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De Leo I, Mosca N, Pezzullo M, Valletta D, Manfrevola F, Mele VG, Chianese R, Russo A, Potenza N. Transcriptomic-Based Identification of miR-125a Novel Targets in Human Hepatocarcinoma Cells. Biomolecules 2025; 15:144. [PMID: 39858538 PMCID: PMC11763984 DOI: 10.3390/biom15010144] [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: 12/17/2024] [Revised: 01/15/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most aggressive and lethal human tumors. Many functional studies have demonstrated the role of non-coding RNAs (ncRNA), particularly microRNAs (miRNA), in the regulation of hepatocarcinogenesis driving pathways. MiR-125a-5p (miR-125a) has been consistently reported as an oncosuppressive miRNA, as demonstrated in vivo and in vitro. However, its HCC relevant targets and molecular mechanisms are still largely unknown. Here, a genome-wide perspective of the whole miR-125a targetome has been achieved. In particular, two different HCC cell lines were subjected to a miRNA boosting by mimic transfections, and consequently many genes were de-regulated, as observed by a transcriptomic approach. The merging of down-regulated genes with results from bioinformatic predictive tools yielded a number of candidate direct targets that were further experimentally validated by luciferase-based reporter assays. Different novel targets were found, in particular ARID3A, CCNJ, LIPA, NR6A1, and NUP210, oncogenes in various tumors and here also related to HCC through miR-125a regulation. The RNA interactions investigated in this work could pave the way to piece together the RNA regulatory networks governed by the miRNA impacting on hepatocarcinogenesis, and be exploited in the future for identifying novel biomarkers and therapeutic targets in HCC.
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Affiliation(s)
- Ilenia De Leo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (I.D.L.); (N.M.); (M.P.); (D.V.); (A.R.)
- Genomix4Life S.r.l., 84081 Baronissi, Italy
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (I.D.L.); (N.M.); (M.P.); (D.V.); (A.R.)
| | - Mariaceleste Pezzullo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (I.D.L.); (N.M.); (M.P.); (D.V.); (A.R.)
| | - Danila Valletta
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (I.D.L.); (N.M.); (M.P.); (D.V.); (A.R.)
| | - Francesco Manfrevola
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (F.M.); (V.G.M.); (R.C.)
| | - Vincenza Grazia Mele
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (F.M.); (V.G.M.); (R.C.)
| | - Rosanna Chianese
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (F.M.); (V.G.M.); (R.C.)
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (I.D.L.); (N.M.); (M.P.); (D.V.); (A.R.)
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (I.D.L.); (N.M.); (M.P.); (D.V.); (A.R.)
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Abstract
Sirtuin 7 (SIRT7) is a member of the sirtuin family and has emerged as a key player in numerous cellular processes. It exhibits various enzymatic activities and is predominantly localized in the nucleolus, playing a role in ribosomal RNA expression, DNA damage repair, stress response and chromatin compaction. Recent studies have revealed its involvement in diseases such as cancer, cardiovascular and bone diseases, and obesity. In cancer, SIRT7 has been found to be overexpressed in multiple types of cancer, including breast cancer, clear cell renal cell carcinoma, lung adenocarcinoma, prostate adenocarcinoma, hepatocellular carcinoma, and gastric cancer, among others. In general, cancer cells exploit SIRT7 to enhance cell growth and metabolism through ribosome biogenesis, adapt to stress conditions and exert epigenetic control over cancer-related genes. The aim of this review is to provide an in-depth understanding of the role of SIRT7 in cancer carcinogenesis, evolution and progression by elucidating the underlying molecular mechanisms. Emphasis is placed on unveiling the intricate molecular pathways through which SIRT7 exerts its effects on cancer cells. In addition, this review discusses the feasibility and challenges associated with the development of drugs that can modulate SIRT7 activity.
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Affiliation(s)
- Francisco Alejandro Lagunas-Rangel
- Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, San Pedro Zacatenco, Gustavo A. Madero, 07480, Mexico City, Mexico.
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3
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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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4
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Zhang X, Xu X, Song J, Xu Y, Qian H, Jin J, Liang ZF. Non-coding RNAs' function in cancer development, diagnosis and therapy. Biomed Pharmacother 2023; 167:115527. [PMID: 37751642 DOI: 10.1016/j.biopha.2023.115527] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/05/2023] [Accepted: 09/15/2023] [Indexed: 09/28/2023] Open
Abstract
While previous research on cancer biology has focused on genes that code for proteins, in recent years it has been discovered that non-coding RNAs (ncRNAs)play key regulatory roles in cell biological functions. NcRNAs account for more than 95% of human transcripts and are an important entry point for the study of the mechanism of cancer development. An increasing number of studies have demonstrated that ncRNAs can act as tumor suppressor genes or oncogenes to regulate tumor development at the epigenetic level, transcriptional level, as well as post-transcriptional level. Because of the importance of ncRNAs in cancer, most clinical trials have focused on ncRNAs to explore whether ncRNAs can be used as new biomarkers or therapies. In this review, we focus on recent studies of ncRNAs including microRNAs (miRNAs), long ncRNAs (lncRNAs), circle RNAs (circRNAs), PIWI interacting RNAs (piRNAs), and tRNA in different types of cancer and explore the application of these ncRNAs in the development of cancer and the identification of relevant therapeutic targets and tumor biomarkers. Graphical abstract drawn by Fidraw.
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Affiliation(s)
- XinYi Zhang
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, Jiangsu, China; Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu university, Zhenjiang, Jiangsu 212013, China
| | - Xiaoqing Xu
- Nanjing Renpin ENT Hospital, Nanjing 210000, Jiangsu, China
| | - Jiajia Song
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, Jiangsu, China; Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu university, Zhenjiang, Jiangsu 212013, China
| | - Yumeng Xu
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, Jiangsu, China; Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu university, Zhenjiang, Jiangsu 212013, China
| | - Hui Qian
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, Jiangsu, China; Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu university, Zhenjiang, Jiangsu 212013, China
| | - Jianhua Jin
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, Jiangsu, China.
| | - Zhao Feng Liang
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, Jiangsu, China; Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu university, Zhenjiang, Jiangsu 212013, China.
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5
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Petővári G, Tóth G, Turiák L, L. Kiss A, Pálóczi K, Sebestyén A, Pesti A, Kiss A, Baghy K, Dezső K, Füle T, Tátrai P, Kovalszky I, Reszegi A. Dynamic Interplay in Tumor Ecosystems: Communication between Hepatoma Cells and Fibroblasts. Int J Mol Sci 2023; 24:13996. [PMID: 37762298 PMCID: PMC10530979 DOI: 10.3390/ijms241813996] [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: 07/30/2023] [Revised: 09/06/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Tumors are intricate ecosystems where cancer cells and non-malignant stromal cells, including cancer-associated fibroblasts (CAFs), engage in complex communication. In this study, we investigated the interaction between poorly (HLE) and well-differentiated (HuH7) hepatoma cells and LX2 fibroblasts. We explored various communication channels, including soluble factors, metabolites, extracellular vesicles (EVs), and miRNAs. Co-culture with HLE cells induced LX2 to produce higher levels of laminin β1, type IV collagen, and CD44, with pronounced syndecan-1 shedding. Conversely, in HuH7/LX2 co-culture, fibronectin, thrombospondin-1, type IV collagen, and cell surface syndecan-1 were dominant matrix components. Integrins α6β4 and α6β1 were upregulated in HLE, while α5β1 and αVβ1 were increased in HuH7. HLE-stimulated LX2 produced excess MMP-2 and 9, whereas HuH7-stimulated LX2 produced excess MMP-1. LX2 activated MAPK and Wnt signaling in hepatoma cells, and conversely, hepatoma-derived EVs upregulated MAPK and Wnt in LX2 cells. LX2-derived EVs induced over tenfold upregulation of SPOCK1/testican-1 in hepatoma EV cargo. We also identified liver cancer-specific miRNAs in hepatoma EVs, with potential implications for early diagnosis. In summary, our study reveals tumor type-dependent communication between hepatoma cells and fibroblasts, shedding light on potential implications for tumor progression. However, the clinical relevance of liver cancer-specific miRNAs requires further investigation.
