2020] [Accepted: 06/05/2020] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is a fatal disease characterized by poor liver function with increasing morbidity and poor prognosis. Extracellular vesicles, released by different cells, have been associated with HCC development. Nevertheless, the mechanisms beyond extracellular vesicles in HCC remain uncharacterized. Therefore, the current study aimed to clarify the mechanism of pro-angiogenic microRNA-584-5p in hepatocellular carcinoma. Our results showed that miR-584-5p was highly-expressed in both cancer cells (Hep3B) and their extracellular vesicles. Hep3B and extracellular vesicles were then respectively co-cultured with human vascular endothelial cell line (Ea.hy926), and they both accelerated Ea.hy926 proliferation and migration. Ea.hy926 cells could internalize extracellular vesicles carrying microRNA-584-5p. Of note, microRNA-584-5p could bind to phosphoenolpyruvate carboxykinase 1 to promote nuclear factor E2-related factor 2. Moreover, silencing microRNA-584-5p was found to decline microvessel density, vascular endothelial growth factor A, and tumor growth in vivo and in vitro. Taken altogether, our findings demonstrated that extracellular vesicles-derived microRNA-584-5p promotes angiogenesis by inhibiting PCK1 -mediating NRF2 activation, which highlights the theoretical basis for potential treatments for HCC.
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Affiliation(s)
- Zigong Shao
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, Shenyang 110000, PR China; The Key Laboratory of Organ Transplantation of Liaoning Province, Shenyang 110000, PR China
| | - Qi Pan
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, Shenyang 110000, PR China; The Key Laboratory of Organ Transplantation of Liaoning Province, Shenyang 110000, PR China
| | - Yijie Zhang
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, Shenyang 110000, PR China; The Key Laboratory of Organ Transplantation of Liaoning Province, Shenyang 110000, PR China.
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Non-Coding RNAs: Regulating Disease Progression and Therapy Resistance in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12051243. [PMID: 32429062 PMCID: PMC7281199 DOI: 10.3390/cancers12051243] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/12/2020] [Accepted: 05/12/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the primary liver cancer arising from hepatocytes, is a universal health problem and one of the most common malignant tumors. Surgery followed by chemotherapy as well as tyrosine kinase inhibitors (TKIs), such as sorafenib, are primary treatment procedures for HCC, but recurrence of disease because of therapy resistance results in high mortality. It is necessary to identify novel regulators of HCC for developing effective targeted therapies that can significantly interfere with progression of the disease process. Non-coding RNAs (ncRNAs) are an abundant group of versatile RNA transcripts that do not translate into proteins, rather serve as potentially functional RNAs. The role of ncRNAs in regulating diverse aspects of the carcinogenesis process are gradually being elucidated. Recent advances in RNA sequencing technology have identified a plethora of ncRNAs regulating all aspects of hepatocarcinogenesis process and serving as potential prognostic or diagnostic biomarkers. The present review provides a comprehensive description of the biological roles of ncRNAs in disease process and therapy resistance, and potential clinical application of these ncRNAs in HCC.
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Zhou Y, Chen E, Tang Y, Mao J, Shen J, Zheng X, Xie S, Zhang S, Wu Y, Liu H, Zhi X, Ma T, Ni H, Chen J, Chai K, Chen W. miR-223 overexpression inhibits doxorubicin-induced autophagy by targeting FOXO3a and reverses chemoresistance in hepatocellular carcinoma cells. Cell Death Dis 2019; 10:843. [PMID: 31695022 PMCID: PMC6834650 DOI: 10.1038/s41419-019-2053-8] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 09/29/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023]
Abstract
Doxorubicin is conventionally used in chemotherapy against hepatocellular carcinoma (HCC), but acquired resistance developed during long-term therapy limits its benefits. Autophagy, a conserved catabolic process for cellular self-protection and adaptation to the changing environment, is regarded as a potential clinical target to overcome doxorubicin resistance. In this study, the potential role of miR-223 in modulating doxorubicin-induced autophagy and sensitivity were evaluated in four transfected human HCC cell lines, and the in vivo relevance was assessed using a mouse xenograft model of HCC. We found that the well-defined miR-223 is expressed at low levels in doxorubicin treated HCC cells and that miR-223 overexpression inhibits the doxorubicin-induced autophagy that contributes to chemoresistance. Blockade of autophagic flux by chloroquine resulted in the failure of miR-223 inhibitor to suppress doxorubicin sensitivity of HCC cells. We further identified FOXO3a as a direct downstream target of miR-223 and primary mediator of the regulatory effect of miR-223 on doxorubicin-induced autophagy and chemoresistance in HCC cells. Finally, we confirmed the enhancement of doxorubicin sensitivity by agomiR-223 in xenograft models of HCC. These findings establish a novel miRNA-based approach for autophagy interference to reverse doxorubicin resistance in future chemotherapy regimens against human HCC.
