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1
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Shen YZ, Yang GP, Ma QM, Wang YS, Wang X. Regulation of lncRNA-ENST on Myc-mediated mitochondrial apoptosis in mesenchymal stem cells: In vitro evidence implicated for acute lung injury therapeutic potential. World J Stem Cells 2025; 17:100079. [PMID: 40160692 PMCID: PMC11947895 DOI: 10.4252/wjsc.v17.i3.100079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 12/04/2024] [Accepted: 02/05/2025] [Indexed: 03/21/2025] Open
Abstract
BACKGROUND Acute lung injury (ALI) is a fatal and heterogeneous disease. While bone marrow mesenchymal stem cells (BMSCs) have shown promise in ALI repair, their efficacy is compromised by a high apoptotic percentage. Preliminary findings have indicated that long noncoding RNA (lncRNA)-ENST expression is markedly downregulated in MSCs under ischemic and hypoxic conditions, establishing a rationale for in vitro exploration. AIM To elucidate the role of lncRNA-ENST00000517482 (lncRNA-ENST) in modulating MSC apoptosis. METHODS Founded on ALI in BEAS-2B cells with lipopolysaccharide, this study employed a transwell co-culture system to study BMSC tropism. BMSCs were genetically modified to overexpress or knockdown lncRNA-ENST. After analyzing the effects on autophagy, apoptosis and cell viability, the lncRNA-ENST/miR-539/c-MYC interaction was confirmed by dual-luciferase assays. RESULTS These findings have revealed a strong correlation between lncRNA-ENST levels and the apoptotic and autophagic status of BMSCs. On the one hand, the over-expression of lncRNA-ENST, as determined by Cell Counting Kit-8 assays, increased the expression of autophagy markers LC3B, ATG7, and ATG5. On the other hand, it reduced apoptosis and boosted BMSC viability. In co-cultures with BEAS-2B cells, lncRNA-ENST overexpression also improved cell vitality. Additionally, by downregulating miR-539 and upregulating c-MYC, lncRNA-ENST was found to influence mitochondrial membrane potential, enhance BMSC autophagy, mitigate apoptosis and lower the secretion of pro-inflammatory cytokines interleukin-6 and interleukin-1β. Collectively, within the in vitro framework, these results have highlighted the therapeutic potential of BMSCs in ALI and the pivotal regulatory role of lncRNA-ENST in miR-539 and apoptosis in lipopolysaccharide-stimulated BEAS-2B cells. CONCLUSION Our in vitro results show that enhanced lncRNA ENST expression can promote BMSC proliferation and viability by modulating the miR-539/c-MYC axis, reduce apoptosis and induce autophagy, which has suggested its therapeutic potential in the treatment of ALI.
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Affiliation(s)
- Ye-Zhou Shen
- Department of Critical Care Medicine, Shanghai East Hospital, Tongji University, Shanghai 200120, China
| | - Guang-Ping Yang
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Qi-Min Ma
- Department of Critical Care Medicine, Shanghai East Hospital, Tongji University, Shanghai 200120, China
| | - Yu-Song Wang
- Department of Critical Care Medicine, Shanghai East Hospital, Tongji University, Shanghai 200120, China
| | - Xin Wang
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China.
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2
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Li B, Yao B, Guo X, Wang Z, Xie W, Wu X, Wang F, Mei Y. c-Myc-induced long noncoding RNA MIRE cooperates with hnRNPK to stabilize ELF2 mRNA and promotes clear cell renal cell carcinogenesis. Cancer Gene Ther 2023; 30:1215-1226. [PMID: 37248433 DOI: 10.1038/s41417-023-00631-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 05/31/2023]
Abstract
Elevated expression of c-Myc is associated with a variety of human cancers including clear cell renal cell carcinoma (ccRCC). Increasing evidence suggests that long noncoding RNAs (lncRNAs) are an important class of molecules that regulate both tumor initiation and progression. Here, we report the lncRNA c-Myc-induced regulator of ELF2 (MIRE) as a transcriptional target of c-Myc. MIRE functions as an oncogenic molecule in ccRCC by increasing ELF2 expression. Mechanistically, MIRE promotes phase separation of the RNA binding protein hnRNPK and facilitates the binding of hnRNPK to ELF2 mRNA, thereby resulting in the stabilization of ELF2 mRNA. Interestingly, MIRE is also under transcriptional control by ELF2, establishing an ELF2-MIRE positive feedback loop. Together, these findings provide new insights into the mechanisms by which c-Myc promotes tumorigenesis. They also implicate MIRE as an important regulator of ccRCC carcinogenesis.
