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Jeng LB, Chan WL, Teng CF. Independent prognostic significance of tissue and circulating microrna biomarkers in hepatocellular carcinoma. Discov Oncol 2025; 16:281. [PMID: 40056315 DOI: 10.1007/s12672-025-02043-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 03/04/2025] [Indexed: 03/10/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Although many therapeutic modalities have been established for treating HCC patients, the outcomes of patients remain unsatisfactory. Development of independent prognostic biomarkers is thus an important need to allow for early diagnosis and timely treatment. MicroRNAs (miRNAs) are the most studied class of small non-coding RNAs. It has been shown that miRNAs play essential roles in the multiple steps of HCC tumorigenesis and progression. Furthermore, the baseline expression levels of many miRNAs are altered in tumor tissues and blood circulation of HCC patients. Therefore, miRNAs have emerged as independent biomarkers for the prediction of HCC prognosis. This review provides a comprehensive literature-based summary of tissue and circulating miRNA biomarkers with independent prognostic significance in HCC.
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Affiliation(s)
- Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung, 404, Taiwan
- Department of Surgery, China Medical University Hospital, Taichung, 404, Taiwan
- Cell Therapy Center, China Medical University Hospital, Taichung, 404, Taiwan
| | - Wen-Ling Chan
- Department of Public Health, College of Public Health, China Medical University, Taichung, 404, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, 413, Taiwan
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung, 404, Taiwan.
- Graduate Institute of Biomedical Sciences, China Medical University, No. 91, Hsueh-Shih Rd., Northern Dist., Taichung, 404, Taiwan.
- Master Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, 404, Taiwan.
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Park HS, Bang JH, Jung WH, Yang JY, Shin HJ, Son JH, Han JW, Lee SH, Chung KH, Kim K, Chang HS, Park TK. Development of Non-Invasive miRNA Markers for Assessing the Quality of Human Induced Pluripotent Stem Cell-Derived Retinal Organoids. Int J Mol Sci 2024; 25:8011. [PMID: 39125582 PMCID: PMC11312389 DOI: 10.3390/ijms25158011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 08/12/2024] Open
Abstract
Human retinal organoids (ROs) have emerged as valuable tools for studying retinal development, modeling human retinal diseases, and screening drugs. However, their application is limited primarily due to time-intensive generation, high costs, and low reproducibility. Quality assessment of RO differentiation is crucial for their application in research. However, traditional methods such as morphological evaluation and immunohistochemical analysis have limitations due to their lack of precision and invasiveness, respectively. This study aims to identify non-invasive biomarkers for RO differentiation quality using exosomal microRNAs (miRNAs), which are known to reflect cell-specific functions and development in the retina. We differentiated ROs from human induced pluripotent stem cells (hiPSCs) and classified them into 'superior' and 'inferior' groups based on morphological and immunohistochemical criteria. Exosomes from the conditioned media were isolated and analyzed for miRNA content. Our findings revealed distinct miRNA profiles between superior and inferior ROs, with superior ROs exhibiting higher miRNA diversity and specifically up- or down-regulated miRNAs. Gene ontology and pathway enrichment analyses indicated that the target genes of these miRNAs are involved in neuron proliferation and differentiation. The study suggests the potential of exosomal hsa-miR-654-3p and hsa-miR-451a as non-invasive biomarkers for real-time monitoring of RO quality, facilitating the development of standardized, efficient, and cost-effective culture methods.
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Affiliation(s)
- Hyo Song Park
- Divisions of Ophthalmology, Soonchunhyang University Bucheon Hospital, College of Medicine, Soonchunhyang University, Bucheon 14584, Republic of Korea; (H.S.P.); (W.H.J.); (J.W.H.); (S.H.L.)
| | - Ji-Hong Bang
- Department of Interdisciplinary Program in Biomedical Science Major, Graduate School, Soonchunhyang University, Asan 31538, Republic of Korea; (J.-H.B.); (H.J.S.)
| | - Wook Hyun Jung
- Divisions of Ophthalmology, Soonchunhyang University Bucheon Hospital, College of Medicine, Soonchunhyang University, Bucheon 14584, Republic of Korea; (H.S.P.); (W.H.J.); (J.W.H.); (S.H.L.)
| | - Jin Young Yang
- Laboratory of Molecular Therapy for Retinal Degeneration, Soonchunhyang University Bucheon Hospital, Bucheon 31538, Republic of Korea; (J.Y.Y.); (K.H.C.)
| | - Hee Jeong Shin
- Department of Interdisciplinary Program in Biomedical Science Major, Graduate School, Soonchunhyang University, Asan 31538, Republic of Korea; (J.-H.B.); (H.J.S.)
- Laboratory of Molecular Therapy for Retinal Degeneration, Soonchunhyang University Bucheon Hospital, Bucheon 31538, Republic of Korea; (J.Y.Y.); (K.H.C.)
| | - Ji-Hye Son
- Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan 33151, Republic of Korea;
| | - Jung Woo Han
- Divisions of Ophthalmology, Soonchunhyang University Bucheon Hospital, College of Medicine, Soonchunhyang University, Bucheon 14584, Republic of Korea; (H.S.P.); (W.H.J.); (J.W.H.); (S.H.L.)
| | - Si Hyung Lee
- Divisions of Ophthalmology, Soonchunhyang University Bucheon Hospital, College of Medicine, Soonchunhyang University, Bucheon 14584, Republic of Korea; (H.S.P.); (W.H.J.); (J.W.H.); (S.H.L.)
| | - Kyung Hwun Chung
- Laboratory of Molecular Therapy for Retinal Degeneration, Soonchunhyang University Bucheon Hospital, Bucheon 31538, Republic of Korea; (J.Y.Y.); (K.H.C.)
| | - Kyunggon Kim
- Department of Digital Medicine, Brain Korea 21 plus, College of Medicine, University of Ulsan and Asan Medical Center, Seoul 05505, Republic of Korea;
| | - Hun Soo Chang
- Department of Interdisciplinary Program in Biomedical Science Major, Graduate School, Soonchunhyang University, Asan 31538, Republic of Korea; (J.-H.B.); (H.J.S.)
- Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan 33151, Republic of Korea;
| | - Tae Kwann Park
- Divisions of Ophthalmology, Soonchunhyang University Bucheon Hospital, College of Medicine, Soonchunhyang University, Bucheon 14584, Republic of Korea; (H.S.P.); (W.H.J.); (J.W.H.); (S.H.L.)
- Department of Interdisciplinary Program in Biomedical Science Major, Graduate School, Soonchunhyang University, Asan 31538, Republic of Korea; (J.-H.B.); (H.J.S.)
- Laboratory of Molecular Therapy for Retinal Degeneration, Soonchunhyang University Bucheon Hospital, Bucheon 31538, Republic of Korea; (J.Y.Y.); (K.H.C.)
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Leng X, Zhang M, Xu Y, Wang J, Ding N, Yu Y, Sun S, Dai W, Xue X, Li N, Yang Y, Shi Z. Non-coding RNAs as therapeutic targets in cancer and its clinical application. J Pharm Anal 2024; 14:100947. [PMID: 39149142 PMCID: PMC11325817 DOI: 10.1016/j.jpha.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 01/12/2024] [Accepted: 02/01/2024] [Indexed: 08/17/2024] Open
Abstract
Cancer genomics has led to the discovery of numerous oncogenes and tumor suppressor genes that play critical roles in cancer development and progression. Oncogenes promote cell growth and proliferation, whereas tumor suppressor genes inhibit cell growth and division. The dysregulation of these genes can lead to the development of cancer. Recent studies have focused on non-coding RNAs (ncRNAs), including circular RNA (circRNA), long non-coding RNA (lncRNA), and microRNA (miRNA), as therapeutic targets for cancer. In this article, we discuss the oncogenes and tumor suppressor genes of ncRNAs associated with different types of cancer and their potential as therapeutic targets. Here, we highlight the mechanisms of action of these genes and their clinical applications in cancer treatment. Understanding the molecular mechanisms underlying cancer development and identifying specific therapeutic targets are essential steps towards the development of effective cancer treatments.
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Affiliation(s)
- Xuejiao Leng
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Mengyuan Zhang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yujing Xu
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jingjing Wang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ning Ding
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yancheng Yu
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Shanliang Sun
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Weichen Dai
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xin Xue
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Nianguang Li
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ye Yang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhihao Shi
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing, 211198, China
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Chen J, He F, Peng H, Guo J. The underlying mechanism and targeted therapy strategy of miRNAs cross-regulating EMT process through multiple signaling pathways in hepatocellular carcinoma. Front Mol Biosci 2024; 11:1378386. [PMID: 38584703 PMCID: PMC10995332 DOI: 10.3389/fmolb.2024.1378386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 03/04/2024] [Indexed: 04/09/2024] Open
Abstract
The consistent notion holds that hepatocellular carcinoma (HCC) initiation, progression, and clinical treatment failure treatment failure are affected by the accumulation of various genetic and epigenetic alterations. MicroRNAs (miRNAs) play an irreplaceable role in a variety of physiological and pathological states. meanwhile, epithelial-mesenchymal transition (EMT) is a crucial biological process that controls the development of HCC. miRNAs regulate the intermediation state of EMTor mesenchymal-epithelial transition (MTE)thereby regulating HCC progression. Notably, miRNAs regulate key HCC-related molecular pathways, including the Wnt/β-catenin pathway, PTEN/PI3K/AKT pathway, TGF-β pathway, and RAS/MAPK pathway. Therefore, we comprehensively reviewed how miRNAs produce EMT effects by multiple signaling pathways and their potential significance in the pathogenesis and treatment response of HCC. emphasizing their molecular pathways and progression in HCC initiation. Additionally, we also pay attention to regulatory mechanisms that are partially independent of signaling pathways. Finally, we summarize and propose miRNA-targeted therapy and diagnosis and defense strategies forHCC. The identification of the mechanism leading to the activation of EMT programs during HCC disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Consequently, we summarize the latest progress in this direction, with a promising path for further insight into this fast-moving field.
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Affiliation(s)
- Juan Chen
- Department of Pathology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Fuguo He
- Department of Pathology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Peng
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Jinjun Guo
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Chongqing, China
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Sato H, Hara T, Meng S, Tsuji Y, Arao Y, Sasaki K, Miyoshi N, Kobayashi S, Doki Y, Eguchi H, Ishii H. Drug Discovery and Development of miRNA-Based Nucleotide Drugs for Gastrointestinal Cancer. Biomedicines 2023; 11:2235. [PMID: 37626731 PMCID: PMC10452413 DOI: 10.3390/biomedicines11082235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 07/29/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
Short non-coding RNAs, miRNAs, play roles in the control of cell growth and differentiation in cancer. Reportedly, the introduction of miRNAs could reduce the biologically malignant behavior of cancer cells, suggesting a possible use as therapeutic reagents. Given that the forced expression of several miRNAs, including miR-302, results in the cellular reprograming of human and mouse cells, which is similar to the effects of the transcription factors Oct4, Sox2, Klf4, and c-Myc, this suggests that the selective introduction of several miRNAs will be able to achieve anti-cancer effects at the epigenetic and metabolic levels. In this review article, we bring together the recent advances made in studies of microRNA-based therapeutic approaches to therapy-resistant cancers, especially in gastrointestinal organs.
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Affiliation(s)
- Hiromichi Sato
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Tomoaki Hara
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
| | - Sikun Meng
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
| | - Yoshiko Tsuji
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
| | - Yasuko Arao
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
| | - Kazuki Sasaki
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Norikatsu Miyoshi
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Hideshi Ishii
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
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Wang JZ, Nassiri F, Aldape K, von Deimling A, Sahm F. The Epigenetic Landscape of Meningiomas. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1416:175-188. [PMID: 37432627 DOI: 10.1007/978-3-031-29750-2_13] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 07/12/2023]
Abstract
Epigenetic changes have been found to be increasingly important in tumor development and progression. These alterations can be present in tumors such as meningiomas in the absence of any gene mutations and alter gene expression without affecting the sequence of the DNA itself. Some examples of these alterations that have been studied in meningiomas include DNA methylation, microRNA interaction, histone packaging, and chromatin restructuring. In this chapter we will describe in detail each of these mechanisms of epigenetic modification in meningiomas and their prognostic significance.