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Affiliation(s)
- Gábor Petővári
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
| | - Gábor Tóth
- MS Proteomics Research Group, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok Körútja 2, H-1117 Budapest, Hungary
| | - Lilla Turiák
- MS Proteomics Research Group, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok Körútja 2, H-1117 Budapest, Hungary
| | - Anna L. Kiss
- Department of Human Morphology and Developmental Biology, Semmelweis University, Tűzoltó u. 58, H-1094 Budapest, Hungary
| | - Krisztina Pálóczi
- Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1085 Budapest, Hungary
| | - Anna Sebestyén
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
| | - Adrián Pesti
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői út 93, H-1091 Budapest, Hungary
| | - András Kiss
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői út 93, H-1091 Budapest, Hungary
| | - Kornélia Baghy
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
| | - Katalin Dezső
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
| | - Tibor Füle
- Thermo Fisher Scientific Inc., Váci út. 41-43, H-1134 Budapest, Hungary
| | - Péter Tátrai
- Charles River Laboratories Hungary, Irinyi József utca 4-20, H-1117 Budapest, Hungary
| | - Ilona Kovalszky
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
| | - Andrea Reszegi
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői út 93, H-1091 Budapest, Hungary
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
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6
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Paula Ceballos M, Darío Quiroga A, Palma NF. Role of sirtuins in hepatocellular carcinoma progression and multidrug resistance: Mechanistical and pharmacological perspectives. Biochem Pharmacol 2023; 212:115573. [PMID: 37127248 DOI: 10.1016/j.bcp.2023.115573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide. Therapeutic strategies are still challenging due to the high relapse rate after surgery and multidrug resistance (MDR). It is essential to better understand the mechanisms for HCC progression and MDR for the development of new therapeutic strategies. Mammalian sirtuins (SIRTs), a family of seven members, are related to tumor progression, MDR and prognosis and were proposed as potential prognostic markers, as well as therapeutic targets for treating cancer. SIRT1 is the most studied member and is overexpressed in HCC, playing an oncogenic role and predicting poor prognosis. Several manuscripts describe the role of SIRTs2-7 in HCC; most of them report an oncogenic role for SIRT2 and -7 and a suppressive role for SIRT3 and -4. The scenario is more confusing for SIRT5 and -6, since information is contradictory and scarce. For SIRT1 many inhibitors are available and they seem to hold therapeutic promise in HCC. For the other members the development of specific modulators has just started. This review is aimed to describe the features of SIRTs1-7 in HCC, and the role they play in the onset and progression of the disease. Also, when possible, we will depict the information related to the SIRTs modulators that have been tested in HCC and their possible implication in MDR. With this, we hope to clarify the role of each member in HCC and to shed some light on the most successful strategies to overcome MDR.
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Affiliation(s)
- María Paula Ceballos
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Suipacha 70 (S2002LRL), Rosario, Argentina.
| | - Ariel Darío Quiroga
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Suipacha 70 (S2002LRL), Rosario, Argentina; Área Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR, Suipachs 570 (S2002LRL), Rosario, Argentina; Centro de Altos Estudios en Ciencias Humanas y de la Salud (CAECIHS) Sede Regional Rosario, Universidad Abierta Interamericana, Av. Pellegrini 1618 (S2000BUG), Rosario, Argentina
| | - Nicolás Francisco Palma
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Suipacha 70 (S2002LRL), Rosario, Argentina; Área Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR, Suipachs 570 (S2002LRL), Rosario, Argentina
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7
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El-Mahdy HA, Sallam AAM, Ismail A, Elkhawaga SY, Elrebehy MA, Doghish AS. miRNAs inspirations in hepatocellular carcinoma: Detrimental and favorable aspects of key performers. Pathol Res Pract 2022; 233:153886. [PMID: 35405621 DOI: 10.1016/j.prp.2022.153886] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/23/2022] [Accepted: 04/01/2022] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. HCC initiation, progression, and therapy failure are all influenced by various variables, including microRNAs (miRNAs). miRNAs are short non-coding RNA sequences that modulate target mRNA expression by deteriorating or repressing translation. miRNAs play an imperative role in HCC pathogenesis by triggering the induction of cancer stem cells (CSCs) and their proliferation, while also delaying apoptosis, sustaining the cell cycle, and inspiring angiogenesis, invasion, and metastasis. Additionally, miRNAs modulate crucial HCC-related molecular pathways such as the p53 pathway, the Wnt/β-catenin pathway, VEGFR2, and PTEN/PI3K/AKT pathway. Consequently, the goal of this review was to give an up-to-date overview of oncogenic and tumor suppressor (TS) miRNAs, as well as their potential significance in HCC pathogenesis and treatment responses, highlighting their underpinning molecular pathways in HCC initiation and progression. Similarly, the biological importance and clinical application of miRNAs in HCC are summarized.
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Affiliation(s)
- Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
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8
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Atteia HH, Arafa MH, Mohammad NS, Amin DM, Sakr AT. Thymoquinone upregulates miR-125a-5p, attenuates STAT3 activation, and potentiates doxorubicin antitumor activity in murine solid Ehrlich carcinoma. J Biochem Mol Toxicol 2021; 35:e22924. [PMID: 34605108 DOI: 10.1002/jbt.22924] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 08/21/2021] [Accepted: 09/20/2021] [Indexed: 12/17/2022]
Abstract
In breast cancer, there has been evidence of atypical activation of signal transduction and activators of transcription 3 (STAT3). Thymoquinone (TQ) exerts its anti-neoplastic effect through diverse mechanisms, including STAT3 inhibition. The tumor suppressor, microRNA-125a-5p was reported to be downregulated in various breast cancer cells. Therefore, we investigated the influence of TQ and/or doxorubicin on microRNA-125a-5p and its correlation with STAT3 activation as well as tumor growth in mice bearing solid Ehrlich tumors. We found that TQ markedly suppressed inducible and constitutive phosphorylation of STAT3 in tumor tissue without affecting STAT5. Moreover, it attenuated tumor growth, downregulated STAT3 downstream target proteins, and increased the apoptotic activities of caspase-3 and -9. Interestingly, TQ-elicited synergism of doxorubicin anti-neoplastic activity was coupled with upregulation of tumoral microRNA-125a-5p. Taken together, the current findings raise the potential of TQ as a promising chemomodulatory adjuvant to augment mammary carcinoma sensitivity to doxorubicin.