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Affiliation(s)
- Bingyan Li
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Bo Yao
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Xiaorui Guo
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Zhongyu Wang
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Wei Xie
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China
- DeepBio Technology Ltd Co., 515 ShenNan Road, Shanghai, 201612, China
| | - Xianning Wu
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China.
| | - Fang Wang
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China.
| | - Yide Mei
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China.
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China.
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3
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García-Caballero D, Hart JR, Vogt PK. Long Non-Coding RNAs as "MYC Facilitators". PATHOPHYSIOLOGY 2023; 30:389-399. [PMID: 37755396 PMCID: PMC10534484 DOI: 10.3390/pathophysiology30030030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 09/28/2023] Open
Abstract
In this article, we discuss a class of MYC-interacting lncRNAs (long non-coding RNAs) that share the following criteria: They are direct transcriptional targets of MYC. Their expression is coordinated with the expression of MYC. They are required for sustained MYC-driven cell proliferation, and they are not essential for cell survival. We refer to these lncRNAs as "MYC facilitators" and discuss two representative members of this class of lncRNAs, SNHG17 (small nuclear RNA host gene) and LNROP (long non-coding regulator of POU2F2). We also present a general hypothesis on the role of lncRNAs in MYC-mediated transcriptional regulation.
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Affiliation(s)
| | | | - Peter K. Vogt
- Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
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4
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García-Caballero D, Hart JR, Vogt PK. The MYC-regulated lncRNA LNROP (ENSG00000254887) enables MYC-driven cell proliferation by controlling the expression of OCT2. Cell Death Dis 2023; 14:168. [PMID: 36849510 PMCID: PMC9971199 DOI: 10.1038/s41419-023-05683-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 02/10/2023] [Accepted: 02/14/2023] [Indexed: 03/01/2023]
Abstract
MYC controls most of the non-coding genome. Several long noncoding transcripts were originally identified in the human B cell line P496-3 and then shown to be required for MYC-driven proliferation of Burkitt lymphoma-derived RAMOS cells. In this study, we used RAMOS cells exclusively as a representative of the human B cell lineage. One of the MYC-controlled lncRNAs required for RAMOS cell proliferation is ENSG00000254887 which we will term LNROP (long non-coding regulator of POU2F2). In the genome, LNROP is located in close proximity of POU2F2, the gene encoding OCT2. OCT2 is a transcription factor with important roles in sustaining the proliferation of human B cells. Here we show that LNROP is a nuclear RNA and a direct target of MYC. Downregulation of LNROP attenuates the expression of OCT2. This effect of LNROP on the expression of OCT2 is unidirectional as downregulation of OCT2 does not alter the expression of LNROP. Our data suggest that LNROP is a cis-acting regulator of OCT2. To illustrate the downstream reach of LNROP, we chose a prominent target of OCT2, the tyrosine phosphatase SHP-1. Downregulation of OCT2 elevates the expression of SHP-1. Our data suggest the following path of interactions: LNROP enables the proliferation of B cells by positively and unidirectionally regulating the growth-stimulatory transcription factor OCT2. In actively proliferating B cells, OCT2 attenuates the expression and anti-proliferative activity of SHP-1.
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Affiliation(s)
- Daniel García-Caballero
- Scripps Research, Department of Molecular Medicine, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
| | - Jonathan R Hart
- Scripps Research, Department of Molecular Medicine, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
| | - Peter K Vogt
- Scripps Research, Department of Molecular Medicine, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
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5
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Winkle M, Tayari MM, Kok K, Duns G, Grot N, Kazimierska M, Seitz A, de Jong D, Koerts J, Diepstra A, Dzikiewicz-Krawczyk A, Steidl C, Kluiver J, van den Berg A. The lncRNA KTN1-AS1 co-regulates a variety of Myc-target genes and enhances proliferation of Burkitt lymphoma cells. Hum Mol Genet 2022; 31:4193-4206. [PMID: 35866590 DOI: 10.1093/hmg/ddac159] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 06/22/2022] [Accepted: 07/07/2022] [Indexed: 01/21/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are involved in many normal and oncogenic pathways through a diverse repertoire of transcriptional and posttranscriptional regulatory mechanisms. LncRNAs that are under tight regulation of well-known oncogenic transcription factors such as c-Myc (Myc) are likely to be functionally involved in their disease-promoting mechanisms. Myc is a major driver of many subsets of B cell lymphoma and to date remains an undruggable target. We identified three Myc-induced and four Myc-repressed lncRNAs by use of multiple in vitro models of Myc-driven Burkitt lymphoma and detailed analysis of Myc binding profiles. We show that the top Myc-induced lncRNA KTN1-AS1 is strongly upregulated in different types of B cell lymphoma compared with their normal counterparts. We used CRISPR-mediated genome editing to confirm that the direct induction of KTN1-AS1 by Myc is dependent on the presence of a Myc E-box-binding motif. Knockdown of KTN1-AS1 revealed a strong negative effect on the growth of three BL cell lines. Global gene expression analysis upon KTN1-AS1 depletion shows a strong enrichment of key genes in the cholesterol biosynthesis pathway as well as co-regulation of many Myc-target genes, including a moderate negative effect on the levels of Myc itself. Our study suggests a critical role for KTN1-AS1 in supporting BL cell growth by mediating co-regulation of a variety of Myc-target genes and co-activating key genes involved in cholesterol biosynthesis. Therefore, KTN1-AS1 may represent a putative novel therapeutic target in lymphoma.