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Affiliation(s)
- Justin Z Wang
- Division of Neurosurgery, Department of Surgery, The University of Toronto, Toronto, ON, Canada
| | - Farshad Nassiri
- Division of Neurosurgery, Department of Surgery, The University of Toronto, Toronto, ON, Canada.
| | - Kenneth Aldape
- Laboratory of Pathology, Center Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Andreas von Deimling
- CCU Neuropathology, German Cancer Research Center (DKFZ), University Heidelberg, Heidelberg, Germany
| | - Felix Sahm
- CCU Neuropathology, German Cancer Research Center (DKFZ), University Heidelberg, Heidelberg, Germany
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Dohmen J, Semaan A, Kobilay M, Zaleski M, Branchi V, Schlierf A, Hettwer K, Uhlig S, Hartmann G, Kalff JC, Matthaei H, Lingohr P, Holdenrieder S. Diagnostic Potential of Exosomal microRNAs in Colorectal Cancer. Diagnostics (Basel) 2022; 12:diagnostics12061413. [PMID: 35741223 PMCID: PMC9221658 DOI: 10.3390/diagnostics12061413] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/01/2022] [Accepted: 05/27/2022] [Indexed: 12/21/2022] Open
Abstract
Background: Despite the significance of colonoscopy for early diagnosis of colorectal adenocarcinoma (CRC), population-wide screening remains challenging, mainly because of low acceptance rates. Herein, exosomal (exo-miR) and free circulating microRNA (c-miR) may be used as liquid biopsies in CRC to identify individuals at risk. Direct comparison of both compartments has shown inconclusive results, which is why we directly compared a panel of 10 microRNAs in this entity. Methods: Exo-miR and c-miR levels were measured using real-time quantitative PCR after isolation from serum specimens in a cohort of 69 patients. Furthermore, results were compared to established tumor markers CEA and CA 19-9. Results: Direct comparison of exo- and c-miR biopsy results showed significantly higher microRNA levels in the exosomal compartment (p < 0.001). Exo-Let7, exo-miR-16 and exo-miR-23 significantly differed between CRC and healthy controls (all p < 0.05), while no c-miR showed this potential. Sensitivity and specificity can be further enhanced using combinations of multiple exosomal miRNAs. Conclusions: Exosomal microRNA should be considered as a promising biomarker in CRC for future studies. Nonetheless, results may show interference with common comorbidities, which must be taken into account in future studies.
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Affiliation(s)
- Jonas Dohmen
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
| | - Alexander Semaan
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
| | - Makbule Kobilay
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
| | - Martin Zaleski
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
| | - Vittorio Branchi
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
| | - Anja Schlierf
- QuoData GmbH-Quality & Statistics, 01309 Dresden, Germany; (A.S.); (K.H.); (S.U.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
| | - Karina Hettwer
- QuoData GmbH-Quality & Statistics, 01309 Dresden, Germany; (A.S.); (K.H.); (S.U.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
| | - Steffen Uhlig
- QuoData GmbH-Quality & Statistics, 01309 Dresden, Germany; (A.S.); (K.H.); (S.U.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
| | - Gunther Hartmann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Jörg C. Kalff
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Hanno Matthaei
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Philipp Lingohr
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital, 53127 Bonn, Germany; (J.D.); (A.S.); (V.B.); (J.C.K.); (H.M.); (P.L.)
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
| | - Stefan Holdenrieder
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, 53127 Bonn, Germany; (M.K.); (M.Z.); (G.H.)
- CEBIO GmbH—Center for Evaluation of Biomarkers, 81679 Munich, Germany
- Center for Integrated Oncology (CIO) Cologne/Bonn, 53127 Bonn, Germany
- Correspondence:
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The Bright and the Dark Side of TGF-β Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications. Cancers (Basel) 2022; 14:cancers14040940. [PMID: 35205692 PMCID: PMC8870127 DOI: 10.3390/cancers14040940] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 01/18/2023] Open
Abstract
Simple Summary Transforming growth factor β (TGF-β) signaling is a preeminent regulator of diverse cellular and physiological processes. Frequent dysregulation of TGF-β signaling has been implicated in cancer. In hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, the autocrine and paracrine effects of TGF-β have paradoxical implications. While acting as a potent tumor suppressor pathway in the early stages of malignancy, TGF-β diverts to a promoter of tumor progression in the late stages, reflecting its bright and dark natures, respectively. Within this context, targeting TGF-β represents a promising therapeutic option for HCC treatment. We discuss here the molecular properties of TGF-β signaling in HCC, attempting to provide an overview of its effects on tumor cells and the stroma. We also seek to evaluate the dysregulation mechanisms that mediate the functional switch of TGF-β from a tumor suppressor to a pro-tumorigenic signal. Finally, we reconcile its biphasic nature with the therapeutic implications. Abstract Hepatocellular carcinoma (HCC) is associated with genetic and nongenetic aberrations that impact multiple genes and pathways, including the frequently dysregulated transforming growth factor β (TGF-β) signaling pathway. The regulatory cytokine TGF-β and its signaling effectors govern a broad spectrum of spatiotemporally regulated molecular and cellular responses, yet paradoxically have dual and opposing roles in HCC progression. In the early stages of tumorigenesis, TGF-β signaling enforces profound tumor-suppressive effects, primarily by inducing cell cycle arrest, cellular senescence, autophagy, and apoptosis. However, as the tumor advances in malignant progression, TGF-β functionally switches to a pro-tumorigenic signal, eliciting aggressive tumor traits, such as epithelial–mesenchymal transition, tumor microenvironment remodeling, and immune evasion of cancer cells. On this account, the inhibition of TGF-β signaling is recognized as a promising therapeutic strategy for advanced HCC. In this review, we evaluate the functions and mechanisms of TGF-β signaling and relate its complex and pleiotropic biology to HCC pathophysiology, attempting to provide a detailed perspective on the molecular determinants underlying its functional diversion. We also address the therapeutic implications of the dichotomous nature of TGF-β signaling and highlight the rationale for targeting this pathway for HCC treatment, alone or in combination with other agents.
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Zhang Y, Shao J, Li S, Liu Y, Zheng M. The Crosstalk Between Regulatory Non-Coding RNAs and Nuclear Factor Kappa B in Hepatocellular Carcinoma. Front Oncol 2021; 11:775250. [PMID: 34804980 PMCID: PMC8602059 DOI: 10.3389/fonc.2021.775250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/18/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal type of malignancies that possesses great loss of life safety to human beings worldwide. However, few effective means of curing HCC exist and its specific molecular basis is still far from being fully elucidated. Activation of nuclear factor kappa B (NF-κB), which is often observed in HCC, is considered to play a significant part in hepatocarcinogenesis and development. The emergence of regulatory non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), is a defining advance in cancer biology, and related research in this branch has yielded many diagnostic and therapeutic opportunities. Recent studies have suggested that regulatory ncRNAs act as inhibitors or activators in the initiation and progression of HCC by targeting components of NF-κB signaling or regulating NF-κB activity. In this review, we attach importance to the role and function of regulatory ncRNAs in NF-κB signaling of HCC and NF-κB-associated chemoresistance in HCC, then propose future research directions and challenges of regulatory ncRNAs mediated-regulation of NF-κB pathway in HCC.
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Affiliation(s)
- Yina Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jiajia Shao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Shuangshuang Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yanning Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Min Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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10
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Min Z, Xunlei Z, Haizhen C, Wenjing Z, Haiyan Y, Xiaoyun L, Jianyun Z, Xudong C, Aiguo S. The Clinicopathologic and Prognostic Significance of c-Myc Expression in Hepatocellular Carcinoma: A Meta-Analysis. FRONTIERS IN BIOINFORMATICS 2021; 1:706835. [PMID: 36303795 PMCID: PMC9581052 DOI: 10.3389/fbinf.2021.706835] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 09/07/2021] [Indexed: 01/10/2023] Open
Abstract
Background: The incidence and mortality rates of hepatocellular carcinoma (HCC) are increasing worldwide. Therefore, there is an urgent need to elucidate the molecular drivers of HCC for potential early diagnosis and individualized treatment. Whether c-Myc expression plays a role in the clinicopathology and prognosis of patients with HCC remains controversial. This meta-analysis aimed to survey the prognostic role of c-Myc in HCC. Methods: We searched PubMed, Cochrane Library, Embase, Web of Science, and Google Scholar databases for studies published through March 2020 that examined the association between c-Myc expression and clinicopathology or prognosis in HCC patients. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used to investigate the prognostic significance of c-Myc expression. Odds ratios were calculated to evaluate the association between c-Myc expression and clinicopathologic features. We also tested for publication bias. Results: Our meta-analysis included nine studies with 981 patients with HCC published between 1999 and 2016. A meta-analysis of these studies demonstrated that high c-Myc expression indicated a poor overall survival (OS) (HR = 2.260, 95% CI: 1.660–3.080, and p < 0.001) and disease-free survival (DFS) (HR = 1.770, 95% CI: 1.430–2.450, and p < 0.001) in patients with HCC. However, high c-Myc expression was not associated with HBsAg, pathological type, TNM stage, or cirrhosis. We did not find any significant publication bias among the included studies, indicating that our estimates were robust and reliable. Conclusion: c-Myc overexpression could predict poor OS and DFS in HCC patients. c-Myc could be a useful prognostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Zhao Min
- Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Zhang Xunlei
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Chen Haizhen
- Cancer Research Center, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Zhao Wenjing
- Cancer Research Center, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Yu Haiyan
- Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Lu Xiaoyun
- Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Zhou Jianyun
- Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Chen Xudong
- Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong, China
- *Correspondence: Chen Xudong, ; Shen Aiguo,
| | - Shen Aiguo
- Cancer Research Center, Affiliated Tumor Hospital of Nantong University, Nantong, China
- *Correspondence: Chen Xudong, ; Shen Aiguo,
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11
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Anti-Hepatocellular Carcinoma Biomolecules: Molecular Targets Insights. Int J Mol Sci 2021; 22:ijms221910774. [PMID: 34639131 PMCID: PMC8509806 DOI: 10.3390/ijms221910774] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/25/2021] [Accepted: 09/26/2021] [Indexed: 12/15/2022] Open
Abstract
This report explores the available curative molecules directed against hepatocellular carcinoma (HCC). Limited efficiency as well as other drawbacks of existing molecules led to the search for promising potential alternatives. Understanding of the cell signaling mechanisms propelling carcinogenesis and driven by cell proliferation, invasion, and angiogenesis can offer valuable information for the investigation of efficient treatment strategies. The complexity of the mechanisms behind carcinogenesis inspires researchers to explore the ability of various biomolecules to target specific pathways. Natural components occurring mainly in food and medicinal plants, are considered an essential resource for discovering new and promising therapeutic molecules. Novel biomolecules normally have an advantage in terms of biosafety. They are also widely diverse and often possess potent antioxidant, anti-inflammatory, and anti-cancer properties. Based on quantitative structure-activity relationship studies, biomolecules can be used as templates for chemical modifications that improve efficiency, safety, and bioavailability. In this review, we focus on anti-HCC biomolecules that have their molecular targets partially or completely characterized as well as having anti-cancer molecular mechanisms that are fairly described.
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12
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Soofiyani SR, Hosseini K, Soleimanian A, Abkhooei L, Hoseini AM, Tarhriz V, Ghasemnejad T. An Overview on the Role of miR-451 in Lung Cancer: Diagnosis, Therapy, and Prognosis. Microrna 2021; 10:181-190. [PMID: 34514995 DOI: 10.2174/2211536610666210910130828] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/15/2021] [Accepted: 08/03/2021] [Indexed: 11/22/2022]
Abstract
MicroRNAs (miRNAs) are highly conserved non-coding RNAs involved in many physiological processes such as cell proliferation, inhibition, development of apoptosis, differentiation, suppresses tumorigenicity, and regulating cell growth. The description of the alterations of miRNA expression patterns in cancers will be helpful to recognize biomarkers for early detection and possible therapeutic intervention in the treatment of cancers. Recent studies have shown that miR-451 is broadly dysregulated in lung cancer and is a crucial agent in lung tumor progression. This review summarizes recent advances of the potential role of miR-451 in lung cancer diagnosis, prognosis, and treatment and provides an insight into the potential use of miR-451 for the development of advanced therapeutic methods in lung cancer.
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Affiliation(s)
- Saiedeh Razi Soofiyani
- Clinical Research Development Unit of Sina Educational, Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz. Iran
| | - Kamram Hosseini
- Student research committee, Shiraz University of Medical Sciences, Shiraz. Iran
| | - Alireza Soleimanian
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz. Iran
| | - Liela Abkhooei
- Department of Medical Biotechnology, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad. Iran
| | - Akbar Mohammad Hoseini
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine and Tabriz Blood Transfusion Center, Tabriz. Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz. Iran
| | - Tohid Ghasemnejad
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz. Iran
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13
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Kang B, Qiu C, Zhang Y. The Effect of lncRNA SNHG3 Overexpression on Lung Adenocarcinoma by Regulating the Expression of miR-890. JOURNAL OF HEALTHCARE ENGINEERING 2021; 2021:1643788. [PMID: 34306585 PMCID: PMC8285187 DOI: 10.1155/2021/1643788] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/25/2021] [Indexed: 12/17/2022]
Abstract
The lncRNA small nucleolar host gene 3 (SNHG3) was discovered to play an important role in the occurrence and development of lung adenocarcinoma (LUAD). However, the underlying molecular mechanism of SNHG3 in LUAD remains unclear. In the present study, SNHG3 expression levels in LUAD tissues and cell lines were analyzed using reverse transcription-quantitative PCR. The effects of SNHG3 on the proliferation, apoptosis, migration, and invasion of LUAD cells were determined using Cell Counting Kit-8, colony formation, flow cytometry, wound healing, and Transwell chamber assays, respectively. The specific underlying mechanism of SNHG3 in LUAD was investigated using bioinformatics analysis and a dual luciferase reporter assay. The results revealed that SNHG3 expression levels were downregulated in LUAD tissues and cell lines. Functionally, SNHG3 overexpression suppressed the proliferation, migration, and invasion of LUAD cells, while promoting apoptosis. Mechanistically, microRNA- (miR-) 890 was identified as a potential target of SNHG3, and its expression was negatively regulated by SNHG3. Notably, SNHG3 was found to promote LUAD progression by targeting miR-890. In conclusion, the findings of the present study revealed that lncRNA SNHG3 promoted the occurrence and progression of LUAD by regulating miR-890 expression.
