|
1
|
Song G, Yu X, Shi H, Sun B, Amateau S. miRNAs in HCC, pathogenesis, and targets. Hepatology 2024:01515467-990000000-01097. [PMID: 39626210 PMCID: PMC12119976 DOI: 10.1097/hep.0000000000001177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Liver cancer is the third leading cause of cancer-related mortality worldwide. HCC, the most common type of primary liver cancer, is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally occurring small noncoding RNAs, play crucial roles in HCC by simultaneously modulating the expression of multiple genes in a fine-tuning manner. Significant progress has been made in understanding how miRNAs influence key oncogenic pathways, including cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), as well as their role in modulating the immune microenvironment in HCC. Due to the unexpected stability of miRNAs in the blood and fixed HCC tumors, recent advancements also highlight their potential as noninvasive diagnostic tools. Restoring or inhibiting specific miRNAs has offered promising strategies for targeted HCC treatment by suppressing malignant hepatocyte growth and enhancing antitumor immunity. In this comprehensive review, we consolidate previous research and provide the latest insights into how miRNAs regulate HCC and their therapeutic and diagnostic potential. We delve into the dysregulation of miRNA biogenesis in HCC, the roles of miRNAs in the proliferation and apoptosis of malignant hepatocytes, angiogenesis and metastasis of HCC, the immune microenvironment in HCC, and drug resistance. We also discuss the therapeutic and diagnostic potential of miRNAs and delivery approaches of miRNA drugs to overcome the limitations of current HCC treatment options. By thoroughly summarizing the roles of miRNAs in HCC, our goal is to advance the development of effective therapeutic drugs with minimal adverse effects and to establish precise tools for early diagnosis of HCC.
Collapse
Affiliation(s)
- Guisheng Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Xiaofan Yu
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Hongtao Shi
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan City, China
| | - Bo Sun
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Stuart Amateau
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| |
Collapse
|
|
2
|
Toro AU, Shukla SK, Bansal P. Emerging role of MicroRNA-Based theranostics in Hepatocellular Carcinoma. Mol Biol Rep 2023; 50:7681-7691. [PMID: 37418086 DOI: 10.1007/s11033-023-08586-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 06/12/2023] [Indexed: 07/08/2023]
Abstract
Hepatocellular carcinoma (HCC), with its high mortality and short survival rate, continues to be one of the deadliest malignancies despite relentless efforts and several technological advances. The poor prognosis of HCC and the few available treatments are to blame for the low survival rate, which emphasizes the importance of creating new, effective diagnostic markers and innovative therapy strategies. In-depth research is being done on the potent biomarker miRNAs, a special class of non-coding RNA and has shown encouraging results in the early identification and treatment of HCC in order to find more viable and successful therapeutics for the disease. It is beyond dispute that miRNAs control cell differentiation, proliferation, and survival and, depending on the genes they target, can either promote tumorigenesis or suppress it. Given the vital role miRNAs play in the biological system and their potential to serve as ground-breaking treatments for HCC, more study is required to fully examine their theranostic potential.
Collapse
Affiliation(s)
- Abdulhakim Umar Toro
- Department of Biomedical Engineering, Shobhit institute of Engineering and Technology (Deemed to-be-University), Modipuram, Meerut, 250110, India
| | - Sudheesh K Shukla
- Department of Biomedical Engineering, Shobhit institute of Engineering and Technology (Deemed to-be-University), Modipuram, Meerut, 250110, India.
| | - Parveen Bansal
- University Centre of Excellence in Research, Baba Farid University of Health Sciences, Faridkot, 151203, India.
| |
Collapse
|
|
3
|
Afolabi LO, Bi J, Li X, Adeshakin AO, Adeshakin FO, Wu H, Yan D, Chen L, Wan X. Synergistic Tumor Cytolysis by NK Cells in Combination With a Pan-HDAC Inhibitor, Panobinostat. Front Immunol 2021; 12:701671. [PMID: 34531855 PMCID: PMC8438531 DOI: 10.3389/fimmu.2021.701671] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 08/17/2021] [Indexed: 01/18/2023] Open
Abstract
Histone deacetylases (HDAC) are frequently overexpressed in tumors, and their inhibition has shown promising anti-tumor effects. However, the synergistic effects of HDAC inhibition with immune cell therapy have not been fully explored. Natural killer (NK) cells are cytotoxic lymphocytes for anti-tumor immune surveillance, with immunotherapy potential. We showed that a pan-HDAC inhibitor, panobinostat, alone demonstrated anti-tumor and anti-proliferative activities on all tested tumors in vitro. Additionally, panobinostat co-treatment or pretreatment synergized with NK cells to mediate tumor cell cytolysis. Mechanistically, panobinostat treatment increased the expression of cell adhesion and tight junction-related genes, promoted conjugation formation between NK and tumor cells, and modulates NK cell-activating receptors and ligands on tumor cells, contributing to the increased tumor cytolysis. Finally, panobinostat therapy led to better tumor control and synergized with anti-PD-L1 therapy. Our data highlights the anti-tumor potential of HDAC inhibition through tumor-intrinsic toxicity and enhancement of NK -based immunotherapy.
Collapse
Affiliation(s)
- Lukman O. Afolabi
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jiacheng Bi
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Xuguang Li
- Department of Stomatology, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen, China
| | - Adeleye O. Adeshakin
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Funmilayo O. Adeshakin
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Haisi Wu
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Dehong Yan
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Liang Chen
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiaochun Wan
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
4
|
Gunel NS, Birden N, Kurt CC, Bagca BG, Shademan B, Sogutlu F, Ozates NP, Avci CB. Effect of valproic acid on miRNAs affecting histone deacetylase in a model of anaplastic thyroid cancer. Mol Biol Rep 2021; 48:6085-6091. [PMID: 34374891 DOI: 10.1007/s11033-021-06616-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 07/29/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Thyroid cancer is the most common malignant tumor of the endocrine system seen in the thyroid gland. More than 90% of thyroid cancers comprise papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although anaplastic thyroid carcinoma (ATC) accounts for less than 2% of thyroid cancer. But patients' lifespan after diagnosis is about 6 months. Surgical interventions, radioactive iodine use, and chemotherapy are not sufficient in the treatment of ATC, so alternative therapies are needed. METHODS AND RESULTS The WST-1 assay test was performed to evaluate the anti-proliferative effects of Valproic acid (VPA). Also, the effect of VPA on miRNAs affecting histone deacetylase was determined by Quantitative RT-PCR. In the SW1736 cell line, IC50 dose for VPA was found 1.6 mg/ml. In our study, the level of oncogenic genes expression in cells treated with VPA, including miR-184, miR-222-5p, miR-124-3p, and miR-328-3p, decreased. Also, the expression of tumor inhibitory genes including miR-323-5p, miR-182-5p, miR-138-5p, miR-217, miR-15a-5p, miR-29b-3p, miR-324-5p and miR-101-5p increased significantly. CONCLUSIONS VPA can ad-just countless gene expression patterns, including microRNAs (miRNAs), by targeting histone deacetylase (HDAC). However, further studies are required for more accurate results.
Collapse
Affiliation(s)
- Nur Selvi Gunel
- Department of Medical Biology, Ege University Medical School, Izmir, Turkey
| | - Nihal Birden
- Department of Medical Biology, Ege University Medical School, Izmir, Turkey
| | | | - Bakiye Goker Bagca
- Department of Medical Biology, Ege University Medical School, Izmir, Turkey
| | - Behrouz Shademan
- Department of Medical Biology, Ege University Medical School, Izmir, Turkey
| | - Fatma Sogutlu
- Department of Medical Biology, Ege University Medical School, Izmir, Turkey
| | | | - Cigir Biray Avci
- Department of Medical Biology, Ege University Medical School, Izmir, Turkey.
| |
Collapse
|
|
5
|
Induction of microRNA hsa-let-7d-5p, and repression of HMGA2, contribute protection against lipid accumulation in macrophage 'foam' cells. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:159005. [PMID: 34274506 DOI: 10.1016/j.bbalip.2021.159005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/08/2021] [Accepted: 07/13/2021] [Indexed: 12/14/2022]
Abstract
Accumulation of excess cholesterol and cholesteryl ester in macrophage 'foam' cells within the arterial intima characterises early 'fatty streak' atherosclerotic lesions, and is accompanied by epigenetic changes, including altered expression of microRNA sequences which determine of gene and protein expression. This study established that exposure to lipoproteins, including acetylated LDL, induced macrophage expression of microRNA hsa-let-7d-5p, a sequence previously linked with tumour suppression, and repressed expression of one of its target genes, high mobility group AT hook 2 (HMGA2). A let-7d-5p mimic repressed expression of HMGA2 (18%; p < 0.05) while a marked increase (2.9-fold; p < 0.05) in expression of HMGA2 was noted in the presence of let-7d-5p inhibitor. Under these conditions, let-7d-5p mimic significantly (p < 0.05) decreased total (10%), free (8%) and cholesteryl ester (21%) mass, while the inhibitor significantly (p < 0.05) increased total (29%) and free cholesterol (29%) mass, compared with the relevant controls. Let-7d-5p inhibition significantly (p < 0.05) increased endogenous biosynthesis of cholesterol (38%) and cholesteryl ester (39%) pools in macrophage 'foam' cells, without altering the cholesterol efflux pathway, or esterification of exogenous radiolabelled oleate. Let-7d-5p inhibition in sterol-loaded cells increased the level of HMGA2 protein (32%; p < 0.05), while SiRNA knockdown of this protein (29%; p < 0.05) resulted in a (21%, p < 0.05) reduction in free cholesterol mass. Thus, induction of let-7d-5p, and repression of its target HMGA2, in macrophages is a protective response to the challenge of increased cholesterol influx into these cells; dysregulation of this response may contribute to atherosclerosis and other disorders such as cancer.
Collapse
|
|
6
|
Afolabi LO, Bi J, Chen L, Wan X. A natural product, Piperlongumine (PL), increases tumor cells sensitivity to NK cell killing. Int Immunopharmacol 2021; 96:107658. [PMID: 33887610 DOI: 10.1016/j.intimp.2021.107658] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/08/2021] [Accepted: 04/03/2021] [Indexed: 12/17/2022]
Abstract
Natural Killer (NK) cells are components of innate immune surveillance against transformed cells. NK cell immunotherapy has attracted attention as a promising strategy for cancer treatment, whose antitumor effects, however, require further improvement. The use of small molecules with immunomodulatory potentials and selective tumor-killing possesses the potential to complement immunotherapy. This study demonstrated that Piperlongumine (PL), a natural alkaloid obtained from long pepper fruit, alone has antitumor and anti-proliferative potential on all the tested tumors in vitro. PL pretreatment of tumor cells also potentiates their susceptibility to NK cell cytolysis at the doses where NK cell functions were preserved. Importantly, PL suppresses both NK -sensitive MHC-I -deficient and MHC-I -sufficient tumor growth in vivo. Mechanistically, PL induces misfolded proteins, impedes autophagy, increases ROS and tumor conjugation with NK cells. Furthermore, PL enhances the expression of NK cell-activating receptors on NK cells and its ligands on tumor cells, possibly leading to increased susceptibility to NK cell killing. Our findings showed the antitumor and immunomodulatory potential of PL, which could be explored to complement NK cell immunotherapy for cancer treatment.
Collapse
MESH Headings
- Animals
- Antineoplastic Agents, Phytogenic/immunology
- Antineoplastic Agents, Phytogenic/pharmacology
- Apoptosis/drug effects
- Autophagy/drug effects
- Biological Products/immunology
- Biological Products/pharmacology
- Cell Line, Tumor
- Cell Survival/drug effects
- Cytotoxicity, Immunologic/drug effects
- Dioxolanes/immunology
- Dioxolanes/pharmacology
- Humans
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Neoplasms/drug therapy
- Neoplasms/immunology
- Reactive Oxygen Species/metabolism
- Receptors, Natural Killer Cell/drug effects
- Receptors, Natural Killer Cell/metabolism
- Xenograft Model Antitumor Assays
- Mice
Collapse
Affiliation(s)
- Lukman O Afolabi
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China; University of Chinese Academy of Sciences, Beijing 100864, PR China
| | - Jiacheng Bi
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China; University of Chinese Academy of Sciences, Beijing 100864, PR China
| | - Liang Chen
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China; University of Chinese Academy of Sciences, Beijing 100864, PR China
| | - Xiaochun Wan
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China; University of Chinese Academy of Sciences, Beijing 100864, PR China.
| |
Collapse
|
|
7
|
Shee K, Seigne JD, Karagas MR, Marsit CJ, Hinds JW, Schned AR, Pettus JR, Armstrong DA, Miller TW, Andrew AS. Identification of Let-7f-5p as a novel biomarker of recurrence in non-muscle invasive bladder cancer. Cancer Biomark 2021; 29:101-110. [PMID: 32623385 DOI: 10.3233/cbm-191322] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Among patients diagnosed with non-muscle invasive bladder cancer (NMIBC), 30% to 70% experience recurrences within 6 to 12 years of diagnosis. The need to screen for these events every 3 to 6 months and ultimately annually by cystoscopy makes bladder cancer one of the most expensive malignancies to manage. OBJECTIVE The purpose of this study was to identify reproducible prognostic microRNAs in resected non-muscle invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype as potential biomarkers and molecular therapeutic targets. METHODS Two independent cohorts of NMIBC patients were analyzed using a biomarker discovery and validation approach, respectively. RESULTS miRNA Let-7f-5p showed the strongest association with recurrence across both cohorts. Let-7f-5p levels in urine and plasma were both found to be significantly correlated with levels in tumor tissue. We assessed the therapeutic potential of targeting Lin28, a negative regulator of Let-7f-5p, with small-molecule inhibitor C1632. Lin28 inhibition significantly increased levels of Let-7f-5p expression and led to significant inhibition of viability and migration of HTB-2 cells. CONCLUSIONS We have identified Let-7f-5p as a miRNA biomarker of recurrence in NMIBC tumors. We further demonstrate that targeting Lin28, a negative regulator of Let-7f-5p, represents a novel potential therapeutic opportunity in NMIBC.