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Affiliation(s)
- Yue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University, School of Medicine, 310009, Hangzhou, Zhejiang, China
| | - Enjiang Chen
- The Second Affiliated Hospital of Zhejiang University, School of Medicine, 310009, Hangzhou, Zhejiang, China
| | - Yuexiao Tang
- Department of Genetics, Research Center for Molecular Medicine, Institute of Cell Biology, Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University School of Medicine, 310058, Hangzhou, Zhejiang, China
- Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, 310012, Hangzhou, Zhejiang, China
| | - Jiayan Mao
- Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, 310012, Hangzhou, Zhejiang, China
| | - Jian Shen
- Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, 310012, Hangzhou, Zhejiang, China
| | - Xiaoxiao Zheng
- Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, 310012, Hangzhou, Zhejiang, China
| | - Shangzhi Xie
- Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, 310012, Hangzhou, Zhejiang, China
| | - Shufen Zhang
- Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, 310012, Hangzhou, Zhejiang, China
| | - Ying Wu
- Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, 310012, Hangzhou, Zhejiang, China
| | - Hao Liu
- Department of Surgery, Anschutz Medical Campus, University of Colorado, Aurora, CO, 80045, USA
| | - Xiao Zhi
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University, School of Medicine, 310009, Hangzhou, Zhejiang, China
| | - Tao Ma
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University, School of Medicine, 310009, Hangzhou, Zhejiang, China
| | - Haibin Ni
- Department of Gastrointestinal Surgery, Tongde Hospital of Zhejiang Province, 310012, Hangzhou, Zhejiang, China
| | - Jiabin Chen
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, 310012, Hangzhou, Zhejiang, China
| | - Kequn Chai
- Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, 310012, Hangzhou, Zhejiang, China.
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, 310012, Hangzhou, Zhejiang, China.
| | - Wei Chen
- Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, 310012, Hangzhou, Zhejiang, China.
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, 310012, Hangzhou, Zhejiang, China.
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Sun JF, Zhang D, Gao CJ, Zhang YW, Dai QS. Exosome-Mediated MiR-155 Transfer Contributes to Hepatocellular Carcinoma Cell Proliferation by Targeting PTEN. Med Sci Monit Basic Res 2019; 25:218-228. [PMID: 31645540 PMCID: PMC6827328 DOI: 10.12659/msmbr.918134] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Most eukaryocytes release nano vesicles (30-120 nm), named exosomes, to various biological fluids such as blood, lymph, and milk. Hepatocellular carcinoma (HCC) is one of the tumors with the highest incidence rate in primary malignant carcinoma of the liver. However, the mechanism of HCC proliferation remains elusive. In this study, we aim to explore whether HCC cell-derived exosomes affect the proliferation of cancer cells. MATERIAL AND METHODS Exosomes were isolated from HCC cells by ultracentrifugation and were visualized the phenotype by transmission electron microscopy. Cell proliferation was detected by Cell Counting Kit-8 assays and EdU (5-ethynyl-2-deoxyuridine) incorporation assays. Dual-luciferase assays were performed to validate the paired correlation of miR-155 and 3'-UTR of PTEN (gene of phosphate and tension homology deleted on chromosome 10). A xenograft mice model was constructed to verify the effect of exosome-mediated miR-155 on cell proliferation in vivo. RESULTS Our finding showed that miR-155 was enriched in exosomes released from HCC cells. The exosome-containing miR-155 transferred into new HCC targeted cells and lead to the elevation of HCC cells' proliferation. Besides, the exosomal miR-155 directly bound to 3'-UTR of PTEN leading to the reduction of relevant targets in recipient liver cells. The knockdown of PTEN attenuated the proliferation of HCC cells treated with the exosomal miR-155. Moreover, nude-mouse experiment results revealed a promotional effect of the exosomal miR-155 on HCC cell-acquired xenografts. CONCLUSIONS Our study indicated that exosomal-specific miR-155 transfers to adjacent and/or more distant cells and stimulates the proliferation of HCC cells.
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Affiliation(s)
- Jing-Feng Sun
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China (mainland)
| | - Dong Zhang
- Department of General Surgery, GuanYun People's Hospital, Guanyun, Jiangsu, China (mainland)
| | - Cai-Jie Gao
- Pediatric Department, The Affiliated Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
| | - Ye-Wei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China (mainland)
| | - Qing-Song Dai
- Department of General Surgery, The Affiliated Sir RunRun Hospital of Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
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Dysregulation of liver developmental microRNA contribute to hepatic carcinogenesis. J Formos Med Assoc 2019; 119:1041-1051. [PMID: 31627983 DOI: 10.1016/j.jfma.2019.09.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/31/2019] [Accepted: 09/27/2019] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND/PURPOSE To investigate the role of microRNA (miRNA) dysregulation in liver cancer by assessing the miRNA profiles of human hepatic stem cells (HpSCs), marker-carrying human hepatoblastoma (HB) cells, and hepatocellular carcinoma (HCC) cells vs. those of fetal hepatocytes. METHODS We subjected human HCC and HB tumor specimens to immunohistochemical (IHC) staining for markers of HpSCs. We analyzed the miRNA patterns of HpSCs, HCC cells, HB cells, and fetal hepatocytes using microarray analysis, with confirmation via quantitative real-time polymerase chain reaction. The roles of the miRNAs in liver cancer stem cells (CSCs) were also elucidated. RESULTS The epithelial cell adhesion molecule (EpCAM) was the most prevalent HpSCs marker in human HB and HCC tumor cells and hepatoma cells. EpCAM-positive HB and HCC cells exhibited greater self-renewal and tumorigenicity than their EpCAM-negative counterparts or EpCAM-positive fetal hepatocytes. In EpCAM-positive fetal hepatocytes, miR-126 expression level increased with gestational age. The EpCAM-positive HB cells exhibited downregulation of miR-126 in comparison to EpCAM-positive fetal hepatocytes. An miR-126 mimic reduced sphere and colony formation in, and induced apoptosis of, HB cells. In comparison to EpCAM-positive fetal hepatocytes, EpCAM-positive HCC cells exhibited downregulation of miR-126, miR-144, and miR-451. Transfection of miR-126, miR-144, and miR-451 induced apoptosis of, and reduced sphere and colony formation in, HCC cells. CONCLUSION Dysregulation of liver developmental miRNAs, which exert a tumor suppressant effect, in EpCAM-positive HpSCs may contribute to liver carcinogenesis by promoting the transformation of HpSCs to CSCs of HB and HCC.