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Affiliation(s)
- Baojie Kang
- Department of Respiratory, Weifang Yidu Central Hospital, Weifang City, Shandong, China
| | - Caihong Qiu
- Department of Respiratory, Weifang Yidu Central Hospital, Weifang City, Shandong, China
| | - Ying Zhang
- Department of ICU, Zibo Central Hospital, Zibo City, Shandong, China
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14
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Fan B, Jin X, Ding Q, Cao C, Shi Y, Zhu H, Zhou W. Expression of miR-451a in Prostate Cancer and Its Effect on Prognosis. IRANIAN JOURNAL OF PUBLIC HEALTH 2021; 50:772-779. [PMID: 34183927 PMCID: PMC8219609 DOI: 10.18502/ijph.v50i4.6002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background: To investigate the expression of miR-451a in prostate cancer tissues and its effect on prognosis. Methods: Each of 78 specimens of prostate cancer tissues and corresponding adjacent normal tissues were collected from patients in Changshu Hospital Affiliated to Soochow University, Changshu, China from Apr 2014 to Jun 2015. Real-time quantitative RT-PCR (qRT-PCR) was used to detect the expression of miR-451a in tissues. The relationship between the expression of miR-451a and clinical pathological parameters was analyzed. The median expression of miR-451a in the experimental group was used to distinguish the high and low expressions of miR-451a in the experimental group. Kaplan-Meier was used to analyze the survival of miR-451a high and low expression groups. Results: The expressions of miR-451a in the patient’s tissues and serum were decreased, and the correlation analysis found that they were positively correlated. ROC curve analysis showed that miR-451a had a high clinical value in the diagnosis of prostate cancer and the area under the curve was 0.921. The incidence of stage III+IV lymph node metastasis, Gleason score of >7 points and a serum Prostate-specific antigen (PSA) level of >20 ng/ml in patients of the low expression group increased significantly. The 5-yr survival rate of patients with low expression was significantly lower than that of those with high expression (P=0.005). MiR-451a was an independent factor affecting the prognosis of patients. Conclusion: miR-451a is lowly expressed in prostate cancer, and patients with low expression have a poor prognosis.
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Affiliation(s)
- Bo Fan
- Department of Urology, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu 215500, P.R. China
| | - Xiaohua Jin
- Department of Urology, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu 215500, P.R. China
| | - Qi Ding
- Department of Urology, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu 215500, P.R. China
| | - Cheng Cao
- Department of Urology, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu 215500, P.R. China
| | - Yi Shi
- Department of Urology, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu 215500, P.R. China
| | - Hailiang Zhu
- Department of Urology, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu 215500, P.R. China
| | - Wenjun Zhou
- Department of Urology, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu 215500, P.R. China
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15
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Zhang MF, Fei ZW, Huang L. Micro-RNA-451 Reduces Proliferation of B-CPAP Human Papillary Thyroid Cancer Cells by Downregulating Expression of Activating Transcription Factor 2. Med Sci Monit 2021; 27:e929774. [PMID: 33724979 PMCID: PMC7980498 DOI: 10.12659/msm.929774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background MicroRNAs (miRNAs) are novel biomarkers that are important in tumorigenesis and cancer treatment resistance. miR-451 is expressed in human papillary thyroid carcinoma (PTC) tissues and is associated with tumor progression. This study investigated the molecular mechanism associated with the effects of miR-451 on B-CPAP human PTC cells in vitro. Material/Methods Binding of miRNAs to the 3′ untranslated region (3′UTR) of messenger RNA (mRNA) was determined with a luciferase reporter assay. miRNAs and plasmids were transfected into human PTC B-CPAP cells with Lipofectamine 2000 Transfection Reagent. Cell viability was tested with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. The levels of miRNAs and mRNA were determined with quantitative polymerase chain reaction and protein levels were analyzed with immunoblotting. Results miR-451 bound to wild-type but not mutant 3′-UTR of activating transcription factor 2 (ATF2). MiR-451 mimics inhibited the growth of B-CPAP cells and reduced mRNA and protein levels in ATF2, whereas miR-451 inhibitors promoted the growth of B-CPAP cells and increased mRNA and protein levels in ATF2. Conclusions miR-451 directly bound to the 3′UTR of ATF2, decreased mRNA and protein levels in ATF2, and inhibited growth of B-CPAP cells. Our findings suggest that miR-451 may be a potential therapeutic target for PTC.
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Affiliation(s)
- Mei-Feng Zhang
- Department of General Surgery, Chongming Branch of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China (mainland)
| | - Zhe-Wei Fei
- Department of General Surgery, Chongming Branch of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China (mainland)
| | - Lei Huang
- Department of General Surgery, Chongming Branch of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China (mainland)
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16
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Liu XY, Wang JQ, Ashby CR, Zeng L, Fan YF, Chen ZS. Gold nanoparticles: synthesis, physiochemical properties and therapeutic applications in cancer. Drug Discov Today 2021; 26:1284-1292. [PMID: 33549529 DOI: 10.1016/j.drudis.2021.01.030] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 08/12/2020] [Accepted: 01/29/2021] [Indexed: 02/07/2023]
Abstract
Gold nanoparticles (AuNPs) have been shown to be useful as carriers of various anticancer drugs as well as diagnosis platforms. In this review, we discuss the synthesis and physiochemical properties of AuNPs. We also highlight the photothermal and photodynamic properties of AuNPs and relevant applications in therapeutic studies. Furthermore, we review the applications of AuNPs in cancer treatment as and their underlying anticancer mechanisms in multiple types of cancer.
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Affiliation(s)
- Xin-Yu Liu
- School of Clinical Medicine, Weifang Medical University, Weifang 261053, Shandong, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA
| | - Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA
| | - Leli Zeng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA; Precision Medicine Center, Research Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong 518107, China
| | - Ying-Fang Fan
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA; Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA.
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17
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Suppression of HELLS by miR-451a represses mTOR pathway to hinder aggressiveness of SCLC. Genes Genomics 2021; 43:105-114. [PMID: 33460027 DOI: 10.1007/s13258-020-01028-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 12/11/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Uncovering molecular pathogenesis and mechanisms of small cell lung cancer (SCLC) will contribute to SCLC therapy. Multiple studies demonstrated that miR-451a acts as an anti-tumor miRNA in non-small cell lung cancer. However, the mechanism of miR-451a in SCLC was ambiguous. OBJECTIVE We aimed to explore the function of miR-451a in SCLC and decipher the underlying mechanisms. METHODS TargetScan and dual-luciferase reporter assays were used to analyze the target genes of miR-451a. Cell counting kit-8 and colony formation assays were performed to assess the roles of miR-451a on cell growth. Gene set enrichment analysis (GSEA) was utilized to enrich biological pathways. Western blot was used to measure protein expression. RESULTS MiR-451a expression was reduced dramatically in SCLC tissues and cell lines (NCI-H1688 and NCI-H446). Helicase, Lymphoid Specific (HELLS) was proved to be a target gene of miR-451a. In addition, cell proliferation assays in SCLC cells transfected with miR-451a mimic and/or HELLS revealed that miR-451a inhibited cell proliferation via targeting HELLS. Moreover, the roles of miR-451a/HELLS in expression of key proteins in mTOR and apoptosis signaling pathways suggested that miR-451a inactivated mTOR and activated apoptosis signaling pathway via directly silencing HELLS. CONCLUSIONS Our study indicated that miR-451a hinders SCLC cell proliferation in vitro through regulating mTOR and apoptosis signaling pathways via silencing HELLS, suggesting that miR-451a could be a promising tumor suppressor in SCLC. And there is a potential for miR-451a to be a drug target and biomarker for SCLC.
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18
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Xu Y, Lai Y, Cao L, Li Y, Chen G, Chen L, Weng H, Chen T, Wang L, Ye Y. Human umbilical cord mesenchymal stem cells-derived exosomal microRNA-451a represses epithelial-mesenchymal transition of hepatocellular carcinoma cells by inhibiting ADAM10. RNA Biol 2020; 18:1408-1423. [PMID: 33206588 DOI: 10.1080/15476286.2020.1851540] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) expressing microRNAs (miRNAs) have been highlighted in human cancers. However, the detailed molecular mechanism of hucMSCs-derived exosomal miR-451a on hepatocellular carcinoma (HCC) remains further investigation. Our study aims to explore the impact of exosomal miR-451a on the progression of HCC. Expression of miR-451a and a disintegrin and metalloprotease 10 (ADAM10) in HCC tissues and adjacent normal tissues were determined. The exosomes were extracted from hucMSCs and co-cultured with Hep3B and SMMC-7721 cell lines. After the treatment of relative exosomes or exosome inhibitor GW4869 in Hep3B and SMMC-7721 cells, the paclitaxel resistance and malignant phenotypes of HCC cells were measured. Moreover, the effect of hucMSCs-derived exosomes on the expression of miR-451a and ADAM10 in HCC cells was assessed. The targeting relationship between miR-451a and ADAM10 was verified to detect the impact of ADAM10-wild type and ADAM10-mutant type (MUT) on HCC cell processes. Low expression of miR-451a and high expression of ADAM10 indicated a poor prognosis of HCC patients. MiR-451a was up-regulated while ADAM10 was down-regulated in HCC cells after co-culture with HucMSC-derived exosomes. The exosomes elevated miR-451a and inhibited ADAM10 to suppress the paclitaxel resistance, cell cycle transition, proliferation, migration and invasion, and promote apoptosis of HCC cells. ADAM10 was verified to be a target gene of miR-451a. ADAM10-MUT promoted HCC process independent of miR-451a mimic. HucMSC-derived exosomal miR-451a could restrict the epithelial-mesenchymal transition of HCC cells by targeting ADAM10, which might provide new targets for HCC treatment.
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Affiliation(s)
- Yunxiuxiu Xu
- Department of Hepato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yu Lai
- Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Linhui Cao
- Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Traditional Chinese Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanshan Li
- Department of Blood Transfusion, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Guangcheng Chen
- Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liang Chen
- Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Intensive Care Unit, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hanqin Weng
- Department of Hepato-Billiary Surgery, Dongguan people's Hospital, Southern Medical University, Guangdong, China
| | - Tao Chen
- Department of Hepato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lingyun Wang
- Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yibiao Ye
- Department of Hepato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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19
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Zhong L, Xu Z, Jin X, He Y, Zhang J, Jiang T, Chen J. miR-451a suppression of IL-6R can inhibit proliferation and increase apoptosis through the JAK2/STAT3 pathway in multiple myeloma. Oncol Lett 2020; 20:339. [PMID: 33123250 PMCID: PMC7583731 DOI: 10.3892/ol.2020.12202] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 08/25/2020] [Indexed: 01/02/2023] Open
Abstract
The IL-6R/JAK2/STAT3 pathway mediated by interleukin-6 (IL-6) plays an important role in the occurrence and development of multiple myeloma (MM), which is associated with decreased microRNA-451a. However, the biological function of microRNA-451a in MM remains unclear. The bone marrow (BM) of patients with MM was sampled, and the plasma cells were enriched. BM miR-451a, IL-6 and IL-6R levels and Ki-67 expression intensity were evaluated using reverse transcription-quantitative PCR, ELISA and flow cytometry, respectively. U266 cell proliferation, viability and apoptosis were measured using BrdU, CCK-8 and Annexin V/propidium iodide assays, respectively. Total and phospo-(p-)JAK2 and p-STAT3 levels were measured by western blotting. Dual-luciferase reporter assays were performed to validate the predicted target binding sites. miR-451a expression was low in patients with MM and was associated with the Revised International Staging System (R-ISS) stage. IL-6 concentrations were significantly higher in patients with MM than in normal controls and were inversely associated with miR-451a levels (r=-0.96, P<0.0001). IL-6R levels were positively correlated with the R-ISS stage. miR-451a was downregulated, and IL-6R was upregulated in myeloma cell lines. Treatment with an miR-451a mimic inhibited viability and induced apoptosis in U266 cells. p-JAK2 and p-STAT3 levels were significantly lower in mimic-treated U266 cells than in control cells. Thus, miR-451a was shown to regulate myeloma cell proliferation and apoptosis via the IL-6R/JAK2/STAT3 pathway and may be used to predict patient prognosis.