Collapse
Affiliation(s)
- Kevin Shee
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - John D Seigne
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Margaret R Karagas
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Carmen J Marsit
- Department of Environmental Health and of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - John W Hinds
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.,Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Alan R Schned
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Jason R Pettus
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - David A Armstrong
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Todd W Miller
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.,Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Angeline S Andrew
- Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| |
Collapse
|
|
8
|
Chu Y, Wang X, Dai Q, Wang Y, Wang Q, Peng S, Wei X, Qiu J, Salahub DR, Xiong Y, Wei DQ. MDA-GCNFTG: identifying miRNA-disease associations based on graph convolutional networks via graph sampling through the feature and topology graph. Brief Bioinform 2021; 22:6261915. [PMID: 34009265 DOI: 10.1093/bib/bbab165] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/02/2021] [Accepted: 04/08/2021] [Indexed: 11/13/2022] Open
Abstract
Accurate identification of the miRNA-disease associations (MDAs) helps to understand the etiology and mechanisms of various diseases. However, the experimental methods are costly and time-consuming. Thus, it is urgent to develop computational methods towards the prediction of MDAs. Based on the graph theory, the MDA prediction is regarded as a node classification task in the present study. To solve this task, we propose a novel method MDA-GCNFTG, which predicts MDAs based on Graph Convolutional Networks (GCNs) via graph sampling through the Feature and Topology Graph to improve the training efficiency and accuracy. This method models both the potential connections of feature space and the structural relationships of MDA data. The nodes of the graphs are represented by the disease semantic similarity, miRNA functional similarity and Gaussian interaction profile kernel similarity. Moreover, we considered six tasks simultaneously on the MDA prediction problem at the first time, which ensure that under both balanced and unbalanced sample distribution, MDA-GCNFTG can predict not only new MDAs but also new diseases without known related miRNAs and new miRNAs without known related diseases. The results of 5-fold cross-validation show that the MDA-GCNFTG method has achieved satisfactory performance on all six tasks and is significantly superior to the classic machine learning methods and the state-of-the-art MDA prediction methods. Moreover, the effectiveness of GCNs via the graph sampling strategy and the feature and topology graph in MDA-GCNFTG has also been demonstrated. More importantly, case studies for two diseases and three miRNAs are conducted and achieved satisfactory performance.
Collapse
Affiliation(s)
- Yanyi Chu
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, China
| | - Xuhong Wang
- School of Electronic, Information and Electrical Engineering (SEIEE), Shanghai Jiao Tong University, China
| | - Qiuying Dai
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, China
| | - Yanjing Wang
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, China
| | - Qiankun Wang
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, China
| | - Shaoliang Peng
- College of Computer Science and Electronic Engineering, Hunan University, China
| | | | | | - Dennis Russell Salahub
- Department of Chemistry, University of Calgary, Fellow Royal Society of Canada and Fellow of the American Association for the Advancement of Science, China
| | - Yi Xiong
- State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint International Research Laboratory of Metabolic & Developmental Sciences and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Dong-Qing Wei
- State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint International Research Laboratory of Metabolic & Developmental Sciences and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| |
Collapse
|
|
9
|
Wang D, Sang Y, Sun T, Kong P, Zhang L, Dai Y, Cao Y, Tao Z, Liu W. Emerging roles and mechanisms of microRNA‑222‑3p in human cancer (Review). Int J Oncol 2021; 58:20. [PMID: 33760107 PMCID: PMC7979259 DOI: 10.3892/ijo.2021.5200] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 01/12/2021] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs/miRs) are a class of small non‑coding RNAs that maintain the precise balance of various physiological processes through regulating the function of target mRNAs. Dysregulation of miRNAs is closely associated with various types of human cancer. miR‑222‑3p is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in tumor occurrence and progression. miR‑222‑3p in human biofluids, such as urine and plasma, may be a potential biomarker for the early diagnosis of tumors. In addition, miR‑222‑3p acts as a prognostic factor for the survival of patients with cancer. The present review first summarizes and discusses the role of miR‑222‑3p as a biomarker for diverse types of cancers, and then focuses on its essential roles in tumorigenesis, progression, metastasis and chemoresistance. Finally, the current understanding of the regulatory mechanisms of miR‑222‑3p at the molecular level are summarized. Overall, the current evidence highlights the crucial role of miR‑222‑3p in cancer diagnosis, prognosis and treatment.
Collapse
Affiliation(s)
| | | | | | - Piaoping Kong
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Lingyu Zhang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Yibei Dai
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Ying Cao
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Zhihua Tao
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Weiwei Liu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| |
Collapse
|
|
10
|
Shek D, Chen D, Read SA, Ahlenstiel G. Examining the gut-liver axis in liver cancer using organoid models. Cancer Lett 2021; 510:48-58. [PMID: 33891996 DOI: 10.1016/j.canlet.2021.04.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 03/29/2021] [Accepted: 04/13/2021] [Indexed: 12/23/2022]
Abstract
The World Health Organization predicts that by 2030 liver cancer will cause 1 million deaths annually, thus becoming the third most lethal cancer worldwide. Hepatocellular carcinoma and cholangiocarcinoma are the two major primary cancer subtypes involving the liver. Both are often diagnosed late, and hence response to treatment and survival are poor. It is therefore of utmost importance to understand the mechanisms by which liver cancers initiate and progress. The causes of primary liver cancer are diverse, resulting primarily from obesity, chronic alcohol abuse or viral hepatitis. Importantly, both alcohol and high fat diet can promote intestinal permeability, enabling microbial translocation from the gut into the liver. As a result, these microbial antigens and metabolites exacerbate hepatic inflammation and fibrosis, increasing the risk of primary liver cancer. Organoids are primary, three-dimensional, stem cell derived liver models that can recapitulate many of the disease phenotypes observed in vivo. This review aims to summarize the advantages of organoid culture to examine the gut-liver axis with respect to cancer initiation and progression. In particular, the use of gut and liver organoid mono- and co-cultures together and with immune cell populations to best recapitulate disease mechanisms and develop therapeutic interventions.
Collapse
Affiliation(s)
- Dmitrii Shek
- Blacktown Clinical School, Western Sydney University, Blacktown, NSW, Australia; Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia; Blacktown Hospital, Blacktown, NSW, Australia
| | - Dishen Chen
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
| | - Scott A Read
- Blacktown Clinical School, Western Sydney University, Blacktown, NSW, Australia; Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia; Blacktown Hospital, Blacktown, NSW, Australia.
| | - Golo Ahlenstiel
- Blacktown Clinical School, Western Sydney University, Blacktown, NSW, Australia; Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia; Blacktown Hospital, Blacktown, NSW, Australia.
| |
Collapse
|
|
11
|
Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
Collapse
|
|
12
|
Nomura K, Kitanaka A, Iwama H, Tani J, Nomura T, Nakahara M, Ohura K, Tadokoro T, Fujita K, Mimura S, Yoneyama H, Kobara H, Morishita A, Okano K, Suzuki Y, Tsutsi K, Himoto T, Masaki T. Association between microRNA-527 and glypican-3 in hepatocellular carcinoma. Oncol Lett 2021; 21:229. [PMID: 33613718 PMCID: PMC7856685 DOI: 10.3892/ol.2021.12490] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 09/19/2020] [Indexed: 12/15/2022] Open
Abstract
The present study aimed to identify the specific microRNAs (miRNAs/miRs) and their corresponding target genes involved in hepatocellular carcinomas (HCCs). Microarray analysis was performed to examine the miRNA expression profiles of four paired HCC and corresponding non-cancerous (N) liver tissues using 985 miRNA probes. The Human miRNA Target database was used to identify the target genes of differentially expressed miRNAs between the HCC and N tissues. The protein expression levels of target genes in the HCC tissues and cell lines were evaluated using western blotting. miRNA-mediated suppression of target gene expression was evaluated by transiently transfecting the miRNA into the HCC cell lines. Of the 985 miRNAs evaluated, four miRNAs were differentially expressed (three upregulated and one downregulated miRNAs). Of these four miRNAs, miRNA-527 was highly downregulated in the HCC tissues. Glypican-3 (GPC-3) was predicted as a target gene of miRNA-527. Western blotting revealed that GPC-3 protein is highly expressed in the HCC tissues and HCC cell lines compared with N and normal cell lines. Transfection with miR-527 resulted in suppression of GPC-3 protein expression in the Cos7 cells. Furthermore, transfection with miR-527 also inhibited the intrinsic expression of GPC-3 in the Huh-7 cell line. This indicated that miR-527 in the HCC tissues may be an important novel miRNA that targets the GPC-3 gene expression. GPC-3, whose expression is regulated by miR-527, may be involved in the development and progression of HCC.
Collapse
Affiliation(s)
- Kei Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Akira Kitanaka
- Department of Laboratory Medicine, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan
| | - Hisakazu Iwama
- Information Technology Center, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Kyoko Ohura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Kunihiko Tsutsi
- Department of Healthy Science, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| | - Takashi Himoto
- Department of Clinical Examination, Faculty of Health Sciences, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761-0123, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan
| |
Collapse
|
|
13
|
Pegoraro S, Ros G, Sgubin M, Petrosino S, Zambelli A, Sgarra R, Manfioletti G. Targeting the intrinsically disordered architectural High Mobility Group A (HMGA) oncoproteins in breast cancer: learning from the past to design future strategies. Expert Opin Ther Targets 2020; 24:953-969. [PMID: 32970506 DOI: 10.1080/14728222.2020.1814738] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat because of its heterogeneity and lack of specific therapeutic targets. High Mobility Group A (HMGA) proteins are chromatin architectural factors that have multiple oncogenic functions in breast cancer, and they represent promising molecular therapeutic targets for this disease. AREAS COVERED We offer an overview of the strategies that have been exploited to counteract HMGA oncoprotein activities at the transcriptional and post-transcriptional levels. We also present the possibility of targeting cancer-associated factors that lie downstream of HMGA proteins and discuss the contribution of HMGA proteins to chemoresistance. EXPERT OPINION Different strategies have been exploited to counteract HMGA protein activities; these involve interfering with their nucleic acid binding properties and the blocking of HMGA expression. Some approaches have provided promising results. However, some unique characteristics of the HMGA proteins have not been exploited; these include their extensive protein-protein interaction network and their intrinsically disordered status that present the possibility that HMGA proteins could be involved in the formation of proteinaceous membrane-less organelles (PMLO) by liquid-liquid phase separation. These unexplored characteristics could open new pharmacological avenues to counteract the oncogenic contributions of HMGA proteins.
Collapse
Affiliation(s)
- Silvia Pegoraro
- Department of Life Sciences, University of Trieste , Trieste, Italy
| | - Gloria Ros
- Department of Life Sciences, University of Trieste , Trieste, Italy
| | - Michela Sgubin
- Department of Life Sciences, University of Trieste , Trieste, Italy
| | - Sara Petrosino
- Department of Life Sciences, University of Trieste , Trieste, Italy
| | | | - Riccardo Sgarra
- Department of Life Sciences, University of Trieste , Trieste, Italy
| | | |
Collapse
|
|
14
|
Elbadawy M, Yamanaka M, Goto Y, Hayashi K, Tsunedomi R, Hazama S, Nagano H, Yoshida T, Shibutani M, Ichikawa R, Nakahara J, Omatsu T, Mizutani T, Katayama Y, Shinohara Y, Abugomaa A, Kaneda M, Yamawaki H, Usui T, Sasaki K. Efficacy of primary liver organoid culture from different stages of non-alcoholic steatohepatitis (NASH) mouse model. Biomaterials 2020; 237:119823. [PMID: 32044522 DOI: 10.1016/j.biomaterials.2020.119823] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with liver fibrosis and cirrhosis, which eventually leads to hepatocellular carcinoma. Although several animal models were developed to understand the mechanisms of NASH pathogenesis and progression, it remains obscure. A 3D organoid culture system can recapitulate organ structures and maintain gene expression profiles of original tissues. We therefore tried to generate liver organoids from different degrees [defined as mild (NASH A), moderate (NASH B) and severe (NASH C)] of methionine- and choline-deficient diet-induced NASH model mice and analyzed the difference of their architecture, cell components, organoid-forming efficacy, and gene expression profiles. Organoids from each stage of NASH model mice were successfully generated. Interestingly, epithelial-mesenchymal transition was observed in NASH C organoids. Expression of Collagen I and an activated hepatic stellite cell marker, α-sma was upregulated in the liver organoids from NASH B and C mice. The analysis of RNA sequencing revealed that several novel genes were upregulated in all NASH liver organoids. These results suggest that our generated liver organoids from different stages of NASH diseased mice might become a useful tool for in vitro studies of the molecular mechanism of NASH development and also for identifying novel biomarkers for early diagnosis of NASH disease.