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microRNA-17 functions as an oncogene by downregulating Smad3 expression in hepatocellular carcinoma. Cell Death Dis 2019; 10:723. [PMID: 31558704 PMCID: PMC6763424 DOI: 10.1038/s41419-019-1960-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 08/06/2019] [Accepted: 09/04/2019] [Indexed: 02/06/2023]
Abstract
The sekelsky mothers against dpp3 (Smad3) functions as a transcriptional modulator activated by transforming growth factor-β (TGF-β). Accumulated evidences indicated that Smad3 played the important roles in carcinogenesis and progression of hepatocellular carcinoma (HCC). Up to now, the regulatory mechanism of Smad3 in HCC still remains unclear. It has been known that some particular microRNAs (miRNAs) involve in carcinogenesis through the regulation of gene expressions with targeting mRNAs. In our study, the unknown candidates of miRNAs that target Smad3 mRNA were searched by using a newly established in vivo approach, the miRNA in vivo precipitation (miRIP). Using a loss-of-function assay, we demonstrated that miR-17 directly targeted Smad3 in HCC cells and inhibition on miR-17 increased Smad3 expression. Furthermore, we found that downregulation on Smad3 expression was consistent with high level of miR-17 in HCC tissues of patients when compared with around normal liver tissues. The manipulated miR-17 silence in HCC cells suppressed their growth of both in vitro and in vivo. Such suppression on cell growth could be recovered through downregulating Smad3. In addition, miR-17 affected cell proliferation through arresting cell cycle in G1 phase. The negative correlation between levels of miR-17 and protein levels of Smad3 was supported by the results of analysis with HCC tissue chip. In summary, for the first time, we confirmed that miR-17 directly targeted Smad3 mRNA and downregulated Smad3 protein expression in HCC. Our results indicated that the increased expression of miR-17 promoted carcinogenesis of HCC through down-regulations of Smad3, suggesting miR-17 might serve as the potential diagnostic and therapeutic targets for clinical HCC.
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Yahyazadeh Mashhadi SM, Kazemimanesh M, Arashkia A, Azadmanesh K, Meshkat Z, Golichenari B, Sahebkar A. Shedding light on the EpCAM: An overview. J Cell Physiol 2019; 234:12569-12580. [DOI: 10.1002/jcp.28132] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 11/30/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Seyed Muhammad Yahyazadeh Mashhadi
- Department of Virology Pasteur Institute of Iran Tehran Iran
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences Mashhad Iran
- Production Expert at Samandaroo 8 (Biotech Pharmaceutical) Co. Mashhad Iran
| | | | - Arash Arashkia
- Department of Virology Pasteur Institute of Iran Tehran Iran
| | | | - Zahra Meshkat
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences Mashhad Iran
| | - Behrouz Golichenari
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences Mashhad Iran
| | - Amirhosein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences Mashhad Iran
- Neurogenic inflammation Research Center, Mashhad University of Medical Sciences Mashhad Iran
- School of Pharmacy, Mashhad University of Medical Sciences Mashhad Iran
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30
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Gu Y, Wei X, Sun Y, Gao H, Zheng X, Wong LL, Jin L, Liu N, Hernandez B, Peplowska K, Zhao X, Zhan QM, Feng XH, Tang ZY, Ji J. miR-192-5p Silencing by Genetic Aberrations Is a Key Event in Hepatocellular Carcinomas with Cancer Stem Cell Features. Cancer Res 2018; 79:941-953. [PMID: 30530815 DOI: 10.1158/0008-5472.can-18-1675] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 10/11/2018] [Accepted: 11/30/2018] [Indexed: 02/07/2023]
Abstract
Various cancer stem cell (CSC) biomarkers have been identified for hepatocellular carcinoma (HCC), but little is known about the implications of heterogeneity and shared molecular networks within the CSC population. Through miRNA profile analysis in an HCC cohort (n = 241) for five groups of CSC+ HCC tissues, i.e., EpCAM+, CD90+, CD133+, CD44+, and CD24+ HCC, we identified a 14-miRNA signature commonly altered among these five groups of CSC+ HCC. miR-192-5p, the top-ranked CSC miRNA, was liver-abundant and -specific and markedly downregulated in all five groups of CSC+ HCC from two independent cohorts (n = 613). Suppressing miR-192-5p in HCC cells significantly increased multiple CSC populations and CSC-related features through targeting PABPC4. Both TP53 mutation and hypermethylation of the mir-192 promoter impeded transcriptional activation of miR-192-5p in HCC cell lines and primary CSC+ HCC. This study reveals the circuit from hypermethylation of the mir-192 promoter through the increase in PABPC4 as a shared genetic regulatory pathway in various groups of primary CSC+ HCC. This circuit may be the driver that steers liver cells toward hepatic CSC cells, leading to hepatic carcinogenesis. SIGNIFICANCE: miR-192-5p and its regulatory pathway is significantly abolished in multiple groups of HCC expressing high levels of CSC markers, which may represent a key event for hepatic carcinogenesis.