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Affiliation(s)
- Ling Zhong
- Department of Clinical Laboratory, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China.,Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan 610041, P.R. China
| | - Zhuyu Xu
- Department of Pharmacy, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Xin Jin
- Department of Clinical Laboratory, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Yuan He
- Department of Clinical Laboratory, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Jianbo Zhang
- Department of Clinical Laboratory, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Tao Jiang
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Jiao Chen
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
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20
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Zhong L, Jin X, Xu Z, Zeng M, Chen D, He Y, Zhang J, Jiang T, Chen J. Circulating miR-451a levels as a potential biomarker to predict the prognosis of patients with multiple myeloma. Oncol Lett 2020; 20:263. [PMID: 32989397 PMCID: PMC7517596 DOI: 10.3892/ol.2020.12126] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 07/22/2020] [Indexed: 12/26/2022] Open
Abstract
The natural course of multiple myeloma (MM) varies greatly between patients. The Revised MM International Staging System (R-ISS) identifies high-risk patients, but it is unsuitable for assessing minimal residual disease (MRD). Furthermore, the focal location of myeloma cells and clonal evolution often produce false negative results in flow cytometry. Extracellular microRNA (miRNA/miR) expression levels are stable in bodily fluids, and are retrievable and measurable from fresh or archived serum or plasma samples. Therefore, the present study aimed to investigate the clinical utility of circulating miRNA levels in patients with MM, particularly miR-451a, which is commonly downregulated in MM, and whether it could predict the prognosis and relapse of patients with MM. In total, 66 patients with MM, stratified using the R-ISS criteria, were recruited, while 10 healthy subjects (transplantation donors) were enrolled as controls. Reverse transcription-quantitative PCR was used to evaluate miR-451a expression in bone marrow (BM) and in the circulation. IL-6 levels were measured using ELISA, while western blotting was conducted to analyze the protein expression levels of the IL-6 receptor (IL-6R). During follow-up, MRD was assessed via multiparameter flow cytometry (MFC). miR-451a was identified to target IL-6R using a dual-luciferase reporter assay. Circulating miR-451a levels were low in patients with MM, and was found to be 0.39 times that of the control group (U=4.00; P<0.001). Among the 66 patients with MM, the median level of miR-451a was 0.73 and 0.41 times that of the control group in R-ISS stage I MM (15 patients) and R-ISS stage II stage (17 patients), respectively; patients with R-ISS stage III MM (34 patients) had the lowest level, at 0.24 times the value of the control group. Circulating miR-451a levels had a strong positive correlation with miR-451a levels in BM, but negatively correlated with IL-6 and IL-6R levels. After two courses of consolidation chemotherapy, 19 patients achieved complete remission, 10 of whom presented steady circulating miR-451a levels during follow-up; the other nine patients had an abrupt decrease in circulating miR-451a levels. The turning points in the trend appeared 4–8 weeks before positive results were obtained via MFC, and 4–16 weeks before clinical relapse. Moreover, miR-451a overexpression notably downregulated the expression of the IL-6R mRNA and protein. Collectively, circulating miR-451a levels potentially represent a novel biomarker to monitor MRD and predict relapse.
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Affiliation(s)
- Ling Zhong
- Department of Clinical and Experimental Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China.,Department of Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan 610041, P.R. China
| | - Xin Jin
- Department of Clinical and Experimental Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Zhuyu Xu
- Department of Pharmacy, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Minghui Zeng
- Department of Pharmacy, Qionglai Municipal Medical Center Hospital of Sichuan Province, Chengdu, Sichuan 611530, P.R. China
| | - Dongmei Chen
- Department of Clinical and Experimental Medicine, Southwest Medical University Clinical Medical School, Luzhou, Sichuan 646000, P.R. China
| | - Yuan He
- Department of Clinical and Experimental Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Jianbo Zhang
- Department of Clinical and Experimental Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Tao Jiang
- Department of Hematology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Jiao Chen
- Department of Hematology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
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Ríos-López DG, Aranda-López Y, Sosa-Garrocho M, Macías-Silva M. La plasticidad del hepatocito y su relevancia en la fisiología y la patología hepática. TIP REVISTA ESPECIALIZADA EN CIENCIAS QUÍMICO-BIOLÓGICAS 2020. [DOI: 10.22201/fesz.23958723e.2020.0.225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
El hígado es uno de los principales órganos encargados de mantener la homeostasis en vertebrados, además de poseer una gran capacidad regenerativa. El hígado está constituido por diversos tipos celulares que de forma coordinada contribuyen para que el órgano funcione eficientemente. Los hepatocitos representan el tipo celular principal de este órgano y llevan a cabo la mayoría de sus actividades; además, constituyen una población heterogénea de células epiteliales con funciones especializadas en el metabolismo. El fenotipo de los hepatocitos está controlado por diferentes vías de señalización, como la vía del TGFβ/Smads, la ruta Hippo/YAP-TAZ y la vía Wnt/β-catenina, entre otras. Los hepatocitos son células que se encuentran normalmente en un estado quiescente, aunque cuentan con una plasticidad intrínseca que se manifiesta en respuesta a diversos daños en el hígado; así, estas células reactivan su capacidad proliferativa o cambian su fenotipo a través de procesos celulares como la transdiferenciación o la transformación, para contribuir a mantener la homeostasis del órgano en condiciones saludables o desarrollar diversas patologías.
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Qin X, Song Y. Bioinformatics Analysis Identifies the Estrogen Receptor 1 (ESR1) Gene and hsa-miR-26a-5p as Potential Prognostic Biomarkers in Patients with Intrahepatic Cholangiocarcinoma. Med Sci Monit 2020; 26:e921815. [PMID: 32435051 PMCID: PMC7257878 DOI: 10.12659/msm.921815] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Intrahepatic cholangiocarcinoma arises from the epithelial cells of the bile ducts and is associated with poor prognosis. This study aimed to use bioinformatics analysis to identify molecular biomarkers of intrahepatic cholangiocarcinoma and their potential mechanisms. Material/Methods MicroRNA (miRNA) and mRNA microarrays from GSE53870 and GSE32879 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DEMs) associated with prognosis were identified using limma software and Kaplan-Meier survival analysis. Predictive target genes of the DEMs were identified using miRWalk, miRTarBase, miRDB, and TargetScan databases of miRNA-binding sites and targets. Target genes underwent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Hub genes were analyzed by constructing the protein-protein interaction (PPI) network using Cytoscape. DEMs validated the hub genes, followed by construction of the miRNA-gene regulatory network. Results Twenty-five DEMs were identified. Fifteen DEMs were upregulated, and ten were down-regulated. Kaplan-Meier survival analysis identified seven upregulated DEMs and nine down-regulated DEMs that were associated with the overall survival (OS), and 130 target genes were selected. GO analysis showed that target genes were mainly enriched for metabolism and development processes. KEGG analysis showed that target genes were mainly enriched for cancer processes and some signaling pathways. Fourteen hub genes identified from the PPI network were associated with the regulation of cell proliferation. The overlap between hub genes and DEMs identified the estrogen receptor 1 (ESR1) gene and hsa-miR-26a-5p. Conclusions Bioinformatics analysis identified ESR1 and hsa-miR-26a-5p as potential prognostic biomarkers for intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Xianzheng Qin
- Queen Mary School of Nanchang University, Nanchang, Jiangxi, China (mainland)
| | - Yuning Song
- Queen Mary School of Nanchang University, Nanchang, Jiangxi, China (mainland)
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Wang T, Zhou Q, Shang Y. MiRNA-451a inhibits airway remodeling by targeting Cadherin 11 in an allergic asthma model of neonatal mice. Int Immunopharmacol 2020; 83:106440. [PMID: 32234673 DOI: 10.1016/j.intimp.2020.106440] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 02/29/2020] [Accepted: 03/21/2020] [Indexed: 12/29/2022]
Abstract
Airway remodeling happens in childhood asthma, in parallel with, but not necessarily subsequent to, airway inflammation. The differentiation of airway epithelial cells into myofibroblasts via epithelial-mesenchymal-transition (EMT) is one of the mechanisms underlying airway remodeling. This study aimed at identifying novel molecules involved in pediatric asthma-associated airway remodeling. Asthma model was established by challenging C57BL/6 mouse pups with ovalbumin (OVA). We found that the expression of Cadherin 11 (CDH11), a type II cadherin, was increased by OVA treatments in the airway epithelium. Our earlier microarray data suggested miRNA-451a-5p (miRNA-451a) as a potential regulator of CDH11. In contrast to CDH11, miRNA-451a expression decreased in the asthmatic lung. MiRNA-451a was then packaged into a lentivirus vector and systematically given to the asthmatic pups. Our data indicated that OVA-induced infiltration of inflammatory cells, including eosnophils, neutrophils, macrophages and lymphocytes, was reduced by miRNA-451a over-expression. EMT was initiated in asthmatic mice as demonstrated by increased alpha-smooth muscle actin (α-SMA) positive cells present in airway epithelium, which was inhibited by miRNA-451a. CDH11 elevation in vivo was also inhibited by miRNA-451a. Dual-Luciferase analysis further showed CDH11 as a novel valid target of miRNA-451a. Additionally, in vitro, EMT was triggered in human 16HBE airway epithelial cells by pro-fibrotic transforming growth factor β (TGF-β). Corresponding to the anti-EMT effects observed in vivo, miRNA-451a also inhibited TGF-β-induced collagen deposition in cultured airway epithelial cells by targeting in CDH11. In summary, our study demonstrates that the deregulated miRNA-451a-CDH11 axis contributes to airway remodeling in childhood asthma.
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Affiliation(s)
- Tianyue Wang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Qianlan Zhou
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Yunxiao Shang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
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Giannelli G, Santoro A, Kelley RK, Gane E, Paradis V, Cleverly A, Smith C, Estrem ST, Man M, Wang S, Lahn MM, Raymond E, Benhadji KA, Faivre S. Biomarkers and overall survival in patients with advanced hepatocellular carcinoma treated with TGF-βRI inhibitor galunisertib. PLoS One 2020; 15:e0222259. [PMID: 32210440 PMCID: PMC7094874 DOI: 10.1371/journal.pone.0222259] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 08/25/2019] [Indexed: 12/15/2022] Open
Abstract
Background Transforming growth factor beta (TGF-β) signalling is involved in the development of hepatocellular carcinoma (HCC). We followed changes in biomarkers during treatment of patients with HCC with the TGF-βRI/ALK5 inhibitor galunisertib. Methods This phase 2 study (NCT01246986) enrolled second-line patients with advanced HCC into one of two cohorts of baseline serum alpha-fetoprotein (AFP): Part A (AFP ≥1.5x ULN) or Part B (AFP <1.5x ULN). Baseline and postbaseline levels of AFP, TGF-β1, E-cadherin, selected miRNAs, and other plasma proteins were monitored. Results The study enrolled 149 patients (Part A, 109; Part B, 40). Median OS was 7.3 months in Part A and 16.8 months in Part B. Baseline AFP, TGF-β1, E-cadherin, and an additional 16 plasma proteins (such as M-CSF, IL-6, ErbB3, ANG-2, neuropilin-1, MIP-3 alpha, KIM-1, uPA, IL-8, TIMP-1, ICAM-1, Apo A-1, CA-125, osteopontin, tetranectin, and IGFBP-1) were found to correlate with OS. In addition, a range of miRs were found to be associated with OS. In AFP responders (21% of patients in Part A with decrease of >20% from baseline) versus non-responders, median OS was 21.5 months versus 6.8 months (p = 0.0015). In TGF-β1 responders (51% of all patients) versus non-responders, median OS was 11.2 months versus 5.3 months (p = 0.0036). Conclusions Consistent with previous findings, both baseline levels and changes from baseline of circulating AFP and TGF-β1 function as prognostic indicators of survival. Future trials are needed to confirm and extend these results.
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Affiliation(s)
- Gianluigi Giannelli
- National Institute of Gastroenterology, “s. De Bellis” Research Hospital, Castellana Grotte, Bari, Italy
- * E-mail:
| | | | - Robin K. Kelley
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, United States of America
| | - Ed Gane
- Auckland City Hospital, Auckland, New Zealand
| | | | - Ann Cleverly
- Eli Lilly and Company, Windlesham, Surrey, United Kingdom
| | - Claire Smith
- Eli Lilly and Company, Windlesham, Surrey, United Kingdom
| | - Shawn T. Estrem
- Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Michael Man
- Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Shuaicheng Wang
- BioStat Solutions, Inc., Frederick, Maryland, United States of America
| | - Michael M. Lahn
- Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Eric Raymond
- Paris Saint-Joseph Hospital Center, Paris, France
| | - Karim A. Benhadji
- Eli Lilly and Company, Indianapolis, Indiana, United States of America
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Lin Q, Zhou CR, Bai MJ, Zhu D, Chen JW, Wang HF, Li MA, Wu C, Li ZR, Huang MS. Exosome-mediated miRNA delivery promotes liver cancer EMT and metastasis. Am J Transl Res 2020; 12:1080-1095. [PMID: 32269736 PMCID: PMC7137059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 01/02/2020] [Indexed: 06/11/2023]
Abstract
The deregulation of exosomal microRNAs (miRNAs) plays an important role in the progression of hepatocarcinogenesis. In this study, we highlight exosomes as mediators involved in modulating miRNA profiles in liver cancer cells after induction of the epithelial-mesenchymal transition (EMT) and metastasis. Initially, we induced EMT in a hepatocellular carcinoma cell (HCC) line (Hep3B) by stimulation with transforming growth factor-β (TGF-β) and confirmed by western blot detection of EMT markers such as vimentin and E-cadherin. Exosomes were then isolated from the cells and identified by nanoparticle tracking analysis (NTA). The isolated exosomal particles from unstimulated Hep3B cells (Hep3B exo) or TGF-β-stimulated EMT Hep3B cells (EMT-Hep3B exo) contained higher levels of exosome marker proteins, CD63 and TSG101. After incubation with EMT-Hep3B exo, Hep3B cell proliferation increased. EMT-Hep3B exo promoted the migration and invasion of Hep3B and 7721 cells. High-throughput sequencing of miRNAs and mRNA within the exosomes showed 119 upregulated and 186 downregulated miRNAs and 156 upregulated and 166 downregulated mRNA sequences in the EMT-Hep3B exo compared with the control Hep3B exo. The most differentially expressed miRNAs and target mRNA sequences were validated by RT-qPCR. Based on the known miRNA targets for specific mRNA sequences, we hypothesized that GADD45A was regulated by miR-374a-5p. Inhibition of miR-374a-5p in Hep3B cells resulted in exosomes that inhibited the proliferation, migration, and invasion of HCC cells. These results enhance our understanding of metastatic progression of liver cancer and provide a foundation for the future development of potential biomarkers for diagnosis and prognosis of hepatic cancer.