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Affiliation(s)
- Hebatallah H Atteia
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.,Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Manar H Arafa
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Nanies S Mohammad
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Dalia M Amin
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Amr T Sakr
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City (USC), Menoufia, Egypt
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9
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The paradoxical role of matrix metalloproteinase-11 in cancer. Biomed Pharmacother 2021; 141:111899. [PMID: 34346316 DOI: 10.1016/j.biopha.2021.111899] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/15/2021] [Accepted: 07/01/2021] [Indexed: 02/08/2023] Open
Abstract
The microenvironment surrounding the tumor affects biological processes, such as cell proliferation, angiogenesis, apoptosis, and invasion. Therefore, the ability to change these environments is an important attribute for tumor cells to obtain specific functions necessary for growth and metastasis. Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic metalloenzymes that facilitate protease-dependent tumor progression by degrading extracellular matrix (ECM) proteins, releasing cytokines, growth factors, and other cell surface molecules. As one of the most widely studied MMPs, MMP-11 is an important protease that is expressed in cancer cells, stromal cells, and the adjacent microenvironment. MMP-11 has a dual effect on tumors. On one hand, MMP-11 promotes tumor development by inhibiting apoptosis and promoting the migration and invasion of cancer cells in the early stage. On the other hand, in animal models, MMP-11 has a protective effect on tumor growth and metastasis at an advanced stage. Based on current findings regarding the importance of MMP-11 in altering the tumor microenvironment, there is a need to further understand how stromal cells and the ECM regulate tumor progression, which may result in the re-examination of MMPs as drug targets for cancer and other diseases. In this review, we summarize the dual role of MMP-11 in cancer and its potential clinical significance.
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10
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Sartorius K, An P, Winkler C, Chuturgoon A, Li X, Makarova J, Kramvis A. The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation. Front Immunol 2021; 12:661204. [PMID: 33995383 PMCID: PMC8117219 DOI: 10.3389/fimmu.2021.661204] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.,Department of Surgery, University of KwaZulu-Natal Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Ping An
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Cheryl Winkler
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Julia Makarova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia.,Higher School of Economics University, Moscow, Russia
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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Shaik S, Martin E, Hayes D, Gimble J, Devireddy R. microRNA Sequencing of CD34+ Sorted Adipose Stem Cells Undergoing Endotheliogenesis. Stem Cells Dev 2021; 30:265-288. [PMID: 33397204 PMCID: PMC7994430 DOI: 10.1089/scd.2020.0173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 01/02/2021] [Indexed: 12/13/2022] Open
Abstract
While several microRNAs (miRNAs) that regulate the endotheliogenesis and further promote angiogenesis have been identified in various cancers, the identification of miRNAs that can drive the differentiation of adipose derived stromal/stem cells (ASCs) into the endothelial lineage has been largely unexplored. In this study, CD34+ ASCs sorted using magnetic bead separation were induced to differentiate along the endothelial pathway. miRNA sequencing of ASCs at day 3, 9, and 14 of endothelial differentiation was performed on Ion Proton sequencing system. The data obtained by this high-throughput method were aligned to the human genome HG38, and the differentially expressed miRNAs during endothelial differentiation at various time points (day 3, 9, and 14) were identified. The gene targets of the identified miRNAs were obtained through miRWalk database. The network-pathway analysis of miRNAs and their targets was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) bioinformatic tools to determine the potential candidate miRNAs that promote endothelial differentiation. Based on these analyses, six upregulated miRNAs (miR-181a-5p, miR-330-5p, miR-335-3p, miR-15b-5p, miR-99a-5p, and miR-199a-5p) and six downregulated miRNAs (miR-145-5p, miR-155-5p, miR-193a-3p, miR-125a-5p, miR-221-5p, and miR-222-3p) were chosen for further studies. In vitro evaluation of these miRNAs to induce endothelial differentiation when transfected into CD34+ sorted ASCs was studied using Von Willebrand Factor (VWF) staining and quantitative real time-polymerase chain reaction (qRT-PCR). Our results suggest that miRNAs: 335-5p, 330-5p, 181a-5p and anti-miRNAs: 125a-5p, 145-5p can likely induce endothelial differentiation in CD34+ sorted ASCs. Further studies are clearly required to elucidate the specific mechanisms on how miRNAs or anti-miRNAs identified through bioinformatics approach can induce the endotheliogenesis in ASCs.
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Affiliation(s)
- Shahensha Shaik
- Bioengineering Laboratory, Department of Mechanical Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Elizabeth Martin
- Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Daniel Hayes
- Department of Biomedical Engineering, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Jeffrey Gimble
- La Cell, LLC and Obatala Sciences, Inc., New Orleans, Louisiana, USA
| | - Ram Devireddy
- Bioengineering Laboratory, Department of Mechanical Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
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12
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Karbasforooshan H, Hayes AW, Mohammadzadeh N, Zirak MR, Karimi G. The possible role of Sirtuins and microRNAs in hepatocellular carcinoma therapy. Cell Cycle 2020; 19:3209-3221. [PMID: 33164623 DOI: 10.1080/15384101.2020.1843813] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Sirtuins are NAD+-dependent histone deacetylases that regulate many cellular processes such as proliferation, apoptosis, and metabolism. SIRT (silent information regulator)-1, 5, 6 and 7, members of the mammalian Sirtuin family of proteins (SIRT1-SIRT7), are involved in carcinogenesis, prognosis, metastasis, and chemical resistant of HCC. These proteins act through the deacetylation of tumor suppressor or oncogenic factors. MicroRNAs (miRNAs) are a group of small non-coding RNAs that down regulate gene expression by targeting the 3'-untranslated region of miRNAs. MiRNAs can function as tumor suppressors or as oncogenes and are involved in progression, differentiation, apoptosis and drug resistance of tumor cells. The focus of this review is to delineate the relationship between some microRNAs and their target, Sirtuins, and to present an overview of their function in HCC as currently understood.
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Affiliation(s)
- Hedyieh Karbasforooshan
- Department of Clinical Pharmacy, Faculty of Pharmacy, Mashhad University of Medical Sciences , Mashhad, Iran
| | - A Wallace Hayes
- University of South Florida College of Public Health , Tampa, FL, USA.,Institute for Integrative Toxicology, Michigan State University , East Lansing, MI, USA
| | | | - Mohammad Reza Zirak
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences , Mashhad, Iran
| | - Gholamreza Karimi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences , Mashhad, Iran.,Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences , Mashhad, Iran
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13
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Di Palo A, Siniscalchi C, Mosca N, Russo A, Potenza N. A Novel ceRNA Regulatory Network Involving the Long Non-Coding Antisense RNA SPACA6P-AS, miR-125a and its mRNA Targets in Hepatocarcinoma Cells. Int J Mol Sci 2020; 21:ijms21145068. [PMID: 32709089 PMCID: PMC7404396 DOI: 10.3390/ijms21145068] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/10/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNA), and more recently long non-coding RNAs (lncRNA), are emerging as a driving force for hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death. In this work, we investigated a possible RNA regulatory network involving two oncosuppressive miRNAs, miR-125a and let-7e, and a long non-coding antisense RNA, SPACA6P-AS (SP-AS), all transcribed from the same locus, with SP-AS in the opposite direction and thus carrying complementary sequences to the miRNAs. In vitro experiments validated the binding of the miRNAs to SP-AS. Then, the boosting of either the miRNAs or SP-AS levels demonstrated their reciprocal inhibition. In addition, overexpression of SP-AS resulted in a reduced silencing activity of miR-125a and let-7e toward their key oncogenic targets, i.e., Lin28b, MMP11, SIRT7, Zbtb7a, Cyclin D1, CDC25B, HMGA2, that resulted significantly upregulated. Finally, the analysis of 374 HCC samples in comparison to 50 normal liver tissues showed an upregulation of SP-AS and a reverse expression of miR-125a, not observed for let-7e; consistently, miR-125a oncogenic targets were upregulated. Overall, the data depict a novel competing endogenous RNA (ceRNA) network, ceRNET, whereby miR-125a can regulate the expression of SP-AS, which in turn regulates the miRNA by competing with the binding to the mRNA targets. We speculate that the unbalancing of any network component may contribute to hepatocarcinogenesis.