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Affiliation(s)
- Yuanzhuo Gu
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Xiyang Wei
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yulin Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongjun Gao
- University of Hawai'i Cancer Center, Honolulu, Hawaii.,Clinical Laboratory, China Meitan General Hospital, Beijing, China
| | | | - Linda L Wong
- University of Hawai'i Cancer Center, Honolulu, Hawaii.,Department of Surgery, John A. Burns School of Medicine, University of Hawai'i, Honolulu, Hawaii
| | - Ling Jin
- University of Hawai'i Cancer Center, Honolulu, Hawaii
| | - Niya Liu
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | | | | | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qi-Min Zhan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xin-Hua Feng
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Zhao-You Tang
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Junfang Ji
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China.
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Chapman WC, Korenblat KM, Fowler KJ, Saad N, Khan AS, Subramanian V, Doyle MBM, Dageforde LA, Tan B, Grierson P, Lin Y, Xu M, Brunt EM. Hepatocellular carcinoma: Where are we in 2018? Curr Probl Surg 2018; 55:450-503. [PMID: 30526875 DOI: 10.1067/j.cpsurg.2018.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- William C Chapman
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO.
| | - Kevin M Korenblat
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | | | - Nael Saad
- University of Rochester, Rochester, NY
| | - Adeel S Khan
- Division of Abdominal Transplant Surgery, Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | - Vijay Subramanian
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | - Maria B Majella Doyle
- Barnes-Jewish Hospital, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO
| | - Leigh Anne Dageforde
- Harvard Medical School, Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA
| | - Benjamin Tan
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | - Patrick Grierson
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | - Yiing Lin
- Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
| | - Min Xu
- Department of Surgery, Washington University School of Medicine, St. Louis, MO
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Zhang J, Ye Y, Chang DW, Lin SH, Huang M, Tannir NM, Matin S, Karam JA, Wood CG, Chen ZN, Wu X. Global and Targeted miRNA Expression Profiling in Clear Cell Renal Cell Carcinoma Tissues Potentially Links miR-155-5p and miR-210-3p to both Tumorigenesis and Recurrence. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:2487-2496. [PMID: 30201497 PMCID: PMC6207099 DOI: 10.1016/j.ajpath.2018.07.026] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 06/26/2018] [Accepted: 07/10/2018] [Indexed: 12/23/2022]
Abstract
About 30% of patients undergoing nephrectomy for renal cell carcinoma (RCC) experience disease recurrence. We profiled miRNAs dysregulated in clear-cell (cc) RCC tumor tissues and predictive of recurrence. The expression levels of 800 miRNAs were assessed in paired tumor and normal tissues from a discovery cohort of 18 ccRCC patients. miRNAs found to be differentially expressed were examined in a validation set of 205 patients, using real-time quantitative PCR. Tumor-normal data from 64 patients in The Cancer Genome Atlas were used for external validation. Twenty-eight miRNAs were consistently dysregulated in tumor tissues. On dichotomized analysis, patients with high levels of miR-155-5p and miR-210-3p displayed an increased risk for ccRCC recurrence (hazard ratio, 2.64; 95% CI, 1.49 to 4.70; P = 0.0009; and hazard ratio, 1.80; 95% CI, 1.04 to 3.12; P = 0.036, respectively) and a shorter median recurrence-free survival time than did patients with low levels [P < 0.01 (log rank test)]. A risk score was generated based on the expression levels of miR-155-5p and miR-210-3p, and the trend test was significant (P = 0.005). On pathway analysis, target genes regulated by miR-155-5p and miR-210-3p were mainly enriched in inflammation-related pathways. We identified and validated multiple miRNAs dysregulated in ccRCC tissues; miR-155-5p and miR-210-3p were predictive of ccRCC recurrence, pointing to potential utility as biomarkers and underlying biological mechanisms.
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Affiliation(s)
- Jinhua Zhang
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas; College of Life Sciences and Bioengineering, School of Science, Beijing Jiaotong University, Beijing, China
| | - Yuanqing Ye
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David W Chang
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shu-Hong Lin
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Maosheng Huang
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nizar M Tannir
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Surena Matin
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jose A Karam
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Christopher G Wood
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zhi-Nan Chen
- College of Life Sciences and Bioengineering, School of Science, Beijing Jiaotong University, Beijing, China; Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer, Fourth Military Medical University, Xi'an, China
| | - Xifeng Wu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Noncoding RNAs in liver cancer stem cells: The big impact of little things. Cancer Lett 2018; 418:51-63. [DOI: 10.1016/j.canlet.2018.01.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 12/21/2017] [Accepted: 01/03/2018] [Indexed: 12/12/2022]
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Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications. Nat Rev Gastroenterol Hepatol 2018; 15:137-151. [PMID: 29317776 DOI: 10.1038/nrgastro.2017.169] [Citation(s) in RCA: 340] [Impact Index Per Article: 48.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading lethal malignancy worldwide. However, the molecular mechanisms underlying liver carcinogenesis remain poorly understood. Over the past two decades, overwhelming evidence has demonstrated the regulatory roles of different classes of non-coding RNAs (ncRNAs) in liver carcinogenesis related to a number of aetiologies, including HBV, HCV and NAFLD. Among the ncRNAs, microRNAs, which belong to a distinct class of small ncRNAs, have been proven to play a crucial role in the post-transcriptional regulation of gene expression. Deregulation of microRNAs has been broadly implicated in the inactivation of tumour-suppressor genes and activation of oncogenes in HCC. Modern high-throughput sequencing analyses have unprecedentedly identified a very large number of non-coding transcripts. Divergent groups of long ncRNAs have been implicated in liver carcinogenesis through interactions with DNA, RNA or proteins. Overall, ncRNAs represent a burgeoning field of cancer research, and we are only beginning to understand the importance and complicity of the ncRNAs in liver carcinogenesis. In this Review, we summarize the common deregulation of small and long ncRNAs in human HCC. We also comprehensively review the pathological roles of ncRNAs in liver carcinogenesis, epithelial-to-mesenchymal transition and HCC metastasis and discuss the potential applications of ncRNAs as diagnostic tools and therapeutic targets in human HCC.