Collapse
Affiliation(s)
- Mohamed Elbadawy
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan; Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, 13736, Moshtohor, Toukh, Elqaliobiya, Egypt
| | - Megumi Yamanaka
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Yuta Goto
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Kimika Hayashi
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Ryouichi Tsunedomi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Shoichi Hazama
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan; Department of Translational Research and Developmental Therapeutics Against Cancer, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Toshinori Yoshida
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Makoto Shibutani
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Ryo Ichikawa
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Junta Nakahara
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Tsutomu Omatsu
- Research and Education Center for Prevention of Global Infectious Disease of Animals, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Tetsuya Mizutani
- Research and Education Center for Prevention of Global Infectious Disease of Animals, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Yukie Katayama
- Research and Education Center for Prevention of Global Infectious Disease of Animals, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Yuta Shinohara
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan; Pet Health & Food Division, Iskara Industry CO., LTD, 1-14-2, Nihonbashi, Chuo-ku, Tokyo, 103-0027, Japan
| | - Amira Abugomaa
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Masahiro Kaneda
- Laboratory of Veterinary Anatomy, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, 35-1, Higashi 23 Ban-cho, Towada, Aomori, 034-8628, Japan
| | - Tatsuya Usui
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan.
| | - Kazuaki Sasaki
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| |
Collapse
|
|
15
|
Li L, Zhuo Z, Yang Z, Zhu J, He X, Yang Z, Zhang J, Xin Y, He J, Zhang T. HMGA2 Polymorphisms and Hepatoblastoma Susceptibility: A Five-Center Case-Control Study. Pharmgenomics Pers Med 2020; 13:51-57. [PMID: 32104047 PMCID: PMC7023882 DOI: 10.2147/pgpm.s241100] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 02/04/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatoblastoma is a rare disease. Its etiology remains obscure. No epidemiological reports have assessed the relationship of High Mobility Group A2 (HMGA2) single nucleotide polymorphisms (SNPs) with hepatoblastoma risk. This case-control study leads as a pioneer to explore whether HMGA2 SNPs (rs6581658 A>G, rs8756 A>C, rs968697 T>C) could impact hepatoblastoma risk. METHODS We acquired samples from 275 hepatoblastoma cases and 1018 controls who visited one of five independent hospitals located in the different regions of China. The genotyping of HMGA2 SNPs was implemented using the PCR-based TaqMan method, and the risk estimates were quantified by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS In the main analysis, we identified that rs968697 T>C polymorphism was significantly related to hepatoblastoma risk in the additive model (adjusted OR=0.73, 95% CI=0.54-0.98, P=0.035). Notably, participants carrying 2-3 favorable genotypes had reduced hepatoblastoma risk (adjusted OR=0.71, 95% CI=0.52-0.96, P=0.028) in contrast to those carrying 0-1 favorable genotypes. Furthermore, stratification analysis revealed a significant correlation between rs968697 TC/CC and hepatoblastoma risk for males and clinical stage I+II. The existence of 2-3 protective genotypes was correlated with decreased hepatoblastoma susceptibility in children ≥17 months old, males, and clinical stage I+II cases, when compared to 0-1 protective genotype. CONCLUSION To summarize, these results indicated that the HMGA2 gene SNPs exert a weak influence on hepatoblastoma susceptibility. Further validation of the current conclusion with a larger sample size covering multi-ethnic groups is warranted.
Collapse
Affiliation(s)
- Li Li
- Kunming Key Laboratory of Children's Infection and Immunity, Yunnan Key Laboratory of Children’s Major Disease Research, Yunnan Institute of Pediatrics Research, Kunming Children’s Hospital, Kunming, Yunnan, 650228, People’s Republic of China
| | - Zhenjian Zhuo
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou510623, Guangdong, People’s Republic of China
| | - Zhen Yang
- Kunming Key Laboratory of Children's Infection and Immunity, Yunnan Key Laboratory of Children’s Major Disease Research, Yunnan Institute of Pediatrics Research, Kunming Children’s Hospital, Kunming, Yunnan, 650228, People’s Republic of China
- Department of Oncology, Kunming Children’s Hospital, Kunming650228, Yunnan, People’s Republic of China
| | - Jinhong Zhu
- Department of Clinical Laboratory, Biobank, Harbin Medical University Cancer Hospital, Harbin150040, Heilongjiang, People’s Republic of China
| | - Xiaoli He
- Kunming Key Laboratory of Children's Infection and Immunity, Yunnan Key Laboratory of Children’s Major Disease Research, Yunnan Institute of Pediatrics Research, Kunming Children’s Hospital, Kunming, Yunnan, 650228, People’s Republic of China
| | - Zhonghua Yang
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang110004, Liaoning, People’s Republic of China
| | - Jiao Zhang
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou450052, Henan, People’s Republic of China
| | - Yijuan Xin
- Clinical Laboratory Medicine Center of PLA, Xijing Hospital, Air Force Medical University, Xi’an710032, Shaanxi, People’s Republic of China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou510623, Guangdong, People’s Republic of China
| | - Tiesong Zhang
- Kunming Key Laboratory of Children's Infection and Immunity, Yunnan Key Laboratory of Children’s Major Disease Research, Yunnan Institute of Pediatrics Research, Kunming Children’s Hospital, Kunming, Yunnan, 650228, People’s Republic of China
| |
Collapse
|
|
16
|
High Mobility Group A (HMGA): Chromatin Nodes Controlled by a Knotty miRNA Network. Int J Mol Sci 2020; 21:ijms21030717. [PMID: 31979076 PMCID: PMC7038092 DOI: 10.3390/ijms21030717] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 12/11/2022] Open
Abstract
High mobility group A (HMGA) proteins are oncofoetal chromatin architectural factors that are widely involved in regulating gene expression. These proteins are unique, because they are highly expressed in embryonic and cancer cells, where they play a relevant role in cell proliferation, stemness, and the acquisition of aggressive tumour traits, i.e., motility, invasiveness, and metastatic properties. The HMGA protein expression levels and activities are controlled by a connected set of events at the transcriptional, post-transcriptional, and post-translational levels. In fact, microRNA (miRNA)-mediated RNA stability is the most-studied mechanism of HMGA protein expression modulation. In this review, we contribute to a comprehensive overview of HMGA-targeting miRNAs; we provide detailed information regarding HMGA gene structural organization and a comprehensive evaluation and description of HMGA-targeting miRNAs, while focusing on those that are widely involved in HMGA regulation; and, we aim to offer insights into HMGA-miRNA mutual cross-talk from a functional and cancer-related perspective, highlighting possible clinical implications.
Collapse
|
|
17
|
Nazarieh M, Rajula HSR, Helms V. Topology Consistency of Disease-specific Differential Co-regulatory Networks. BMC Bioinformatics 2019; 20:550. [PMID: 31694523 PMCID: PMC6833256 DOI: 10.1186/s12859-019-3107-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 09/20/2019] [Indexed: 12/14/2022] Open
Abstract
Background Sets of differentially expressed genes often contain driver genes that induce disease processes. However, various methods for identifying differentially expressed genes yield quite different results. Thus, we investigated whether this affects the identification of key players in regulatory networks derived by downstream analysis from lists of differentially expressed genes. Results While the overlap between the sets of significant differentially expressed genes determined by DESeq, edgeR, voom and VST was only 26% in liver hepatocellular carcinoma and 28% in breast invasive carcinoma, the topologies of the regulatory networks constructed using the TFmiR webserver for the different sets of differentially expressed genes were found to be highly consistent with respect to hub-degree nodes, minimum dominating set and minimum connected dominating set. Conclusions The findings suggest that key genes identified in regulatory networks derived by systematic analysis of differentially expressed genes may be a more robust basis for understanding diseases processes than simply inspecting the lists of differentially expressed genes.
Collapse
Affiliation(s)
- Maryam Nazarieh
- Center for Bioinformatics, University of Saarland, Saarbruecken, Germany.,Graduate School of Computer Science, University of Saarland, Saarbruecken, Germany
| | | | - Volkhard Helms
- Center for Bioinformatics, University of Saarland, Saarbruecken, Germany.
| |
Collapse
|
|
18
|
Klieser E, Mayr C, Kiesslich T, Wissniowski T, Fazio PD, Neureiter D, Ocker M. The Crosstalk of miRNA and Oxidative Stress in the Liver: From Physiology to Pathology and Clinical Implications. Int J Mol Sci 2019; 20:5266. [PMID: 31652839 PMCID: PMC6862076 DOI: 10.3390/ijms20215266] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/14/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023] Open
Abstract
The liver is the central metabolic organ of mammals. In humans, most diseases of the liver are primarily caused by an unhealthy lifestyle-high fat diet, drug and alcohol consumption- or due to infections and exposure to toxic substances like aflatoxin or other environmental factors. All these noxae cause changes in the metabolism of functional cells in the liver. In this literature review we focus on the changes at the miRNA level, the formation and impact of reactive oxygen species and the crosstalk between those factors. Both, miRNAs and oxidative stress are involved in the multifactorial development and progression of acute and chronic liver diseases, as well as in viral hepatitis and carcinogenesis, by influencing numerous signaling and metabolic pathways. Furthermore, expression patterns of miRNAs and antioxidants can be used for biomonitoring the course of disease and show potential to serve as possible therapeutic targets.
Collapse
Affiliation(s)
- Eckhard Klieser
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Christian Mayr
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Tobias Kiesslich
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Till Wissniowski
- Department of Gastroenterology and Endocrinology, Philipps University Marburg, 35043 Marburg, Germany.
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany.
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Matthias Ocker
- Translational Medicine Oncology, Bayer AG, 13353 Berlin, Germany.
- Department of Gastroenterology CBF, Charité University Medicine Berlin, 12200 Berlin, Germany.
| |
Collapse
|
|
19
|
Autin P, Blanquart C, Fradin D. Epigenetic Drugs for Cancer and microRNAs: A Focus on Histone Deacetylase Inhibitors. Cancers (Basel) 2019; 11:E1530. [PMID: 31658720 PMCID: PMC6827107 DOI: 10.3390/cancers11101530] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/09/2019] [Accepted: 10/03/2019] [Indexed: 02/06/2023] Open
Abstract
Over recent decades, it has become clear that epigenetic abnormalities are involved in the hallmarks of cancer. Histone modifications, such as acetylation, play a crucial role in cancer development and progression, by regulating gene expression, such as for oncogenes or tumor suppressor genes. Therefore, histone deacetylase inhibitors (HDACi) have recently shown efficacy against both hematological and solid cancers. Designed to target histone deacetylases (HDAC), these drugs can modify the expression pattern of numerous genes including those coding for micro-RNAs (miRNA). miRNAs are small non-coding RNAs that regulate gene expression by targeting messenger RNA. Current research has found that miRNAs from a tumor can be investigated in the tumor itself, as well as in patient body fluids. In this review, we summarized current knowledge about HDAC and HDACi in several cancers, and described their impact on miRNA expression. We discuss briefly how circulating miRNAs may be used as biomarkers of HDACi response and used to investigate response to treatment.
Collapse
Affiliation(s)
- Pierre Autin
- CRCINA, INSERM, Université d'Angers, Université de Nantes, 44007 Nantes, France.
| | - Christophe Blanquart
- CRCINA, INSERM, Université d'Angers, Université de Nantes, 44007 Nantes, France.
| | - Delphine Fradin
- CRCINA, INSERM, Université d'Angers, Université de Nantes, 44007 Nantes, France.
| |
Collapse
|
|
20
|
Xu X, Zou H, Luo L, Wang X, Wang G. MicroRNA-9 exerts antitumor effects on hepatocellular carcinoma progression by targeting HMGA2. FEBS Open Bio 2019; 9:1784-1797. [PMID: 31408273 PMCID: PMC6768112 DOI: 10.1002/2211-5463.12716] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 07/24/2019] [Accepted: 08/12/2019] [Indexed: 12/12/2022] Open
Abstract
Accumulating evidence has demonstrated that the aberrant expression of microRNAs (miRs or miRNAs) may contribute to the initiation and progression of various types of human cancer and may also constitute biomarkers for cancer diagnosis and therapy. However, the specific function of miR‐9 in hepatocellular carcinoma (HCC) remains unclear, and the mechanisms that underlie HCC are incompletely understood. Here, we report that miR‐9 expression was significantly decreased in clinical tumor tissue samples, as well as in a cohort of HCC cell lines. In addition, it was demonstrated that overexpression of miR‐9 suppressed the proliferative and migratory capacity of HCC cells and impaired cell cycle progression. Furthermore, high mobility group AT‐hook 2 (HMGA2) was verified as a downstream target gene of miR‐9 using a luciferase reporter assay. Quantitative RT‐PCR and western blotting implicated HMGA2 in the miR‐9‐mediated reduction of HCC cell growth. In vivo, transfection with miR‐9 mimics down‐regulated the expression of HMGA2, thus leading to a dramatic reduction in tumor growth in a mouse xenograft model. These results suggest that miR‐9 may exert critical antitumor effects on HCC by directly targeting HMGA2, and the miR9/HMGA2 signaling pathway may be of use for the diagnosis and prognosis of patients with HCC.
Collapse
Affiliation(s)
- Xiangang Xu
- Department of Hepatobiliary Surgery, Guizhou Provincial People's Hospital, Guiyang, China
| | - Haibo Zou
- Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Lanyun Luo
- Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Xiankui Wang
- Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Guan Wang
- Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| |
Collapse
|
|
21
|
Chen X, Xie D, Zhao Q, You ZH. MicroRNAs and complex diseases: from experimental results to computational models. Brief Bioinform 2019; 20:515-539. [PMID: 29045685 DOI: 10.1093/bib/bbx130] [Citation(s) in RCA: 423] [Impact Index Per Article: 70.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 08/13/2017] [Indexed: 12/22/2022] Open
Abstract
Plenty of microRNAs (miRNAs) were discovered at a rapid pace in plants, green algae, viruses and animals. As one of the most important components in the cell, miRNAs play a growing important role in various essential and important biological processes. For the recent few decades, amounts of experimental methods and computational models have been designed and implemented to identify novel miRNA-disease associations. In this review, the functions of miRNAs, miRNA-target interactions, miRNA-disease associations and some important publicly available miRNA-related databases were discussed in detail. Specially, considering the important fact that an increasing number of miRNA-disease associations have been experimentally confirmed, we selected five important miRNA-related human diseases and five crucial disease-related miRNAs and provided corresponding introductions. Identifying disease-related miRNAs has become an important goal of biomedical research, which will accelerate the understanding of disease pathogenesis at the molecular level and molecular tools design for disease diagnosis, treatment and prevention. Computational models have become an important means for novel miRNA-disease association identification, which could select the most promising miRNA-disease pairs for experimental validation and significantly reduce the time and cost of the biological experiments. Here, we reviewed 20 state-of-the-art computational models of predicting miRNA-disease associations from different perspectives. Finally, we summarized four important factors for the difficulties of predicting potential disease-related miRNAs, the framework of constructing powerful computational models to predict potential miRNA-disease associations including five feasible and important research schemas, and future directions for further development of computational models.
