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1
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Song G, Yu X, Shi H, Sun B, Amateau S. miRNAs in HCC, pathogenesis, and targets. Hepatology 2024:01515467-990000000-01097. [PMID: 39626210 DOI: 10.1097/hep.0000000000001177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [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.
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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
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2
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Murshed A, Alnoud MAH, Ahmad S, Khan SU, Alissa M, Alsuwat MA, Ahmed AE, Khan MU. Genetic Alchemy unveiled: MicroRNA-mediated gene therapy as the Artisan craft in the battlefront against hepatocellular carcinoma-a comprehensive chronicle of strategies and innovations. Front Genet 2024; 15:1356972. [PMID: 38915826 PMCID: PMC11194743 DOI: 10.3389/fgene.2024.1356972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 05/03/2024] [Indexed: 06/26/2024] Open
Abstract
Investigating therapeutic miRNAs is a rewarding endeavour for pharmaceutical companies. Since its discovery in 1993, our understanding of miRNA biology has advanced significantly. Numerous studies have emphasised the disruption of miRNA expression in various diseases, making them appealing candidates for innovative therapeutic approaches. Hepatocellular carcinoma (HCC) is a significant malignancy that poses a severe threat to human health, accounting for approximately 70%-85% of all malignant tumours. Currently, the efficacy of several HCC therapies is limited. Alterations in various biomacromolecules during HCC progression and their underlying mechanisms provide a basis for the investigation of novel and effective therapeutic approaches. MicroRNAs, also known as miRNAs, have been identified in the last 20 years and significantly impact gene expression and protein translation. This atypical expression pattern is strongly associated with the onset and progression of various malignancies. Gene therapy, a novel form of biological therapy, is a prominent research area. Therefore, miRNAs have been used in the investigation of tumour gene therapy. This review examines the mechanisms of action of miRNAs, explores the correlation between miRNAs and HCC, and investigates the use of miRNAs in HCC gene therapy.
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Affiliation(s)
- Abduh Murshed
- Department of Intensive Care Unit, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Mohammed A. H. Alnoud
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Saleem Ahmad
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Safir Ullah Khan
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Mohammed Alissa
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Meshari A. Alsuwat
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Ahmed Ezzat Ahmed
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
- Prince Sultan Bin Abdelaziz for Environmental Research and Natural Resources Sustainability Center, King Khalid University, Abha, Saudi Arabia
| | - Munir Ullah Khan
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, International Research Center for XPolymers, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
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Tavakoli Pirzaman A, Alishah A, Babajani B, Ebrahimi P, Sheikhi SA, Moosaei F, Salarfar A, Doostmohamadian S, Kazemi S. The Role of microRNAs in Hepatocellular Cancer: A Narrative Review Focused on Tumor Microenvironment and Drug Resistance. Technol Cancer Res Treat 2024; 23:15330338241239188. [PMID: 38634139 PMCID: PMC11025440 DOI: 10.1177/15330338241239188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/26/2024] [Accepted: 02/26/2024] [Indexed: 04/19/2024] Open
Abstract
Globally, hepatic cancer ranks fourth in terms of cancer-related mortality and is the sixth most frequent kind of cancer. Around 80% of liver cancers are hepatocellular carcinomas (HCC), which are the leading cause of cancer death. It is well known that HCC may develop resistance to the available chemotherapy treatments very fast. One of the biggest obstacles in providing cancer patients with appropriate care is drug resistance. According to reports, more than 90% of cancer-specific fatalities are caused by treatment resistance. By binding to the 3'-untranslated region of target messenger RNAs (mRNAs), microRNAs (miRNAs), a group of noncoding RNAs which are around 17 to 25 nucleotides long, regulate target gene expression. Moreover, they play role in the control of signaling pathways, cell proliferation, and cell death. As a result, miRNAs play an important role in the microenvironment of HCC by changing immune phenotypes, hypoxic conditions, and acidification, as well as angiogenesis and extracellular matrix components. Moreover, changes in miRNA levels in HCC can effectively resist cancer cells to chemotherapy by affecting various cellular processes such as autophagy, apoptosis, and membrane transporter activity. In the current work, we narratively reviewed the role of miRNAs in HCC, with a special focus on tumor microenvironment and drug resistance.
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Affiliation(s)
| | - Ali Alishah
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Bahareh Babajani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Pouyan Ebrahimi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Ali Sheikhi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Farhad Moosaei
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | | | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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4
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Lin YH. The effects of intracellular and exosomal ncRNAs on cancer progression. Cancer Gene Ther 2023; 30:1587-1597. [PMID: 37884579 DOI: 10.1038/s41417-023-00679-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 10/03/2023] [Accepted: 10/17/2023] [Indexed: 10/28/2023]
Abstract
Altered gene expression as well as mislocalization of a gene's encoded product (proteins or noncoding RNAs (ncRNAs)) can lead to disease and cancer formation. Multiple studies have indicated that exosomes and their contents act as cell-to-cell communicators and play a key role in cancer progression. Moreover, exosomes contain several functional molecules, including ncRNAs. NcRNAs function as master regulators to coordinate cell growth, cell motility and drug resistance. However, intracellular ncRNAs, which can be transferred to recipient cells via exosomes (exosomal ncRNAs), mediate common/distinct downstream molecules, signaling pathways and functions that are less emphasized concepts in cancer development research. In this study, by using exosomes as a model, we comprehensively discuss the current knowledge regarding (1) the functional role of ncRNAs, both their intracellular and exosomal forms, in cancer progression, (2) the possible mechanism of ncRNA incorporation into exosomes and (3) the therapeutic applications and limitations of exosomes based on current knowledge.
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Affiliation(s)
- Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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5
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Wang HC, Yin WX, Jiang M, Han JY, Kuai XW, Sun R, Sun YF, Ji JL. Function and biomedical implications of exosomal microRNAs delivered by parenchymal and nonparenchymal cells in hepatocellular carcinoma. World J Gastroenterol 2023; 29:5435-5451. [PMID: 37900996 PMCID: PMC10600808 DOI: 10.3748/wjg.v29.i39.5435] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/13/2023] [Accepted: 10/16/2023] [Indexed: 10/19/2023] Open
Abstract
Small extracellular vesicles (exosomes) are important components of the tumor microenvironment. They are small membrane-bound vesicles derived from almost all cell types and play an important role in intercellular communication. Exosomes transmit biological molecules obtained from parent cells, such as proteins, lipids, and nucleic acids, and are involved in cancer development. MicroRNAs (miRNAs), the most abundant contents in exosomes, are selectively packaged into exosomes to carry out their biological functions. Recent studies have revealed that exosome-delivered miRNAs play crucial roles in the tumorigenesis, progression, and drug resistance of hepatocellular carcinoma (HCC). In addition, exosomes have great industrial prospects in the diagnosis, treatment, and prognosis of patients with HCC. This review summarized the composition and function of exosomal miRNAs of different cell origins in HCC and highlighted the association between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC. Finally, we described the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC.
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Affiliation(s)
- Hai-Chen Wang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Xuan Yin
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Meng Jiang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Jia-Yi Han
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Xing-Wang Kuai
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Rui Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Yu-Feng Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Ju-Ling Ji
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
- Department of Pathology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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6
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Sukmana BI, Al-Hawary SIS, Abosaooda M, Adile M, Gupta R, Saleh EAM, Alwaily ER, Alsaab HO, Sapaev IB, Mustafa YF. A thorough and current study of miR-214-related targets in cancer. Pathol Res Pract 2023; 249:154770. [PMID: 37660658 DOI: 10.1016/j.prp.2023.154770] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/13/2023] [Accepted: 08/15/2023] [Indexed: 09/05/2023]
Abstract
Cancer is a complex genetic anomaly involving coding and non-coding transcript structural and expressive irregularities. A class of tiny non-coding RNAs known as microRNAs (miRNAs) regulates gene expression at the post-transcriptional level by binding only to messenger RNAs (mRNAs). Due to their capacity to target numerous genes, miRNAs have the potential to play a significant role in the development of tumors by controlling several biological processes, including angiogenesis, drug resistance, metastasis, apoptosis, proliferation, and drug resistance. According to several recent studies, miRNA-214 has been linked to the emergence and spread of tumors. The human genome's q24.3 arm contains the DNM3 gene, which is about 6 kb away and includes the microRNA-214. Its primary purpose was the induction of apoptosis in cancerous cells. The multifaceted and complex functions of miR-214 as a modulator in neoplastic conditions have been outlined in the current review.
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Affiliation(s)
- Bayu Indra Sukmana
- Departement of Oral Biology, Lambung Mangkurat University, Banjarmasin, Indonesia
| | | | | | - Mohaned Adile
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Reena Gupta
- Institute of Pharmaceutical Research, GLA University, District-Mathura, Uttar Pradesh 281406, India.
| | - Ebraheem Abdu Musad Saleh
- Department of Chemistry, Prince Sattam Bin Abdulaziz University, College of Arts and Science, Wadi Al-Dawasir 11991, Saudi Arabia
| | - Enas R Alwaily
- Microbiology Research Group, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Hashem O Alsaab
- Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia
| | - I B Sapaev
- Tashkent Institute of Irrigation and Agricultural Mechanization Engineers" National Research University, Tashkent, Uzbekistan; New Uzbekistan University, Tashkent, Uzbekistan
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
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7
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Jiang Z, Zhou J, Deng J, Li L, Wang R, Han Y, Zhou J, Tao R, Peng L, Wang D, Huang T, Yu Y, Zhou Z, Li J, Ousmane D, Wang J. Emerging roles of ferroptosis-related miRNAs in tumor metastasis. Cell Death Discov 2023; 9:193. [PMID: 37369681 DOI: 10.1038/s41420-023-01486-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 06/02/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Ferroptosis, a novel mode of cell death dependent on iron and reactive oxygen species, has been extensively explored during malignant tumors metastasis. Ferroptosis can interact with multiple components of the tumor microenvironment to regulate metastasis. These interactions generally include the following aspects: (1) Epithelial-mesenchymal transformation, which can help cancer cells increase their sensitivity to ferroptosis while they have multiple mechanisms to fight against it; (2) Disorder of iron metabolism in cancer stem cells which maintains their stem characteristics; (3) Polarization of M0 macrophages to M2. (4) The paradoxical effects of iron metabolism and CD8 + T cells induced by ferroptosis (5) Regulation of angiogenesis. In addition, ferroptosis can be regulated by miRNAs through the reprogramming of various intracellular metabolism processes, including the regulation of the glutathione- glutathione peroxidase 4 pathway, glutamic acid/cystine transport, iron metabolism, lipid metabolism, and oxidative stress. Therefore, there are many potential interactions between ferroptosis-related miRNAs and tumor metastasis, including interaction with cancer cells and immune cells, regulating cytokines, and angiogenesis. This review focuses on the role of ferroptosis-related miRNA in tumor metastasis, aiming to help readers understand their relationship and provide a new perspective on the potential treatment strategies of malignant tumors.