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Affiliation(s)
- Armando Di Palo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (A.D.P.); (C.S.); (A.R.)
| | - Chiara Siniscalchi
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (A.D.P.); (C.S.); (A.R.)
| | - Nicola Mosca
- Inserm, BMGIC, U1035, University of Bordeaux, 33076 Bordeaux, France;
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (A.D.P.); (C.S.); (A.R.)
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (A.D.P.); (C.S.); (A.R.)
- Correspondence:
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14
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Yanai M, Kurata M, Muto Y, Iha H, Kanao T, Tatsuzawa A, Ishibashi S, Ikeda M, Kitagawa M, Yamamoto K. Clinicopathological and molecular analysis of SIRT7 in hepatocellular carcinoma. Pathology 2020; 52:529-537. [PMID: 32586688 DOI: 10.1016/j.pathol.2020.03.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 03/24/2020] [Accepted: 03/29/2020] [Indexed: 12/24/2022]
Abstract
Sirtuin 7 (SIRT7) is a NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase that is reported to contribute to tumour growth and invasion by selectively acting on histone H3K18. It is overexpressed in several cancers including hepatocellular carcinoma (HCC). In this study, we investigated the relationship between SIRT7 expression, proliferation (Ki-67 index) in human HCC tissues, and patient prognosis. We analysed 219 HCC samples obtained retrospectively, for clinicopathological features, and with immunohistochemistry. SIRT7 overexpression was observed in 73 cases (33%) and correlated with vascular invasion and poor differentiation of HCC. Ki-67 labelling index was observed to be significantly higher in SIRT7 overexpressing cases. Interestingly, the Ki-67 labelling index was higher in SIRT7 overexpressing cases regardless of the differentiation status of HCC. Multivariate analysis demonstrated SIRT7 overexpression as an independent factor predictive of poor prognosis (p=0.016). In vitro, SIRT7 knockdown led to reduced growth in cells and resulted in a lower percentage of G0/G1 cells compared to controls. In addition, the ratio of apoptotic cells following sorafenib treatment was significantly higher in SIRT7 knockdown cells than control cells (p=0.040), implying that SIRT7 knockdown potentiated the effect of sorafenib. In conclusion, our study showed that overexpression of SIRT7 was associated with increased proliferative activity in HCC and predictive of poor prognosis. In addition, our in vitro model showed that SIRT7 knockdown was associated with reduced proliferation, and suggested abrogation of SIRT7 may potentiate the effect of sorafenib. Therefore, we propose that SIRT7 expression by HCC may be used as a prognostic biomarker, and that SIRT7 may be a potential target for new therapeutic modalities.
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Affiliation(s)
- Masae Yanai
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Morito Kurata
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yutaka Muto
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroto Iha
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Department of Pathology and Cell Biology, Graduate School of Medicine and Faculty of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Toshinori Kanao
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Anna Tatsuzawa
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sachiko Ishibashi
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masumi Ikeda
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masanobu Kitagawa
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kouhei Yamamoto
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
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15
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Proto-oncogene Zbtb7a represses miR-125a-5p transcription in hepatocellular carcinoma cells. Mol Biol Rep 2020; 47:4875-4878. [PMID: 32410140 DOI: 10.1007/s11033-020-05512-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 05/08/2020] [Indexed: 02/07/2023]
Abstract
Zbtb7a is a transcription factor whose dysfunction is correlated to the development of several types of cancer, including hepatocellular carcinoma (HCC). It generally acts as a repressor of transcription downregulating the expression of several target genes including oncosuppressors ARF and Rb. In this study, Zbtb7a was found to suppress the expression of miR-125a, an oncosuppressive miRNA that is often downregulated in HCC. This effect is mediated by the binding of the transcription factor to a regulatory sequence in the promoter of the transcription unit of miR-125a located 14 bp upstream of the transcription start site. Consistent with this observation, the analysis of 370 HCC samples showed an upregulation of Zbtb7a compared to 50 normal liver tissues and a reverse correlation with miR-125a expression. These data suggest that miR-125a may support the oncogenic potential of Zbtb7a.
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16
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Morishita A, Fujita K, Iwama H, Chiyo T, Fujihara S, Oura K, Tadokoro T, Mimura S, Nomura T, Tani J, Yoneyama H, Kobayashi K, Kamada H, Guan Y, Nishiyama A, Okano K, Suzuki Y, Himoto T, Shimotohno K, Masaki T. Role of microRNA-210-3p in hepatitis B virus-related hepatocellular carcinoma. Am J Physiol Gastrointest Liver Physiol 2020; 318:G401-G409. [PMID: 31905024 DOI: 10.1152/ajpgi.00269.2019] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared with nontumor tissue. Thus, we examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002-2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: 1) HBV-related HCC and adjacent nontumor tissue, 2) HCV-related HCC and adjacent nontumor tissue, and 3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes, including HBx in the HBV-positive HCC cells. MiR-210-3p might, thus, be a new biomarker for the risk of HBV-related HCC.NEW & NOTEWORTHY Our present study demonstrated that miR-210-3p is the only microRNA with enhanced expression in HBV-related HCC, and the enhanced expression of miR-210-3p upregulates HBx expression. Therefore, miR-210-3p might be a pivotal biomarker of HBV-related hepatocarcinogenesis, and the inhibition of miR-210-3p could prevent inducing hepatocarcinogenesis related to HBV infection.
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Affiliation(s)
- Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, Kagawa, Japan
| | - Taiga Chiyo
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Shintaro Fujihara
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Kiyoyuki Kobayashi
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hideki Kamada
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Yu Guan
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa, Japan
| | - Kunitada Shimotohno
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
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17
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Li W, Jiang H. Up-regulation of miR-498 inhibits cell proliferation, invasion and migration of hepatocellular carcinoma by targeting FOXO3. Clin Res Hepatol Gastroenterol 2020; 44:29-37. [PMID: 31208923 DOI: 10.1016/j.clinre.2019.04.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 04/25/2019] [Accepted: 04/29/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND To unravel the fundamental role of miR-498 in the context of hepatocellular carcinoma cells and understands underlying potential mechanism. METHODS Relative viability was interrogated using MTT method and cell proliferation was determined with colony formation assay. The protein levels of cleaved Caspase-3, Bcl-2, Cyclin D, CDK4, FOXO3 and β-actin were analyzed by western blotting. Cell invasion and migration was evaluated by transwell assay and wound healing, respectively. The relative abundance of Cyclin D, CDK4, FOXO3 and miR-498 transcripts was measured using real-time PCR. The regulatory action of miR-498 on FOXO3 expression was analyzed with luciferase reporter. RESULTS Ectopic over-expression of miR-498 significantly inhibited viability and proliferation, suppressed cell migration and invasion, delayed cell cycle progression. We further identified FOXO3 as downstream target gene of miR-498, and positively modulated FOXO3 translation in miR-498-proficient cells consequently contributed to its anti-tumoral properties. CONCLUSIONS Our data highlighted the tumor suppressor role of miR-498-FOXO3 signaling in hepatocellular carcinoma cells, which might hold promise for therapeutic exploitation.