Collapse
Affiliation(s)
- Xing Chen
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, China
| | - Di Xie
- School of Mathematics, Liaoning University
| | - Qi Zhao
- School of Mathematics, Liaoning University
| | - Zhu-Hong You
- Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Science
| |
Collapse
|
|
22
|
Ponnusamy V, Yip PK. The role of microRNAs in newborn brain development and hypoxic ischaemic encephalopathy. Neuropharmacology 2019; 149:55-65. [PMID: 30716413 DOI: 10.1016/j.neuropharm.2018.11.041] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 11/28/2018] [Accepted: 11/30/2018] [Indexed: 02/08/2023]
Abstract
Neonates can develop hypoxic-ischaemic encephalopathy (HIE) due to lack of blood supply or oxygen, resulting in a major cause of death and disability among term newborns. However, current definitive treatment of therapeutic hypothermia, will only benefit one out of nine babies. Furthermore, the mechanisms of HIE and therapeutic hypothermia are not fully understood. Recently, microRNAs (miRNAs) have become of interest to many researchers due to their important role in post-transcriptional control and deep evolutionary history. Despite this, role of miRNAs in newborns with HIE remains largely unknown due to limited research in this field. Therefore, this review aims to understand the role of miRNAs in normal brain development and HIE pathophysiology with reliance on extrapolated data from other diseases, ages and species due to current limited data. This will provide us with an overview of how miRNAs in normal brain development changes after HIE. Furthermore, it will indicate how miRNAs are affected specifically or globally by the various pathophysiological events. In addition, we discuss about how drugs and commercially available agents can specifically target certain miRNAs as a mechanism of action and potential safety issue with off-target effects. Improving our understanding of the role of miRNAs on the cellular response after HIE would enhance the success of effective diagnosis, prognosis, and treatment of newborns with HIE.
Collapse
Affiliation(s)
- Vennila Ponnusamy
- Centre of Genomics and Child Health, Blizard Institute, Barts and London School of Medicine and Dentistry, Queen Mary University of London, UK; Neonatal Intensive Care Unit, Ashford and St. Peter's Hospitals NHS Trust, Chertsey, UK.
| | - Ping K Yip
- Center of Neuroscience, Surgery and Trauma, Blizard Institute, Barts and London School of Medicine and Dentistry, Queen Mary University of London, UK.
| |
Collapse
|
|
23
|
Biersack B. Interplay of non-coding RNAs and approved antimetabolites such as gemcitabine and pemetrexed in mesothelioma. Noncoding RNA Res 2018; 3:213-225. [PMID: 30809600 PMCID: PMC6257890 DOI: 10.1016/j.ncrna.2018.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 11/03/2018] [Accepted: 11/03/2018] [Indexed: 12/13/2022] Open
Abstract
Gemcitabine and pemetrexed are clinically approved antimetabolites for the therapy of mesothelioma diseases. These drugs are often applied in combination with platinum complexes and other drugs. The activity of antimetabolites depended on the expression levels of certain non-coding RNAs, in particular, of small microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The development of tumor resistance towards antimetabolites was regulated by non-coding RNAs. An overview of the interplay between gemcitabine/pemetrexed antimetabolites and non-coding RNAs in mesothelioma is provided. Further to this, various non-coding RNA-modulating agents are discussed which displayed positive effects on gemcitabine or pemetrexed treatment of mesothelioma diseases. A detailed knowledge of the connections of non-coding RNAs with antimetabolites will be constructive for the design of improved therapies in future.
Collapse
Key Words
- AKBA, 3-acetyl-11-keto-β-boswellic acid
- Anticancer drugs
- Bcl-2, B-cell lymphoma 2
- DADS, diallyl sulfide
- DHA, docosahexaenoic acid
- DIM, 3,3‘-diindolylmethane
- DMPM, diffuse malignant peritoneal mesothelioma
- EGCG, epigallocatechin-3-gallate
- EMT, epithelial-mesenchymal transition
- Gemcitabine
- HOTAIR, HOX transcript antisense RNA
- I3C, indole-3-carbinol
- Long non-coding RNA
- MALAT1, metastasis-associated lung adenocarcinoma transcript 1
- MPM, malignant pleural mesothelioma
- Mesothelioma
- MicroRNA
- NSCLC, non-small cell lung cancer
- NaB, sodium butyrate
- PDCD4, programmed cell death 4
- PEG, polyethylene glycole
- PEITC, phenethylisothiocyanate
- PTEN, phosphatase and tensin homolog
- Pemetrexed
- RA, retinoic acid
- SAHA, suberoylanilide hydroxamic acid
- SFN, sulforaphane
- TSA, trichostatin A
Collapse
|
|
24
|
Tsilimigras DI, Ntanasis-Stathopoulos I, Moris D, Spartalis E, Pawlik TM. Histone deacetylase inhibitors in hepatocellular carcinoma: A therapeutic perspective. Surg Oncol 2018; 27:611-618. [PMID: 30449480 DOI: 10.1016/j.suronc.2018.07.015] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 07/06/2018] [Accepted: 07/29/2018] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a major contributor to the global cancer burden. Given the current limited options to treat advanced HCC, understanding the molecular basis of HCC carcinogenesis and pinpointing druggable targets will be important to identify future HCC treatments. Epigenetic modification by inhibiting histone deacetylases (HDAC) is an emerging approach with promising results in cancer treatment. In the preclinical setting, HDAC inhibitors such as valproic acid sodium, panobinostat, vorinostat, trichostatin A, sodium butyrate, belinostat and romidepsin have demonstrated antitumor efficacy via activation of classic and alternative cell death molecular cascades. Combination regimens with the tyrosine kinase inhibitor sorafenib, poly(ADP-ribose) polymerases, proteasome and mammalian target of rapamycin inhibitors have shown promise. Phase I/II clinical studies with belinostat monotherapy and the combination of resminostat with sorafenib have suggested response and survival benefits. The safety profile was favorable with manageable adverse events and a low incidence of grade 3/4 toxicity. We herein review the role and potential therapeutic impact of epigenetic regulation through histone deacetylase inhibitors (HDACi) in the treatment of HCC.
Collapse
Affiliation(s)
- Diamantis I Tsilimigras
- School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Laboratory of Experimental Surgery and Surgical Research, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Demetrios Moris
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, OH, USA
| | - Eleftherios Spartalis
- Laboratory of Experimental Surgery and Surgical Research, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, OH, USA.
| |
Collapse
|
|
25
|
Wu Y, Liu L, Bian C, Diao Q, Nisar MF, Jiang X, Bartsch JW, Zhong M, Hu X, Zhong JL. MicroRNA let-7b inhibits keratinocyte differentiation by targeting IL-6 mediated ERK signaling in psoriasis. Cell Commun Signal 2018; 16:58. [PMID: 30219085 PMCID: PMC6138911 DOI: 10.1186/s12964-018-0271-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 08/31/2018] [Indexed: 12/16/2022] Open
Abstract
Background The extensive involvement of microRNA (miRNA) in the pathophysiology of psoriasis is well documented. However, in order for this information to be useful in therapeutic manipulation of miRNA levels, it is essential that detailed functional mechanisms are elucidated. This study aimed to explore the effects of IL-6 targeting by let-7b and ERK1/2 mediated signaling on keratinocyte differentiation in psoriasis. Methods Following imiquimod cream (IMQ) application to let-7bTG (keratinocyte-specific let-7b overexpression mouse) and control mice for 7 days, we analyzed erythema, scaling and thickening of skin. A dual luciferase reporter assay and bioinformatics was carried out to detect target gene of let-7b. Additionally, the differentiation markers were measured. Immunohistochemistry analyses demonstrate a relationship of let-7b with IL-6 and ERK signaling. Results we found let-7bTG inhibits acanthosis and reduces the disease severity by treatment with IMQ compared to wild-type mice. Further study illustrated that let-7b promotes differentiation of keratinocytes in vivo and in vitro. Using bioinformatics and reporter gene assays, we found that IL-6 is a target gene of let-7b. In psoriasis, high expression levels of IL-6 lead to increased acivation of p-ERK1/2. High levels of let-7bTG transgene expression suppresses IL-6 expression and leads to increased keratinocyte differentiation. Moreover, let-7b acts as an upstream negative regulator of the ERK signaling pathway in keratinocytes of psoriasis. Conclusions Our result reveals a previously unknown mechanism for regulation of IL-6 levels during psoriasis by let-7b and highlights a critical role for the ERK1/2 signaling pathway in epidermal differentiation during psoriasis. Trial registration The ethical approval for this study was from the Affiliated Hospital of Medical University of Anhui _ Fast_ PJ2017–11–14. Electronic supplementary material The online version of this article (10.1186/s12964-018-0271-9) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Yan Wu
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, college of Bioengineering, Chongqing University, Chongqing, 400044, China.,Department of Dermatology, Chongqing First People's Hospital and Chongqing Traditional Chinese Medicine Hospital, No. 40 Daomenkou St., District Yuzhong, Chongqing, 400011, China
| | - Liu Liu
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, college of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Chunxiang Bian
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, college of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Qingchun Diao
- Department of Dermatology, Chongqing First People's Hospital and Chongqing Traditional Chinese Medicine Hospital, No. 40 Daomenkou St., District Yuzhong, Chongqing, 400011, China
| | - Muhammad Farrukh Nisar
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, college of Bioengineering, Chongqing University, Chongqing, 400044, China.,Interdisciplinary Research Center in Biomedical Materials (IRCBM), COMSATS University Islamabad, Lahore Campus, Lahore, 54000, Pakistan
| | - Xuemei Jiang
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, college of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Jörg W Bartsch
- Philipps University Marburg, Department of Neurosurgery, Baldingerstr, 35033, Marburg, Germany
| | - Maojiao Zhong
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, college of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Xiangyu Hu
- Department of Dermatology, Chongqing First People's Hospital and Chongqing Traditional Chinese Medicine Hospital, No. 40 Daomenkou St., District Yuzhong, Chongqing, 400011, China
| | - Julia Li Zhong
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, college of Bioengineering, Chongqing University, Chongqing, 400044, China. .,Department of Dermatology, Chongqing First People's Hospital and Chongqing Traditional Chinese Medicine Hospital, No. 40 Daomenkou St., District Yuzhong, Chongqing, 400011, China.
| |
Collapse
|
|
26
|
Wirries A, Jabari S, Jansen EP, Roth S, Figueroa-Juárez E, Wissniowski TT, Neureiter D, Klieser E, Lechler P, Ruchholtz S, Bartsch DK, Boese CK, Di Fazio P. Panobinostat mediated cell death: a novel therapeutic approach for osteosarcoma. Oncotarget 2018; 9:32997-33010. [PMID: 30250645 PMCID: PMC6152475 DOI: 10.18632/oncotarget.26038] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 08/16/2018] [Indexed: 02/07/2023] Open
Abstract
Osteosarcoma is an aggressive cancer with a poor long term prognosis. Neo-adjuvant poly-chemotherapy followed by surgical resection remains the standard treatment, which is restricted by multi-drug resistance. If first-line therapy fails, disease control and patient survival rate drop dramatically. We aimed to identify alternative apoptotic mechanisms induced by the histone deacetylase inhibitor panobinostat in osteosarcoma cells. Saos-2, MG63 and U2-OS osteosarcoma cell lines, the immortalized human osteoblast line hFOB and the mouse embryo osteoblasts (MC3T3-E1) were treated with panobinostat. Real time viability and FACS confirmed the cytotoxicity of panobinostat. Cell stress/death related factors were analysed by RT-qPCR and western blot. Cell morphology was assessed by electron microscopy. 10 nM panobinostat caused cell viability arrest and death in all osteosarcoma and osteoblast cells. P21 up-regulation was observed in osteosarcoma cells, while over-expression of p73 was restricted to Saos-2 (TP53-/-). Survivin and Bcl-2 were suppressed by panobinostat. Endoplasmic reticulum (ER) stress markers BiP, CHOP, ATF4 and ATF6 were induced in osteosarcoma cells. The un-spliced Xbp was no further detectable after treatment. Autophagy players Beclin1, Map1LC3B and UVRAG transcripts over-expressed after 6 hours. Protein levels of Beclin1, Map1LC3B and p62 were up-regulated at 72 hours. DRAM1 was stable. Electron micrographs revealed the fragmentation and the disappearance of the ER and the statistically significant increase of autophagosome vesiculation after treatment. Panobinostat showed a synergistic suppression of survival and promotion of cell death in osteosarcoma cells. Panobinostat offers new perspectives for the treatment of osteosarcoma and other malignant bone tumours.