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Affiliation(s)
- Zhongyi Jiang
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
- Ultrapathology (Biomedical electron microscopy) Center, Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jing Zhou
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
- Ultrapathology (Biomedical electron microscopy) Center, Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Junqi Deng
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Luohong Li
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Ruifeng Wang
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Yingying Han
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Junyu Zhou
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Rui Tao
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Lushan Peng
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Dan Wang
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Tao Huang
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Yupei Yu
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Zongjiang Zhou
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Jinghe Li
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Diabate Ousmane
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China
| | - Junpu Wang
- Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China.
- Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China.
- Ultrapathology (Biomedical electron microscopy) Center, Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China.
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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8
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Saha S, Pradhan N, B N, Mahadevappa R, Minocha S, Kumar S. Cancer plasticity: Investigating the causes for this agility. Semin Cancer Biol 2023; 88:138-156. [PMID: 36584960 DOI: 10.1016/j.semcancer.2022.12.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 12/09/2022] [Accepted: 12/19/2022] [Indexed: 12/30/2022]
Abstract
Cancer is not a hard-wired phenomenon but an evolutionary disease. From the onset of carcinogenesis, cancer cells continuously adapt and evolve to satiate their ever-growing proliferation demands. This results in the formation of multiple subtypes of cancer cells with different phenotypes, cellular compositions, and consequently displaying varying degrees of tumorigenic identity and function. This phenomenon is referred to as cancer plasticity, during which the cancer cells exist in a plethora of cellular states having distinct phenotypes. With the advent of modern technologies equipped with enhanced resolution and depth, for example, single-cell RNA-sequencing and advanced computational tools, unbiased cancer profiling at a single-cell resolution are leading the way in understanding cancer cell rewiring both spatially and temporally. In this review, the processes and mechanisms that give rise to cancer plasticity include both intrinsic genetic factors such as epigenetic changes, differential expression due to changes in DNA, RNA, or protein content within the cancer cell, as well as extrinsic environmental factors such as tissue perfusion, extracellular milieu are detailed and their influence on key cancer plasticity hallmarks such as epithelial-mesenchymal transition (EMT) and cancer cell stemness (CSCs) are discussed. Due to therapy evasion and drug resistance, tumor heterogeneity caused by cancer plasticity has major therapeutic ramifications. Hence, it is crucial to comprehend all the cellular and molecular mechanisms that control cellular plasticity. How this process evades therapy, and the therapeutic avenue of targeting cancer plasticity must be diligently investigated.
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Affiliation(s)
- Shubhraneel Saha
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
| | - Nikita Pradhan
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
| | - Neha B
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
| | - Ravikiran Mahadevappa
- Department of Biotechnology, School of Science, Gandhi Institute of Technology and Management, Deemed to be University, Bengaluru, Karnataka 562163, India
| | - Shilpi Minocha
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
| | - Saran Kumar
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
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9
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Zheng L, Chen X, Yin Q, Gu J, Chen J, Chen M, Zhang Y, Dong M, Jiang H, Yin N, Chen H, Li X. RNA-m6A modification of HDGF mediated by Mettl3 aggravates the progression of atherosclerosis by regulating macrophages polarization via energy metabolism reprogramming. Biochem Biophys Res Commun 2022; 635:120-127. [DOI: 10.1016/j.bbrc.2022.10.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/04/2022] [Accepted: 10/07/2022] [Indexed: 11/30/2022]
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10
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Hu H, Zhang T, Wu Y, Deng M, Deng H, Yang X. Cross-regulation between microRNAs and key proteins of signaling pathways in hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2022; 16:753-765. [PMID: 35833844 DOI: 10.1080/17474124.2022.2101994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a subtype of primary liver cancer and a major cause of death. Although miRNA plays an important role in hepatocellular carcinoma, the specific regulatory network remains unclear. Therefore, this paper comprehensively describes the miRNA-related signaling pathways in HCC and the possible interactions among different signaling pathways. The aim is to lay the foundation for the discovery of new molecular targets and multi-target therapy. AREAS COVERED Based on miRNA, HCC, and signaling pathways, the literature was searched on Web of Science and PubMed. Then, common targets between different signaling pathways were found from KEGG database, and possible cross-regulation mechanisms were further studied. In this review, we elaborated from two aspects, respectively, laying a foundation for studying the regulatory mechanism and potential targets of miRNA in HCC. EXPERT OPINION Non-coding RNAs have become notable molecules in cancer research in recent years, and many types of targeted drugs have emerged. From the outset, molecular targets and signal pathways are interlinked, which suggests that signal pathways and regulatory networks should be concerned in basic research, which also provides a strong direction for future mechanism research.
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Affiliation(s)
- Haihong Hu
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Taolan Zhang
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yiwen Wu
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Meina Deng
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Huiling Deng
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Xiaoyan Yang
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China.,The Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, Hunan, China
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11
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Abstract
The tumor microenvironment (TME) is a well-recognized system that plays an essential role in tumor initiation, development, and progression. Intense intercellular communication between tumor cells and other cells (especially macrophages) occurs in the TME and is mediated by cell-to-cell contact and/or soluble messengers. Emerging evidence indicates that noncoding RNAs (ncRNAs) are critical regulators of the relationship between cells within the TME. In this review, we provide an update on the regulation of ncRNAs (primarily micro RNAs [miRNAs], long ncRNAs [lncRNAs], and circular RNAs [circRNAs]) in the crosstalk between macrophages and tumor cells in hepatocellular carcinoma (HCC). These ncRNAs are derived from macrophages or tumor cells and act as oncogenes or tumor suppressors, contributing to tumor progression not only by regulating the physiological and pathological processes of tumor cells but also by controlling macrophage infiltration, activation, polarization, and function. Herein, we also explore the options available for clinical therapeutic strategies targeting crosstalk-related ncRNAs to treat HCC. A better understanding of the relationship between macrophages and tumor cells mediated by ncRNAs will uncover new diagnostic biomarkers and pharmacological targets in cancer.
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12
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Targeted inhibition of the expression of both MCM5 and MCM7 by miRNA-214 impedes DNA replication and tumorigenesis in hepatocellular carcinoma cells. Cancer Lett 2022; 539:215677. [DOI: 10.1016/j.canlet.2022.215677] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/12/2022] [Accepted: 03/29/2022] [Indexed: 12/12/2022]
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13
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Long Noncoding RNA TUG1 Inhibits Tumor Progression through Regulating Siglec-15-Related Anti-Immune Activity in Hepatocellular Carcinoma. J Immunol Res 2022; 2022:9557859. [PMID: 35237695 PMCID: PMC8885264 DOI: 10.1155/2022/9557859] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 12/11/2021] [Accepted: 12/13/2021] [Indexed: 12/16/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death, and its biology remains poorly understood, especially in regards to the immunosuppression induced by immune checkpoints, such as Siglec-15. Most cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs display a better therapeutic effect in the clinic, including tumor progression inhibition and immunosuppression breaks. However, two or more drugs will result in a greater possibility of adverse effects. Thus, a double-function target is necessary for developing antitumor drugs, such as RNAi therapy. Methods The expression of TUG1, Siglec-15, and miRNAs was evaluated by qPCR, and protein expression was analyzed by western blotting. The immune responses were evaluated by a Jurkat-reporter gene assay, a T cell-induced cytotoxicity assay, and IFN-γ/IL-2 release. The interactions among TUG1, Siglec-15, and miRNAs were verified by dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. CCK-8 and Transwell assays were used to determine tumor cell proliferation, migration, and invasion. Results In HCC patients and cells, increased TUG1 levels were observed, positively regulating Siglec-15 expression. TUG1-induced Siglec-15 upregulation resulted in the suppression of the immune response of HCC cells. hsa-miR-582-5p directly targeted TUG1 and Siglec-15 mRNA, and ihsa-miR-582-5p knockout prevented the regulation of Siglec-15 induced by THU1. Changes in hsa-miR-582-5p expression negatively regulated Siglec-15 levels and immunosuppression but had no influence on TUG1 levels. siRNA knockdown of TUG1 effectively led to tumor progression inhibition and immune response improvement in HCC cells both in vitro and in vivo. Conclusion TUG1 increases the Siglec-15 level in HCC cells as a sponge to hsa-miR-582-5p, resulting in enhanced immunosuppression. TUG1 knockdown induced by siRNA not only reduces immunosuppression but also suppresses tumor progression both in vitro and in vivo. These novel findings may provide a potential and appropriate target for RNAi therapy to develop drugs with dual antitumor activity.
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14
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MicroRNA-214 in Health and Disease. Cells 2021; 10:cells10123274. [PMID: 34943783 PMCID: PMC8699121 DOI: 10.3390/cells10123274] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/16/2021] [Accepted: 11/20/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenously expressed, non-coding RNA molecules that mediate the post-transcriptional repression and degradation of mRNAs by targeting their 3′ untranslated region (3′-UTR). Thousands of miRNAs have been identified since their first discovery in 1993, and miR-214 was first reported to promote apoptosis in HeLa cells. Presently, miR-214 is implicated in an extensive range of conditions such as cardiovascular diseases, cancers, bone formation and cell differentiation. MiR-214 has shown pleiotropic roles in contributing to the progression of diseases such as gastric and lung cancers but may also confer cardioprotection against excessive fibrosis and oxidative damage. These contrasting functions are achieved through the diverse cast of miR-214 targets. Through silencing or overexpressing miR-214, the detrimental effects can be attenuated, and the beneficial effects promoted in order to improve health outcomes. Therefore, discovering novel miR-214 targets and understanding how miR-214 is dysregulated in human diseases may eventually lead to miRNA-based therapies. MiR-214 has also shown promise as a diagnostic biomarker in identifying breast cancer and coronary artery disease. This review provides an up-to-date discussion of miR-214 literature by describing relevant roles in health and disease, areas of disagreement, and the future direction of the field.
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G3BP2 regulated by the lncRNA LINC01554 facilitates esophageal squamous cell carcinoma metastasis through stabilizing HDGF transcript. Oncogene 2021; 41:515-526. [PMID: 34782720 PMCID: PMC8782723 DOI: 10.1038/s41388-021-02073-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Metastasis is the leading cause of death of patients with esophageal squamous cell carcinoma (ESCC). Although an increasing number of studies have demonstrated the involvement of G3BP2 in several human cancers, how G3BP2 interacts with long noncoding RNAs and regulates mRNA transcripts in mediating ESCC metastasis remains unclear. In this study, we uncovered that G3BP2 was upregulated in ESCC. Further analysis revealed that upregulation of G3BP2 was significantly correlated with lymph node metastasis, depth of tumor invasion and unfavorable outcomes in ESCC patients. Both in vitro and in vivo functional assays demonstrated that G3BP2 dramatically enhanced ESCC cell migration and invasion. Mechanistically, LINC01554 maintained the high G3BP2 expression in ESCC by protecting G3BP2 from degradation through ubiquitination and the interaction domains within LINC01554 and G3BP2 were identified. In addition, RNA-seq revealed that HDGF was regulated by G3BP2. G3BP2 bound to HDGF mRNA transcript to stabilize its expression. Ectopic expression of HDGF effectively abolished the G3BP2 depletion-mediated inhibitory effect on tumor cell migration. Intriguingly, introduction of compound C108 which can inhibit G3BP2 remarkedly suppressed ESCC cell metastasis in vitro and in vivo. Collectively, this study describes a newly discovered regulatory axis, LINC01554/G3BP2/HDGF, that facilitates ESCC metastasis and will provide novel therapeutic strategies for ESCC.