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Affiliation(s)
- Wenqin Li
- Department of gastroenterology, the Second Clinical Medical College, Yangtze University, 434020 Jingzhou, Hubei, China
| | - Hua Jiang
- The Ninth People's Hospital of Chongqing, No 69, Jialing Village, 400700 Chongqing, Beibei District, China.
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18
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Liu R, Wang M, Li E, Yang Y, Li J, Chen S, Shen WJ, Azhar S, Guo Z, Hu Z. Dysregulation of microRNA-125a contributes to obesity-associated insulin resistance and dysregulates lipid metabolism in mice. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158640. [PMID: 31988048 DOI: 10.1016/j.bbalip.2020.158640] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 12/27/2019] [Accepted: 01/23/2020] [Indexed: 12/14/2022]
Abstract
Obesity is associated with an increased risk of developing insulin resistance (IR) and type 2 diabetes (T2D). A diverse group of factors including miRNA has been implicated in the pathogenesis of these two metabolic conditions, although underlying molecular mechanisms involved are not well defined. Here, we provide evidence that hepatic miR-125a levels are diminished in both genetic as well as dietary mouse models of obesity. Overexpression of miR-125a enhanced insulin signaling and attenuated cellular lipid accumulation in HepG2 cells and Hepa1-6 cells. Likewise, treatment of mice with ago-miR-125a increased insulin sensitivity, similar to overexpression of miR-125a, whereas treatment of mice with antago-miR-125a blunted the insulin sensitivity. Furthermore, overexpression of miR-125a in mice previously fed a high-fat diet (HFD), significantly improved insulin sensitivity, and attenuated obesity-linked hepatic steatosis and hepatocyte lipid accumulation. In addition, we show that ELOVL fatty acid elongase 6 (Elovl6) is a direct target of miR-125a, and participates in miR-125a mediated regulation of insulin sensitivity and lipid metabolism. These data led us to conclude that dysregulated miR-125a expression augments the development of obesity-induced IR and that miR-125a might serve as a therapeutic target for the development of new drug(s) in the clinical management of metabolic diseases.
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Affiliation(s)
- Rui Liu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Meina Wang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Enjie Li
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Yang Yang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Jiaxin Li
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Siyu Chen
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Wen-Jun Shen
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA; Division of Endocrinology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Salman Azhar
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA; Division of Endocrinology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Zhigang Guo
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Zhigang Hu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China.
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19
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Yang M, Tang X, Wang Z, Wu X, Tang D, Wang D. miR-125 inhibits colorectal cancer proliferation and invasion by targeting TAZ. Biosci Rep 2019; 39:BSR20190193. [PMID: 31782506 PMCID: PMC6911154 DOI: 10.1042/bsr20190193] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 11/06/2019] [Accepted: 11/28/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignant tumor worldwide and is a serious threat to human health. MicroRNAs (miRNAs) play a key role in oncogenesis and cancer progression. MiRNA-125 (miR-125) is an important miRNA that is dysregulated in several kinds of cancers. Thus, we investigated the expression and effects of miR-125 and Transcriptional co-activator with PDZ-binding motif (TAZ) for a better understanding of the underlying mechanism of tumor progression in CRC, which may provide an emerging biomarker for diagnosis and treatment of CRC. We measured the expression levels of miR-125 in CRC tissues, adjacent tissues, and cell lines (e.g. HCT116, SW480, FHC) by quantitative real-time polymerase chain reaction (qRT-PCR). The effect of miR-125 on proliferation and invasion in CRC cells was detected by Cell Counting Kit-8 (CCK-8), clone formation assay, and transwell assay. Western blotting and qRT-PCR were used to investigate the expression of TAZ after knocking down miR-125 in HCT116 cells or overexpressing miR-125 in SW480 cells. MiR-125 was significantly down-regulated in CRC compared with pericarcinomatous tissue from 18 patients. An miR-125 inhibitor promoted CRC cell proliferation and invasion, while miR-125 mimic had the opposite effect. Moreover, we found that TAZ was an miR-125 target and the siRNA knockdown of TAZ could reverse the effect of the miR-125 inhibitor on proliferation and invasion in HCT116 cells. The present study shows that miR-125 suppresses CRC proliferation and invasion by targeting TAZ.
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Affiliation(s)
- Meiyuan Yang
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Renmin Road No.139, Changsha 410001, China
| | - Xiaoli Tang
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Renmin Road No.139, Changsha 410001, China
| | - Zheng Wang
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
| | - Xiaoqing Wu
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
| | - Dong Tang
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
- Department of General Surgery, Medical College, Yangzhou University, Northern Jiangsu Province Hospital, General Surgery Institute of Yangzhou University, Nantong Road No.98, Yangzhou 225001, China
| | - Daorong Wang
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
- Department of General Surgery, Medical College, Yangzhou University, Northern Jiangsu Province Hospital, General Surgery Institute of Yangzhou University, Nantong Road No.98, Yangzhou 225001, China
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20
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miR-22-3p is involved in gluconeogenic pathway modulated by 3,5-diiodo-L-thyronine (T2). Sci Rep 2019; 9:16645. [PMID: 31719576 PMCID: PMC6851083 DOI: 10.1038/s41598-019-53019-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 10/21/2019] [Indexed: 12/17/2022] Open
Abstract
The 3,5-diiodo-L-thyronine (T2) has emerged as an active iodothyronine and its beneficial effects on glucose metabolism including glucose tolerance and insulin resistance is well established. However, little is known about its molecular mechanisms. Given the emerging importance of microRNAs in various metabolic diseases, in this study a possible link between the effects of T2 on glucose metabolism and miRNA expression was investigated by using an in vivo model in which T2 was administered in rats receiving a high fat diet, a condition known to impair glucose homeostasis. The results showed that T2-treated rats had a better tolerance to glucose load and a better performance at the insulin tolerance test in comparison to high fat diet animals. Interestingly, in the serum of the animals treated with T2 there was a general decrease of miRNAs with miR-22a-3p, miR-34c-5p and miR-33a-3p significantly downregulated. Furthermore, miR-22a-3p had the largest variation pointing toward its preeminent role in T2 metabolic effect. In fact, in liver there was an up-regulation of its target (Transcription Factor 7) Tcf7, which had an important impact on gluconeogenesis. This study provide, for the first time, evidences that miRNAs are involved in the effects exerted by T2 on glucose homeostasis.
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21
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Mao D, Li H, Zhang L, Xu J, Yu C, Zhang Q. Bilobalide alleviates IL-17-induced inflammatory injury in ATDC5 cells by downregulation of microRNA-125a. J Biochem Mol Toxicol 2019; 33:e22405. [PMID: 31593333 DOI: 10.1002/jbt.22405] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 08/01/2019] [Accepted: 09/18/2019] [Indexed: 01/03/2023]
Abstract
Ankylosing spondylitis (AS) is a high disability and greatly destructive disease. In this study, we preliminarily studied the function and mechanism of bilobalide (BIL) on interleukin (IL)-17-induced inflammatory injury in ATDC5 cells. CCK-8 and migration assays were used to detect the functions of IL-7, BIL, and microRNA (miR)-125a on cell viability and migration. The miR-125a level was changed by transfection, and tested by real-time quantitative polymerase chain reaction. Additionally, Western blot tested the levels of inflammatory factors (IL-6 and tumor necrosis factor-α), matrix metalloproteinases (MMPs), and pathway-related proteins. Moreover, the enzyme-linked immunosorbent assay also was used to detect inflammatory factor levels. IL-7 was used to construct an inflammatory injury model in ATDC5 cells. Based on this, BIL inhibited IL-17-induced cell viability, migration, and expressions of inflammatory factors and MMPs. Furthermore, we found BIL negatively regulated miR-125a, and the miR-125a mimic could partly reverse the effects of BIL on IL-17-injury. Finally, we showed that BIL inhibited the c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-κB) pathways, and the miR-125a mimic had the opposite effect. BIL inhibited IL-17-induced inflammatory injury in ATDC5 cells by downregulation of miR-125a via JNK and NF-κB signaling pathways.