Collapse
Affiliation(s)
- André Wirries
- Center of Orthopaedics and Trauma Surgery, Philipps University of Marburg, Baldingerstrasse 35043 Marburg, Germany
- Orthopaedic Clinics, Hessing Foundation, 86199 Augsburg, Germany
| | - Samir Jabari
- Institute of Anatomy I, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
| | - Esther P. Jansen
- Center of Orthopaedics and Trauma Surgery, Philipps University of Marburg, Baldingerstrasse 35043 Marburg, Germany
| | - Silvia Roth
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Baldingerstrasse 35043 Marburg, Germany
| | - Elizabeth Figueroa-Juárez
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Baldingerstrasse 35043 Marburg, Germany
| | - Thaddeus T. Wissniowski
- Department of Gastroenterology and Endocrinology, Philipps University of Marburg, Baldingerstrasse 35043 Marburg, Germany
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
- Salzburg Cancer Research Institute, 5020 Salzburg, Austria
| | - Eckhard Klieser
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
- Salzburg Cancer Research Institute, 5020 Salzburg, Austria
| | - Philipp Lechler
- Center of Orthopaedics and Trauma Surgery, Philipps University of Marburg, Baldingerstrasse 35043 Marburg, Germany
| | - Steffen Ruchholtz
- Center of Orthopaedics and Trauma Surgery, Philipps University of Marburg, Baldingerstrasse 35043 Marburg, Germany
| | - Detlef K. Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Baldingerstrasse 35043 Marburg, Germany
| | - Christoph K. Boese
- Department of Orthopaedic and Trauma Surgery, University Hospital of Cologne, 50937 Cologne, Germany
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Baldingerstrasse 35043 Marburg, Germany
| |
Collapse
|
|
27
|
miR-505 enhances doxorubicin-induced cytotoxicity in hepatocellular carcinoma through repressing the Akt pathway by directly targeting HMGB1. Biomed Pharmacother 2018; 104:613-621. [PMID: 29803174 DOI: 10.1016/j.biopha.2018.05.087] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Revised: 05/02/2018] [Accepted: 05/18/2018] [Indexed: 12/21/2022] Open
Abstract
Compelling evidence has suggested the relevance of miRNAs in resistance to chemotherapeutic agents in HCC. miR-505 was reported to be downregulated and function as a tumor suppressor in HCC cells by binding to high-mobility group box 1 (HMGB1). Whether miR-505/HMGB1 axis was involved in ADM cytotoxicity in HCC remains to be addressed. The aim of this study was to explore the effect of miR-505/HMGB1 axis on ADM cytotoxicity in HCC cells. MTT, flow cytometry analysis, and caspase-3 activity assays were conducted to assess ADM-induced cytotoxicity. The protein level of phosphorylation of histone H2 AX at Ser139 (γH2AX) was detected to evaluate DNA damage. The effects of miR-505 and HMGB1 on the protein kinase B (Akt) pathway were determined by examining the protein levels of phosphorylated Akt (p-Akt), Akt, phosphorylated glycogen synthase kinase-3β (p-GSK-3β), and GSK-3β. We found that HMGB1 knockdown and miR-505 overexpression exacerbated ADM-induced cell viability inhibition, enhanced ADM-induced apoptosis, and increased caspase-3 activity in ADM-treated HCC cells. However, HMGB1 overexpression reversed the effects of miR-505 on ADM-induced cytotoxicity in HCC cells. HMGB1 knockdown and miR-505 overexpression promoted ADM-induced DNA damage in HCC cells, which was abated by HMGB1 overexpression. On a molecular mechanism level, HMGB1 silencing and miR-505 overexpression inactivated the Akt pathway in HCC cells, while exogenous HMGB1 resisted miR-505-induced Akt pathway inactivation. In conclusion, miR-505 overexpression enhanced ADM-induced cytotoxicity in HCC cells, at least partly by targeting HMGB1 and inactivating the Akt pathway.
Collapse
|
|
28
|
Wächter S, Wunderlich A, Roth S, Mintziras I, Maurer E, Hoffmann S, Verburg FA, Fellinger SA, Holzer K, Bartsch DK, Di Fazio P. Individualised Multimodal Treatment Strategies for Anaplastic and Poorly Differentiated Thyroid Cancer. J Clin Med 2018; 7:115. [PMID: 29762469 PMCID: PMC5977154 DOI: 10.3390/jcm7050115] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 05/08/2018] [Accepted: 05/09/2018] [Indexed: 02/07/2023] Open
Abstract
The prognosis of anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC) is poor, due to their radioiodine refractoriness (RAI-R), high metastatic potential and current lack of effective treatment strategies. We aimed to examine the efficacy of the tyrosine kinase inhibitors (TKIs) sorafenib and selumetinib and the histone deacetylase inhibitor (HDACI) panobinostat in patient-derived tumor tissue (PDTT) of ATCs/PDTCs, the expression of sodium iodide symporter (NIS) and radioiodine up-take (RAI-U). High Mobility Group AT-Hook 2 (HMGA2) and associated miRNAs expression was correlated with the clinical course of the patients. Inhibitory effects of panobinostat, sorafenib and selumetinib were measured by real time cell analyser xCELLigence in five PDTTs and human foreskin fibroblasts (HF) used as control. Expression of NIS, HMGA2 and associated miRNAs hsa-let-7f-5p, hsa-let-7b-5p, hsa-miR-146b-5p and hsa-miR-146b-3p was performed by RT-qPCR and Western blot. RAI-U was performed by Gamma Counter with I-131. Panobinostat showed the strongest cytotoxic effect (10 nM) in all PDTTs and HF and caused a significant over-expression of NIS transcript. TKIs were able to up-regulate NIS transcript in patient 5 and in HF. RAI-U was up-regulated after 24 h of treatment with TKIs and panobinostat in all PDTT and HF, except in patient 5. Selumetinib caused a significant suppression of HMGA2 in PDTT 1, 2, 4, 5 and HF; whereas sorafenib caused no change of HMGA2 expression. Panobinostat suppressed significantly HMGA2 in PDTT 2, 4 and HF. The expression of miRNAs hsa-let-7f-5p, has-let-7b-5p hsa-miR-146b-5p and hsa-miR-146b-3p was modulated heterogeneously. NIS protein level was over-expressed in three PDTTs (patients 1, 3 and 4) after 24 h of treatment with selumetinib, sorafenib and in particular with panobinostat. HF showed a stable NIS protein level after treatment. Panobinostat showed the strongest cytotoxicity in all treated PDTTs at the lowest dosage in comparison with TKI. All three compounds were able to modulate differently NIS, HMGA2 and related miRNAs. These factors represent valuable markers in PDTT for new treatment strategies for patients suffering from ATC/PDTC. Thus, the establishment of PDTT could be a useful tool to test the efficacy of compounds and to develop new and individualised multimodal treatment options for PDTCs and ATCs.
Collapse
Affiliation(s)
- Sabine Wächter
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Annette Wunderlich
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Silvia Roth
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Ioannis Mintziras
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Elisabeth Maurer
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Sebastian Hoffmann
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Frederik A Verburg
- Department of Nuclear Medicine, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Sebastian A Fellinger
- Department of Nuclear Medicine, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Katharina Holzer
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Detlef K Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| |
Collapse
|
|
29
|
Tie Y, Chen C, Yang Y, Qian Z, Yuan H, Wang H, Tang H, Peng Y, Du X, Liu B. Upregulation of let-7f-5p promotes chemotherapeutic resistance in colorectal cancer by directly repressing several pro-apoptotic proteins. Oncol Lett 2018; 15:8695-8702. [PMID: 29805607 DOI: 10.3892/ol.2018.8410] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 01/18/2018] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently occurring primary malignant tumors worldwide. Chemotherapeutic resistance is a major clinical problem in the treatment of CRC. Therefore, it is of great importance to investigate novel biomarkers that may predict chemoresistance and facilitate the development of individualized treatment for patients with CRC. The present study reported that let-7f-5p expression was elevated in chemotherapy-resistant CRC tissues compared with chemotherapy-sensitive tissues. Furthermore, upregulating let-7f-5p increased the expression levels of the anti-apoptotic proteins, B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), and decreased the activity of caspase-3 and caspase-9 in CRC cells. By contrast, downregulating let-7f-5p yielded the opposite effect. Notably, the results indicated that let-7f-5p promoted chemotherapeutic resistance by directly repressing the expression of several pro-apoptotic proteins, including tumor protein p53, tumor protein p53-inducible nuclear protein 1, tumor protein p53-inducible nuclear protein 2 and caspase-3. Therefore, a novel mechanism by which let-7f-5p enhances the resistance of CRC cells to chemotherapeutics has been revealed, indicating that silencing let-7f-5p may become an effective therapeutic strategy against CRC.
Collapse
Affiliation(s)
- Yateng Tie
- Department of Pathology, Lanzhou General Hospital of the People's Liberation Army, Lanzhou, Gansu 730050, P.R. China.,Department of Pathology, College of Basic Medicine, Lanzhou University, Lanzhou, Gansu 730030, P.R. China
| | - Chong Chen
- Department of Neurosurgery, 451st Central Hospital of the People's Liberation Army, Xi'an, Shaanxi 710054, P.R. China
| | - Yanli Yang
- Department of Pathology, Lanzhou General Hospital of the People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
| | - Zhen Qian
- Department of Pathology, Lanzhou General Hospital of the People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
| | - Hang Yuan
- Department of Pathology, Lanzhou General Hospital of the People's Liberation Army, Lanzhou, Gansu 730050, P.R. China.,Department of Pathology, College of Basic Medicine, Lanzhou University, Lanzhou, Gansu 730030, P.R. China
| | - Huan Wang
- Department of Pathology, Tianjin Children's Hospital, Tianjin 300134, P.R. China
| | - Haili Tang
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yao Peng
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xilin Du
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Bin Liu
- Department of Pathology, Lanzhou General Hospital of the People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
| |
Collapse
|
|
30
|
Wächter S, Damanakis AI, Elxnat M, Roth S, Wunderlich A, Verburg FA, Fellinger SA, Bartsch DK, Di Fazio P. Epigenetic Modifications in Thyroid Cancer Cells Restore NIS and Radio-Iodine Uptake and Promote Cell Death. J Clin Med 2018; 7:61. [PMID: 29561759 PMCID: PMC5920435 DOI: 10.3390/jcm7040061] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 03/15/2018] [Accepted: 03/15/2018] [Indexed: 02/07/2023] Open
Abstract
Epigenetic modifications have been identified as being responsible for the de-differentiation of thyroid tissue and its malignant transformation. Cell proliferation inhibitory effects of the pan-deacetylase inhibitors panobinostat, SAHA and Trichostatin A (TSA), the modulation of the sodium iodide symporter (NIS; SLC5A5), thyroid transcription factor 1 (TTF1), high mobility group A2 (HMGA2), and H19 and their putative targeting miRNAs have been evaluated in vitro. The cell viability was measured in five thyroid cancer cell lines (FTC133, TPC1, BCPAP, 8505C, C643) by real time cell analyzer xCELLigence. Expression of the above mentioned markers was performed by RT-qPCR and Western Blot. Radioiodine up-take was detected by Gamma Counter with I131. Cell viability decreased after treatment in all five cell lines. 10 nM panobinostat; 1 µM TSA or 10 µM SAHA caused a significant over-expression of NIS transcript in all five cell lines, whereas NIS protein was up-regulated in FTC133, BCPAP, and C643 cell lines only. Radioiodine up-take increased in FTC133 and C643 cells after 48 h of treatment with 10 nM panobinostat and 1 µM TSA. A significant down-regulation of the oncogene HMGA2 was detected in all five cell lines; except for TPC1 cells that were treated with 1 µM TSA. In accordance, hsa-let-7b-5p and hsa-let-7f-5p were stable or significantly over-expressed in all of the cell lines, except for TPC1 cells that were treated with 10 µM SAHA. TTF1 was significantly down-regulated in FTC133, BCPAP, and 8505C cells; whereas, TPC1 and C643 showed an up-regulated or stable expression. TTF1 was over-expressed in samples of human anaplastic thyroid cancer; whereas, it was down-regulated in follicular and undetectable in papillary thyroid cancer. H19 was over-expressed after 48 h treatment, except for BCPAP cells that were treated with panobinostat and SAHA. H19 was differently expressed in human anaplastic, follicular and papillary thyroid tumor samples. Deacetylase inhibitors reduced cell viability, restored NIS and H19, and suppressed the oncogenes HMGA2 and TTF1 in thyroid cancer cells.
Collapse
Affiliation(s)
- Sabine Wächter
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany.
| | - Alexander I Damanakis
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany.
| | - Moritz Elxnat
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany.
| | - Silvia Roth
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany.
| | - Annette Wunderlich
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany.
| | - Frederik A Verburg
- Department of Nuclear Medicine, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany.
| | - Sebastian A Fellinger
- Department of Nuclear Medicine, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany.
| | - Detlef K Bartsch
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany.
| | - Pietro Di Fazio
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany.
| |
Collapse
|
|
31
|
Li Y, Pi XY, Boland K, Lad S, Johnson K, Verfaillie C, Morris RJ. Hmga2 translocation induced in skin tumorigenesis. Oncotarget 2018; 8:30019-30029. [PMID: 28415789 PMCID: PMC5444722 DOI: 10.18632/oncotarget.16272] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 03/06/2017] [Indexed: 01/05/2023] Open
Abstract
Hmga2 protein, a transcription factor involved in chromatin architecture, is expressed chiefly during development, where it has many key biological functions. When expressed in adult tissues from in various organs, Hmga2 is always related to cancer development. The role of Hmga2 in skin tumorigenesis is, however, not yet understood. We demonstrated that Hmga2 can be found in non-transformed epidermis, specifically located to the membrane of keratinocytes (KCs) in epidermis. Ex vivo culture of KCs and development of skin carcinomas in DMBA and TPA mouse models was associated with translocation of the Hmga2 protein from the membrane into the nucleus, where Hmga2 induced its own expression by binding to the Hmga2 promoter. Panobinostat, an HDAC inhibitor, downregulated Hmga2 expression by preventing Hmga2 to bind its own promoter, and thus inhibiting Hmga2 promoter activity. Hmga2 translocation to the nucleus could in part be prevented by an inhibitor for ROCK1. Our findings demonstrate that upon program of benign papilloma to malignant cSCC of skin tumorigenesis, Hmga2 translocates in a ROCK-dependent manner from the membrane to the nucleus, where it serves as an autoregulatory transcription factor, causing cell transformation.