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16
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Abstract
Liver cancer is the fourth leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 80% of all liver cancers. The serum concentration of alpha-fetoprotein (AFP) is the only validated biomarker for HCC diagnosis. MicroRNAs (miRNAs) are small non-coding RNAs of 21–30 nucleotides playing a critical role in human carcinogenesis, with types of miRNAs with oncogenic (oncomiRs) or tumor suppressor features. The altered expression of miRNAs in HCC is associated with many pathological processes, such as cancer initiation, tumor growth, apoptosis escape, promotion of migration and invasion. Moreover, circulating miRNAs have been increasingly investigated as non-invasive biomarkers for HCC diagnosis. MiRNAs’ expression patterns are altered in HCC and several single miRNAs or miRNAs panels have been found significantly up or downregulated in HCC with respect to healthy controls or non-oncological patients (cirrhotic or with viral hepatitis). However, any of the investigated miRNAs or miRNAs panels has entered clinical practice so far. This has mostly to do with lack of protocols standardization, small sample size and discrepancies in the measurement techniques. This review summarizes the major findings regarding the diagnostic role of miRNAs in HCC and their possible use together with standard biomarkers in order to obtain an early diagnosis and easier differential diagnosis from non-cancerous liver disease.
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17
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Jia M, Zhang H, Qin Q, Hou Y, Zhang X, Chen D, Zhang H, Chen Y. Ferroptosis as a new therapeutic opportunity for nonviral liver disease. Eur J Pharmacol 2021; 908:174319. [PMID: 34252441 DOI: 10.1016/j.ejphar.2021.174319] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 06/04/2021] [Accepted: 07/07/2021] [Indexed: 12/18/2022]
Abstract
Nonviral liver disease is a global public health problem due to its high mortality and morbidity. However, its underlying mechanism is unclear. Ferroptosis is a novel form of cell death that is involved in a variety of disease processes. Both abnormal iron metabolism (e.g., iron overload) and lipid peroxidation, which is induced by deletion of glutathione (GSH) or glutathione peroxidase 4 (GPX4), and the accumulation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) trigger ferroptosis. Recently, ferroptosis has been involved in the pathological process of nonviral liver diseases [including alcohol-related liver disease (ALD); nonalcoholic fatty liver disease (NAFLD); hereditary hemochromatosis (HH); drug-, ischemia/reperfusion- or immune-induced liver injury; liver fibrosis; and liver cancer]. Hepatocyte ferroptosis is activated in ALD; NAFLD; HH; drug-, ischemia/reperfusion- or immune-induced liver injury; and liver fibrosis, whereas hepatic stellate cell and liver cancer cell ferroptosis are inhibited in liver fibrosis and liver cancer, respectively. Thus, ferroptosis is an ideal target for nonviral liver diseases. In the present review, we discuss the latest findings on ferroptosis and potential drugs targeting ferroptosis for nonviral liver diseases. This review will highlight further directions for the treatment and prevention of nonviral liver diseases.
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Affiliation(s)
- Min Jia
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Hongmei Zhang
- The First Affiliated Hospital of Xi'an Medical University, Xi'an Medical University, Xi'an, Shaanxi, 710077, China
| | - Qiaohong Qin
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Ying Hou
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Xin Zhang
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Di Chen
- School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Hong Zhang
- Department of Infectious Diseases, Shaanxi Provincial People's Hospital (the Affiliated Hospital of Xi'an Medical University), Xi'an Medical University, Xi'an, Shaanxi, 710068, China.
| | - Yulong Chen
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China.
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18
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Qiu L, Ma Y, Chen X, Zhou L, Zhang H, Zhong G, Zhang L, Tang J. Heparin-binding growth factor (HDGF) drives radioresistance in breast cancer by activating the STAT3 signaling pathway. J Transl Med 2021; 19:344. [PMID: 34376200 PMCID: PMC8353798 DOI: 10.1186/s12967-021-03021-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/03/2021] [Indexed: 12/12/2022] Open
Abstract
Although reports implicate radioresistance as an important obstacle for the management of breast cancer, its molecular mechanism is elusive. Herein, we found that high HDGF levels are expressed significantly in breast cancer and exhibit a positive association with poor survival prognosis. Heparin-binding growth factor (HDGF) was upregulated in radioresistant breast cancer cells, however, its knockdown could reduce breast cancer radioresistant both in vitro and in vivo. Additionally, the binding of RXRα to HDGF promoter blocked HDGF transcriptional activity, consequently inhibiting breast cancer radioresistance. The enhanced radioresistant activity of HDGF is induced by TKT and STAT3, impacting the STAT3-Tyr705 and STAT3-Ser727 phosphorylation and STAT3 transcriptional activity. Notably, HDGF depletion renders radioresistant hypersensitive to the drug that targets STAT3 phosphorylation. This article demonstrates the novel function of HDGF as a promising molecular target for predicting radioresistance in breast cancer.
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Affiliation(s)
- Lingyun Qiu
- Oncology Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Yan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Xiaohua Chen
- Department of Radiation Oncology, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
| | - Liheng Zhou
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Haibo Zhang
- Oncology Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Guansheng Zhong
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China
| | - Lei Zhang
- Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.
| | - Jianming Tang
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China.
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19
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Huang PS, Chang CC, Wang CS, Lin KH. Functional roles of non-coding RNAs regulated by thyroid hormones in liver cancer. Biomed J 2021; 44:272-284. [PMID: 33077406 PMCID: PMC8358202 DOI: 10.1016/j.bj.2020.08.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/19/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023] Open
Abstract
Recent reports have shown the important role of the non-coding part of human genome RNA (ncRNA) in cancer formation and progression. Among several kinds of ncRNAs, microRNAs (miRNA) play a pivotal role in cancer biology. Accumulating researches have been focused on the importance of non-coding genes in various diseases. In addition to miRNAs, long non-coding RNAs (lncRNAs) have also been extensively documented. Recently, the study of human liver cancer has gradually shifted to these non-coding RNAs that were originally considered "junk". Notably, dysregulated ncRNAs maybe influence on cell proliferation, angiogenesis, anti-apoptosis, and metastasis. Thyroid hormones play critical roles in human development and abnormalities in thyroid hormone levels are associated with various diseases, such as liver cancer. Thyroid hormone receptors (TR) act as ligand-activated nuclear transcription factors to affect multiple functions through the gene-level regulation in the cells and several studies have revealed that thyroid hormone associated with ncRNAs expression. TR actions are complex and tissue- and time-specific, aberrant expression of the various TR isoforms have different effects and are associated with different types of tumor or stages of development. In this review, we discuss various aspects of the research on the thyroid hormones modulated ncRNAs to affect the functions of human liver cells.
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Affiliation(s)
- Po-Shuan Huang
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Chih Chang
- Department of General Surgery, Chang Gung Memorial Hospital at Chia yi, Chia yi, Taiwan
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital at Chia yi, Chia yi, Taiwan
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
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20
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Zhou Z, Li Y, Ma X, Cao B, Peng T, Sheng Y, Peng H, Li R, Cao Y, Xi R, Li F, Wang M, Sun H, Zhang G, Zhang H, Hu K, Xiao W, Wang F. Identification of a Novel TAR RNA-Binding Protein 2 Modulator with Potential Therapeutic Activity against Hepatocellular Carcinoma. J Med Chem 2021; 64:7404-7421. [PMID: 34038111 DOI: 10.1021/acs.jmedchem.1c00018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Imbalance miRNAs contribute to tumor formation; therefore, the development of small-molecule compounds that regulate miRNA biogenesis is an important strategy in oncotherapy. Here, (-)-Gomisin M1 (GM) was found to modulate miRNA biogenesis to inhibit the proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells. GM modulated expression profiles of miRNA and protein in HCC cells and suppressed tumor growth in a mouse model. Mechanistically, GM affected miRNA maturation by targeting TAR RNA-binding protein 2 (TRBP), with an efficacy higher than that of enoxacin, and promoted the binding of TRBP with Dicer. Structural simplification and a preliminary structure-activity relationship study via the synthesis of 20 GM derivatives showed that compound 9 exhibited more potent inhibitory activity in HCC cell proliferation and affinity for TRBP than did GM. These results suggest that TRBP may be a novel potential therapeutic target in HCC and compound 9 may be a potential drug candidate for the treatment of HCC.
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Affiliation(s)
- Zongyuan Zhou
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yiming Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Xiaofang Ma
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Biyun Cao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Ting Peng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuwen Sheng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huipan Peng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Runze Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yu Cao
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ruiying Xi
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fu Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Mengru Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Handong Sun
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Guolin Zhang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Hongbin Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Kaifeng Hu
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Weilie Xiao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Fei Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,Xiongan Institute of Innovation, Chinese Academy of Sciences, Hebei 071700, China
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21
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MicroRNA-214 enriched exosomes from human cerebral endothelial cells (hCEC) sensitize hepatocellular carcinoma to anti-cancer drugs. Oncotarget 2021; 12:185-198. [PMID: 33613846 PMCID: PMC7869574 DOI: 10.18632/oncotarget.27879] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/19/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor worldwide. Current medical therapy for HCC has limited efficacy. The present study tests the hypothesis that human cerebral endothelial cell-derived exosomes carrying elevated miR-214 (hCEC-Exo-214) can amplify the efficacy of anti-cancer drugs on HCC cells. Treatment of HepG2 and Hep3B cells with hCEC-Exo-214 in combination with anti-cancer agents, oxaliplatin or sorafenib, significantly reduced cancer cell viability and invasion compared with monotherapy with either drug. Additionally, the therapeutic effect of the combination therapy was detected in primary tumor cells derived from patients with HCC. The ability of hCEC-Exo-214 in sensitizing HCC cells to anti-cancer drugs was specific, in that combination therapy did not affect the viability and invasion of human liver epithelial cells and non-cancer primary cells. Furthermore, compared to monotherapy with oxaliplatin and sorafenib, hCEC-Exo-214 in combination with either drug substantially reduced protein levels of P-glycoprotein (P-gp) and splicing factor 3B subunit 3 (SF3B3) in HCC cells. P-gp and SF3B3 are among miR-214 target genes and are known to mediate drug resistance and cancer cell proliferation, respectively. In conclusion, the present in vitro study provides evidence that hCEC-Exo-214 significantly enhances the anti-tumor efficacy of oxaliplatin and sorafenib on HCC cells.