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Affiliation(s)
- Qu Lin
- Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
| | - Chu-Ren Zhou
- Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
| | - Ming-Jun Bai
- Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
| | - Duo Zhu
- Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
| | - Jun-Wei Chen
- Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
| | - Hao-Fan Wang
- Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
| | - Ming-An Li
- Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
| | - Chun Wu
- Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
| | - Zheng-Ran Li
- Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
| | - Ming-Sheng Huang
- Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510630, China
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Omran NM, El-Sherbini SM, Hegazy O, Elshaarawy AA, Talaat RM. Crosstalk between miR-215 and epithelial-mesenchymal transition specific markers (E-cadherin and N-cadherin) in different stages of chronic HCV Infection. J Med Virol 2019; 92:1231-1238. [PMID: 31769519 DOI: 10.1002/jmv.25637] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022]
Abstract
The main causes of death among patients with hepatocellular carcinoma (HCC) are a recurrence, metastasis, and deterioration of primary tumors by the epithelial-to-mesenchymal transition (EMT) which is controlled by several molecules including E-cadherin and N-cadherin. Microribonucleic acids (miRNAs) have been identified to play a regulatory role in EMT. miR-215 is important in repressing migration/invasion of cancer cells. In this study, we aimed to evaluate the crosstalk between miR-215 and EMT specific markers (E-cadherin and N-cadherin) with a spotlight on its role in the EMT process in hepatitis C virus (HCV)-infected patients. One hundred forty-five patients were studied, 75 had HCV-induced cirrhosis classified into child A, B, and C and 25 had HCC. In parallel, 45 healthy volunteers considered as controls. Serum levels of E- and N-cadherin were measured using enzyme-linked immunosorbent assay and miR-215 expression measured by a quantitative reverse transcription-polymerase chain reaction. Insignificant change in serum levels of E-cadherin and N-cadherin in HCV-infected patients compared with normal controls was observed with a slight increase in E-cadherin and N-cadherin in the child B group. HCC patients had the lowest amount of E-cadherin and N-cadherin compared with cirrhotic and normal subjects. A maximum reduction in miR-215 was observed in HCC patients compared with cirrhotic and control ones. A positive correlation (r = .202; P < .05) was observed between miR-215 and E-cadherin. Our data stressed on the potential role of miR-215 as an important mediator in HCC progression. miRNAs participating in EMT needs further studies to provide insight into the metastasis of HCC.
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Affiliation(s)
- Nermeen M Omran
- Department of Clinical Pathology, National Liver Institute, Menofia University, Al Minufya, Egypt
| | - Sherif M El-Sherbini
- Department of Molecular Biology, Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Sadat City, Egypt
| | - Osama Hegazy
- Department of Hepatopancreatobiliary Surgery and Liver Transplantation, National Liver Institute, Menofia University, Al Minufya, Egypt
| | - Ahmed A Elshaarawy
- Department of Clinical Pathology, National Liver Institute, Menofia University, Al Minufya, Egypt
| | - Roba M Talaat
- Department of Molecular Biology, Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Sadat City, Egypt
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Bai H, Wu S. miR-451: A Novel Biomarker and Potential Therapeutic Target for Cancer. Onco Targets Ther 2019; 12:11069-11082. [PMID: 31908476 PMCID: PMC6924581 DOI: 10.2147/ott.s230963] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 11/28/2019] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded small RNAs involved in a variety of cellular processes, including ontogeny, cell proliferation, differentiation, and apoptosis. They can also function as oncogenes or tumor suppressor genes. Recent studies have revealed that miRNA-451 (miR-451) is involved in the regulation of various human physiological and pathological processes. Furthermore, it has been shown that miR-451 not only directly affects the biological functions of tumor cells but also indirectly affects tumor cell invasion and metastasis upon secretion into the tumor microenvironment via exosomes. Thus, miR-451 also influences the progression of tumorigenesis and drug resistance. This review summarizes the expression of miR-451 in various cancer types and the relationship between miR-451 and the diagnosis, treatment, and drug resistance of solid tumors. In addition, we address possible mechanisms of action of miR-451 and its potential application as a biomarker in the diagnosis and treatment of human cancers.
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Affiliation(s)
- Hua Bai
- Department of Gynecology and Obstetrics, Shanxi Dayi Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Suhui Wu
- Department of Gynecology and Obstetrics, Shanxi Dayi Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
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MicroRNAs in Animal Models of HCC. Cancers (Basel) 2019; 11:cancers11121906. [PMID: 31805631 PMCID: PMC6966618 DOI: 10.3390/cancers11121906] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/27/2019] [Accepted: 11/28/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.
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Kong W, Feng L, Yang M, Chen Q, Wang H, Wang X, Hou J. Prognostic value of microRNA-451 in various cancers: A meta-analysis. Pathol Res Pract 2019; 215:152726. [PMID: 31708373 DOI: 10.1016/j.prp.2019.152726] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/13/2019] [Accepted: 10/26/2019] [Indexed: 01/11/2023]
Abstract
BACKGROUND Increasing evidence shows microRNA-451 plays a crucial role in various tumors, but there is inconsistency. The aim of this study was to explore the prognostic role of miR-451 in various tumors. METHODS Online PubMed, EMBASE, Web of Science, and the Cochrane library database were searched through February 2019. Hazard ratios (HRs) were extracted and used to describe the association between expression of microRNA-451 and survival outcome, and the correlation between microRNA-451 and clinicopathologic features were described by pooled odds ratios (ORs). RESULTS Sixteen retrospective studies containing 2122 patients were incorporated in this meta-analysis. High expression of miR-451 was considered statistically associated with prolonged overall survival (OS) (HR = 0.62, 95% CI 0.49-0.80, p < 0.001) as well as RFS/DFS (HR = 0.55, 95% CI 0.42-0.71, p < 0.001) compared with low expression of miR-451. Besides, the pooled ORs revealed significant association between high expression of miR-451 with lymph node invasion (yes vs. no) (OR = 0.64, 95% CI 0.46-0.90, P = 0.01), tumor diameter (big vs. small) (OR = 0.77, 95% CI 0.60-0.97, P = 0.028) and tumor stage (III + IV vs. I + II) (OR = 0.62, 95% CI 0.42-0.93, P = 0.019). CONCLUSION MicroRNA-451 may serve as a promising clinical prognostic biomarker in various carcinomas.
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Affiliation(s)
- Weihao Kong
- Department of Emergency Surgery, Department of Emergency Medicine, The First affiliated hospital of Anhui Medical University, Heifei, China
| | - Linfei Feng
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Mingwei Yang
- Department of Radiation Oncology, The First affiliated hospital of Anhui Medical University, Heifei, China
| | - Qihang Chen
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hengyi Wang
- Department of Emergency Surgery, Department of Emergency Medicine, The First affiliated hospital of Anhui Medical University, Heifei, China.
| | - Xingyu Wang
- Department of Emergency Surgery, Department of Emergency Medicine, The First affiliated hospital of Anhui Medical University, Heifei, China.
| | - Jun Hou
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
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Fan X, Jin S, Li Y, Khadaroo PA, Dai Y, He L, Zhou D, Lin H. Genetic And Epigenetic Regulation Of E-Cadherin Signaling In Human Hepatocellular Carcinoma. Cancer Manag Res 2019; 11:8947-8963. [PMID: 31802937 PMCID: PMC6801489 DOI: 10.2147/cmar.s225606] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 09/27/2019] [Indexed: 12/24/2022] Open
Abstract
E-cadherin is well known as a growth and invasion suppressor and belongs to the large cadherin family. Loss of E-cadherin is widely known as the hallmark of epithelial-to-mesenchymal transition (EMT) with the involvement of transcription factors such as Snail, Slug, Twist and Zeb1/2. Tumor cells undergoing EMT could migrate to distant sites and become metastases. Recently, numerous studies have revealed how the expression of E-cadherin is regulated by different kinds of genetic and epigenetic alteration, which are implicated in several crucial transcription factors and pathways. E-cadherin signaling plays an important role in hepatocellular carcinoma (HCC) initiation and progression considering the highly mutated frequency of CTNNB1 (27%). Combining the data from The Cancer Genome Atlas (TCGA) database and previous studies, we have summarized the roles of gene mutations, chromosome instability, DNA methylation, histone modifications and non-coding RNA in E-cadherin in HCC. In this review, we discuss the current understanding of the relationship between these modifications and HCC. Perspectives on E-cadherin-related research in HCC are provided.
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Affiliation(s)
- Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Shengxi Jin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
- School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Parikshit Asutosh Khadaroo
- School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Yili Dai
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
- School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Lifeng He
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Daizhan Zhou
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
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Khordadmehr M, Jigari-Asl F, Ezzati H, Shahbazi R, Sadreddini S, Safaei S, Baradaran B. A comprehensive review on miR-451: A promising cancer biomarker with therapeutic potential. J Cell Physiol 2019; 234:21716-21731. [PMID: 31140618 DOI: 10.1002/jcp.28888] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 05/07/2019] [Accepted: 05/09/2019] [Indexed: 12/16/2022]
Abstract
MicroRNAs (miRNAs) are proposed as a family of short noncoding molecules able to manage and control the expression of the gene targets at the posttranscriptional level. They contribute in several fundamental physiological mechanisms as well as a verity of human and animal diseases such as cancer progression. Among these tiny RNAs, miR-451 placed on chromosome 17 at 17q11.2 presents an essential role in many biological processes in health condition and also in pathogenesis of different diseases. Besides, it has been recently considered as a valuable biomarker for cancer detection, prognosis and treatment. Therefore, this review will provide the critical functions of miR-451 on biological mechanisms including cell cycle and proliferation, cell survival and apoptosis, differentiation and development as well as disease initiation and progression such as tumor formation, migration, invasion, and metastasis.
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Affiliation(s)
- Monireh Khordadmehr
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Farinaz Jigari-Asl
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Hamed Ezzati
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Roya Shahbazi
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Sanam Sadreddini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Mamoori A, Wahab R, Vider J, Gopalan V, Lam AKY. The tumour suppressor effects and regulation of cancer stem cells by macrophage migration inhibitory factor targeted miR-451 in colon cancer. Gene 2019; 697:165-174. [PMID: 30802541 DOI: 10.1016/j.gene.2019.02.046] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 01/31/2019] [Accepted: 02/04/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND This study aimed to investigate the impact of miR-451 on the biological behaviours of colon cancer cells along with its targets interactions. METHOD The levels of miR-451 were tested in colon cancer cell lines (SW480 and SW48). Multiple functional and immunological assays were performed to analyse miR-451 induced growth changes in-vitro and downstream effects on target proteins. RESULTS Overexpression of miR-451 in colon cancer cells led to reduced cell proliferation, increased apoptosis and decrease accumulation of the cells at the G0/G1 phase of the cell cycle. In addition, a significant increase in the number of the cells was noted in the G2-M phase of cell cycle. Moreover, miR-451 reduced the expression of Oct-4, Sox-2 and Snail indicating its role in stem cell and epithelial-mesenchymal transition (EMT) regulation. An inverse correlation between miR-451 and macrophage migration inhibitory protein (MIF) protein expression occurred in colon cancer cells. Furthermore, restoration the level of miR-451 in colon cancer cells inhibits tumour spheres formation. CONCLUSION miR-451 has tumour suppressor effects in vitro, which can inhibit the cancer-related signalling pathways in colon cancer.
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Affiliation(s)
- Afraa Mamoori
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia; Department of Pathology and Forensic Medicine, College of Medicine, University of Babylon, Iraq
| | - Riajul Wahab
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia
| | - Jelena Vider
- School of Medical Science, Griffith University, Gold Coast, Gold Coast, Queensland, Australia
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia; School of Medical Science, Griffith University, Gold Coast, Gold Coast, Queensland, Australia.
| | - Alfred King-Yin Lam
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.