Collapse
Affiliation(s)
- Yong Li
- The Hormel Institute University of Minnesota, Austin, MN 55912, United States
| | - Xiang-Ying Pi
- The Hormel Institute University of Minnesota, Austin, MN 55912, United States
| | - Kelsey Boland
- The Hormel Institute University of Minnesota, Austin, MN 55912, United States
| | - Sonali Lad
- The Hormel Institute University of Minnesota, Austin, MN 55912, United States
| | - Kelly Johnson
- The Hormel Institute University of Minnesota, Austin, MN 55912, United States
| | - Catherine Verfaillie
- Department Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven 3000, Belgium
| | - Rebecca J Morris
- The Hormel Institute University of Minnesota, Austin, MN 55912, United States
| |
Collapse
|
|
32
|
Liu KY, Wang LT, Hsu SH. Modification of Epigenetic Histone Acetylation in Hepatocellular Carcinoma. Cancers (Basel) 2018; 10:cancers10010008. [PMID: 29301348 PMCID: PMC5789358 DOI: 10.3390/cancers10010008] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 12/19/2017] [Accepted: 12/30/2017] [Indexed: 12/14/2022] Open
Abstract
Cells respond to various environmental factors such as nutrients, food intake, and drugs or toxins by undergoing dynamic epigenetic changes. An imbalance in dynamic epigenetic changes is one of the major causes of disease, oncogenic activities, and immunosuppressive effects. The aryl hydrocarbon receptor (AHR) is a unique cellular chemical sensor present in most organs, and its dysregulation has been demonstrated in multiple stages of tumor progression in humans and experimental models; however, the effects of the pathogenic mechanisms of AHR on epigenetic regulation remain unclear. Apart from proto-oncogene activation, epigenetic repressions of tumor suppressor genes are involved in tumor initiation, procession, and metastasis. Reverse epigenetic repression of the tumor suppressor genes by epigenetic enzyme activity inhibition and epigenetic enzyme level manipulation is a potential path for tumor therapy. Current evidence and our recent work on deacetylation of histones on tumor-suppressive genes suggest that histone deacetylase (HDAC) is involved in tumor formation and progression, and treating hepatocellular carcinoma with HDAC inhibitors can, at least partially, repress tumor proliferation and transformation by recusing the expression of tumor-suppressive genes such as TP53 and RB1.
Collapse
Affiliation(s)
- Kwei-Yan Liu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
| | - Li-Ting Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
| | - Shih-Hsien Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
| |
Collapse
|
|
33
|
de Brot S, S. Rutland C, P. Mongan N, James V. Epigenetic Control of MicroRNA Expression and Cancer. CANCER AND NONCODING RNAS 2018:373-380. [DOI: 10.1016/b978-0-12-811022-5.00020-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
34
|
Di Fazio P, Maass M, Roth S, Meyer C, Grups J, Rexin P, Bartsch DK, Kirschbaum A. Expression of hsa-let-7b-5p, hsa-let-7f-5p, and hsa-miR-222-3p and their putative targets HMGA2 and CDKN1B in typical and atypical carcinoid tumors of the lung. Tumour Biol 2017; 39:1010428317728417. [PMID: 29017393 DOI: 10.1177/1010428317728417] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Typical and atypical carcinoid tumors belong to the neuroendocrine lung tumors. They have low recurrence and proliferation rate, lymph node, and distant metastases. Nevertheless, these tumors have shown a more aggressive behavior. In the last years, microRNAs were screened as new tumor markers for their potential diagnostic and therapeutic relevance. The expression of hsa-let-7b-5p, hsa-let-7f-5p, hsa-miR-222-3p, and their targets HMGA2 (high-mobility group A2) and CDKN1B (cyclin-dependent kynase inhibitor 1B, p27kip1) was evaluated in this rare small group of patients. We analyzed the clinical data of all typical and atypical carcinoid tumors of patients who underwent surgical operation at Marburg University Hospital (n = 18) from 2000. Quantitative reverse transcription polymerase chain reaction was performed in formalin-fixed paraffin-embedded tumor tissue versus four tumor-free lung tissue samples. HMGA2 was stable or downregulated; only one patient showed a significant overexpression. CDKN1B showed a significant overexpression or a stable level; it was downregulated in two samples only. Hsa-miR-222-3p resulted almost stable or overexpressed except for two samples (significantly downregulated). Hsa-let-7f-5p was stable or overexpressed in the majority of analyzed samples, whereas hsa-let-7b-5p was significantly downregulated. HMGA2 and CDKN1B are differently expressed between atypical and typical carcinoid tumors, thus representing valid biomarkers for the classification of the two tumor groups. Hsa-let-7f-5p and HMGA2 are inversely correlated. Hsa-miR-222-3p does not correlate with its predicted target CDKN1B.
Collapse
Affiliation(s)
- Pietro Di Fazio
- 1 Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Moritz Maass
- 1 Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Silvia Roth
- 1 Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Christian Meyer
- 1 Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Joana Grups
- 1 Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Peter Rexin
- 2 Institute for Pathology, Philipps University of Marburg, Marburg, Germany
| | - Detlef K Bartsch
- 1 Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Andreas Kirschbaum
- 1 Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| |
Collapse
|
|
35
|
Dattilo V, D’Antona L, Talarico C, Capula M, Catalogna G, Iuliano R, Schenone S, Roperto S, Bianco C, Perrotti N, Amato R. SGK1 affects RAN/RANBP1/RANGAP1 via SP1 to play a critical role in pre-miRNA nuclear export: a new route of epigenomic regulation. Sci Rep 2017; 7:45361. [PMID: 28358001 PMCID: PMC5371792 DOI: 10.1038/srep45361] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 02/27/2017] [Indexed: 12/15/2022] Open
Abstract
The serum- and glucocorticoid-regulated kinase (SGK1) controls cell transformation and tumor progression. SGK1 affects mitotic stability by regulating the expression of RANBP1/RAN. Here, we demonstrate that SGK1 fluctuations indirectly modify the maturation of pre-miRNAs, by modulating the equilibrium of the RAN/RANBP1/RANGAP1 axis, the main regulator of nucleo-cytoplasmic transport. The levels of pre-miRNAs and mature miRNAs were assessed by qRT-PCR, in total extracts and after differential nuclear/cytoplasmic extraction. RANBP1 expression is the limiting step in the regulation of SGK1-SP1 dependent nuclear export. These results were validated in unrelated tumor models and primary human fibroblasts and corroborated in tumor-engrafted nude mice. The levels of pri-miRNAs, DROSHA, DICER and the compartmental distribution of XPO5 were documented. Experiments using RANGTP conformational antibodies confirmed that SGK1, through RANBP1, decreases the level of the GTP-bound state of RAN. This novel mechanism may play a role in the epigenomic regulation of cell physiology and fate.
Collapse
Affiliation(s)
- Vincenzo Dattilo
- University “Magna Graecia” of Catanzaro, Dept. of “Scienze della Salute”, Viale Europa Catanzaro, Italy
| | - Lucia D’Antona
- University “Magna Graecia” of Catanzaro, Dept. of “Scienze della Salute”, Viale Europa Catanzaro, Italy
| | - Cristina Talarico
- University “Magna Graecia” of Catanzaro, Dept. of “Scienze della Salute”, Viale Europa Catanzaro, Italy
| | - Mjriam Capula
- University “Magna Graecia” of Catanzaro, Dept. of “Scienze della Salute”, Viale Europa Catanzaro, Italy
| | - Giada Catalogna
- University “Magna Graecia” of Catanzaro, Dept. of “Scienze della Salute”, Viale Europa Catanzaro, Italy
| | - Rodolfo Iuliano
- University “Magna Graecia” of Catanzaro, Dept. of “Medicina Sperimentale e Clinica”, Viale Europa Catanzaro, Italy
| | - Silvia Schenone
- University of Genova, Dept of Farmacia, Viale Benedetto XV 3, Genova, Italy
| | - Sante Roperto
- University “Federico II” of Naple, Dept of Medicina Veterinaria e Produzioni Animali, Via Federico Delpino 1, Napoli, Italy.
| | - Cataldo Bianco
- University “Magna Graecia” of Catanzaro, Dept. of “Medicina Sperimentale e Clinica”, Viale Europa Catanzaro, Italy
| | - Nicola Perrotti
- University “Magna Graecia” of Catanzaro, Dept. of “Scienze della Salute”, Viale Europa Catanzaro, Italy
| | - Rosario Amato
- University “Magna Graecia” of Catanzaro, Dept. of “Scienze della Salute”, Viale Europa Catanzaro, Italy
| |
Collapse
|
|
36
|
Yang J, Zhang Z, Guo W, Ma Y, Emin RM, Abudubari K, Hayrat G, Wali H, Qi X, Liu C, Ma M, Nurbek P. Single nucleotide polymorphisms in microRNA genes are associated with cervical cancer susceptibility in a population from Xinjiang Uygur. Oncotarget 2016; 7:71447-71454. [PMID: 27677077 PMCID: PMC5342091 DOI: 10.18632/oncotarget.12212] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 08/15/2016] [Indexed: 12/12/2022] Open
Abstract
The goal of this study was to explore the correlation between single nucleotide polymorphisms (SNPs) and susceptibility to cervical cancer (CC) in a population from Xinjiang Uygur. Participating were 247 patients with CC and 285 healthy women. Fourteen SNPs in nine miRNA genes were selected. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. Multivariate logistic regression analysis was used to assess the correlation of SNPs with CC. The minor allele "C" of rs300574 in SPRY1 was associated with an increased risk of CC based on analysis of the allele, codominant, recessive and log-additive models, but an opposite result was found with the over-dominant model. The minor allele "C" of rs1042725 in HMGA2 was associated with an increased risk of CC in the allele, dominant and log-additive models. In clinical stage III/IVCC patients, rs4728 in SPRY2 was associated with decreased risk. Finally, rs3744935 in BCL2 was associated with CC in the allele and codominant models. In sum, we have detected associations between four SNPs, rs300574 (SPRY1), rs3744935 (BCL2), rs1042725 (HMGA2), and rs4728 (SPRY2), and CC risk in women from Xinjiang Uygur.
Collapse
Affiliation(s)
- Jie Yang
- Radiotherapy Second Department, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China
| | - Zegao Zhang
- Radiotherapy Second Department, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China
| | - Wen Guo
- Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Yuhua Ma
- Radiotherapy Second Department, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China
| | - Raila Muhammed Emin
- Radiotherapy Second Department, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China
| | - Karima Abudubari
- Radiotherapy Second Department, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China
| | - Glmira Hayrat
- Radiotherapy Second Department, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China
| | - Hasiyet Wali
- Radiotherapy Second Department, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China
| | - Xiaoli Qi
- Radiotherapy Second Department, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China
| | - Chunhua Liu
- Radiotherapy Second Department, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China
| | - Miaomiao Ma
- Radiotherapy Second Department, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China
| | - Pulat Nurbek
- Radiotherapy Second Department, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China
| |
Collapse
|
|
37
|
Damanakis AI, Eckhardt S, Wunderlich A, Roth S, Wissniowski TT, Bartsch DK, Di Fazio P. MicroRNAs let7 expression in thyroid cancer: correlation with their deputed targets HMGA2 and SLC5A5. J Cancer Res Clin Oncol 2016; 142:1213-1220. [PMID: 26960757 DOI: 10.1007/s00432-016-2138-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 02/22/2016] [Indexed: 02/07/2023]
Abstract
PURPOSE Thyroid cancer (TC), the most common endocrine malignancy, increases its incidence worldwide. MicroRNAs have been shown to be abnormally expressed in tumors and could represent valid diagnostic markers for patients affected by TC. Our aim was to analyze the expression of tumorsuppressor hsa-let7b-5p and hsa-let7f-5p, together with their predicted targets SLC5A5 (NIS) and HMGA2, in papillary (PTC), follicular (FTC) and anaplastic (ATC). METHODS 8 FTC, 14 PTC, 12 ATC and three normal thyroid tissue samples were analyzed for the expression of pre-let7b, hsa-let7b-5p and hsa-let7f-5p as SLC5A5 and HMGA2 by RT-qPCR. Data were analyzed by REST 2008. RESULTS FTC patients showed a significant down-regulation of hsa-let7b-5p and its precursor. hsa-let7f-5p was overexpressed, and SLC5A5 was strongly suppressed. HMGA2 was overexpressed, reflecting no correlation with its regulatory let7 miRNAs. PTC samples were characterized by up-regulation of hsa-let7b-5p, its precursor and hsa-let7f-5p. SLC5A5 was strongly suppressed in comparison with normal thyroid tissue. HMGA2 was overexpressed, as shown in FTC, also. ATC samples showed a similar miRNAs profile as PTC. In contrast with FTC and PTC, these patients showed a stable or up-regulated SLC5A5 and HMGA2. CONCLUSIONS Expression of HMGA2 is not correlated with the regulatory let7 miRNAs. Interestingly, SLC5A5 was down-regulated in FTC and PTC. Its expression could be modulated by hsa-let-7f-5p. ATC showed a loss of SLC5A5/hsa-let7f-5p correlation. SLC5A5, in ATC, needs further investigation to clarify the genetic/epigenetic mechanism altering its expression.