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22
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Qian F, Wang J, Wang Y, Gao Q, Yan W, Lin Y, Shen L, Xie Y, Jiang X, Shen B. MiR-378a-3p as a putative biomarker for hepatocellular carcinoma diagnosis and prognosis: Computational screening with experimental validation. Clin Transl Med 2021; 11:e307. [PMID: 33634974 PMCID: PMC7882078 DOI: 10.1002/ctm2.307] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/14/2021] [Accepted: 01/18/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a malignant disease with high morbidity and mortality, and the molecular mechanism for the genesis and progression is complex and heterogeneous. Biomarker discovery is crucial for the personalized and precision treatment of HCC. The accumulation of reported microRNA biomarkers makes it possible to combine computational identification with experimental validation to accelerate the discovery of novel biomarker. RESULTS In the present work, we applied a rational computer-aided biomarker discovery model to screen for the HCC diagnosis biomarker. Two HCC-associated networks were constructed based on the microRNA and mRNA expression profiles, and the potential microRNA biomarkers were identified based on their unique regulatory and influential power in the network. These putative biomarkers were then experimentally validated. One prominent example among these identified biomarkers is MiR-378a-3p: It was shown to independently regulate several important transcription factors such as PLAGL2 and β-catenin, affecting the β-catenin signaling. Such mechanism may indicate a potential tumor suppressor role of MiR-378a-3p and the impact of its abnormal expression on the cell growth and invasion of HCC. CONCLUSIONS A bioinformatics model with network topological and functional characterization was successfully applied to the identification of HCC biomarkers. The predicted microRNA biomarkers were than validated with experiments using human HCC cell lines, model animal, and clinical specimens. The results confirmed the prediction by our proposed model that miR-378a-3p was a putative biomarker for diagnosis and prognosis of HCC.
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Affiliation(s)
- Fuliang Qian
- Center for Systems BiologySoochow UniversitySuzhouChina
| | - Jinghan Wang
- Department of the First Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery HospitalNavy Military Medical UniversityShanghaiChina
| | - Ying Wang
- Department of the First Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery HospitalNavy Military Medical UniversityShanghaiChina
| | - Qian Gao
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Wenying Yan
- Center for Systems BiologySoochow UniversitySuzhouChina
| | - Yuxin Lin
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Li Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease‐related Molecular Network, West China HospitalSichuan UniversityChengduChina
| | - Yufeng Xie
- Center for Systems BiologySoochow UniversitySuzhouChina
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Xiaoqing Jiang
- Department of the First Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery HospitalNavy Military Medical UniversityShanghaiChina
| | - Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease‐related Molecular Network, West China HospitalSichuan UniversityChengduChina
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Exosomal MiR-1290 Promotes Angiogenesis of Hepatocellular Carcinoma via Targeting SMEK1. JOURNAL OF ONCOLOGY 2021; 2021:6617700. [PMID: 33564307 PMCID: PMC7864765 DOI: 10.1155/2021/6617700] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/05/2021] [Accepted: 01/15/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC), the most common primary liver cancer, relies on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its proangiogenic function, at least in part, by alleviating the inhibition of VEGFR2 phosphorylation done by SMEK1. Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.
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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.
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Li W, Yan P, Meng X, Zhang J, Yang Y. The microRNA cluster miR-214/miR-3120 prevents tumor cell switching from an epithelial to a mesenchymal-like phenotype and inhibits autophagy in gallbladder cancer. Cell Signal 2020; 80:109887. [PMID: 33340658 DOI: 10.1016/j.cellsig.2020.109887] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 12/13/2020] [Accepted: 12/14/2020] [Indexed: 12/29/2022]
Abstract
Tumor cells switch from an epithelial to a mesenchymal-like phenotype, which represents a key hallmark of human cancer metastasis, including gallbladder cancer (GBC). A large set of microRNAs (miRNAs/miRs) have been studied to elucidate their functions in initiating or inhibiting this phenotypic switching in GBC cells. In this paper, we attempted to identify the expression pattern of the miR-214/-3120 cluster and its mode of action in the context of GBC, with a specific focus being placed on their effects on EMT and autophagy in GBC cells. Human GBC cells GBC-SD were assayed for their migration, invasion, and autophagy using the Transwell chamber system, MDC staining, and transmission electron microscopy. The tumorigenicity and metastatic behavior of GBC-SD cells were tested in nude mice. The expression of EMT- and autophagy-specific markers (E-cadherin, N-cadherin, vimentin, ATG5, LC3II/LC3I, and Beclin1) was analyzed in cultured GBC-SD cells and in human GBC-SD xenografts. The E2F3 luciferase reporter activity in the presence of miR-214/-3120 was evaluated by a dual luciferase assay. The miR-214/-3120 was downregulated in GBC. Exogenous miR-214/-3120 inhibited the phenotypic switching of GBC cells from epithelial to mesenchymal, prevented autophagy, and suppressed the tumorigenicity and metastatic behavior of GBC-SD cells in vitro and in vivo. E2F3 was demonstrated to be the target gene of miR-214/-3120, and its knockdown in part mimicked the effect of miR-214/-3120 on the EMT, autophagy, tumorigenicity, and metastatic behavior of GBC-SD cells. These results demonstrated that the miR-214/-3120 cluster blocks the process of EMT and autophagy to limit GBC metastasis by repressing E2F3 expression.
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Affiliation(s)
- Wujun Li
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, PR China; Department of General Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an 710077, Shaanxi Province, PR China
| | - Pu Yan
- Department of General Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an 710077, Shaanxi Province, PR China
| | - Xiaofen Meng
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, PR China
| | - Jinpei Zhang
- Department of Encephalopathy, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, PR China.
| | - Yi Yang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, PR China.
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Grzywa TM, Klicka K, Włodarski PK. Regulators at Every Step-How microRNAs Drive Tumor Cell Invasiveness and Metastasis. Cancers (Basel) 2020; 12:E3709. [PMID: 33321819 PMCID: PMC7763175 DOI: 10.3390/cancers12123709] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Tumor cell invasiveness and metastasis are the main causes of mortality in cancer. Tumor progression is composed of many steps, including primary tumor growth, local invasion, intravasation, survival in the circulation, pre-metastatic niche formation, and metastasis. All these steps are strictly controlled by microRNAs (miRNAs), small non-coding RNA that regulate gene expression at the post-transcriptional level. miRNAs can act as oncomiRs that promote tumor cell invasion and metastasis or as tumor suppressor miRNAs that inhibit tumor progression. These miRNAs regulate the actin cytoskeleton, the expression of extracellular matrix (ECM) receptors including integrins and ECM-remodeling enzymes comprising matrix metalloproteinases (MMPs), and regulate epithelial-mesenchymal transition (EMT), hence modulating cell migration and invasiveness. Moreover, miRNAs regulate angiogenesis, the formation of a pre-metastatic niche, and metastasis. Thus, miRNAs are biomarkers of metastases as well as promising targets of therapy. In this review, we comprehensively describe the role of various miRNAs in tumor cell migration, invasion, and metastasis.
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Affiliation(s)
- Tomasz M. Grzywa
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Klaudia Klicka
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Paweł K. Włodarski
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
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Identification of an immune gene signature for predicting the prognosis of patients with uterine corpus endometrial carcinoma. Cancer Cell Int 2020; 20:541. [PMID: 33292199 PMCID: PMC7650210 DOI: 10.1186/s12935-020-01560-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 09/17/2020] [Indexed: 12/24/2022] Open
Abstract
Background Uterine corpus endometrial carcinoma (UCEC) is a frequent gynecological malignancy with a poor prognosis particularly at an advanced stage. Herein, this study aims to construct prognostic markers of UCEC based on immune-related genes to predict the prognosis of UCEC. Methods We analyzed expression data of 575 UCEC patients from The Cancer Genome Atlas database and immune genes from the ImmPort database, which were used for generation and validation of the signature. We constructed a transcription factor regulatory network based on Cistrome databases, and also performed functional enrichment and pathway analyses for the differentially expressed immune genes. Moreover, the prognostic value of 410 immune genes was determined using the Cox regression analysis. We then constructed and verified a prognostic signature. Finally, we performed immune infiltration analysis using TIMER-generating immune cell content. Results The immune cell microenvironment as well as the PI3K-Akt, and MARK signaling pathways were involved in UCEC development. The established prognostic signature revealed a ten-gene prognostic signature, comprising of PDIA3, LTA, PSMC4, TNF, SBDS, HDGF, HTR3E, NR3C1, PGR, and CBLC. This signature showed a strong prognostic ability in both the training and testing sets and thus can be used as an independent tool to predict the prognosis of UCEC. In addition, levels of B cells and neutrophils were significantly correlated with the patient’s risk score, while the expression of ten genes was associated with immune cell infiltrates. Conclusions In summary, the ten-gene prognostic signature may guide the selection of the immunotherapy for UCEC.
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Wang EM, Hu TH, Huang CC, Chang YC, Yang SM, Huang ST, Wu JC, Ma YL, Chan HH, Liu LF, Lu WB, Kung ML, Wen ZH, Wang JC, Ko CY, Tsai WL, Chu TH, Tai MH. Hepatoma-derived growth factor participates in concanavalin A-induced hepatitis. FASEB J 2020; 34:16163-16178. [PMID: 33063394 DOI: 10.1096/fj.202000511rr] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 09/13/2020] [Accepted: 09/28/2020] [Indexed: 12/12/2022]
Abstract
Hepatitis is an important health problem worldwide. Novel molecular targets are in demand for detection and management of hepatitis. Hepatoma-derived growth factor (HDGF) has been delineated to participate in hepatic fibrosis and liver carcinogenesis. However, the relationship between hepatitis and HDGF remains unclear. This study aimed to elucidate the role of HDGF during hepatitis using concanavalin A (ConA)-induced hepatitis model. In cultured hepatocytes, ConA treatment-elicited HDGF upregulation at transcriptional level and promoted HDGF secretion while reducing intracellular HDGF protein level and cellular viability. Similarly, mice receiving ConA administration exhibited reduced hepatic HDGF expression and elevated circulating HDGF level, which was positively correlated with serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. By using HDGF knockout (KO) mice, it was found the ConA-evoked cell death was prominently alleviated in KO compared with control. Besides, it was delineated HDGF ablation conferred protection by suppressing the ConA-induced neutrophils recruitment in livers. Above all, the ConA-mediated activation of tumor necrosis factor-α (TNF-α)/interleukin-1β (IL-1β)/interleukin-6 (IL-6)/cyclooxygenase-2 (COX-2) inflammatory signaling was significantly abrogated in KO mice. Treatment with recombinant HDGF (rHDGF) dose-dependently stimulated the expression of TNF-α/IL-1β/IL-6/COX-2 in hepatocytes, further supporting the pro-inflammatory function of HDGF. Finally, application of HDGF antibody not only attenuated the ConA-mediated inflammatory cascade in hepatocytes, but also ameliorated the ConA-induced hepatic necrosis and AST elevation in mice. In summary, HDGF participates in ConA-induced hepatitis via neutrophils recruitment and may constitute a therapeutic target for acute hepatitis.