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Hu Y, Guo X, Wang J, Liu Y, Gao H, Fan H, Nong X, Yang X, Liu M, Li S, Tang H. A novel microRNA identified in hepatocellular carcinomas is responsive to LEF1 and facilitates proliferation and epithelial-mesenchymal transition via targeting of NFIX. Oncogenesis 2018; 7:22. [PMID: 29472529 PMCID: PMC5833431 DOI: 10.1038/s41389-017-0010-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 10/27/2017] [Accepted: 11/08/2017] [Indexed: 12/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers. It has been demonstrated that various cellular microRNAs (miRNAs) play an important role in HCC development. Here, we analyzed the miRNA profile in HCC tissues by Solexa sequencing, and we identified a novel microRNA, miR-HCC1, which is upregulated in HCC tissues. Further experiments showed that miR-HCC1 promoted HCC cell proliferation in vivo and in vitro, and migration and invasion resulting from the epithelial-mesenchymal transition (EMT) process. Nuclear factor I/X (NFIX), which inhibited cell proliferation, migration and invasion in HCC cells, was identified as a direct and functional target of miR-HCC1. Furthermore, lymphoid enhancer binding factor 1 (LEF1), a transcription factor, was shown to bind the promoter of miR-HCC1 and activate its expression. Collectively, these results indicate that LEF1-upregulated miR-HCC1 functions as an oncogene through the negative regulation of NFIX expression, which links the LEF1/miR-HCC1/NFIX axis to contribute to cell proliferation, migration and invasion of HCC cells and could provide novel insights into miRNA function and hepatocarcinogenesis and potential biomarkers for HCC.
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Affiliation(s)
- Yaqi Hu
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Xu Guo
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Jinxia Wang
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Yankun Liu
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.,The Cancer Institute, Tangshan People's Hospital, 063001, Tangshan, China
| | - Huijie Gao
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Hongxia Fan
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | | | | | | | - Shengping Li
- Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, 510060, Guangzhou, China
| | - Hua Tang
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
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Zhang R, Zhang LJ, Yang ML, Huang LS, Chen G, Feng ZB. Potential role of microRNA‑223‑3p in the tumorigenesis of hepatocellular carcinoma: A comprehensive study based on data mining and bioinformatics. Mol Med Rep 2017; 17:2211-2228. [PMID: 29207133 PMCID: PMC5783470 DOI: 10.3892/mmr.2017.8167] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 10/02/2017] [Indexed: 02/07/2023] Open
Abstract
The aims of the present study were to examine the potential role of microRNA‑233‑3p (miR)‑223‑3p in the tumorigenesis of hepatocellular carcinoma (HCC), and to investigate its diagnostic accuracy and potential molecular mechanisms. The expression data of miR‑223‑3p in HCC were obtained from the Gene Expression Omnibus (GEO). Data for the precursor miR‑223 were obtained from The Cancer Genome Atlas (TCGA). The diagnostic role of miR‑223‑3p was identified by the receiver operating curve (ROC), and the diagnostic value of miR‑223‑3p in HCC was calculated from qualified reports in the literature. In addition, associated data from the GEO, TCGA and qualified experiments were pooled for comprehensive meta‑analysis. Genes, which intersected between online prediction databases, natural language processing and differentially expressed genes from TCGA were regarded as potential targets of miR‑223‑3p in HCC. The Gene Ontology enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes pathways of potential targets were performed using the Database for Annotation, Visualization and Integrated Discovery. The protein‑protein interactions were mapped using the Search Tool for the Retrieval of Interacting Genes. Among 15 qualified microarray data sets from GEO, seven showed that a significantly lower level of miR‑223‑3p was present in the HCC tissues, compared with that in non‑cancerous tissues (P<0.05). In addition, five GEO data sets revealed diagnostic values of miR‑223‑3p, with an area under the curve (AUC) of >0.80 (P<0.05). The diagnostic accuracy of the precursor miR‑223 in TCGA was also calculated (AUC=0.78, P<0.05). Similarly, the precursor miR‑223 showed a higher level of downregulation in HCC tissues, compared with that in healthy controls in TCGA (P<0.001). A summary ROC was also calculated as 0.89 (95% CI, 0.85‑0.91) in the meta‑analysis. A total of 72 potential targets were extracted, mainly involved in the terms 'microRNAs in cancer', 'ATP binding' and 'prostate cancer'. Five potential target genes were considered the hub genes of miR‑223‑3p in HCC, including checkpoint kinase 1, DNA methyltransferase 1, baculoviral IAP repeat containing 5, kinesin family member 23, and collagen, type I, α1. Based on TCGA, the hub genes were significantly upregulated in HCC (P<0.05). Collectively, these results showed that miR‑223‑3p may be crucial in HCC carcinogenesis showing high diagnostic accuracy, and may be mediated by several hub genes.