Collapse
Affiliation(s)
- Alexander I Damanakis
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Sabine Eckhardt
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Annette Wunderlich
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Silvia Roth
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Thaddeus T Wissniowski
- Division of Gastroenterology and Endocrinology, Philipps University Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Detlef K Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043, Marburg, Germany.
| |
Collapse
|
|
38
|
Di Fazio P, Waldegger P, Jabari S, Lingelbach S, Montalbano R, Ocker M, Slater EP, Bartsch DK, Illig R, Neureiter D, Wissniowski TT. Autophagy-related cell death by pan-histone deacetylase inhibition in liver cancer. Oncotarget 2016; 7:28998-29010. [PMID: 27058414 PMCID: PMC5045373 DOI: 10.18632/oncotarget.8585] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 03/18/2016] [Indexed: 02/07/2023] Open
Abstract
Autophagy is a homeostatic, catabolic degradation process and cell fate essential regulatory mechanism. Protracted autophagy triggers cell death; its aberrant function is responsible for several malignancies. Panobinostat, a potent pan-deacetylase inhibitor, causes endoplasmic reticulum stress-induced cell death. The aim of this study was to investigate the role of autophagy in deacetylase inhibitor-triggered liver cancer cell death.HepG2 (p53wt) and Hep3B (p53 null) liver cancer cell lines were exposed to panobinostat. RT-qPCR and western blot confirmed autophagic factor modulation. Immuno-fluorescence, -precipitation and -histochemistry as well as transmission electron microscopy verified autophagosome formation. The cytotoxicity of panobinostat and autophagy modulators was detected using a real time cell viability assay.Panobinostat induced autophagy-related factor expression and aggregation. Map1LC3B and Beclin1 were significantly over-expressed in HepG2 xenografts in nude mice treated with panobinostat for 4 weeks. Subcellular distribution of Beclin1 increased with the appearance of autophagosomes-like aggregates. Cytosolic loss of p53, in HepG2, and p73, in Hep3B cells, and a corresponding gain of their nuclear level, together with modulation of DRAM1, were observed. Autophagosome aggregation was visible after 6 h of treatment. Treatment of cells stably expressing GFP-RFPtag Map1LC3B resulted in aggregation and a fluorescence switch, thus confirming autophagosome formation and maturation. Tamoxifen, an inducer of autophagy, caused only a block in cell proliferation; but in combination with panobinostat it resulted in cell death.Autophagy triggers cell demise in liver cancer. Its modulation by the combination of tamoxifen and panobinostat could be a new option for palliative treatment of hepatocellular carcinoma.
Collapse
Affiliation(s)
- Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Petra Waldegger
- Institute for Biomedical Aging Research, University of Innsbruck, Rennweg, Innsbruck, Austria
| | - Samir Jabari
- Institute for Anatomy I, University of Erlangen-Nurnberg, Erlangen, Germany
| | | | - Roberta Montalbano
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Matthias Ocker
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
- Experimental Medicine Oncology, Bayer Pharma AG, Berlin Germany
| | - Emily P. Slater
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Detlef K. Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Romana Illig
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Thaddeus T. Wissniowski
- Department of Gastroenterology and Endocrinology, Philipps University of Marburg, Marburg, Germany
| |
Collapse
|
|
39
|
Montalbano R, Honrath B, Wissniowski TT, Elxnat M, Roth S, Ocker M, Quint K, Churin Y, Roederfeld M, Schroeder D, Glebe D, Roeb E, Fazio PD. Exogenous hepatitis B virus envelope proteins induce endoplasmic reticulum stress: involvement of cannabinoid axis in liver cancer cells. Oncotarget 2016; 7:20312-20323. [PMID: 26967385 PMCID: PMC4991457 DOI: 10.18632/oncotarget.7950] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 02/13/2016] [Indexed: 02/07/2023] Open
Abstract
HBV represents the most common chronic viral infection and major cause of hepatocellular carcinoma (HCC), although its exact role in liver tumorigenesis is unclear. Massive storage of the small (SHBs), middle (MHBs) and large surface (LHBs) HBV envelope proteins leads to cell stress and sustained inflammatory responses. Cannabinoid (CB) system is involved in the pathogenesis of liver diseases, stimulating acute and chronic inflammation, liver damage and fibrogenesis; it triggers endoplasmic reticulum (ER) stress response. The aim of our work was to investigate the activation of ER stress pathway after ectopic HBV envelope proteins expression, in liver cancer cells, and the role exerted by CB receptors. PCR, immunofluorescence and western blotting showed that exogenous LHBs and MHBs induce a clear ER stress response in Huh-7 cells expressing CB1 receptor. Up-regulation of the chaperone BiP/GRP78 (Binding Immunoglobulin Protein/Glucose-Regulated Protein 78) and of the transcription factor CHOP/GADD153 (C/EBP Homologous Protein/Growth Arrest and DNA Damage inducible gene 153), phosphorylation of PERK (PKR-like ER Kinase) and eIF2α (Eukaryotic Initiation Factor 2α) and splicing of XBP1 (X-box binding protein 1) was observed. CB1-/- HepG2 cells did not show any ER stress activation. Inhibition of CB1 receptor counteracted BiP expression in transfected Huh-7 and in HBV+ PLC/PRF/5 cells; whereas no effect was observed in HBV- HLF cells. These results suggest that HBV envelope proteins are able to induce the ER stress pathway. CB1 expression is directly correlated with ER stress function. Further investigations are needed to clarify the involvement of cannabinoid in HCC progression after HBV infection.
Collapse
Affiliation(s)
- Roberta Montalbano
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Birgit Honrath
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | | | - Moritz Elxnat
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Silvia Roth
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Matthias Ocker
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
- Present address: Department of Gastroenterology CBF, Charité University Medicine Berlin and Bayer Pharma AG, Experimental Medicine Oncology, Berlin, Germany
| | - Karl Quint
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
| | - Yuri Churin
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Martin Roederfeld
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Dirk Schroeder
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, Justus Liebig University, Giessen, Germany
| | - Elke Roeb
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| |
Collapse
|
|
40
|
Hsieh TH, Hsu CY, Tsai CF, Long CY, Chai CY, Hou MF, Lee JN, Wu DC, Wang SC, Tsai EM. miR-125a-5p is a prognostic biomarker that targets HDAC4 to suppress breast tumorigenesis. Oncotarget 2016; 6:494-509. [PMID: 25504437 PMCID: PMC4381610 DOI: 10.18632/oncotarget.2674] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 11/02/2014] [Indexed: 12/18/2022] Open
Abstract
Identifying stably expressed tumor markers that can be used easily to detect cancer is currently an important area of cancer research. By using miRNA microarray, we identified 20 differentially expressed miRNAs in serum samples of breast cancer patients. Expression of miR-125a-5p was relatively lower in patients with shorter survival compared to long-term survivors. In a cohort of breast cancer patients (N = 300), serum expression of miR-125a-5p was negatively and significantly correlated with tumor grade (P = 0.004), lymph-node status (P = 0.004), and tumor size (P < 0.001). Low miR-125a-5p expression was an independent prognostic marker (OR = 0.421; 95% CI = 0.184 to 0.961; P = 0.04) associated with poor survival rates (P = 0.0062). We show that miR-125a-5p directly inhibits expression of the HDAC4 gene, resulting in tumor suppression in vitro and in vivo. Together these results demonstrate that serum miR-125a-5p level in breast cancer may be a useful prognostic biomarker and offer a novel therapeutic avenue by targeting HDAC4 in breast cancer.
Collapse
Affiliation(s)
- Tsung-Hua Hsieh
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chia-Yi Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Cheng-Fang Tsai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Cheng-Yu Long
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chee-Yin Chai
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Feng Hou
- Department of General Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jau-Nan Lee
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Deng-Chyang Wu
- Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shao-Chun Wang
- Department of Cancer Biology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267, USA
| | - Eing-Mei Tsai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. Center for Research Resources and Development, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| |
Collapse
|
|
41
|
Maschauer S, Gahr S, Gandesiri M, Tripal P, Schneider-Stock R, Kuwert T, Ocker M, Prante O. In vivo monitoring of the anti-angiogenic therapeutic effect of the pan-deacetylase inhibitor panobinostat by small animal PET in a mouse model of gastrointestinal cancers. Nucl Med Biol 2016; 43:27-34. [PMID: 26702784 DOI: 10.1016/j.nucmedbio.2015.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 09/29/2015] [Accepted: 10/16/2015] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Deacetylase inhibitors have recently been established as a novel therapeutic approach to solid and hematologic cancers and have also been demonstrated to possess anti-angiogenic properties. Although these compounds show a good efficacy in vitro and in vivo, no data on monitoring and predicting treatment response are currently available. We therefore investigated the effect of the pan-deacetylase inhibitor panobinostat (LBH589) on gastrointestinal cancer models and the suitability of 2-[(18)F]FGlc-RGD as a specific agent for imaging integrin αvβ3 expression during tumor angiogenesis using small animal positron emission tomography (PET). METHODS The effect of panobinostat on cell viability in vitro was assessed with a label-free impedance based real-time analysis. Nude mice bearing HT29 and HepG2 tumors were treated with daily i.p. injections of 10mg/kg panobinostat for 4 weeks. During this time, tumor size was determined with a calliper and mice were repeatedly subjected to PET imaging. Tumor tissues were analyzed immunohistochemically with a focus on proliferation and endothelial cell markers (Ki-67, Meca-32) and by Western blot applying specific markers of apoptosis. RESULTS In vitro, panobinostat inhibited the proliferation of HepG2 and HT29 cells. Contrary to the situation in HepG2 tumors in vivo, where panobinostat treatment is known to reduce proliferation and vascularization resulting in a decreased tumor growth, HT29 tumors did not show any effect on these parameters. We demonstrated by Western blotting, that panobinostat induced apoptosis in HT29 tumors in vivo. Longitudinal PET imaging studies in HepG2 tumor-bearing mice using 2-[(18)F]FGlc-RGD demonstrated that the standard uptake value (SUVmax) in HepG2 tumors was significantly decreased by 39% at day 7 after treatment. The comparative PET study using HT29 tumor-bearing animals did not reveal any response of the tumors to panobinostat treatment. CONCLUSIONS Small-animal PET imaging using 2-[(18)F]FGlc-RGD was successfully applied to the non-invasive monitoring of the HepG2-tumor response to panobinostat in nude mice early after begin of treatment. Thus, PET imaging of angiogenesis using 2-[(18)F]FGlc-RGD could be a valuable tool to monitor panobinostat therapy in further preclinical studies. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE When successfully translated to the clinical surrounding, PET imaging of angiogenesis could therefore facilitate therapy planning and monitoring of therapy success with panobinostat in hepatocellular carcinoma.
Collapse
Affiliation(s)
- Simone Maschauer
- Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University (FAU), Erlangen, Germany
| | - Susanne Gahr
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Muktheshwar Gandesiri
- Experimental Tumorpathology, Department of Pathology, Friedrich Alexander University (FAU), Erlangen, Germany
| | - Philipp Tripal
- Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University (FAU), Erlangen, Germany
| | - Regine Schneider-Stock
- Experimental Tumorpathology, Department of Pathology, Friedrich Alexander University (FAU), Erlangen, Germany
| | - Torsten Kuwert
- Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University (FAU), Erlangen, Germany
| | - Matthias Ocker
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany.
| | - Olaf Prante
- Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University (FAU), Erlangen, Germany.
| |
Collapse
|
|
42
|
Wang L, Yue Y, Wang X, Jin H. Function and clinical potential of microRNAs in hepatocellular carcinoma. Oncol Lett 2015; 10:3345-3353. [PMID: 26788134 DOI: 10.3892/ol.2015.3759] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 08/25/2015] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs involved in the initiation and progression of several types of human cancer, including hepatocellular carcinoma (HCC), which is one of the most common types of cancer and the third leading cause of cancer-related mortality worldwide. Mounting evidence has demonstrated that miRNAs play a vital role in HCC, hepatitis, alcoholic liver disease, liver cell development and the metabolic functions of the liver. The aim of the present review was to summarize the most recent findings on the functions of miRNAs in the liver and discuss their potential roles in the diagnosis, prognosis and treatment of HCC.
Collapse
Affiliation(s)
- Lijuan Wang
- Department of Hematology, Hematology Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong 276003, P.R. China
| | - Yongfang Yue
- Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Xian Wang
- Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Hongchuan Jin
- Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| |
Collapse
|
|
43
|
Wu Z, Eguchi-Ishimae M, Yagi C, Iwabuki H, Gao W, Tauchi H, Inukai T, Sugita K, Ishii E, Eguchi M. HMGA2 as a potential molecular target in KMT2A-AFF1-positive infant acute lymphoblastic leukaemia. Br J Haematol 2015; 171:818-29. [PMID: 26403224 DOI: 10.1111/bjh.13763] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 07/29/2015] [Indexed: 12/30/2022]
Abstract
Acute lymphoblastic leukaemia (ALL) in infants is an intractable cancer in childhood. Although recent intensive chemotherapy progress has considerably improved ALL treatment outcome, disease cure is often accompanied by undesirable long-term side effects, and efficient, less toxic molecular targeting therapies have been anticipated. In infant ALL cells with KMT2A (MLL) fusion, the microRNA let-7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. We show here that the expression of HMGA2, one of the oncogenes repressed by MIRLET7B, is reversely upregulated in infant ALL leukaemic cells, particularly in KMT2A-AFF1 (MLL-AF4) positive ALL. In addition to the suppression of MIRLET7B, KMT2A fusion proteins positively regulate the expression of HMGA2. HMGA2 is one of the negative regulators of CDKN2A gene, which encodes the cyclin-dependent kinase inhibitor p16(INK4A) . The HMGA2 inhibitor netropsin, when combined with demethylating agent 5-azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppression of KMT2A-AFF1-expressing cell lines. This effect was more apparent compared to treatment with 5-azacytidine alone. These results indicate that the MIRLET7B-HMGA2-CDKN2A axis plays an important role in cell proliferation of leukaemic cells and could be a possible molecular target for the therapy of infant ALL with KMT2A-AFF1.