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Affiliation(s)
- E-Ming Wang
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Biobank and Tissue Bank, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yi-Chen Chang
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan
| | - Shih-Ming Yang
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Shih-Tsung Huang
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan.,LabTurbo Biotech Corporation, Taipei, Taiwan
| | - Jian-Ching Wu
- Biobank and Tissue Bank, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yi-Ling Ma
- Division of Nephrology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Hoi-Hung Chan
- Division of Gastroenterology, Department of Medicine, Conde S. Januário Hospital, Macau, China
| | - Li-Feng Liu
- Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan
| | - Wen-Bin Lu
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Jui-Chu Wang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chou-Yuan Ko
- Department of Gastroenterology, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Wei-Lun Tsai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Tian-Huei Chu
- Biobank and Tissue Bank, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ming-Hong Tai
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.,Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan.,Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.,Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
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Peng JM, Tseng RH, Shih TC, Hsieh SY. CAMK2N1 suppresses hepatoma growth through inhibiting E2F1-mediated cell-cycle signaling. Cancer Lett 2020; 497:66-76. [PMID: 33068700 DOI: 10.1016/j.canlet.2020.10.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 09/23/2020] [Accepted: 10/11/2020] [Indexed: 01/24/2023]
Abstract
Human kinome/phosphatome screen identified CAMK2N1 genes suppressing the development of human hepatocellular carcinoma (HCC). CAMK2N1 downregulation was found in 47% HCCs and associated with poor prognosis. The downregulation was mainly attributed to its genome deletion (28.4%) and DNA hypermethylation of its promoter (12.5%). Silencing and ectopic expression of CAMK2N1 respectively enhanced and suppressed cell proliferation, colony formation, and xenograft tumor growth in nude mice. Comparative proteomics revealed that CAMK2N1 silencing transcriptionally deregulated the genes regulated by E2F1 (89 out of the 114 E2F-signaling targets, P = 8.8E-240). The promoter assays revealed that CAMK2N1 suppressed E2F1-mediated transcriptional activities. CAMK2N1 silencing induced cyclins D/E expression, whereas its ectopic expression induced P27/KIP1 expression and suppressed the cell cycle. CAMK2N1 was translocated from the nuclei to the cytoplasm when cell proliferation reached the stationary phase, where its functions as an endogenous inhibitor of CAMK2. In conclusion, CAMK2NA is a novel 1p36 tumor suppressor gene that inhibits E2F1 transcriptional activities and induces P27/KIP1 expression. CAMK2N1-CAMK2 signaling forms a mechanism that restricts the cell cycle progression. Its deregulation could lead to tumorigenesis and might serve as promising therapeutic targets.
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Affiliation(s)
- Jei-Ming Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ruo-Han Tseng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
| | - Tsung-Chieh Shih
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
| | - Sen-Yung Hsieh
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; Chang Gung University, Institute of Biomedical Sciences, College of Medicine, Taoyuan, 333, Taiwan.
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Uncovering the Roles of miR-214 in Hepatitis E Virus Replication. J Mol Biol 2020; 432:5322-5342. [PMID: 32735806 DOI: 10.1016/j.jmb.2020.07.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/15/2020] [Accepted: 07/22/2020] [Indexed: 12/11/2022]
Abstract
Viral pathogenesis is a complex event and its regulation involve dynamic interactions with various host factors, of which microRNAs are the key players. In the current study, we have identified the functional importance of an interplay between hepatitis E virus (HEV) and miR-214. Computational analysis indicated that miR-214 binding site is significantly conserved among HEV and related RNA viruses. Intact miR-214 binding site is imperative for HEV replication. miR-214 is an essential host factor for HEV replication. Herein, we demonstrate that miR-214 interacts directly with HEV RNA to enhance HEV replication and HEV genome translation. Augmented translation results in increased levels of HEV ORF2, which is a factor responsible for upregulation of miR-214. HEV usurps host cellular machinery for improving viral fitness and elevates miR-214 expression for amplifying the expression of proviral host factor intracellular active thrombin. This is because miR-214 represses the expression of the negative regulator of thrombin, i.e., protein C. Another viral factor, HEV ORF3, also contributes to the enhancement of intracellular active thrombin. Furthermore, miR-214 directly targets antiviral host factor 2'-5'-oligoadenylate synthetase. Conclusively, we identified a novel mechanism of positive regulation of HEV replication. miR-214 interacts directly with HEV genome and fine-tunes host factors expression. This results in outweighing the proviral factors on the proviral-antiviral axis probably for generating virus supportive environment.
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Ruiz-Llorente L, Albiñana V, Botella LM, Bernabeu C. Differential Expression of Circulating Plasma miRNA-370 and miRNA-10a from Patients with Hereditary Hemorrhagic Telangiectasia. J Clin Med 2020; 9:E2855. [PMID: 32899377 PMCID: PMC7565099 DOI: 10.3390/jcm9092855] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 08/23/2020] [Accepted: 08/31/2020] [Indexed: 02/06/2023] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, vascular disorder that presents with telangiectases and arteriovenous malformations. HHT is a genetically heterogeneous disorder, involving mutations in endoglin (ENG; HHT1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT2) genes that account for over 85% of all HHT patients. The current diagnosis of HHT patients remains at the clinical level, but many suspected patients do not have a clear HHT diagnosis or do not show pathogenic mutations in HHT genes. This situation has prompted the search for biomarkers to help in the early diagnosis of the disease. We have analyzed the plasma levels in HHT patients of selected micro-RNAs (miRNAs), small single-stranded RNAs that regulate gene expression at the transcriptional level by interacting with specific RNA targets. A total of 16 HHT1 and 17 HHT2 plasma samples from clinically confirmed patients and 16 controls were analyzed in this study. Total RNA was purified from plasma, and three selected miRNAs (miRNA-10a, miRNA-214, and miRNA-370), related to the pathobiology of cardiovascular diseases and potentially targeting ENG or ALK1, were measured by quantitative polymerase chain reaction. Compared with controls, levels of miRNA-370, whose putative target is ENG, were significantly downregulated in HHT1, but not in HHT2, whereas the levels of miRNA-10a, whose putative target is ALK1, were significantly upregulated in HHT2, but not in HHT1. In addition, the levels of miRNA-214, potentially targeting ENG and ALK1, did not change in either HHT1 or HHT2 patients versus control samples. While further studies are warranted, these results suggest that dysregulated plasma levels of miRNA-370 or miRNA-10a could help to identify undiagnosed HHT1 or HHT2 patients, respectively.
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Affiliation(s)
- Lidia Ruiz-Llorente
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain; (L.R.-L.); (V.A.); (L.M.B.)
- Department of Systems Biology, School of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid, Spain
| | - Virginia Albiñana
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain; (L.R.-L.); (V.A.); (L.M.B.)
| | - Luisa M. Botella
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain; (L.R.-L.); (V.A.); (L.M.B.)
| | - Carmelo Bernabeu
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain; (L.R.-L.); (V.A.); (L.M.B.)
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Li N, Jiang S, Shi J, Fu R, Wu H, Lu M. Construction of a potential microRNA, transcription factor and mRNA regulatory network in hepatocellular carcinoma. Transl Cancer Res 2020; 9:5528-5543. [PMID: 35117917 PMCID: PMC8799260 DOI: 10.21037/tcr-20-686] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 07/17/2020] [Indexed: 12/12/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the third leading cause of cancer-related death. MicroRNAs and transcription factors (TFs) cooperate to regulate the same target gene, thus affecting the progression of HCC. Methods Differentially expressed miRNAs and mRNAs were screened. Functional enrichment analysis of these HCC-related mRNAs was performed, and a protein-protein interaction network was constructed. TFs that regulate these miRNAs and hub genes were also screened. Results Ten differentially upregulated miRNAs and 5 differentially downregulated miRNAs were screened. Additionally, 183 downregulated mRNAs and 303 upregulated mRNAs that are potentially bound to these differentially expressed miRNAs were identified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that the differentially expressed mRNAs were significantly enriched in pathways in cancer, the Wnt signaling pathway, and the Rap1 signaling pathway. Then, 220 TFs were identified for 5 candidate genes of the downregulated mRNAs, and 258 TFs were identified for 9 candidate genes of the upregulated mRNAs. Finally, the 9 upregulated hub genes were related to higher overall survival (OS) in the low-expression group, and 4/5 downregulated hub genes were related to higher OS in the high-expression group. Conclusions This study constructed a potential regulatory network between candidate molecules and that need to be further verified. These regulatory relationships are expected to clarify the new molecular mechanisms of the occurrence and development of HCC.
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Affiliation(s)
- Ning Li
- Department of HBP SURGERY II, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Shaotao Jiang
- Department of HBP SURGERY II, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jiewei Shi
- Department of General Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Rongdang Fu
- Department of Hepatic Surgery, the First People's Hospital of Foshan, Affiliated Foshan Hospital of Sun Yat-sen University, Foshan, China
| | - Huijie Wu
- Department of Obstetrics, the First People's Hospital of Foshan, Affiliated Foshan Hospital of Sun Yat-sen University, Foshan, China
| | - Minqiang Lu
- Department of HBP SURGERY II, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
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Lin YH, Lin KH, Yeh CT. Thyroid Hormone in Hepatocellular Carcinoma: Cancer Risk, Growth Regulation, and Anticancer Drug Resistance. Front Med (Lausanne) 2020; 7:174. [PMID: 32528965 PMCID: PMC7258858 DOI: 10.3389/fmed.2020.00174] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 04/15/2020] [Indexed: 12/16/2022] Open
Abstract
Thyroid hormone (TH) and its receptor (TR) are involved in differentiation, metabolic process, and growth regulation in hepatocellular carcinoma (HCC). The TH/TR complexes are ligand-dependent transcriptional factors, functioning through binding to thyroid hormone response elements (TREs) upstream of the target genes. To date, deciphering the biological effects of TH in cancer progression remains challenging. Several lines of evidence suggest a growth inhibitory effect of TH in liver cancer. Mutation and aberrant expression of TRs are highly correlated with several types of cancers including HCC. Several reports show that TH inhibits cell growth in liver cancer through regulation of cell-cycle-related genes and non-coding RNAs. A case–control study indicates that hypothyroidism is associated with an increased risk of HCC. Moreover, TH/TR suppresses hepatocarcinogenesis via selective autophagy. Conversely, other groups have indicated that TH promotes cancer cell proliferation. In vitro and in vivo experiments show that TH/TR enhances cancer cell migration and invasion, anticancer drug resistance, angiogenesis, and cancer stem cell self-renewal. Adding to the complexity of this issue, non-genomic effects of TH mediated by integrin receptor on cell surface can also modulate several biological functions. Accumulating evidence indicate that regulations by genomic and non-genomic effects of TH overlap. Taken together, these observations suggest that the functions of TH depend largely on cell context, and TH/TR plays a duel role in cancer progression. Therefore, understanding the maze of biological effects of TH has become a necessity when attempting to develop effective therapeutic and preventive strategies in liver cancer.