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Affiliation(s)
- Dongmei Mao
- Department of Cardiology, Shengli Oilfield Central Hospital, Dongying, Shandong, China
| | - Hong Li
- Department of Critical Care Medicine, Shengli Oilfield Central Hospital, Dongying, Shandong, China
| | - Lei Zhang
- Department of Rheumatology and Immunology, Shengli Oilfield Central Hospital, Dongying, Shandong, China
| | - Jian Xu
- Department of Rheumatology and Immunology, Shengli Oilfield Central Hospital, Dongying, Shandong, China
| | - Chunyan Yu
- Department of Rheumatology and Immunology, Shengli Oilfield Central Hospital, Dongying, Shandong, China
| | - Qi Zhang
- Department of Rheumatology and Immunology, Shengli Oilfield Central Hospital, Dongying, Shandong, China
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22
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Xu X, Tao Y, Niu Y, Wang Z, Zhang C, Yu Y, Ma L. miR-125a-5p inhibits tumorigenesis in hepatocellular carcinoma. Aging (Albany NY) 2019; 11:7639-7662. [PMID: 31527306 PMCID: PMC6781988 DOI: 10.18632/aging.102276] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 09/07/2019] [Indexed: 04/16/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers world-wide. miR-125a-5p is a tumor suppressor in HCC and other cancers, but its mechanisms of action during HCC tumorigenesis remain largely unknown. In this study, we found that miR-125a-5p expression was significantly lower in HCC tissues and cell lines than matched normal tissues and liver cells. miR-125a-5p overexpression inhibited HCC cell proliferation and induced apoptosis in vitro and in vivo, while miR-125a-5p knockdown had the opposite effects. In addition, PTPN1 and MAP3K11 were identified as targets of miR-125a-5p. Knocking down PTPN1 and MAP3K11 activated the JNK MAPK signaling pathway to suppress HCC cell proliferation and induce apoptosis. Our findings suggest that miR-125a-5p may be a useful therapeutic target for treatment of HCC patients.
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Affiliation(s)
- Xin Xu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Yuquan Tao
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Yongjie Niu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Zhixian Wang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Congcong Zhang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Yongchun Yu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
- Institute for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Lifang Ma
- Institute for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
- Department of Clinical Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
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23
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Wang JK, Wang Z, Li G. MicroRNA-125 in immunity and cancer. Cancer Lett 2019; 454:134-145. [PMID: 30981762 DOI: 10.1016/j.canlet.2019.04.015] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/09/2019] [Accepted: 04/09/2019] [Indexed: 12/31/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play a wide variety of critical roles in different biological processes by post-transcriptionally regulating gene expression. They access diverse regulatory pathways during various stages of cellular differentiation, growth, and apoptosis, and can contribute to both normal and diseased functions. One important family of miRNAs involved in these functions is the miR-125 family (miR-125a and miR-125b). Investigations have been made to increasingly uncover the mechanisms by which the miR-125 family regulates normal homeostasis and growth in a variety of cell types including immune cells, and how dysregulation of miR-125a and miR-125b can lead to disease pathogenesis and tumorigenesis. In this review, we summarize what is currently known about miR-125a and miR-125b, mainly focusing on their roles in immune cell development and function as well as tumor suppression and promotion.
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Affiliation(s)
- Jessica K Wang
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States
| | - Zhe Wang
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China; Suzhou Institute of Systems Medicine, Suzhou, 215123, China
| | - Guideng Li
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States; Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China; Suzhou Institute of Systems Medicine, Suzhou, 215123, China.
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24
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Yu H, Shi G. Cisplatin chemotherapy-induced miRNA-210 signaling inhibits hepatocellular carcinoma cell growth. Transl Cancer Res 2019; 8:626-634. [PMID: 35116795 PMCID: PMC8799276 DOI: 10.21037/tcr.2019.03.26] [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: 08/27/2018] [Accepted: 03/08/2019] [Indexed: 11/17/2022]
Abstract
BACKGROUND Chemotherapy has improved the survival of hepatocellular carcinoma (HCC) patients, but the underlying mechanisms are still not fully understood. MicroRNAs (miRNAs) are critical regulators in carcinogenesis and involved in response to cancer therapy. However, the correlation between miRNAs and chemotherapy is not well-established, and the detailed mechanisms and responsive targets remain unclear. Here, we investigated the function and mechanism of miR-210 in HCC chemotherapy with cisplatin. METHODS This study involved samples from patients after HCC surgery, including tumor and non-tumor liver tissues. Total RNA was extracted from the fresh tissue samples and the levels of miR-210 were assessed by qRT-PCR analysis. Cisplatin treatment was performed in HepG2 and PLC cell lines, and ephrin A3 (EFNA3) levels were determined by Western blotting. RESULTS We observed that miR-210 expression was up-regulated in HCC tissues and correlated with HCC progression. Notably, HCC patients underwent recurrences after chemotherapy showed high levels of miR-210 expression in tumors, indicating that miR-210 might be involved in regulating the chemotherapeutic efficacy. We also demonstrated that cisplatin treatment decreased the expression of miR-210 and increased the expression of miR-210 target EFNA3 in HCC cells. Moreover, miR-210 overexpression prevented the effects of cisplatin and rescued HCC cell growth, and miR-210 inhibition contributed to improved chemosensitivity of cisplatin in HCC cells. CONCLUSIONS Our findings defined a novel mechanism underlying the efficacious effects of cisplatin chemotherapy in HCC, and miR-210-induced EFNA3 signaling might be a potential target of cisplatin in HCC treatment.
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Affiliation(s)
- Huan Yu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Guangyue Shi
- Department of Medical Oncology, the Affiliated Tumor Hospital, Harbin Medical University, Harbin 150001, China
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25
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Russo A, Potenza N. Antiproliferative Activity of microRNA-125a and its Molecular Targets. Microrna 2018; 8:173-179. [PMID: 30394225 DOI: 10.2174/2211536608666181105114739] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/18/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND MicroRNA-125a is present in all animals with bilateral symmetry and displays a conserved nucleotide sequence with a section of 11 bases including the seed region that is identical in all considered species. It primarily downregulates the expression of LIN28, thereby promoting cell differentiation and larval phase transitions in nematodes, mammals and insects. OBJECTIVE In this review, we focus on the cellular control of miR-125a expression and its antiproliferative activity. RESULTS In mammalians, microRNA-125a is present in most adult organs and tissues in which it targets proteins involved in the mitogenic response, such as membrane receptors, intracellular signal transducers, or transcription factors, with the overall effect of inhibiting cell proliferation. Tissue levels of miR-125a generally raise during differentiation but it is often downregulated in cancers, e.g. colon, cervical, gastric, ovarian, lung, and breast cancers, osteosarcoma, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma and hepatocellular carcinoma. CONCLUSION The antiproliferative activity of miR-125a, demonstrated in many cell types, together with the notion that this miRNA is downregulated in several kinds of cancers, give a substantial support to the concept that miR-125a plays an oncosuppressive role.