Collapse
Affiliation(s)
- Zhouying Wu
- Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | | | - Chihiro Yagi
- Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Hidehiko Iwabuki
- Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Wenming Gao
- Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Hisamichi Tauchi
- Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Takeshi Inukai
- Department of Paediatrics, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Kanji Sugita
- Department of Paediatrics, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Eiichi Ishii
- Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Mariko Eguchi
- Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| |
Collapse
|
|
44
|
Gahr S, Mayr C, Kiesslich T, Illig R, Neureiter D, Alinger B, Ganslmayer M, Wissniowski T, Fazio PD, Montalbano R, Ficker JH, Ocker M, Quint K. The pan-deacetylase inhibitor panobinostat affects angiogenesis in hepatocellular carcinoma models via modulation of CTGF expression. Int J Oncol 2015; 47:963-970. [PMID: 26202945 DOI: 10.3892/ijo.2015.3087] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 06/08/2015] [Indexed: 02/07/2023] Open
Abstract
Post-translational modifications of chromatin components are significantly involved in the regulation of tumor suppressor gene and oncogene expression. Connective tissue growth factor (CTGF) is an epigenetically regulated growth factor with functions in angiogenesis and cell-matrix interactions and plays a pivotal role in hepatocellular carcinoma (HCC). The pharmacologic inhibition of histone and protein deacetylases represents a new approach to interfere with pathways of apoptosis and angiogenesis. We investigated the effect of the pan-deacetylase inhibitor panobinostat (LBH589) on human HCC cell lines HepG2 (p53wt) and Hep3B (p53null) and in a subcutaneous xenograft model and explored the influence on angiogenesis. Specimens were characterized by quantitative real-time PCR. Protein was separated for western blotting against CTGF, VEGF, VEGF receptor-1 (VEGFR-1/FLT-1), VEGF receptor-2 (VEGFR-2/KDR), MAPK and phospho-MAPK. In vivo, HepG2 cells were xenografted to NMRI mice and treated with daily i.p. injections of 10 mg/kg panobinostat. After 1, 7 and 28 days, real-time PCR was performed. Immunohistochemistry and western blotting were examined after 28 days. An increased significant expression of CTGF was only seen after 24 h treatment with 0.1 µM panobinostat in HepG2 cells and Hep3B cells, whereas after 72 h treatment CTGF expression clearly decreased. In the xenografts, treatment with panobinostat showed a minimal CTGF expression after 1 day and 4 weeks, respectively. In vitro as well as in vivo, VEGF was not affected by panobinostat treatment at any time. In conclusion, panobinostat influences extracellular signaling cascades via CTGF-dependent pathways.
Collapse
Affiliation(s)
- Susanne Gahr
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Christian Mayr
- Laboratory for Tumour Biology and Experimental Therapies, Paracelsus Medical University, Salzburg, Austria
| | - Tobias Kiesslich
- Laboratory for Tumour Biology and Experimental Therapies, Paracelsus Medical University, Salzburg, Austria
| | - Romana Illig
- Institute of Pathology, Salzburger Landeskliniken, Paracelsus Private Medical University, Salzburg, Austria
| | - Daniel Neureiter
- Institute of Pathology, Salzburger Landeskliniken, Paracelsus Private Medical University, Salzburg, Austria
| | - Beate Alinger
- Institute of Pathology, Salzburger Landeskliniken, Paracelsus Private Medical University, Salzburg, Austria
| | - Marion Ganslmayer
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Till Wissniowski
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Pietro Di Fazio
- Institute for Surgical Research, Phillips University Marburg, Marburg, Germany
| | - Roberta Montalbano
- Institute for Surgical Research, Phillips University Marburg, Marburg, Germany
| | - Joachim H Ficker
- Klinikum Nuernberg, Department of Respiratory Medicine, Allergology and Sleep Medicine, Nuremberg, Germany
| | - Matthias Ocker
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Karl Quint
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| |
Collapse
|
|
45
|
Ali SR, Humphreys KJ, McKinnon RA, Michael MZ. Impact of Histone Deacetylase Inhibitors on microRNA Expression and Cancer Therapy: A Review. Drug Dev Res 2015; 76:296-317. [PMID: 26303212 DOI: 10.1002/ddr.21268] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Chromatin-modifying drugs, such as histone deacetylase inhibitors (HDACi), have shown potential as cancer therapeutics, either alone or in combination with other therapies. HDACi have the ability to reverse aberrant epigenetic modifications associated with cancer, namely dysregulated histone acetylation. There are currently three FDA approved HDACi; vorinostat, romidepsin, and panobinostat. Epigenetic modifications can regulate the expression of protein coding genes, and in addition can alter expression of microRNA (miRNA) genes. Many miRNAs play key roles in cell proliferation and apoptosis, and are commonly dysregulated in cancer states. A number of in vitro and in vivo studies have demonstrated the ability of chromatin-modifying drugs to alter miRNA expression, which may provide the basis for further investigation of miRNAs as therapeutic targets or as biomarkers of drug response. This review summarises findings from studies investigating the effects of HDACi on miRNA expression, as well as key clinical trials involving HDACi. Understanding how chromatin-modifying drugs epigenetically modulate miRNA genes provides further insight into the cellular mechanisms that deliver therapeutic responses, and may assist in refining treatment strategies.
Collapse
Affiliation(s)
- Saira R Ali
- Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, South Australia, Australia
| | - Karen J Humphreys
- Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, South Australia, Australia
| | - Ross A McKinnon
- Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, South Australia, Australia
| | - Michael Z Michael
- Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, South Australia, Australia.,Department of Gastroenterology and Hepatology, Flinders Medical Centre, Adelaide, South Australia, Australia
| |
Collapse
|
|
46
|
Henrici A, Montalbano R, Neureiter D, Krause M, Stiewe T, Slater EP, Quint K, Ocker M, Di Fazio P. The pan-deacetylase inhibitor panobinostat suppresses the expression of oncogenic miRNAs in hepatocellular carcinoma cell lines. Mol Carcinog 2015; 54:585-597. [PMID: 24375802 DOI: 10.1002/mc.22122] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 11/18/2013] [Accepted: 11/26/2013] [Indexed: 02/05/2023]
Abstract
Deacetylase inhibitors (DACi) are a new class of drugs with a broad spectrum of mechanisms that favor their application in cancer therapy. Currently, the exact mechanisms and cellular effects of DACi have not been fully elucidated. In addition to their effects on histone acetylation, DACi can interfere with gene expression via miRNA pathways. Treatment with panobinostat (LBH589), a novel potent DACi, led to the highly aberrant modulation of several miRNAs in hepatocellular carcinoma (HCC) cell lines as shown by miRNA array analysis. Among them, hsa-miR-19a, hsa-miR-19b1 and the corresponding precursors were down-regulated by panobinostat in TP53(-/-) Hep3B and TP53(+/+) HepG2 cell lines; hsa-miR30a-5p mature form only was suppressed in both HCC cell lines, as confirmed by further RT-qPCR analysis. In HCC cell lines, panobinostat caused the upregulation of the predicted miRNA targets APAF1 and Beclin1 protein levels. Transfection with oligonucleotides mimicking these miRNAs led to an increase in the viability rate of both cell lines as analyzed by impedance-based real-time cell analysis. In addition, transfecting miRNA mimicking oligonucleotides resulted in the decrease of APAF1, Beclin1 and PAK6 at the protein level, proving the regulating influence of the investigated miRNAs on gene final products. The overexpression of the above mentioned oncomiRs in Hep3B and HepG2 cell lines leads to cell proliferation and downregulation of cell death associated proteins. In our model, panobinostat exerts its anti-cancer effect by suppressing these miRNAs and restoring the expression of their corresponding tumor suppressor targets.
Collapse
Affiliation(s)
- Alexander Henrici
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
| | - Roberta Montalbano
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Private Medical University, Salzburg, Austria
| | - Michael Krause
- Institute of Molecular Biology and Tumor Research, Philipps University of Marburg, Marburg, Germany
| | - Thorsten Stiewe
- Institute of Molecular Biology and Tumor Research, Philipps University of Marburg, Marburg, Germany
| | - Emily Prentice Slater
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Karl Quint
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
| | - Matthias Ocker
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
| | - Pietro Di Fazio
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| |
Collapse
|
|
47
|
Bae HJ, Jung KH, Eun JW, Shen Q, Kim HS, Park SJ, Shin WC, Yang HD, Park WS, Lee JY, Nam SW. MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer. J Hepatol 2015; 63:408-419. [PMID: 25817558 DOI: 10.1016/j.jhep.2015.03.019] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 03/04/2015] [Accepted: 03/16/2015] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Most common reason behind changes in histone deacetylase (HDAC) function is its overexpression in cancer. However, among HDACs in liver cancer, HDAC6 is uniquely endowed with a tumor suppressor, but the mechanism underlying HDAC6 inactivation has yet to be uncovered. METHODS Microarray profiling and target prediction programs were used to identify miRNAs targeting HDAC6. A series of inhibitors, activators and siRNAs was introduced to validate regulatory mechanisms for microRNA-221-3p (miR-221) governing HDAC6 in hepatocarcinogenesis. RESULTS Comprehensive miRNA profiling analysis identified seven putative endogenous miRNAs that are significantly upregulated in hepatocellular carcinoma (HCC). While miR-221 was identified as a suppressor of HDAC6 by ectopic expression of miRNA mimics in Dicer knockdown cells, targeted-disruption of miR-221 repressed cancer cell growth through derepressing HDAC6 expression. Suppression of HDAC6 via miR-221 was induced by JNK/c-Jun signaling in liver cancer cells but not in normal hepatic cells. Additionally, cytokine-induced NF-κBp65 independently regulated miR-221, thereby suppressing HDAC6 expression in HCC cells. HCC tissues derived from chemical-induced rat and H-ras12V transgenic mice liver cancer models validated that JNK/c-Jun activation and NF-κBp65 nuclear translocation are essential for the transcription of miR-221 leading to repression of HDAC6 in HCC. CONCLUSIONS Our findings suggest that the functional loss or suppression of the tumor suppressor HDAC6 is caused by induction of miR-221 through coordinated JNK/c-Jun- and NF-κB-signaling pathways during liver tumorigenesis, providing a novel target for the molecular treatment of liver malignancies.
Collapse
Affiliation(s)
- Hyun Jin Bae
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Kwang Hwa Jung
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Jung Woo Eun
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Qingyu Shen
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Hyung Seok Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Se Jin Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Woo Chan Shin
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Hee Doo Yang
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Won Sang Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Jung Young Lee
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Suk Woo Nam
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Cancer Evolution Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
| |
Collapse
|
|
48
|
|
|
49
|
Lyra-González I, Flores-Fong LE, González-García I, Medina-Preciado D, Armendáriz-Borunda J. MicroRNAs dysregulation in hepatocellular carcinoma: Insights in genomic medicine. World J Hepatol 2015; 7:1530-1540. [PMID: 26085912 PMCID: PMC4462691 DOI: 10.4254/wjh.v7.i11.1530] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 12/22/2014] [Accepted: 05/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading primary liver cancer and its clinical outcome is still poor. MicroRNAs (miRNAs) have demonstrated an interesting potential to regulate gene expression at post-transcriptional level. Current findings suggest that miRNAs deregulation in cancer is caused by genetic and/or epigenetic, transcriptional and post-transcriptional modifications resulting in abnormal expression and hallmarks of malignant transformation: aberrant cell growth, cell death, differentiation, angiogenesis, invasion and metástasis. The important role of miRNAs in the development and progression of HCC has increased the efforts to understand and develop mechanisms of control overt this single-stranded RNAs. Several studies have analyzed tumoral response to the regulation and control of deregulated miRNAs with good results in vitro and in vivo, proving that targeting aberrant expression of miRNAs is a powerful anticancer therapeutic. Identification of up and/or down regulated miRNAs related to HCC has led to the discovery of new potential application for detection of their presence in the affected organism. MiRNAs represent a relevant new target for diagnosis, prognosis and treatment in a wide variety of pathologic entities, including HCC. This manuscript intends to summarize current knowledge regarding miRNAs and their role in HCC development.
Collapse
|
|
50
|
IGF-1R, a target of let-7b, mediates crosstalk between IRS-2/Akt and MAPK pathways to promote proliferation of oral squamous cell carcinoma. Oncotarget 2015; 5:2562-74. [PMID: 24810113 PMCID: PMC4058027 DOI: 10.18632/oncotarget.1812] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Insulin-like growth factor (IGF) signaling is involved in oral squamous cell carcinoma (OSCC), but IGF-1 receptor (IGF-1R)-mediated intricate regulatory networks among molecular interactions and signalling path ways in OSCC remain unclear. Here, we found that overexpression of IGF-1R and insulin receptor substrate-2 (IRS-2) was negatively associated with histological differentiation. IGF signaling stimulated OSCC cell growth. Conversely, overexpression of let-7b inhibited proliferation and colony formation and triggered S/G2 cell cycle arrest by targeting IGF-1R and IRS-2 through the Akt pathway. Also, the inverse relationship between expression of let-7b and IGF-1R/IRS-2 was confirmed in OSCC tumor xenografts and clinical specimens. Furthermore, by activating ERK1/2, IGF-1R transcriptionally upregulated IRS-2. Our results indicate that let-7b/IGF-1R-mediated crosstalk between IRS-2/Akt and MAPK is involved in OSCC and is a potential therapeutic target for therapy.
Collapse
|