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Affiliation(s)
- Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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Qu S, Shi Q, Xu J, Yi W, Fan H. Weighted Gene Coexpression Network Analysis Reveals the Dynamic Transcriptome Regulation and Prognostic Biomarkers of Hepatocellular Carcinoma. Evol Bioinform Online 2020; 16:1176934320920562. [PMID: 32523331 PMCID: PMC7235675 DOI: 10.1177/1176934320920562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 03/30/2020] [Indexed: 12/14/2022] Open
Abstract
This study was aimed at revealing the dynamic regulation of mRNAs, long noncoding RNAs (lncRNAs), and microRNAs (miRNAs) in hepatocellular carcinoma (HCC) and to identify HCC biomarkers capable of predicting prognosis. Differentially expressed mRNAs (DEmRNAs), lncRNAs, and miRNAs were acquired by comparing expression profiles of HCC with normal samples, using an expression data set from The Cancer Genome Atlas. Altered biological functions and pathways in HCC were analyzed by subjecting DEmRNAs to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Gene modules significantly associated with disease status were identified by weighted gene coexpression network analysis. An lncRNA-mRNA and an miRNA-mRNA coexpression network were constructed for genes in disease-related modules, followed by the identification of prognostic biomarkers using Kaplan-Meier survival analysis. Differential expression and association with the prognosis of 4 miRNAs were verified in independent data sets. A total of 1220 differentially expressed genes were identified between HCC and normal samples. Differentially expressed mRNAs were significantly enriched in functions and pathways related to “plasma membrane structure,” “sensory perception,” “metabolism,” and “cell proliferation.” Two disease-associated gene modules were identified. Among genes in lncRNA-mRNA and miRNA-mRNA coexpression networks, 9 DEmRNAs and 7 DEmiRNAs were identified to be potential prognostic biomarkers. MIMAT0000102, MIMAT0003882, and MIMAT0004677 were successfully validated in independent data sets. Our results may advance our understanding of molecular mechanisms underlying HCC. The biomarkers may contribute to diagnosis in future clinical practice.
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Affiliation(s)
- Shuping Qu
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Qiuyuan Shi
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jing Xu
- Department of Interventional Oncology, Shanghai Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wanwan Yi
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hengwei Fan
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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Zheng Q, Wei X, Rao J, Zhou C. Identification of key miRNAs in the progression of hepatocellular carcinoma using an integrated bioinformatics approach. PeerJ 2020; 8:e9000. [PMID: 32411519 PMCID: PMC7210814 DOI: 10.7717/peerj.9000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 03/26/2020] [Indexed: 12/28/2022] Open
Abstract
Backgroud It has been shown that aberrant expression of microRNAs (miRNAs) and transcriptional factors (TFs) is tightly associated with the development of HCC. Therefore, in order to further understand the pathogenesis of HCC, it is necessary to systematically study the relationship between the expression of miRNAs, TF and genes. In this study, we aim to identify the potential transcriptomic markers of HCC through analyzing common microarray datasets, and further establish the differential co-expression network of miRNAs-TF-mRNA to screen for key miRNAs as candidate diagnostic markers for HCC. Method We first downloaded the mRNA and miRNA expression profiles of liver cancer from the GEO database. After pretreatment, we used a linear model to screen for differentially expressed genes (DEGs) and miRNAs. Further, we used weighed gene co-expression network analysis (WGCNA) to construct the differential gene co-expression network for these DEGs. Next, we identified mRNA modules significantly related to tumorigenesis in this network, and evaluated the relationship between mRNAs and TFs by TFBtools. Finally, the key miRNA was screened out in the mRNA-TF-miRNA ternary network constructed based on the target TF of differentially expressed miRNAs, and was further verified with external data set. Results A total of 465 DEGs and 215 differentially expressed miRNAs were identified through differential genes expression analysis, and WGCNA was used to establish a co-expression network of DEGs. One module that closely related to tumorigenesis was obtained, including 33 genes. Next, a ternary network was constructed by selecting 256 pairs of mRNA-TF pairs and 100 pairs of miRNA-TF pairs. Network mining revealed that there were significant interactions between 18 mRNAs and 25 miRNAs. Finally, we used another independent data set to verify that miRNA hsa-mir-106b and hsa-mir-195 are good classifiers of HCC and might play key roles in the progression of HCC. Conclusion Our data indicated that two miRNAs-hsa-mir-106b and hsa-mir-195-are identified as good classifiers of HCC.
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Affiliation(s)
- Qi Zheng
- Department of Oncology, Fuzhou First People's Hospital, Fuzhou, Jiangxi, China
| | - Xiaoyong Wei
- Department of Hepatobiliary Surgery, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China
| | - Jun Rao
- Department of Hepatobiliary Surgery, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China
| | - Cuncai Zhou
- Department of Hepatobiliary Surgery, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China
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Ciesielski O, Biesiekierska M, Panthu B, Vialichka V, Pirola L, Balcerczyk A. The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression. Int J Mol Sci 2020; 21:ijms21072606. [PMID: 32283668 PMCID: PMC7177242 DOI: 10.3390/ijms21072606] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/04/2020] [Accepted: 04/06/2020] [Indexed: 02/07/2023] Open
Abstract
Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both tumor progression and metastasis. Angiogenesis is tightly regulated by a balance of angiogenic and antiangiogenic factors. Angiogenic factors of the vascular endothelial growth factor (VEGF) family lead to the activation of endothelial cells, proliferation, and neovascularization. Significant VEGF-A upregulation is commonly observed in cancer cells, also due to hypoxic conditions, and activates endothelial cells (ECs) by paracrine signaling stimulating cell migration and proliferation, resulting in tumor-dependent angiogenesis. Conversely, antiangiogenic factors inhibit angiogenesis by suppressing ECs activation. One of the best-known anti-angiogenic factors is thrombospondin-1 (TSP-1). In pathological angiogenesis, the balance shifts towards the proangiogenic factors and an angiogenic switch that promotes tumor angiogenesis. Here, we review the current literature supporting the notion of the existence of two different endothelial lineages: normal endothelial cells (NECs), representing the physiological form of vascular endothelium, and tumor endothelial cells (TECs), which are strongly promoted by the tumor microenvironment and are biologically different from NECs. The angiogenic switch would be also important for the explanation of the differences between NECs and TECs, as angiogenic factors, cytokines and growth factors secreted into the tumor microenvironment may cause genetic instability. In this review, we focus on the epigenetic differences between the two endothelial lineages, which provide a possible window for pharmacological targeting of TECs.
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Affiliation(s)
- Oskar Ciesielski
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; (O.C.); (M.B.); (V.V.)
- The Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Marta Biesiekierska
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; (O.C.); (M.B.); (V.V.)
| | - Baptiste Panthu
- INSERM Unit 1060, CarMeN Laboratory, Lyon 1 University, 165 Chemin du Grand Revoyet—BP12, F-69495 Pierre Bénite CEDEX, France; (B.P.); (L.P.)
| | - Varvara Vialichka
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; (O.C.); (M.B.); (V.V.)
| | - Luciano Pirola
- INSERM Unit 1060, CarMeN Laboratory, Lyon 1 University, 165 Chemin du Grand Revoyet—BP12, F-69495 Pierre Bénite CEDEX, France; (B.P.); (L.P.)
| | - Aneta Balcerczyk
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; (O.C.); (M.B.); (V.V.)
- Correspondence: ; Tel.: +48-42-635-45-10
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Orso F, Quirico L, Dettori D, Coppo R, Virga F, Ferreira LC, Paoletti C, Baruffaldi D, Penna E, Taverna D. Role of miRNAs in tumor and endothelial cell interactions during tumor progression. Semin Cancer Biol 2020; 60:214-224. [DOI: 10.1016/j.semcancer.2019.07.024] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 07/29/2019] [Indexed: 12/18/2022]
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Bai T, Liang R, Zhu R, Wang W, Zhou L, Sun Y. MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells. J Cell Physiol 2020; 235:5637-5648. [PMID: 31960438 DOI: 10.1002/jcp.29496] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 01/08/2020] [Indexed: 12/29/2022]
Abstract
Primary liver cancer is the second most frequent cause of cancer-related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA-214-3p (miR-214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR-214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR-214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre-miR-214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti-miR-214 sponge showed the opposite effect. Additionally, pre-miR-214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre-miR-214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR-214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR-214-induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR-214 elevated the ferroptosis-promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis-promoting effects of miR-214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.
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Affiliation(s)
- Tao Bai
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ruopeng Liang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, Henan, China
| | - Rongtao Zhu
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Institute of Hepatopancreatobiliary Diseases of Zhengzhou University, Zhengzhou, Henan, China
| | - Weijie Wang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Institute of Hepatopancreatobiliary Diseases of Zhengzhou University, Zhengzhou, Henan, China
| | - Lin Zhou
- Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, Henan, China.,Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuling Sun
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, Henan, China.,Institute of Hepatopancreatobiliary Diseases of Zhengzhou University, Zhengzhou, Henan, China
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Wang J, Xu Y, Wang J, Ying H. Circulating miR-214-3p predicts nasopharyngeal carcinoma recurrence or metastasis. Clin Chim Acta 2020; 503:54-60. [PMID: 31926154 DOI: 10.1016/j.cca.2020.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 12/18/2019] [Accepted: 01/07/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Due to the remarkably stable form in the bloodstream, circulating microRNAs (miRNAs) are indicated as promising novel minimally invasive biomarkers in many cancers. However, available data of miRNAs in nasopharyngeal carcinoma (NPC) are relatively limited. METHODS Based on the GEO database and previous published reports, 21 dysregulated miRNAs were selected for screening via microarray analysis (20 NPC samples vs 10 controls). Dysregulated miRNAs were then detected and verified by the method of quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in the training and validation sets. The candidate miR-214-3p was then evaluated in the evaluation set, including the association between miR-214-3p and clinicopathological characteristics, dynamic changes in NPC patients and the predictive value for NPC recurrence or metastasis. RESULTS Seven miRNAs were significantly altered in comparison with healthy controls by microarray analysis. MiR-214-3p was the most significantly expressed in training and validation sets by qRT-PCR. Plasma miR-214-3p expressions were significantly associated with UICC stages and NPC recurrence or metastasis. Plasma miR-214-3p expressions showed a gradual decrease during the follow-up after treatment in NPC patients. Patients with recurrence or metastasis were always accompanied with higher levels of plasma miR-214-3p at the same time point. High pretreatment miR-214-3p expression (≥3.12) was significantly associated with NPC recurrence or metastasis by log-rank test using Kaplan-Meier survival curve analysis (P = 0.006). CONCLUSIONS Circulating miR-214-3p can serve as a noninvasive biomarker for the prediction of recurrence or metastasis in NPC patients.