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Affiliation(s)
- Rui Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Li-Jie Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Mei-Ling Yang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Lan-Shan Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhen-Bo Feng
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Chen J, Li X, Cheng Q, Ning D, Ma J, Zhang Z, Chen X, Jiang L. Retracted
: Effects of cyclin D1 gene silencing on cell proliferation, cell cycle, and apoptosis of hepatocellular carcinoma cells. J Cell Biochem 2017; 119:2368-2380. [DOI: 10.1002/jcb.26400] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 08/30/2017] [Indexed: 12/19/2022]
Affiliation(s)
- Jin Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanP.R. China
| | - Xue Li
- Department of Clinical Immunology, School of Medical LaboratoryTianjin Medical UniversityTianjinP.R. China
| | - Qi Cheng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanP.R. China
| | - Deng Ning
- Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanP.R. China
| | - Jie Ma
- Department of Thyroid and Breast SurgeryJining No.1 People's HospitalJiningP.R. China
| | - Zhi‐Ping Zhang
- Department of Thyroid and Breast SurgeryJining No.1 People's HospitalJiningP.R. China
| | - Xiao‐Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanP.R. China
| | - Li Jiang
- Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanP.R. China
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Zhang Y, Zhao W, Han H, Li S, Chen D, Zhang Z. MicroRNA-31 suppresses the self-renewal capability of α2δ1 + liver tumor-initiating cells by targeting ISL1. Oncotarget 2017; 8:87647-87657. [PMID: 29152108 PMCID: PMC5675660 DOI: 10.18632/oncotarget.21140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 08/26/2017] [Indexed: 01/15/2023] Open
Abstract
Accumulating evidence demonstrates that miRNAs, a class of small non-coding RNAs, are involved in the regulation of tumor-initiating cells (TICs) which are considered to be the origin of cancer development according to the cancer stem cell hypothesis. We have previously identified that miR-31 may play suppressive roles in α2δ1+ hepatocellular carcinoma (HCC) TICs. Here, we confirm that the expression of miR-31 is significantly downregulated in α2δ1+ HCC TICs. Overexpression of miR-31 in α2δ1+ HCC TICs results in significant suppression of the self-renewal and tumorigenicity abilities of these cells. Conversely, knockdown the expression of miR-31 in PLC/PRF/5 cells is able to reprogram them into TICs with stem cell-like properties. Furthermore, the expression of ISL LIM Homeobox 1(ISL1), a transcription factor involved in recognition of undifferentiated cardiac progenitors, is negatively regulated by miR-31, and the luciferase reporters’ activities with the 3′-UTRs of ISL1 are inhibited significantly by miR-31. Collectively, our results suggest that miR-31 can negatively regulate the self-renewal ability of α2δ1+ liver TICs via silencing ISL1.
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Affiliation(s)
- Yuan Zhang
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Wei Zhao
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Haibo Han
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Sheng Li
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Dongji Chen
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Zhiqian Zhang
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
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Involvement of inflammation and its related microRNAs in hepatocellular carcinoma. Oncotarget 2017; 8:22145-22165. [PMID: 27888618 PMCID: PMC5400654 DOI: 10.18632/oncotarget.13530] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 11/02/2016] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed type of cancer. The tumor inflammatory microenvironment regulates almost every step towards liver tumorigenesis and subsequent progression, and regulation of the inflammation-related signaling pathways, cytokines, chemokines and non-coding RNAs influences the proliferation, migration and metastasis of liver tumor cells. Inflammation fine-tunes the cancer microenvironment to favor epithelial-mesenchymal transition, in which cancer stem cells maintain tumorigenic potential. Emerging evidence points to inflammation-related microRNAs as crucial molecules to integrate the complex cellular and molecular crosstalk during HCC progression. Thus understanding the mechanisms by which inflammation regulates microRNAs might provide novel and admissible strategies for preventing, diagnosing and treating HCC. In this review, we will update three hypotheses of hepatocarcinogenesis and elaborate the most predominant inflammation signaling pathways, i.e. IL-6/STAT3 and NF-κB. We also try to summarize the crucial tumor-promoting and tumor-suppressing microRNAs and detail how they regulate HCC initiation and progression and collaborate with other critical modulators in this review.
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Wang Z, Wu Z, Huang P. The function of miRNAs in hepatocarcinogenesis induced by hepatitis B virus X protein. Oncol Rep 2017. [DOI: 10.3892/or.2017.5716] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Fu X, Wen H, Jing L, Yang Y, Wang W, Liang X, Nan K, Yao Y, Tian T. MicroRNA-155-5p promotes hepatocellular carcinoma progression by suppressing PTEN through the PI3K/Akt pathway. Cancer Sci 2017; 108:620-631. [PMID: 28132399 PMCID: PMC5406601 DOI: 10.1111/cas.13177] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 01/17/2017] [Accepted: 01/24/2017] [Indexed: 12/12/2022] Open
Abstract
MicroRNA‐155‐5p (miR‐155‐5p) has been reported to play an oncogenic role in different human malignancies; however, its role in hepatocellular carcinoma (HCC) progression is not clearly understood. In this study, we used real‐time PCR in 20 rats with chemically‐induced HCC, 28 human HCC tissues, and the matched paracarcinoma tissues, and HCC cell lines to determine the expression patterns of miR‐155‐5p and PTEN mRNA. Algorithm‐based and experimental strategies, such as dual luciferase gene reporter assays, real‐time PCR and western blots were used to identify PTEN as a candidate miR‐155‐5p target. Gain‐ and loss‐of‐function experiments and administration of a PI3K/Akt pathway inhibitor (wortmannin) were used to identify the effects of miR‐155‐5p and PTEN in MTT assays, flow cytometric analysis, wound healing assays and transwell assays. The results showed that miR‐155‐5p was highly overexpressed; however, PTEN was underexpressed in the HCC rat models, human HCC tissues and cell lines. In addition, miR‐155‐5p upregulation and PTEN downregulation were significantly associated with TNM stage (P < 0.05). Through in vitro experiments, we found that miR‐155‐5p promoted proliferation, invasion and migration, but inhibited apoptosis in HCC by directly targeting the 3′‐UTR of PTEN. Western blots showed that miR‐155‐5p inactivated Bax and caspase‐9, but activated Bcl‐2 to inhibit apoptosis, and it activated MMP to promote migration and invasion via the PI3K/Akt pathway. A xenograft tumor model was used to demonstrate that miR‐155‐5p targets PTEN and activates the PI3K/Akt pathway in vivo as well. Our study highlighted the importance of miR‐155‐5p and PTEN associated with aggressive HCC both in vitro and in vivo.