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Affiliation(s)
- Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
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26
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Sagnelli E, Potenza N, Onorato L, Sagnelli C, Coppola N, Russo A. Micro-RNAs in hepatitis B virus-related chronic liver diseases and hepatocellular carcinoma. World J Hepatol 2018; 10:558-570. [PMID: 30310534 PMCID: PMC6177563 DOI: 10.4254/wjh.v10.i9.558] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 04/24/2018] [Accepted: 05/30/2018] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression at the post-transcriptional level by affecting both the stability and translation of complementary mRNAs. Several studies have shown that miRNAs are important regulators in the conflicting efforts between the virus (to manipulate the host for its successful propagation) and the host (to inhibit the virus), culminating in either the elimination of the virus or its persistence. An increasing number of studies report a role of miRNAs in hepatitis B virus (HBV) replication and pathogenesis. In fact, HBV is able to modulate different host miRNAs, particularly through the transcriptional transactivator HBx protein and, conversely, different cellular miRNAs can regulate HBV gene expression and replication by a direct binding to HBV transcripts or indirectly targeting host factors. The present review will discuss the role of miRNAs in the pathogenesis of HBV-related diseases and their role as a biomarker in the management of patients with HBV-related disease and as therapeutic targets.
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Affiliation(s)
- Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy.
| | - Nicoletta Potenza
- DISTABIF, University of Campania "Luigi Vanvitelli", Naples 80100, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Aniello Russo
- DISTABIF, University of Campania "Luigi Vanvitelli", Naples 80100, Italy
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27
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Vasuri F, Visani M, Acquaviva G, Brand T, Fiorentino M, Pession A, Tallini G, D’Errico A, de Biase D. Role of microRNAs in the main molecular pathways of hepatocellular carcinoma. World J Gastroenterol 2018; 24:2647-2660. [PMID: 29991871 PMCID: PMC6034147 DOI: 10.3748/wjg.v24.i25.2647] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/18/2018] [Accepted: 06/16/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignant neoplasia. HCC is characterized by a poor prognosis. The need to find new molecular markers for its diagnosis and prognosis has led to a progressive increase in the number of scientific studies on this topic. MicroRNAs (miRNAs) are small non-coding RNA that play a role in almost all main cellular pathways. miRNAs are involved in the regulation of expression of the major tumor-related genes in carcinogenesis, acting as oncogenes or tumor suppressor genes. The aim of this review was to identify papers published in 2017 investigating the role of miRNAs in HCC tumorigenesis. miRNAs were classified according to their role in the main molecular pathways involved in HCC tumorigenesis: (1) mTOR; (2) Wnt; (3) JAK/STAT; (4) apoptosis; and (5) MAPK. The role of miRNAs in prognosis/response prediction was taken into consideration. Bearing in mind that the analysis of miRNAs in serum and other body fluids would be crucial for clinical management, the role of circulating miRNAs in HCC patients was also investigated. The most represented miRNA-regulated pathway in HCC is mTOR, but apoptosis, Wnt, JAK/STAT or MAPK pathways are also influenced by miRNA expression levels. These miRNAs could thus be used in clinical practice as diagnostic, prognostic or therapeutic targets for HCC treatment.
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Affiliation(s)
- Francesco Vasuri
- Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S.Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Michela Visani
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna - School of Medicine, Bologna 40138, Italy
| | - Giorgia Acquaviva
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna - School of Medicine, Bologna 40138, Italy
| | - Thomas Brand
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie), University of Bologna, Bologna 40127, Italy
| | - Michelangelo Fiorentino
- Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S.Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Annalisa Pession
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna 40138, Italy
| | - Giovanni Tallini
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna - School of Medicine, Bologna 40138, Italy
| | - Antonia D’Errico
- Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S.Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna 40138, Italy
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28
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Coppola N, Onorato L, Panella M, de Stefano G, Mosca N, Minichini C, Messina V, Potenza N, Starace M, Alessio L, Farella N, Sagnelli E, Russo A. Correlation Between the Hepatic Expression of Human MicroRNA hsa-miR-125a-5p and the Progression of Fibrosis in Patients With Overt and Occult HBV Infection. Front Immunol 2018; 9:1334. [PMID: 29951066 PMCID: PMC6008383 DOI: 10.3389/fimmu.2018.01334] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 05/29/2018] [Indexed: 12/16/2022] Open
Abstract
AIMS To evaluate the correlation between the hepatic expression pattern of hsa-miR-125a-5p and HBV-DNA and the progression of fibrosis in patients with overt or occult HBV infection. METHODS We enrolled all the HBsAg-positive treatment naive patients (overt HBV group) and all the HBsAg-negative patients with hepatocellular carcinoma and with a positive HBV-DNA in their hepatic tissue (occult HBV group), who underwent a diagnostic liver biopsy between April 2007 and April 2015. Tissue concentrations of HBV-DNA and hsa-miR-125a-5p were then analyzed by real-time quantitative PCR. Necroinflammatory activity and fibrosis were evaluated according to the Ishak score. RESULTS During the study period, we enrolled 64 patients with overt and 10 patients with occult HBV infection. In the overt HBV group, 35 of 64 (54.7%) showed a mild fibrosis (staging 0-2), 17 (26.6%) a moderate fibrosis (staging 3-4), while the remaining 12 (18.7%) had a cirrhosis. All patients in the occult HBV group were cirrhotic. Patients with more advanced fibrosis stage showed a higher mean age when compared with those with mild (p < 0.00001) or moderate fibrosis (p < 0.00001) and were more frequently male than patients with staging 0-2 (p = 0.04). Similarly, patients with occult B infection were older than HBsAg-positive patients. Liver concentrations of miR-125a-5p were significantly higher in patients with cirrhosis (9.75 ± 4.42 AU) when compared with patients with mild (1.39 ± 0.94, p = 0.0002) or moderate fibrosis (2.43 ± 2.18, p = 0.0006) and were moderately higher in occult than in overt HBV infection (p = 0.09). Moreover, we found an inverse correlation, although not statistically significant, between the tissue HBV-DNA levels and the staging of fibrosis. CONCLUSION This study suggests a correlation between the tissue expression of hsa-miR-125a-5p and the progression of liver damage in a group of patients with occult or overt HBV infection. If confirmed, these data suggest the hsa-miR-125a-5p may be a novel biomarker of hepatic damage.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, University of Campania, Luigi Vanvitelli, Naples, Italy
- Infectious Diseases Unit, AORN Sant’Anna e San Sebastiano, Caserta, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, University of Campania, Luigi Vanvitelli, Naples, Italy
| | - Marta Panella
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, Caserta, Italy
| | - Giorgio de Stefano
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, Caserta, Italy
| | - Carmine Minichini
- Department of Mental Health and Public Medicine, University of Campania, Luigi Vanvitelli, Naples, Italy
| | - Vincenzo Messina
- Infectious Diseases Unit, AORN Sant’Anna e San Sebastiano, Caserta, Italy
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, Caserta, Italy
| | - Mario Starace
- Department of Mental Health and Public Medicine, University of Campania, Luigi Vanvitelli, Naples, Italy
| | - Loredana Alessio
- Infectious Diseases Unit, AORN Sant’Anna e San Sebastiano, Caserta, Italy
| | - Nunzia Farella
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, University of Campania, Luigi Vanvitelli, Naples, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, Caserta, Italy
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29