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Affiliation(s)
- Jianfeng Wang
- Department and Institution: Department of Otolaryngology, HwaMei Hospital, University of Chinese Academy of Sciences, China
| | - Yi Xu
- Department and Institution: Department of Otolaryngology, HwaMei Hospital, University of Chinese Academy of Sciences, China.
| | - Jiyun Wang
- Department and Institution: Department of Otolaryngology, HwaMei Hospital, University of Chinese Academy of Sciences, China
| | - Haiyue Ying
- Department and Institution: Department of Otolaryngology, HwaMei Hospital, University of Chinese Academy of Sciences, China.
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Tsai CL, Chang JS, Yu MC, Lee CH, Chen TC, Chuang WY, Kuo WL, Lin CC, Lin SM, Hsieh SY. Functional Genomics Identifies Hepatitis-Induced STAT3-TYRO3-STAT3 Signaling as a Potential Therapeutic Target of Hepatoma. Clin Cancer Res 2019; 26:1185-1197. [PMID: 31831556 DOI: 10.1158/1078-0432.ccr-18-3531] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 03/27/2019] [Accepted: 12/09/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE Hepatitis promotes the development and recurrence of hepatocellular carcinoma (HCC). Receptor tyrosine kinases (RTK) play critical roles in the development of many cancers. We explored the potential roles of RTKs in hepatitis-related liver cancers. EXPERIMENTAL DESIGN We conducted loss-of-function screening to elucidate the roles of RTKs in the development of HCC in vitro and in vivo. RESULTS Many RTKs were coexpressed in HCC and were involved in tumor development and growth. Of these, TYRO3 promoted tumor growth and was clinically associated with hepatitis activity and poor prognosis. In mice, chemical-induced hepatitis transcriptionally activated Tyro3 expression via IL-6/IL6R-STAT3 signaling. Moreover, hepatitis-associated apoptotic cells facilitated the presentation of GAS6, a TYRO3 ligand, to further activate TYRO3-mediated signaling. Furthermore, TYRO3 activation elicited intracellular SRC- and STAT3 signaling. In mice, hepatitis and Tyro3 synergistically promoted HCC development. Silencing TYRO3 expression or inhibiting its kinase activity suppressed xenograft HCC growth in nude mice. CONCLUSIONS Many RTKs are simultaneously involved in HCC development. Hepatitis exerts dual effects on the activation of TYRO3-mediated signaling in HCC cells, which further elicits the "TYRO3-STAT3-TYRO3" signaling loop to facilitate tumor growth. Our findings unveil a previously unrecognized link between RTKs and hepatitis-associated HCC and suggest TYRO3 as a marker and therapeutic target for the HCCs with higher hepatitis activity.
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Affiliation(s)
- Chia-Liang Tsai
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Graduate Institute of Biomedical Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jeng-Shou Chang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ming-Chin Yu
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chern-Horng Lee
- Department of General Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Tse-Ching Chen
- Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wen-Yu Chuang
- Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wei-Liang Kuo
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chen-Chun Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Shi-Ming Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Sen-Yung Hsieh
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. .,Graduate Institute of Biomedical Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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He QL, Qin SY, Tao L, Ning HJ, Jiang HX. Prognostic value and prospective molecular mechanism of miR-100-5p in hepatocellular carcinoma: A comprehensive study based on 1,258 samples. Oncol Lett 2019; 18:6126-6142. [PMID: 31788087 PMCID: PMC6865135 DOI: 10.3892/ol.2019.10962] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023] Open
Abstract
The prognostic value and molecular mechanism of microRNA-100-5p (miR-100-5p) in hepatocellular carcinoma (HCC) are still unclear. To explore the prognostic value and the mechanism of miR-100-5p in HCC, the present study analyzed the results of 18 previous studies and bioinformatic datasets. The clinical significance of miR-100-5p and its targets in HCC were investigated using The Cancer Genome Atlas and the Gene Expression Omnibus, as well as relevant literature. In total, 12 online tools were used to predict the target genes of miR-100-5p. Bioinformatics analysis and Spearman correlation analysis were performed, and genomic alterations of the hub genes were evaluated. A meta-analysis with 1,258 samples revealed that miR-100-5p was significantly downregulated in HCC [standard mean difference (SMD), -0.94; 95% confidence interval (CI), -1.14 to -0.74; I2, 35.2%]. Lower miR-100-5p expression was associated with poorer clinical characteristics and a poorer prognosis for patients with HCC. Additionally, bioinformatics analysis revealed that the 'regulation of transcription', 'chromatin remodeling complex', 'transcription regulator activity', 'pathways in cancer' and 'heparan sulfate biosynthesis' were the most enriched terms. Furthermore, expression of histone deacetylase (HDAC)2, HDAC3, SHC-transforming protein 1 (SHC1), Ras-related protein Rac1 (RAC1) and E3 ubiquitin-protein ligase CBL (CBL) was negatively correlated with miR-100-5p expression. Among these, upregulated HDAC2 [hazard ratio (HR), 1.910; 95% CI, 1.309-2.787; P=0.0007], HDAC3 (HR, 1.474; 95% CI, 1.012-2.146; P=0.0435), SHC1 (HR, 1.52; 95% CI, 1.043-2.215; P=0.0281) and RAC1 (HR, 1.817; 95% CI, 1.248-2.645; P=0.0022) were associated with shorter survival. Alterations in HDAC2, SHC1, RAC1 and IGF1R were linked with a poorer outcome for HCC, and alternative splicing of SHC and RAC1 were significantly decreased and increased in HCC, respectively. In summary, the downregulation of miR-100-5p may be involved in the progression and prognosis of HCC. The upregulation of HDAC2, HDAC3, SHC1 and RAC1 may indicate a poorer survival rate for patients with HCC. Thus, miR-100-5p and these 4 potential target genes may provide novel therapeutic targets and prognostic predictors for patients with HCC.
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Affiliation(s)
- Qing-Lin He
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Shan-Yu Qin
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Lin Tao
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hong-Jian Ning
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hai-Xing Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Tang X, Feng D, Li M, Zhou J, Li X, Zhao D, Hao B, Li D, Ding K. Transcriptomic Analysis of mRNA-lncRNA-miRNA Interactions in Hepatocellular Carcinoma. Sci Rep 2019; 9:16096. [PMID: 31695090 PMCID: PMC6834564 DOI: 10.1038/s41598-019-52559-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 10/21/2019] [Indexed: 01/11/2023] Open
Abstract
Fully elucidating the molecular mechanisms of non-coding RNAs (ncRNAs), including micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), underlying hepatocarcinogenesis is challenging. We characterized the expression profiles of ncRNAs and constructed a regulatory mRNA-lncRNA-miRNA (MLMI) network based on transcriptome sequencing (RNA-seq) of hepatocellular carcinoma (HCC, n = 9) patients. Of the identified miRNAs (n = 203) and lncRNAs (n = 1,090), we found 16 significantly differentially expressed (DE) miRNAs and three DE lncRNAs. The DE RNAs were highly enriched in 21 functional pathways implicated in HCC (p < 0.05), including p53, MAPK, and NAFLD signaling. Potential pairwise interactions between DE ncRNAs and mRNAs were fully characterized using in silico prediction and experimentally-validated evidence. We for the first time constructed a MLMI network of reciprocal interactions for 16 miRNAs, three lncRNAs, and 253 mRNAs in HCC. The predominant role of MEG3 in the MLMI network was validated by its overexpression in vitro that the expression levels of a proportion of MEG3-targeted miRNAs and mRNAs was changed significantly. Our results suggested that the comprehensive MLMI network synergistically modulated carcinogenesis, and the crosstalk of the network provides a new avenue to accurately describe the molecular mechanisms of hepatocarcinogenesis.
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Affiliation(s)
- Xia Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China
| | - Delong Feng
- Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Min Li
- Department of Hepatobiliary Surgery, Suining Central Hospital, Suining, Sichuan Province, P.R. China
| | - Jinxue Zhou
- Department of Hepatobiliary Surgery, Henan Tumor Hospital, Zhengzhou, Henan, P.R. China
| | - Xiaoyuan Li
- Department of Medical Oncology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, P.R. China
| | - Dachun Zhao
- Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, P.R. China
| | - Bingtao Hao
- Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong, P.R. China.,Henan Medical Genetics Institute, People's Hospital of Henan University, Zhengzhou, Henan, P.R. China
| | - Dewei Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Keyue Ding
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China. .,Department of Bioinformatics, School of Basic Medicine, Chongqing Medical University, Chongqing, P.R. China.
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Zhang Y, Qian H, Xu J, Gao W. ADAR, the carcinogenesis mechanisms of ADAR and related clinical applications. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:686. [PMID: 31930087 DOI: 10.21037/atm.2019.11.06] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Adenosine deaminases acting on RNA (ADARs) catalyze the conversion of adenosine (A) to inosine (I) in double-stranded RNA, which can change the codons after transcription. Abnormal ADAR editing is present in a variety of cancers. However, the study of the biological effects of ADARs in cancer is not very deep. Here, we review current important ADAR-mediated editing events, related carcinogenic mechanisms and applications in clinical medicine. Further exploration in ADARs can provide a new direction for cancer treatment.
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Affiliation(s)
- Yue Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Huizhu Qian
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jing Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Wen Gao
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Xiong X, Yuan J, Zhang N, Zheng Y, Liu J, Yang M. Silencing of lncRNA PVT1 by miR-214 inhibits the oncogenic GDF15 signaling and suppresses hepatocarcinogenesis. Biochem Biophys Res Commun 2019; 521:478-484. [PMID: 31677796 DOI: 10.1016/j.bbrc.2019.10.137] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Accepted: 10/18/2019] [Indexed: 12/12/2022]
Abstract
The prognosis for hepatocellular carcinoma (HCC) is dismal. Long noncoding RNA PVT1 has been linked to malignancies and might be a deleterious therapy target. However, the key events controlling its expression in HCC remain undetermined. Here, we address how PVT1 is fine-regulated and its downstream signaling in hepatoma cells. Interestingly, we found that c-Myc and P53 could divergently regulate PVT1 transcription. Oncoprotein c-Myc enhances PVT1 expression, whereas P53 suppresses its expression. We also identified miR-214 as a crucial, negative regulator of PVT1. Consistently, high miR-214 levels were significantly correlated with diminished PVT1 expression in HCC specimens. Silencing of PVT1 by ectopic miR-214 or siRNAs markedly inhibited viability and invasion of HCC cells. In opposition, inhibition of endogenous miR-214 promoted PVT1 expression and enhanced cell proliferation. Notably, oncogenic GDF15 is a potential downstream target of the miR-214-PVT1 signaling. Collectively, our results show that the c-Myc/P53/miR-214-PVT1-GDF15 axis is implicated in HCC development, shedding light on the mechanistic actions of PVT1 and representing potential targets for HCC clinical intervention.