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Affiliation(s)
- Xiao Fu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hongqing Wen
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Respiratory, Third Hospital of Xi'an, Xi'an, Shaanxi, China
| | - Li Jing
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yujuan Yang
- The third Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China
| | - Wenjuan Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xuan Liang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Kejun Nan
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yu Yao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Tao Tian
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Devhare PB, Steele R, Di Bisceglie AM, Kaplan DE, Ray RB. Differential Expression of MicroRNAs in Hepatitis C Virus-Mediated Liver Disease Between African Americans and Caucasians: Implications for Racial Health Disparities. Gene Expr 2017; 17:89-98. [PMID: 27765085 PMCID: PMC8751126 DOI: 10.3727/105221616x693594] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
African Americans (AAs) have higher hepatocellular carcinoma (HCC) mortality rates than Caucasian Americans (CAs). Chronic hepatitis C virus (HCV) infection leads to cirrhosis and HCC. HCV infection is highly prevalent in the AA population compared to other racial groups. AAs are also less likely to naturally clear HCV, potentially contributing to higher prevalence of HCV. However, the explanation for this disparity is currently unknown. Circulating microRNAs (miRNAs) in the blood are emerging as biomarkers for pathological conditions. Expression analysis of miRNAs in major racial groups would be important for optimizing personalized treatment strategies. Here we assessed the differential expression of circulatory miRNAs from HCV-infected AA and CA patients. We identified increased expression of miR-146a, miR-150, and miR-155 in HCV-infected AA patient sera compared to that of CA. Further analysis demonstrated that these miRNAs were significantly elevated in AA patients diagnosed with HCV-mediated HCC. Higher expression of miR-150 was also noted in cirrhosis and HCC in AA patients, which may serve as a predictor of liver disease progression in this population. The differential expression of miRNAs suggests that these miRNAs and their target genes could be useful to gain further mechanistic insight of racial disparity associated with HCV-mediated pathogenesis.
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Affiliation(s)
- Pradip B. Devhare
- *Department of Pathology, Saint Louis University, St. Louis, MO, USA
| | - Robert Steele
- *Department of Pathology, Saint Louis University, St. Louis, MO, USA
| | - Adrian M. Di Bisceglie
- †Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA
- ‡Saint Louis University Liver Center, Saint Louis University, St. Louis, MO, USA
| | - David E. Kaplan
- §Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ratna B. Ray
- *Department of Pathology, Saint Louis University, St. Louis, MO, USA
- †Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA
- ‡Saint Louis University Liver Center, Saint Louis University, St. Louis, MO, USA
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Hernandez-Alcoceba R, Fortes P. Cancer stem cell-associated microRNAs: searching for markers and targets in hepatocellular carcinoma. Transl Gastroenterol Hepatol 2017; 1:16. [PMID: 28138583 DOI: 10.21037/tgh.2016.03.11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 02/22/2016] [Indexed: 01/06/2023] Open
Affiliation(s)
- Ruben Hernandez-Alcoceba
- Department of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), IdiSNA, Navarra Institute for Health Research, University of Navarra. Pio XII 55, 31008 Pamplona, Spain
| | - Puri Fortes
- Department of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), IdiSNA, Navarra Institute for Health Research, University of Navarra. Pio XII 55, 31008 Pamplona, Spain
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Abstract
Liver cancer is an often fatal malignant tumor with a high recurrence rate and chemoresistance. The major malignant phenotypes of cancer, including recurrence, metastasis, and chemoresistance, are related to the presence of cancer stem cells (CSCs). In the past few decades, CSCs have been identified and characterized in many tumors including liver cancer. Accumulated evidence has revealed many aspects of the biological behavior of liver CSCs and the mechanism of their regulation. Based on these findings, a number of studies have investigated eradication of liver CSCs. This review focuses on the recent advances in our understanding of the biology of liver CSCs and the development of strategies for their treatment.