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Zhao Y, Ma K, Yang S, Zhang X, Wang F, Zhang X, Liu H, Fan Q. MicroRNA-125a-5p enhances the sensitivity of esophageal squamous cell carcinoma cells to cisplatin by suppressing the activation of the STAT3 signaling pathway. Int J Oncol 2018; 53:644-658. [PMID: 29767234 PMCID: PMC6017156 DOI: 10.3892/ijo.2018.4409] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/09/2018] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence has demonstrated that microRNAs (miRNAs or miRs) play a variety of roles in tumor development, progression and chemosensitivity in a wide range of tumors. In this study, we found that miR-125a-5p exhibited a low expression in esophageal squamous cell carcinoma (ESCC) tissues and cells, and that its low expression was associated with higher tumor staging and shorter a survival time of patients with ESCC. Moreover, miR-125a-5p overexpression contributed to the suppression of cell proliferation, cell cycle arrest, cell apoptosis and a decrease in cell migratory and invasive abilities, whereas the downregulation of miR-125a-5p promoted cell proliferation, accelerated cell cycle progression, suppressed apoptosis and enhanced the migratory and invasive abilities of ESCC EC1 and TE1 cells, which may be tightly associated with the epithelial-mesenchymal transition (EMT) process in ESCC. Importantly, miR-125a-5p enhanced the cytotoxic effects of cisplatin on EC1 and TE1 cells, and co-treatment with miR-125a-5p and cisplatin significantly induced cell apoptosis and reduced the cell migratory and invasive abilities of EC1 and TE1 cells, coupled with an increase in the E-cadherin level and a decrease in the N-cadherin and Vimentin levels. Most notably, signal transducer and activator of transcription-3 (STAT3) was found to be a direct target of miR-125a-5p in ESCC cells, and miR-125a-5p overexpression significantly reduced the protein levels of t-STAT3, p-STAT3 and vascular endothelial growth factor (VEGF) in EC1 and TE1 cells. Furthermore, the combination of miR-125a-5p and cisplatin markedly inactivated the STAT3 signaling pathway; however, interleukin (IL)-6, a widely reported activator of the STAT3 signaling pathway, reversed the suppressive effects of miR-125a-5p/cisplatin in ESCC cells on the activation of the STAT3 signaling pathway. Of note, we found that IL-6 markedly reversed the altered cell phenotype mediated by the combination of miR-125a-5p and cisplatin in ESCC cells. These findings suggest that miR-125a-5p may play a pivotal role in the development and progression of ESCC, which may be achieved via the manipulation of the STAT3 signaling pathway.
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Affiliation(s)
- Yan Zhao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Ke Ma
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Shujun Yang
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Xiaosan Zhang
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Feng Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xiaqing Zhang
- College of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Hongtao Liu
- College of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Qingxia Fan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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30
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Panella M, Mosca N, Di Palo A, Potenza N, Russo A. Mutual suppression of miR-125a and Lin28b in human hepatocellular carcinoma cells. Biochem Biophys Res Commun 2018; 500:824-827. [PMID: 29689270 DOI: 10.1016/j.bbrc.2018.04.167] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 04/20/2018] [Indexed: 12/15/2022]
Abstract
MicroRNA-125a exhibits an antiproliferative activity and is downregulated in several types of tumors, including hepatocellular carcinoma where it targets sirtuin-7, matrix metalloproteinase-11, and c-Raf. Another target of miR-125a is Lin28, a pluripotency factor that is generally undetectable in differentiated cells but is often upregulated/reactivated in tumors where it acts as an oncogenic factor promoting cell proliferation and tumor progression. In this study we show that downregulation of Lin28b by miR-125a partially accounts for its antiproliferative activity toward hepatocellular carcinoma cells. We also found that Lin28b is able to bind a conserved GGAG motif of pre-miR-125a and to inhibit its maturation in hepatocellular carcinoma cells. Reciprocal inhibition between miR-125a and Lin28b reasonably generates a positive feedback loop where reactivation of Lin-28b inhibits the expression of both miR-125a and let-7, reinforcing its own expression and leading to a marked overexpression of the mitogenic targets of the two miRNAs. On the other hand, perturbation of these circuits by overexpression of miR-125a suppresses Lin28b leading to a decreased cell proliferation. Overall, these data support a tumor suppressive role for miR-125a and contribute to the elucidation of its molecular targets.
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Affiliation(s)
- Marta Panella
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Armando Di Palo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy.
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31
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Huang WT, Tsai YH, Chen SH, Kuo CW, Kuo YL, Lee KT, Chen WC, Wu PC, Chuang CY, Cheng SM, Lin CH, Leung EY, Chang YC, Cheung CHA. HDAC2 and HDAC5 Up-Regulations Modulate Survivin and miR-125a-5p Expressions and Promote Hormone Therapy Resistance in Estrogen Receptor Positive Breast Cancer Cells. Front Pharmacol 2017; 8:902. [PMID: 29326587 PMCID: PMC5736991 DOI: 10.3389/fphar.2017.00902] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 11/27/2017] [Indexed: 12/18/2022] Open
Abstract
Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER+) breast cancer patients. Even though dysregulations of histone deacetylases (HDACs) are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER+ breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER+, hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER+ hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan-Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER+ breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER+ MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.
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Affiliation(s)
- Wen-Tsung Huang
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, Tainan, Taiwan
| | - Yu-Hsuan Tsai
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shang-Hung Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Division of Oncology and Hematology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ching-Wen Kuo
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yao-Lung Kuo
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kuo-Ting Lee
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Chung Chen
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei Chih Wu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
| | - Chun-Yu Chuang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
| | - Siao Muk Cheng
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-Hui Lin
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Euphemia Yee Leung
- Auckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Yung-Chieh Chang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun Hei Antonio Cheung
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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32
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Potenza N, Panella M, Castiello F, Mosca N, Amendola E, Russo A. Molecular mechanisms governing microRNA-125a expression in human hepatocellular carcinoma cells. Sci Rep 2017; 7:10712. [PMID: 28878257 PMCID: PMC5587745 DOI: 10.1038/s41598-017-11418-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 08/24/2017] [Indexed: 12/13/2022] Open
Abstract
MicroRNA-125a-5p (miR-125a) is a vertebrate homolog of lin-4, the first discovered microRNA, and plays a fundamental role in embryo development by downregulating Lin-28 protein. MiR-125a is also expressed in differentiated cells where it generally acts as an antiproliferative factor by targeting membrane receptors or intracellular transductors of mitogenic signals. MiR-125a expression is downregulated in several tumors, including hepatocellular carcinoma (HCC) where it targets sirtuin-7, matrix metalloproteinase-11, VEGF-A, Zbtb7a, and c-Raf. In this study, we have isolated the transcription promoter of human miR-125a and characterized its activity in HCC cells. It is a TATA-less Pol II promoter provided with an initiator element and a downstream promoter element, located 3939 bp upstream the genomic sequence of the miRNA. The activity of the promoter is increased by the transcription factor NF-kB, a master regulator of inflammatory response, and miR-125a itself was found to strengthen this activation through inhibition of TNFAIP3, a negative regulator of NF-kB. This finding contributes to explain the increased levels of miR-125a observed in the liver of patients with chronic hepatitis B.
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Affiliation(s)
- Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Marta Panella
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Filomena Castiello
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Elena Amendola
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131, Napoli, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy.
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