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Affiliation(s)
- Xiangyu Xiong
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Jupeng Yuan
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Nasha Zhang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Yan Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Jibing Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
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Huang PS, Wang CS, Yeh CT, Lin KH. Roles of Thyroid Hormone-Associated microRNAs Affecting Oxidative Stress in Human Hepatocellular Carcinoma. Int J Mol Sci 2019; 20:E5220. [PMID: 31640265 PMCID: PMC6834183 DOI: 10.3390/ijms20205220] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress occurs as a result of imbalance between the generation of reactive oxygen species (ROS) and antioxidant genes in cells, causing damage to lipids, proteins, and DNA. Accumulating damage of cellular components can trigger various diseases, including metabolic syndrome and cancer. Over the past few years, the physiological significance of microRNAs (miRNA) in cancer has been a focus of comprehensive research. In view of the extensive level of miRNA interference in biological processes, the roles of miRNAs in oxidative stress and their relevance in physiological processes have recently become a subject of interest. In-depth research is underway to specifically address the direct or indirect relationships of oxidative stress-induced miRNAs in liver cancer and the potential involvement of the thyroid hormone in these processes. While studies on thyroid hormone in liver cancer are abundantly documented, no conclusive information on the potential relationships among thyroid hormone, specific miRNAs, and oxidative stress in liver cancer is available. In this review, we discuss the effects of thyroid hormone on oxidative stress-related miRNAs that potentially have a positive or negative impact on liver cancer. Additionally, supporting evidence from clinical and animal experiments is provided.
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Affiliation(s)
- Po-Shuan Huang
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33302, Taiwan.
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33302, Taiwan.
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33302, Taiwan.
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Patras L, Banciu M. Intercellular Crosstalk Via Extracellular Vesicles in Tumor Milieu as Emerging Therapies for Cancer Progression. Curr Pharm Des 2019; 25:1980-2006. [DOI: 10.2174/1381612825666190701143845] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 06/19/2019] [Indexed: 02/07/2023]
Abstract
:Increasing evidence has suggested that extracellular vesicles (EV) mediated bidirectional transfer of functional molecules (such as proteins, different types of RNA, and lipids) between cancer cells and tumor stromal cells (immune cells, endothelial cells, fibroblasts, stem cells) and strongly contributed to the reinforcement of cancer progression. Thus, intercellular EV-mediated signaling in tumor microenvironment (TME) is essential in the modulation of all processes that support and promote tumor development like immune suppression, angiogenesis, invasion and metastasis, and resistance of tumor cells to anticancer treatments.:Besides EV potential to revolutionize our understanding of the cancer cell-stromal cells crosstalk in TME, their ability to selectively transfer different cargos to recipient cells has created excitement in the field of tumortargeted delivery of specific molecules for anticancer treatments. Therefore, in tight connection with previous findings, this review brought insight into the dual role of EV in modulation of TME. Thus, on one side EV create a favorable phenotype of tumor stromal cells for tumor progression; however, as a future new class of anticancer drug delivery systems EV could re-educate the TME to overcome main supportive processes for malignancy progression.
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Affiliation(s)
- Laura Patras
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Manuela Banciu
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania
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48
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Song Y, Wang G, Zhuang J, Ni J, Zhang S, Ye Y, Xia W. MicroRNA‑584 prohibits hepatocellular carcinoma cell proliferation and invasion by directly targeting BDNF. Mol Med Rep 2019; 20:1994-2001. [PMID: 31257521 DOI: 10.3892/mmr.2019.10424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Accepted: 05/22/2019] [Indexed: 11/05/2022] Open
Abstract
In recent decades, an increasing number of studies have demonstrated that numerous microRNAs (miRNAs) are dysregulated in hepatocellular carcinoma (HCC); these aberrantly expressed miRNAs are contributing regulators of HCC formation and progression. Thus, revealing the biological roles of miRNAs in HCC may provide novel information on the identification of effective therapeutic targets and valuable diagnosis methods. Herein, reverse transcription‑quantitative PCR was performed to determine the expression profile of miRNA‑584 (miR‑584) in HCC tissues and cell lines. Cell Counting Kit‑8 and cell invasion assays were utilized to evaluate the influence of mIR‑584 overexpression on HCC cell proliferation and invasion, respectively. The present study demonstrated that miR‑584 expression was reduced in HCC tissues and cell lines compared with normal controls. Clinical analysis indicated that decreased miR‑584 expression was significantly associated with tumor size, TNM stage and lymph node metastasis of patients with HCC. Additionally, resumption of miR‑584 expression inhibited proliferation and invasion of HCC cells. Mechanistically, it was demonstrated that miR‑584 can directly interact with the 3'‑untranslated regions of brain‑derived neurotrophic factor (BDNF) mRNA, and reduce its mRNA and protein levels in HCC cells. Furthermore, BDNF was upregulated in HCC tissues, and its level was inversely correlated with miR‑584 expression. Notably, restored BDNF expression antagonized the inhibitory effects of miR‑584 overexpression on HCC cells. In conclusion, miR‑584 may serve tumor‑suppressive roles in HCC by directly targeting BDNF, thus suggesting that miR‑584 may serve as a potential candidate for treatment of patients with this disease.
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Affiliation(s)
- Yanan Song
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Guoyu Wang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Juhua Zhuang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Jing Ni
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Suiliang Zhang
- Department of Oncology, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Ying Ye
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Wei Xia
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
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Prabhakar K, Rodrίguez CI, Jayanthy AS, Mikheil DM, Bhasker AI, Perera RJ, Setaluri V. Role of miR-214 in regulation of β-catenin and the malignant phenotype of melanoma. Mol Carcinog 2019; 58:1974-1984. [PMID: 31338875 DOI: 10.1002/mc.23089] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 07/05/2019] [Accepted: 07/10/2019] [Indexed: 12/15/2022]
Abstract
Wnt/β-catenin signaling plays an important role in melanocyte biology, especially in the early stages of melanocyte transformation and melanomagenesis. β-catenin, encoded by the gene CTNNB1, is an intracellular signal transducer of Wnt signaling and activates transcription of genes important for cell proliferation and survival. Wnt/β-catenin signaling is frequently activated in melanoma through oncogenic mutations of β-catenin and elevated β-catenin levels are positively correlated with melanoma aggressiveness. Molecular mechanisms that regulate β-catenin expression in melanoma are not fully understood. MicroRNA-214 is known to function as a tumor suppressor by targeting β-catenin in several types of cancer cells. Here, we investigated the regulation of β-catenin by miR-214 and its role in melanoma. We show that β-catenin mRNA levels are negatively correlated with miR-214 in melanoma. However, overexpression of miR-214 paradoxically increased β-catenin protein levels and promoted malignant properties of melanoma cells including resistance to mitogen-activated protein kinase inhibitors (MAPKi). RNA-seq analysis revealed that melanoma cells predominantly express a β-catenin mRNA isoform lacking miR-214 target site. Using matched miRNA and mRNA-seq and bioinformatics analysis, we identified novel miR-214 targets, ankyrin repeat domain 6 (ANKRD6) and C-terminal binding protein 1 (CTBP1), that are involved in negative regulation of Wnt signaling. Overexpression of miR-214 or knockdown of the novel miR-214 targets, ANKRD6 or CTBP1, increased melanoma cell proliferation, migration, and decreased sensitivity to MAPKi. Our data suggest that in melanoma cells β-catenin is not regulated by miR-214 and the functions of miR-214 in melanoma are mediated partly by regulating proteins involved in attenuation of Wnt/β-catenin signaling.
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Affiliation(s)
- Kirthana Prabhakar
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Carlos I Rodrίguez
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Ashika S Jayanthy
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Dareen M Mikheil
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Aishwarya Iyer Bhasker
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Ranjan J Perera
- Sanford-Burham Prebys Medical Discovery Institute, Orlando, Florida
| | - Vijayasaradhi Setaluri
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.,William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin
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50
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Shan H, Zhou X, Chen C. MicroRNA‑214 suppresses the viability, migration and invasion of human colorectal carcinoma cells via targeting transglutaminase 2. Mol Med Rep 2019; 20:1459-1467. [PMID: 31173203 PMCID: PMC6625444 DOI: 10.3892/mmr.2019.10325] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 02/21/2019] [Indexed: 12/17/2022] Open
Abstract
Colorectal carcinoma (CRC) is a common malignancy of the digestive tract. MicroRNA (miR)-214 is considered a key hub that controls tumor networks; therefore, the effects of miR-214 on CRC were examined and its target gene was investigated in this study. The expression levels of transglutaminase 2 (TGM2) and miR-214 were detected in CRC and adjacent normal tissues by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, and luciferase activity was analyzed by dual luciferase reporter analysis. In addition, cell viability, invasion and migration were measured by Cell Counting kit-8 and Transwell assays, respectively. The expression levels of epithelial-mesenchymal transition-related proteins, and phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) signaling-associated factors were detected using RT-qPCR and western blotting. The results demonstrated that miR-214 expression was downregulated in CRC tissue, whereas TGM2 expression was upregulated. According to TargetScan prediction, miR-214 possesses a binding site to TGM2. In addition, transfection with miR-214 mimics markedly suppressed the viability of LoVo cells. miR-214 overexpression also inhibited cell invasion and migration by increasing E-cadherin and tissue inhibitor of metalloproteinases-2 expression, and decreasing matrix metalloproteinase (MMP)-2 and MMP-9 expression. Furthermore, miR-214 downregulated phosphorylation of PI3K and Akt; however, the expression levels of total PI3K and Akt were not affected by miR-214. In conclusion, this study indicated that TGM2 was a target gene of miR-214, and a negative correlation between miR-214 and TGM2 expression was determined in CRC. Notably, miR-214 markedly suppressed the viability, invasion and migration of CRC cells, which may be associated with a downregulation in PI3K/Akt signaling. These findings suggested that miR-214 may be considered a novel target for the treatment of CRC.
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Affiliation(s)
- Huiguo Shan
- Department of Oncology, The Affiliated Dongtai Hospital of Nantong University, Dongtai, Jiangsu 224200, P.R. China
| | - Xuefeng Zhou
- Department of Oncology, The Affiliated Dongtai Hospital of Nantong University, Dongtai, Jiangsu 224200, P.R. China
| | - Chuanjun Chen
- Department of Medical Oncology, Xinchang People's Hospital, Shaoxing, Zhejiang 312500, P.R. China
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