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Joshi P, Kooshki M, Aldrich W, Varghai D, Zborowski M, Singh AD, Triozzi PL. Expression of natural killer cell regulatory microRNA by uveal melanoma cancer stem cells. Clin Exp Metastasis 2016; 33:829-838. [PMID: 27565163 PMCID: PMC9082981 DOI: 10.1007/s10585-016-9815-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 08/08/2016] [Indexed: 12/11/2022]
Abstract
Natural killer (NK) cells are implicated in the control of metastasis in uveal melanoma, a process that has been ascribed to its cancer stem cell subpopulation. NK cell activation is regulated by specific microRNA (miR). The NK cell sensitivity and regulatory miR production of uveal melanoma cancer stem cells was examined. Cancer stem cells enriched from aggressively metastatic MUM2B uveal melanoma cells by selecting CD271+ cells or propagating as non-adherent spheres in stem-cell supportive were more resistant to NK cell cytolysis than cancer stem cells enriched from less aggressively metastatic OCM1 uveal melanoma cells. Both MUM2B and OCM1 cells expressed and secreted NK cell regulatory miRs, including miR 146a, 181a, 20a, and 223. MUM2B cells expressed and secreted miR-155; OCM1 cells did not. Transfecting MUM2B cells with anti-miR-155 increased NK cell sensitivity. CD271+ cells were identified in the blood of patients with metastatic uveal melanoma and were characterized by low expression of melanocyte differentiation determinants and by the ability to form non-adherent spheres in stem-cell supportive media. These cells also expressed NK cell regulatory miRs, including miR-155. These results indicate that uveal melanoma cancer stem cells can vary in their sensitivity to NK cell lysis and their expression of NK cell regulatory miRs. Circulating CD271+ cells from patients with metastatic uveal melanoma manifest cancer stem cell features and express miRs associated with NK cell suppression, including miR-155, that may contribute to metastatic progression.
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Affiliation(s)
- Powrnima Joshi
- Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA
| | - Mitra Kooshki
- Comprehensive Cancer Center, Wake Forest University, Winston-Salem, NC, 27157, USA
| | - Wayne Aldrich
- Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA
| | - Daniel Varghai
- Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA
| | - Maciej Zborowski
- Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA
| | - Arun D Singh
- Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA
| | - Pierre L Triozzi
- Comprehensive Cancer Center, Wake Forest University, Winston-Salem, NC, 27157, USA.
- Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
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Moreno FS, Heidor R, Pogribny IP. Nutritional Epigenetics and the Prevention of Hepatocellular Carcinoma with Bioactive Food Constituents. Nutr Cancer 2016; 68:719-733. [PMID: 27266713 DOI: 10.1080/01635581.2016.1180410] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive and life-threatening disease often diagnosed at intermediate or advanced stages, which substantially limits therapeutic approaches to its successful treatment. This indicates that the prevention of HCC may be the most promising strategy in reducing its incidence and mortality. Emerging evidence indicates that numerous nutrients and nonnutrient dietary bioactive components can reduce the occurrence and/or delay the development of HCC through modifications of deregulated epigenetic mechanisms. This review examines the existing knowledge on the epigenetic mechanism-based studies in in vitro and in vivo models of HCC on the chemopreventive potential of epigenetic food components, including dietary methyl-group donors, epigallocatechin-3-gallate, sodium butyrate, resveratrol, curcumin, and sulforaphane, on liver carcinogenesis. Future direction and potential challenges in the effective use of bioactive food constituents in the prevention of HCC are highlighted and discussed.
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Affiliation(s)
- Fernando Salvador Moreno
- a Laboratory of Diet, Nutrition, and Cancer , Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo , São Paulo , Brazil
| | - Renato Heidor
- a Laboratory of Diet, Nutrition, and Cancer , Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo , São Paulo , Brazil
| | - Igor P Pogribny
- b Division of Biochemical Toxicology, National Center for Toxicological Research , Jefferson , Arkansas , USA
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Zhu M, Li W, Lu Y, Dong X, Chen Y, Lin B, Xie X, Guo J, Li M. Alpha fetoprotein antagonizes apoptosis induced by paclitaxel in hepatoma cells in vitro. Sci Rep 2016; 6:26472. [PMID: 27255186 PMCID: PMC4891737 DOI: 10.1038/srep26472] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 04/29/2016] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) cell resistance to the effects of paclitaxel has not been adequately addressed. In this study, we found that paclitaxel significantly inhibited the viability of HLE, Bel 7402 and L-02 cells in a dose- and time-dependent manner. HLE cells and L-02 cells resisted the cytotoxicity of paclitaxel when transfected with pcDNA3.1-afp vectors. However, Bel 7402 cell sensitivity to paclitaxel was increased when transfected with alpha fetoprotein (AFP)-siRNA. Bel 7402 cell resistance to paclitaxel was associated with the expression of the “stemness” markers CD44 and CD133. Paclitaxel significantly inhibited growth and promoted apoptosis in HLE cells and L-02 cells by inducing fragmentation of caspase-3 and inhibiting the expression of Ras and Survivin, but pcDNA3.1-afp vectors prevented these effects. However, paclitaxel could not significantly promote the cleavage of caspase-3 or suppress the expression of Ras and Survivin in Bel 7402 cells. Silenced expression of AFP may be synergistic with paclitaxel to restrain proliferation and induce apoptosis, enhance cleavage of caspase-3, and suppress the expression of Ras and Survivin. Taken together, AFP may be an important molecule acting against paclitaxel-inhibited proliferation and induced apoptosis in HCC cells via repressing the activity of caspase-3 and stimulating the expression of Ras and Survivin. Targeted inhibition of AFP expression after treatment with paclitaxel is an available strategy for the therapy of patients with HCC.
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Affiliation(s)
- Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, P.R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571159, P.R. China
| | - Wei Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, P.R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571159, P.R. China
| | - Yan Lu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, P.R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571159, P.R. China
| | - Xu Dong
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, P.R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571159, P.R. China
| | - Yi Chen
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, P.R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571159, P.R. China
| | - Bo Lin
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, P.R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571159, P.R. China
| | - Xieju Xie
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, P.R. China.,Department of Pathophysiology, Hainan Medical College, Haikou 571199, China
| | - Junli Guo
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, P.R. China
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, P.R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571159, P.R. China.,Institution of Tumours, Hainan Medical College, Haikou 570102, P.R. China
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