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MicroRNA-451 Inhibits Migration of Glioblastoma while Making It More Susceptible to Conventional Therapy. Noncoding RNA 2019; 5:ncrna5010025. [PMID: 30875963 PMCID: PMC6468936 DOI: 10.3390/ncrna5010025] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/08/2019] [Accepted: 03/11/2019] [Indexed: 12/18/2022] Open
Abstract
Malignant glioblastoma (GBM, glioma) is the most common and aggressive primary adult brain tumor. The prognosis of GBM patients remains poor, despite surgery, radiation and chemotherapy. The major obstacles for successful remedy are invasiveness and therapy resistance of GBM cells. Invasive glioma cells leave primary tumor core and infiltrate surrounding normal brain leading to inevitable recurrence, even after surgical resection, radiation and chemotherapy. Therapy resistance allowing for selection of more aggressive and resistant sub-populations including GBM stem-like cells (GSCs) upon treatment is another serious impediment to successful treatment. Through their regulation of multiple genes, microRNAs can orchestrate complex programs of gene expression and act as master regulators of cellular processes. MicroRNA-based therapeutics could thus impact broad cellular programs, leading to inhibition of invasion and sensitization to radio/chemotherapy. Our data show that miR-451 attenuates glioma cell migration in vitro and invasion in vivo. In addition, we have found that miR-451 sensitizes glioma cells to conventional chemo- and radio-therapy. Our data also show that miR-451 is regulated in vivo by AMPK pathway and that AMPK/miR-451 loop has the ability to switch between proliferative and migratory pattern of glioma cells behavior. We therefore postulate that AMPK/miR-451 negative reciprocal feedback loop allows GBM cells/GSCs to adapt to tumor “ecosystem” by metabolic and behavioral flexibility, and that disruption of such a loop reduces invasiveness and diminishes therapy resistance.
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Shao Y, Dong LJ, Takahashi Y, Chen J, Liu X, Chen Q, Ma JX, Li XR. miRNA-451a regulates RPE function through promoting mitochondrial function in proliferative diabetic retinopathy. Am J Physiol Endocrinol Metab 2019; 316:E443-E452. [PMID: 30576241 PMCID: PMC6459296 DOI: 10.1152/ajpendo.00360.2018] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The purpose of this study was to explore the role of microRNA-451a (miR-451a) in diabetic retinopathy through activating transcription factor 2 (ATF2). The epiretinal membrane samples from patients with proliferative diabetic retinopathy (PDR) were immunolabeled with an antibody for Ki-67 to identify the proliferative cells. The expression of miR-451a was measured by qRT-PCR in the retina of Akita mice and in RPE cells under diabetic conditions. The potential downstream targets of miR-451a were predicted by bioinformatics and confirmed by dual luciferase assay, qRT-PCR, and Western blotting. Mitochondrial function, cell proliferation, and migration assays were used to detect the functional change after transfection of miR-451a mimic and inhibitor. Proliferative RPE cells were identified in the epiretinal membrane from PDR patients. The expression of miR-451a was downregulated both in the retina of Akita mice and 4-hydroxynonenal (4-HNE)-treated RPE cells. Bioinformatic analysis and luciferase assay identified ATF2 as a potential target of miR-451a. miR-451a inhibited proliferation and migration of RPE cells. The mitochondrial function was enhanced by miR-451a mimic, but suppressed by miR-451a inhibitor. In diabetic conditions, miR-451a showed a protective effect on mitochondrial function. The results of qRT-PCR and Western blotting revealed that overexpression of miR-451a downregulated the expression of ATF2 and its downstream target genes CyclinA1, CyclinD1, and MMP2. In conclusion, miR-451a/ATF2 plays a vital role in the regulation of proliferation and migration in RPE cells through regulation of mitochondrial function, which may provide new perspectives for developing effective therapies for PDR.
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Affiliation(s)
- Yan Shao
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology , Tianjin , China
- Department of Physiology, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma
| | - Li-Jie Dong
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology , Tianjin , China
| | - Yusuke Takahashi
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma
- Department of Medicine, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma
| | - Jianglei Chen
- Department of Physiology, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma
| | - Xun Liu
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology , Tianjin , China
| | - Qian Chen
- Department of Physiology, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma
- Eye Institute of Xiamen University & Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen University , Xiamen, Fujian , China
| | - Jian-Xing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma
| | - Xiao-Rong Li
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology , Tianjin , China
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Xu K, Han B, Bai Y, Ma XY, Ji ZN, Xiong Y, Miao SK, Zhang YY, Zhou LM. MiR-451a suppressing BAP31 can inhibit proliferation and increase apoptosis through inducing ER stress in colorectal cancer. Cell Death Dis 2019; 10:152. [PMID: 30770794 PMCID: PMC6377610 DOI: 10.1038/s41419-019-1403-x] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 12/23/2018] [Accepted: 01/18/2019] [Indexed: 02/05/2023]
Abstract
The global morbidity and mortality of colorectal cancer (CRC) are ranked the third among gastrointestinal tumors in the world. MiR-451a is associated with several types of cancer, including CRC. However, the roles and mechanisms of miR-451a in CRC have not been elucidated. BAP31 is a predicted target gene of miR-451a in our suppression subtractive hybridization library. Its relationship with miR-451a and function in CRC are unclear. We hypothesized that miR-451a could induce apoptosis through suppressing BAP31 in CRC. Immunohistochemistry and real-time PCR were used to measure BAP31 expressions in CRC tissues and pericarcinous tissues from 57 CRC patients and CRC cell lines. Dual-luciferase reporter assay was used to detect the binding of miR-451a to BAP31. The expression of BAP31 protein in CRC tissues was significantly higher than that in pericarcinous tissues, which was correlated with distant metastasis and advanced clinical stages of CRC patients. The expression of BAP31 was higher in HCT116, HT29, SW620, and DLD cells than that in the normal colonic epithelial cell line NCM460. The expression of BAP31 was absolutely down-regulated when over-expressing miR-451a in HCT116 and SW620 cells compared with control cells. Mir-451a inhibited the expression of BAP31 by binding to its 5'-UTR. Over-expressing miR-451a or silencing BAP31 suppressed the proliferation and apoptosis of CRC cells by increasing the expressions of endoplasmic reticulum stress (ERS)-associated proteins, including GRP78/BIP, BAX, and PERK/elF2α/ATF4/CHOP, which resulted in increased ERS, cytoplasmic calcium ion flowing, and apoptosis of CRC cells. These changes resulting from over-expressing miR-451a were reversed by over-expressing BAP31 with mutated miR-451a-binding sites. Over-expressing miR-451a or silencing BAP31 inhibited tumor growth by inducing ERS. The present study demonstrated that miR-451a can inhibit proliferation and increase apoptosis through inducing ERS by binding to the 5'-UTR of BAP31 in CRC.
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Affiliation(s)
- Ke Xu
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, China
- 985 Science and Technology Platform for Innovative Drugs, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Bin Han
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, China
- 985 Science and Technology Platform for Innovative Drugs, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yang Bai
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, China
- 985 Science and Technology Platform for Innovative Drugs, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Xiu-Ying Ma
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China
| | - Zhen-Ni Ji
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, China
- 985 Science and Technology Platform for Innovative Drugs, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yao Xiong
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, China
- 985 Science and Technology Platform for Innovative Drugs, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Shi-Kun Miao
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, China
- 985 Science and Technology Platform for Innovative Drugs, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yuan-Yuan Zhang
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, China.
- 985 Science and Technology Platform for Innovative Drugs, Sichuan University, Chengdu, Sichuan, 610041, China.
| | - Li-Ming Zhou
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, China.
- 985 Science and Technology Platform for Innovative Drugs, Sichuan University, Chengdu, Sichuan, 610041, China.
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Pomatto MAC, Bussolati B, D'Antico S, Ghiotto S, Tetta C, Brizzi MF, Camussi G. Improved Loading of Plasma-Derived Extracellular Vesicles to Encapsulate Antitumor miRNAs. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2019; 13:133-144. [PMID: 30788382 PMCID: PMC6370572 DOI: 10.1016/j.omtm.2019.01.001] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 01/03/2019] [Indexed: 12/26/2022]
Abstract
Extracellular vesicles (EVs) carry various molecules involved in intercellular communication and have raised great interest as drug delivery systems. Several engineering methods have been investigated for vesicle loading. Here, we studied the electroporation of EVs isolated from plasma to load antitumor microRNAs (miRNAs). First, we optimized the transfection protocol using miRNA cel-39 by evaluating different parameters (voltage and pulse) for their effect on vesicle morphology, loading capacity, and miRNA transfer to target cells. When compared with direct incubation of EVs with miRNA, mild electroporation allowed more efficient loading and better protection of miRNA from RNase degradation. Moreover, electroporation preserved the naive vesicle cargo, including RNAs and proteins, and their ability to be taken up by target cells, supporting the absence of vesicle damage. EVs engineered with antitumor miRNAs (miR-31 and miR-451a) successfully promoted apoptosis of the HepG2 hepatocellular carcinoma cell line, silencing target genes involved in anti-apoptotic pathways. Our findings indicate an efficient and functional miRNA encapsulation in plasma-derived EVs following an electroporation protocol that preserves EV integrity.
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Affiliation(s)
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
| | - Sergio D'Antico
- Blood Bank, A.O.U. Città della Salute e della Scienza, 10126 Turin, Italy
| | - Sara Ghiotto
- Blood Bank, A.O.U. Città della Salute e della Scienza, 10126 Turin, Italy
| | | | | | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy.,2i3T Scarl, Univerity of Turin, 10126 Turin, Italy
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Cui XW, Qian ZL, Li C, Cui SC. Identification of miRNA and mRNA expression profiles by PCR microarray in hepatitis B virus‑associated hepatocellular carcinoma. Mol Med Rep 2018; 18:5123-5132. [PMID: 30272372 DOI: 10.3892/mmr.2018.9516] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 08/23/2018] [Indexed: 02/07/2023] Open
Abstract
The present study aimed to identify differentially expressed microRNAs (miRNAs) and mRNAs in hepatitis B virus‑associated hepatocellular carcinoma (HCC). A total of five HCC tissues and paired adjacent non‑tumor tissues were screened to identify the differentially expressed miRNAs and target mRNAs using polymerase chain reaction microarrays. The interaction between differential miRNA and mRNA expression was concurrently analyzed using bioinformatics methods. A total of 32 differentially expressed miRNAs (four upregulated miRNAs and 28 downregulated miRNAs) and 16 differentially expressed mRNAs (11 upregulated mRNAs and five downregulated mRNAs) were identified. Among these, upregulated hsa‑miRNA (miR)‑96‑5p and hsa‑miR‑18b‑5p suppressed their target mRNAs forkhead box O1 and MET transcriptional regulator MACC1 (MACC1). Downregulation of hsa‑miR‑199a‑5p led to upregulation of its target mRNAs, cyclin dependent kinase 4 and insulin like growth factor 2 (IGF2). The high‑level expression of IGF2 mRNA and cyclin E1 mRNA was due to the low‑level expression of hsa‑miR‑145‑5p, hsa‑miR‑181a‑5p, hsa‑miR‑199a‑5p and hsa‑miR‑223a‑3p, and hsa‑miR‑26a‑5p and hsa‑miR‑26b‑5p, respectively. The low‑level expression of coronin 1A mRNA and MACC1 mRNA was due to overexpression of hsa‑miR‑517a‑3p and hsa‑miR‑18a‑5p, and hsa‑miR‑18b‑5p, respectively. Numerous gene ontology terms were associated with oncogenesis. The most enriched pathways targeted by the dysregulated miRNAs and mRNAs were associated with cancer and oncogenesis pathways. The present data suggested that differential miRNA and mRNA expression is present in HCC. Thus, interactions between certain miRNAs and mRNAs may be involved in the pathogenesis of HCC.
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Affiliation(s)
- Xiong-Wei Cui
- Interventional Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Zhi-Ling Qian
- Interventional Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Cong Li
- Interventional Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Shi-Chang Cui
- Interventional Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
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Sun H, Jiang P. MicroRNA-451a acts as tumor suppressor in cutaneous basal cell carcinoma. Mol Genet Genomic Med 2018; 6:1001-1009. [PMID: 30209892 PMCID: PMC6305666 DOI: 10.1002/mgg3.473] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 08/17/2018] [Accepted: 08/21/2018] [Indexed: 11/14/2022] Open
Abstract
Background Basal cell carcinoma (BCC) is the most common type of skin cancer. The underlying mechanism leading to BCC formation is not fully uncovered. The aim of this study was to characterize miRNA‐451a as a novel tumor suppressor in cutaneous BCC. Methods We first evaluated miRNA‐451a level in human BCC clinical tissues and inducible BCC mouse model. Then we studied the impact of overexpressing or inhibiting miR‐451a in cell proliferation, colony formation potential, and cell cycle pattern. Next, we employed luciferase reporter assay and western blotting to evaluate TBX1 as a downstream target of miRNA‐451a. Lastly, we confirmed TBX1 expressional change in BCC tissues by qPCR. Results miRNA‐451a was significantly reduced in human BCC tissues. The downregulation of miRNA‐451a was also confirmed in BCC mouse model. Overexpressing miRNA‐451a in tumor cells markedly suppressed cell growth through G1 cell cycle arrest. However, inhibiting miRNA‐451a in primary cells promoted cell growth and colony formation capacity. TBX1 (602054) was predicted as a downstream target of miRNA‐451a and this was confirmed by luciferase assay and protein expression. Finally, TBX1 level was shown upregulated in BCC tissues as inversely to miR451a. Conclusion Our studies revealed that miRNA‐451a/TBX1 axis played a pivotal role in BCC tumorigenesis.
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Affiliation(s)
- Hui Sun
- Department of Dermatology, Wuxi No.2 People's Hospital, Wuxi, Jiangsu, China
| | - Pingdong Jiang
- Department of Dermatology, Wuxi No.2 People's Hospital, Wuxi, Jiangsu, China
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Lin H, Huang ZP, Liu J, Qiu Y, Tao YP, Wang MC, Yao H, Hou KZ, Gu FM, Xu XF. MiR-494-3p promotes PI3K/AKT pathway hyperactivation and human hepatocellular carcinoma progression by targeting PTEN. Sci Rep 2018; 8:10461. [PMID: 29992971 PMCID: PMC6041272 DOI: 10.1038/s41598-018-28519-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 06/21/2018] [Indexed: 12/14/2022] Open
Abstract
Recent studies have shown that miR-494-3p is oncogene and has a central role in many solid tumors; however, the role of miR-494-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. In this study, it was found that miR-494-3p was up-regulated in HCC tissues. The high level of miR-494-3p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. Functional study demonstrated that miR-494-3p significantly promoted HCC cell metastasis in vitro and vivo. Since phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) signaling is a basic oncogenic driver in HCC, a potential role of miR-494-3p was explored as well as its target genes in PI3K/AKT activation. Of all the predicted target genes of miR-494-3p, the tumor-suppressor phosphatase and tensin homolog (PTEN) were identified. In conclusion, the data we collected could define an original mechanism of PI3K/AKT hyperactivation and sketch the regulatory role of miR-494-3p in suppressing the expression of PTEN. Therefore, targeting miR-494-3p could provide an effective therapeutic method for the treatment of the disease.
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Affiliation(s)
- Hui Lin
- The First Department of General Surgeny, Shidong Hospital, Yangpu District, Shanghai, Anhui Medical University, 999 Shiguang Road, Shanghai, 200438, China
| | - Zhi-Ping Huang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Jiao Liu
- Department of Hepatobiliary Surgery, Shanghai Public Health Clinical Center Affiliated to Fudan University, 921 Tongxin Road, Hongkou, Shanghai, 200080, China
| | - Yun Qiu
- Department of Radiotherapy, Shidong Hospital, Yangpu District, Shanghai, Anhui Medical University, 999 Shiguang Road, Shanghai, 200438, China
| | - Yuan-Ping Tao
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Meng-Chao Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Hui Yao
- Department of Radiotherapy, Shidong Hospital, Yangpu District, Shanghai, Anhui Medical University, 999 Shiguang Road, Shanghai, 200438, China
| | - Ke-Zhu Hou
- The First Department of General Surgeny, Shidong Hospital, Yangpu District, Shanghai, Anhui Medical University, 999 Shiguang Road, Shanghai, 200438, China.
| | - Fang-Ming Gu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
| | - Xuan-Fu Xu
- Department of Gastroenterology, Shidong Hospital, Yangpu District, Shanghai, Anhui Medical University, 999 Shiguang Road, Shanghai, 200438, China.
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Nie X, Liu Y, Chen WD, Wang YD. Interplay of miRNAs and Canonical Wnt Signaling Pathway in Hepatocellular Carcinoma. Front Pharmacol 2018; 9:657. [PMID: 29977206 PMCID: PMC6021530 DOI: 10.3389/fphar.2018.00657] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 06/01/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma is one of the leading causes of cancer death worldwide and the activation of canonical Wnt signaling pathway is universal in hepatocellular carcinoma patients. MicroRNAs are found to participate in the pathogenesis of hepatocellular carcinoma by activating or inhibiting components in the canonical Wnt signaling pathway. Meanwhile, transcriptional activation of microRNAs by canonical Wnt signaling pathway also contributes to the occurrence and progression of hepatocellular carcinoma. Pharmacological inhibition of hepatocellular carcinoma pathogenesis and other cancers by microRNAs are now in clinical trials despite the challenges of identifying efficient microRNAs candidates and safe delivery vehicles. The focus of this review is on the interplay mechanisms between microRNAs and canonical Wnt signaling pathway in hepatocellular carcinoma, and a deep understanding of the crosstalk will promote to develop a better management of this disease.
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Affiliation(s)
- Xiaobo Nie
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, China
| | - Yiran Liu
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, China.,Department of Pathology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, China.,Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
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Chen E, Xu X, Liu R, Liu T. Small but Heavy Role: MicroRNAs in Hepatocellular Carcinoma Progression. BIOMED RESEARCH INTERNATIONAL 2018; 2018:6784607. [PMID: 29951542 PMCID: PMC5987324 DOI: 10.1155/2018/6784607] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 02/08/2018] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC), which accounts for 85-90% of primary liver cancer, is the fifth most common malignant tumor and the third leading cause of cancer-related deaths worldwide, but the pathological mechanism of HCC is still not fully elucidated. miRNAs are evolutionarily endogenous small noncoding RNAs that negatively regulate gene expression via posttranscriptional inhibition or target mRNA degradation in several diseases, especially human cancer. Therefore, discovering the roles of miRNAs is appealing to scientific researchers. Emerging evidence has shown that the aberrant expressions of numerous miRNAs are involved in many HCC biological processes. In hepatocarcinogenesis, miRNAs with dysregulated expression can exert their function as oncogenes or tumor suppressors depending on their cellular target during the cell cycle, and in tumor development, differentiation, apoptosis, angiogenesis, metastasis, and progression of the tumor microenvironment. In this review, we summarize current findings on miRNAs and assess their functions to explore the molecular mechanisms of tumor progression in HCC.
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Affiliation(s)
- Erbao Chen
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaojing Xu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ruiqi Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
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42
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Li S, Yao J, Xie M, Liu Y, Zheng M. Exosomal miRNAs in hepatocellular carcinoma development and clinical responses. J Hematol Oncol 2018; 11:54. [PMID: 29642941 PMCID: PMC5896112 DOI: 10.1186/s13045-018-0579-3] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 02/21/2018] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma remains the sixth most lethal malignancy in the world. While HCC is often diagnosed via current biomarkers at a late stage, early detection of HCC has proven to be very difficult. Recent studies have focused on using exosomal miRNAs in clinical diagnostics and therapeutics, because they have improved stability in exosomes than as free miRNAs themselves. Exosomal miRNAs act through novel mechanisms for inducing cellular responses in a variety of biological circumstances. Dysregulated expression of miRNAs in exosomes can also accelerate HCC progression, including cell proliferation and metastasis, via alteration of a network of genes. Growing evidence demonstrates that exosomal miRNAs can affect many aspects of physiological and pathological conditions in HCC and indicates that miRNAs in exosomes can not only serve as sensitive biomarkers for cancer diagnostics and recurrence but can also potentially be used as therapeutics to target HCC progression. In this review, we summarize the latest findings between exosomal miRNAs and HCC, in order to better comprehend the functions and applications in HCC. Moreover, we discuss critical issues to consider when developing anti-tumor exosomal miRNAs as a novel therapeutic strategy for treating HCC in the clinic.
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Affiliation(s)
- Shuangshuang Li
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,Clinical research center for hepatobiliary and pancreatic diseases of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Jiping Yao
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,Clinical research center for hepatobiliary and pancreatic diseases of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Mingjie Xie
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,Clinical research center for hepatobiliary and pancreatic diseases of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Yanning Liu
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,Clinical research center for hepatobiliary and pancreatic diseases of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Min Zheng
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,Clinical research center for hepatobiliary and pancreatic diseases of Zhejiang Province, Zhejiang University, Hangzhou, China.
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43
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Zu C, Liu S, Cao W, Liu Z, Qiang H, Li Y, Cheng C, Ji L, Li J, Li J. MiR-590-3p suppresses epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma by inhibiting SIP1 expression. Oncotarget 2018; 8:34698-34708. [PMID: 28423728 PMCID: PMC5471004 DOI: 10.18632/oncotarget.16150] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 02/08/2017] [Indexed: 12/29/2022] Open
Abstract
The functional roles and clinical significances of miR-590-3p in ICC remain unclear. In the current study, we investigated the expression of miR-590-3p in tissues and sera of ICC by real-time quantitative polymerase chain reaction. We found miR-590-3p was significantly down-regulated in the sera and tissues of ICC patients, especially in those patients with lymph node metastasis or distant metastasis. AUC curves and Cox proportional hazards mode revealed serum miR-590-3p could be novel diagnostic and prognostic biomarker for ICC patients. MiR-590-3p dramatically suppressed epithelial-mesenchymal transition, cell migration, and invasion of ICC cells. SIP1 was identified as direct and functional target of miR-590-3p in ICC cells by luciferase assays. Finally, we found SIP1 expression was inversely correlated with miR-590-3p and closely related to diminished survival in ICC patients. These findings reveal functional and mechanistic roles of miR-590-3p and EMT activator SIP1 in the pathogenesis of ICC.
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Affiliation(s)
- Chao Zu
- Department of Surgical Oncology, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Shizhang Liu
- Department of Orthopaedics, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Wei Cao
- Department of Surgical Oncology, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Zongzhi Liu
- Department of Orthopaedics, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Hui Qiang
- Department of Orthopaedics, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Yong Li
- Department of Orthopaedics, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Chong Cheng
- Department of Surgical Oncology, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Le Ji
- Department of Orthopaedics, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Jianhui Li
- Department of Surgical Oncology, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Jingyuan Li
- Department of Orthopaedics, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
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Tumor suppressor activity of miR-451: Identification of CARF as a new target. Sci Rep 2018; 8:375. [PMID: 29321561 PMCID: PMC5762681 DOI: 10.1038/s41598-017-18559-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 12/13/2017] [Indexed: 12/15/2022] Open
Abstract
microRNAs (miRs) have recently emerged as small non-coding regulators of gene expression. We performed a loss-of-function screening by recruiting retrovirus mediated arbitrary manipulation of genome coupled with escape of cells from 5-Aza-2′-deoxycytidine (5-Aza-dC)-induced senescence. miRNA pool from cells that emerged from 5-Aza-dC-induced senescence was subjected to miR-microarray analysis with respect to the untreated control. We identified miR-451 as one of the upregulated miRs and characterized its functional relevance to drug resistance, cell growth, tumor suppressor proteins p53 and pRb, and stress response. We report that miR-451 caused growth arrest in cells leading to their resistance to 5-Aza-dC-induced senescence. Decrease in cyclin D1, CDK4 and phosphorylated pRB supported the growth arrest in miR-451 transfected cells. We demonstrate that Collaborator of ARF (CARF) protein is a new target of miR-451 that intermediates its function in tumor suppressor and stress signaling.
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45
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Li C, Qin F, Hu F, Xu H, Sun G, Han G, Wang T, Guo M. Characterization and selective incorporation of small non-coding RNAs in non-small cell lung cancer extracellular vesicles. Cell Biosci 2018; 8:2. [PMID: 29344346 PMCID: PMC5763536 DOI: 10.1186/s13578-018-0202-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 01/04/2018] [Indexed: 12/31/2022] Open
Abstract
Background Extracellular vesicles (EVs) play important roles in intercellular communication through the delivery of their cargoes, which include proteins, lipids, and RNAs. Increasingly, multiple studies have reported the association between EV small non-coding RNAs and cancer, due to their regulatory functions in gene expression. Hence, analysis of the features of small non-coding RNA expression and their incorporation into EVs is important for cancer research. Results We performed deep sequencing to investigate the expression of small RNAs in plasma EVs from lung adenocarcinoma (ADC) patients, lung squamous cell carcinoma (SQCC) patients, and healthy controls. Then, eighteen differently expressed miRNAs in plasma EVs was validated by QRT-PCR. The small RNA expression profiles of plasma EVs were different among lung ADC, SQCC patients, and healthy controls. And many small RNAs, including 5′ YRNA hY4-derived fragments, miR-451a, miR-122-5p, miR-20a-5p, miR-20b-5p, miR-30b-5p, and miR-665, were significantly upregulated in non-small cell lung cancer (NSCLC) EVs. And the cell viability assays indicated that hY4-derived fragments inhibited the proliferation of lung cancer cell A549. By comparing the cellular and EV expression levels of six miRNAs in NSCLC cells, we found that miR-451a and miR-122-5p were significantly downregulated in NSCLC cell lysates, while significantly upregulated in NSCLC EVs. Conclusions The differently expressed EV small RNAs may serve as potential circulating biomarkers for the diagnosis of NSCLC. Particularly, YRNA hY4-derived fragments can serve as a novel class of biomarkers, which function as tumor suppressors in NSCLC. Additionally, miR-451a and miR-122-5p may be sorted into NSCLC EVs in a selective manner. Electronic supplementary material The online version of this article (10.1186/s13578-018-0202-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Chuang Li
- 1Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072 Hubei People's Republic of China
| | - Fang Qin
- 1Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072 Hubei People's Republic of China
| | - Fen Hu
- 2Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei People's Republic of China
| | - Hui Xu
- 2Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei People's Republic of China
| | - Guihong Sun
- 3School of Basic Medical Sciences, Wuhan University, Wuhan, 430071 Hubei People's Republic of China
| | - Guang Han
- 4Department of Radiation Oncology, Hubei Cancer Hospital, 116 Zhuodaoquan South Road, Wuhan, 430079 Hubei People's Republic of China.,5Department of Oncology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Street, Wuhan, 430060 Hubei People's Republic of China
| | - Tao Wang
- 2Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei People's Republic of China
| | - Mingxiong Guo
- 1Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072 Hubei People's Republic of China
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Minna E, Romeo P, Dugo M, De Cecco L, Todoerti K, Pilotti S, Perrone F, Seregni E, Agnelli L, Neri A, Greco A, Borrello MG. miR-451a is underexpressed and targets AKT/mTOR pathway in papillary thyroid carcinoma. Oncotarget 2017; 7:12731-47. [PMID: 26871295 PMCID: PMC4914318 DOI: 10.18632/oncotarget.7262] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 01/26/2016] [Indexed: 12/18/2022] Open
Abstract
Papillary Thyroid Carcinoma (PTC) is the most frequent thyroid cancer. Although several PTC-specific miRNA profiles have been reported, only few upregulated miRNAs are broadly recognized, while less consistent data are available about downregulated miRNAs. In this study we investigated miRNA deregulation in PTC by miRNA microarray, analysis of a public dataset from The Cancer Genome Atlas (TCGA), literature review and meta-analysis based on a univocal miRNA identifier derived from miRBase v21. A list of 18 miRNAs differentially expressed between PTC and normal thyroid was identified and validated in the TCGA dataset. Furthermore, we compared our signature with miRNA profiles derived from 15 studies selected from literature. Then, to select possibly functionally relevant miRNA, we integrated our miRNA signature with those from two in vitro cell models based on the PTC-driving oncogene RET/PTC1. Through this strategy, we identified commonly deregulated miRNAs, including miR-451a, which emerged also by our meta-analysis as the most frequently reported downregulated miRNA. We showed that lower expression of miR-451a correlates with aggressive clinical-pathological features of PTC as tall cell variant, advanced stage and extrathyroid extension. In addition, we demonstrated that ectopic expression of miR-451a impairs proliferation and migration of two PTC-derived cell lines, reduces the protein levels of its recognized targets MIF, c-MYC and AKT1 and attenuates AKT/mTOR pathway activation. Overall, our study provide both an updated overview of miRNA deregulation in PTC and the first functional evidence that miR-451a exerts tumor suppressor functions in this neoplasia.
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Affiliation(s)
- Emanuela Minna
- Department of Experimental Oncology and Molecular Medicine, Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paola Romeo
- Department of Experimental Oncology and Molecular Medicine, Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Matteo Dugo
- Department of Experimental Oncology and Molecular Medicine, Functional Genomics Core Facility, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Loris De Cecco
- Department of Experimental Oncology and Molecular Medicine, Functional Genomics Core Facility, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Katia Todoerti
- Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy
| | - Silvana Pilotti
- Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Perrone
- Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Ettore Seregni
- Department of Diagnostic Imaging and Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Agnelli
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Antonino Neri
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.,Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Angela Greco
- Department of Experimental Oncology and Molecular Medicine, Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Grazia Borrello
- Department of Experimental Oncology and Molecular Medicine, Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Prognostic value of microRNAs in hepatocellular carcinoma: a meta-analysis. Oncotarget 2017; 8:107237-107257. [PMID: 29291025 PMCID: PMC5739810 DOI: 10.18632/oncotarget.20883] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 08/29/2017] [Indexed: 12/20/2022] Open
Abstract
Background Numerous articles reported that dysregulated expression levels of miRNAs correlated with survival time of HCC patients. However, there has not been a comprehensive meta-analysis to evaluate the accurate prognostic value of miRNAs in HCC. Design Meta-analysis. Materials and Methods Studies, published in English, estimating expression levels of miRNAs with any survival curves in HCC were identified up until 15 April, 2017 by performing online searches in PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews by two independent authors. The pooled hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the correlation between miRNA expression and overall survival (OS). Results 54 relevant articles about 16 miRNAs, with 6464 patients, were ultimately included. HCC patients with high expression of tissue miR-9 (HR = 2.35, 95% CI = 1.46–3.76), miR-21 (HR = 1.76, 95% CI = 1.29–2.41), miR-34c (HR = 1.64, 95% CI = 1.05–2.57), miR-155 (HR = 2.84, 95% CI = 1.46–5.51), miR-221 (HR = 1.76, 95% CI = 1.02–3.04) or low expression of tissue miR-22 (HR = 2.29, 95% CI = 1.63–3.21), miR-29c (HR = 1.35, 95% CI = 1.10–1.65), miR-34a (HR = 1.84, 95% CI = 1.30–2.59), miR-199a (HR = 2.78, 95% CI = 1.89–4.08), miR-200a (HR = 2.64, 95% CI = 1.86–3.77), miR-203 (HR = 2.20, 95% CI = 1.61–3.00) have significantly poor OS (P < 0.05). Likewise, HCC patients with high expression of blood miR-21 (HR = 1.73, 95% CI = 1.07–2.80), miR-192 (HR = 2.42, 95% CI = 1.15–5.10), miR-224 (HR = 1.56, 95% CI = 1.14–2.12) or low expression of blood miR-148a (HR = 2.26, 95% CI = 1.11–4.59) have significantly short OS (P < 0.05). Conclusions In conclusion, tissue miR-9, miR-21, miR-22, miR-29c, miR-34a, miR-34c, miR-155, miR-199a, miR-200a, miR-203, miR-221 and blood miR-21, miR-148a, miR-192, miR-224 demonstrate significantly prognostic value. Among them, tissue miR-9, miR-22, miR-155, miR-199a, miR-200a, miR-203 and blood miR-148a, miR-192 are potential prognostic candidates for predicting OS in HCC.
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48
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Ge S, Xu Y, Wang H, Sun Y, Tian X, Cao Z, Lin X, Xu J, Wang Q. Downregulation of esophageal cancer-related gene 4 promotes proliferation and migration of hepatocellular carcinoma. Oncol Lett 2017; 14:3689-3696. [PMID: 28927132 PMCID: PMC5588079 DOI: 10.3892/ol.2017.6616] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 03/21/2017] [Indexed: 11/26/2022] Open
Abstract
Esophageal cancer-related gene 4 (ECRG4) is a candidate tumor suppressor gene, which is involved in cell apoptosis, migration, infection and inflammation responsiveness; however, its expression level and clinical significance in hepatocellular carcinoma (HCC) remains unclear. In the present study, the authors aim to evaluate the clinical significance and potential role of ECRG4 in HCC. Level of ECRG4 protein expression in HCC and peripheral tissues was investigated in tissue specimens obtained from 56 consecutive HCC patients by immunohistochemistry. Cell proliferation, cell migration and invasion regulations were examined by MTT curves, flow cytometry, Transwell assays and western blotting. ECRG4 expression was weak positive in normal liver cells but was downregulated in HCC cells in vivo or in vitro. A decreased expression of ECRG4 was associated with the age of the patients, metastasis and Ki-67 proliferation index. However, decreased ECRG4 expression was not associated with differentiation, tumor size, the presence of portal vein tumor thrombosis, satellite lesions, tumor relapse or mortality. Further investigations revealed that ectopic expression of ECRG4 inhibited cell proliferation, migration and invasion and promoted cell apoptosis in SMMC-7721 cells, which was mediated by the regulation of BAX and B cell lymphoma-2, in addition to the upregulation of epithelial-mesenchymal transition markers. In conclusion, the results of the present study indicated that ECRG4 was downregulated in HCC and served important roles in promoting cell proliferation and migration.
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Affiliation(s)
- Shujian Ge
- Department of Science and Education, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Yali Xu
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Hongliang Wang
- Shandong Academy of Occupational Health and Occupational Medicine, Jinan, Shandong 250062, P.R. China
| | - Yaxin Sun
- Shandong Academy of Occupational Health and Occupational Medicine, Jinan, Shandong 250062, P.R. China
| | - Xiangguo Tian
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Zhixin Cao
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xiaoyan Lin
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Jiawen Xu
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Qiangxiu Wang
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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He SJ, Xiang CQ, Zhang Y, Lu XT, Chen HW, Xiong LX. Recent progress on the effects of microRNAs and natural products on tumor epithelial-mesenchymal transition. Onco Targets Ther 2017; 10:3435-3451. [PMID: 28744148 PMCID: PMC5513877 DOI: 10.2147/ott.s139546] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Epithelial–mesenchymal transition (EMT) is a biological process of phenotypic transition of epithelial cells that can promote physiological development as well as tissue healing and repair. In recent years, cancer researchers have noted that EMT is closely related to the occurrence and development of tumors. When tumor cells undergo EMT, they can develop enhanced migration and local tissue invasion abilities, which can lead to metastatic growth. Nevertheless, two researches in NATURE deny its necessity in specific tumors and that is discussed in this review. The degree of EMT and the detection of EMT-associated marker molecules can also be used to judge the risk of metastasis and to evaluate patients’ prognosis. MicroRNAs (miRNAs) are noncoding small RNAs, which can inhibit gene expression and protein translation through specific binding with the 3′ untranslated region of mRNA. In this review, we summarize the miRNAs that are reported to influence EMT through transcription factors such as ZEB, SNAIL, and TWIST, as well as some natural products that regulate EMT in tumors. Moreover, mutual inhibition occurs between some transcription factors and miRNAs, and these effects appear to occur in a complex regulatory network. Thus, understanding the role of miRNAs in EMT and tumor growth may lead to new treatments for malignancies. Natural products can also be combined with conventional chemotherapy to enhance curative effects.
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Affiliation(s)
- Shu-Jin He
- Department of Pathophysiology, Medical College, Nanchang University.,Second Clinical Medical College, Nanchang University
| | - Chu-Qi Xiang
- Department of Pathophysiology, Medical College, Nanchang University.,First Clinical Medical College, Nanchang University
| | - Yu Zhang
- First Clinical Medical College, Nanchang University
| | - Xiang-Tong Lu
- Department of Pathophysiology, Medical College, Nanchang University
| | - Hou-Wen Chen
- Department of Pathophysiology, Medical College, Nanchang University.,Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang, People's Republic of China
| | - Li-Xia Xiong
- Department of Pathophysiology, Medical College, Nanchang University.,Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang, People's Republic of China
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50
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Lee AF, Chen MC, Chen CJ, Yang CJ, Huang MS, Liu YP. Reverse epithelial-mesenchymal transition contributes to the regain of drug sensitivity in tyrosine kinase inhibitor-resistant non-small cell lung cancer cells. PLoS One 2017; 12:e0180383. [PMID: 28683123 PMCID: PMC5500319 DOI: 10.1371/journal.pone.0180383] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 06/14/2017] [Indexed: 01/06/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) are currently the first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. These patients receive platinum-based chemotherapy as the second-line treatment after they develop resistance to TKIs. Many patients regain sensitivity to the TKIs used in the first-line treatment after the failure of chemotherapy. However, the molecular mechanism for the regain of TKI sensitivity is largely unknown. In this study, we established gefitinib-resistant PC9 and HCC827 cell lines, which did not harbor the EGFR T790M mutation and MET amplification but exhibited the epithelial-mesenchymal transition (EMT) phenotype. Overexpression of EMT inducers, Snail or Slug, in the parental lines promoted their resistance to gefitinib. The gefitinib-resistant cell lines regained their sensitivity to gefitinib and displayed reverse EMT phenotypes after long-term culture in gefitinib-free culture medium. Blockage of reverse EMT by stable expression of Snail or Slug prevented the regain of TKI sensitivity. In conclusion, reverse EMT is one of the major mechanisms for the regain of TKI sensitivity in TKI-resistant NSCLC cells, suggesting that the development of small molecules targeting the EMT process may prolong the efficacy of TKIs in NSCLC patients with EGFR mutations.
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Affiliation(s)
- An-Fu Lee
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Man-Chin Chen
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chao-Ju Chen
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chih-Jen Yang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- * E-mail: (YPL); (MSH); (CJY)
| | - Ming-Shyang Huang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Geriatrics and Gerontology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- * E-mail: (YPL); (MSH); (CJY)
| | - Yu-Peng Liu
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- * E-mail: (YPL); (MSH); (CJY)
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