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Affiliation(s)
- Melanie Winkle
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands.,Department of Translational Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mina M Tayari
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands.,Department of Human Genetics, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Klaas Kok
- Department of Genetics, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands
| | - Gerben Duns
- Department of Lymphoid Cancer Research, BC Cancer Center, Vancouver, BC, Canada
| | - Natalia Grot
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Marta Kazimierska
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Annika Seitz
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands
| | - Debora de Jong
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands
| | - Jasper Koerts
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands
| | - Arjan Diepstra
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands
| | | | - Christian Steidl
- Department of Lymphoid Cancer Research, BC Cancer Center, Vancouver, BC, Canada
| | - Joost Kluiver
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands
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6
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Ziel-Swier LJYM, Liu Y, Seitz A, de Jong D, Koerts J, Rutgers B, Veenstra R, Razak FRA, Dzikiewicz-Krawczyk A, van den Berg A, Kluiver J. The Role of the MYC/miR-150/MYB/ZDHHC11 Network in Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma. Genes (Basel) 2022; 13:genes13020227. [PMID: 35205272 PMCID: PMC8871936 DOI: 10.3390/genes13020227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 12/04/2022] Open
Abstract
We previously described involvement of the MYC/miR-150/MYB/ZDHHC11 network in the growth of Burkitt lymphoma (BL) cells. Here we studied the relevance of this network in the two other B-cell lymphomas: Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL). Expression levels of the network components were assessed at the RNA and protein level. The effect of modulating levels of the network components on cell growth was determined through GFP competition assay. AGO2-RNA immunoprecipitation was performed to validate targeting by miR-150. Expression levels of MYC, MYB and ZDHHC11 were increased, while miR-150 levels were decreased similar to the pattern observed in BL. The knockdown of MYC, MYB and ZDHHC11 decreased the growth of HL and DLBCL cells. In contrast, overexpression of miR-150 did not induce clear phenotypes in HL, and limited the effects in DLBCL. This could not be explained by the differences in overexpression levels. Furthermore, we showed that in HL, ZDHHC11 and MYB are efficiently targeted by miR-150. To conclude, MYC, MYB and ZDHHC11 are critical for the growth of HL and DLBCL cells consistent with the role observed in BL cells, while low endogenous miR-150 levels appeared to be less critical for the growth of HL and DLBCL cells despite the effective targeting of ZDHHC11 and MYB.
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Affiliation(s)
- Lotteke J. Y. M. Ziel-Swier
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.J.Y.M.Z.-S.); (Y.L.); (A.S.); (D.d.J.); (J.K.); (B.R.); (R.V.); (A.v.d.B.)
| | - Yichen Liu
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.J.Y.M.Z.-S.); (Y.L.); (A.S.); (D.d.J.); (J.K.); (B.R.); (R.V.); (A.v.d.B.)
| | - Annika Seitz
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.J.Y.M.Z.-S.); (Y.L.); (A.S.); (D.d.J.); (J.K.); (B.R.); (R.V.); (A.v.d.B.)
| | - Debora de Jong
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.J.Y.M.Z.-S.); (Y.L.); (A.S.); (D.d.J.); (J.K.); (B.R.); (R.V.); (A.v.d.B.)
| | - Jasper Koerts
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.J.Y.M.Z.-S.); (Y.L.); (A.S.); (D.d.J.); (J.K.); (B.R.); (R.V.); (A.v.d.B.)
| | - Bea Rutgers
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.J.Y.M.Z.-S.); (Y.L.); (A.S.); (D.d.J.); (J.K.); (B.R.); (R.V.); (A.v.d.B.)
| | - Rianne Veenstra
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.J.Y.M.Z.-S.); (Y.L.); (A.S.); (D.d.J.); (J.K.); (B.R.); (R.V.); (A.v.d.B.)
| | | | | | - Anke van den Berg
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.J.Y.M.Z.-S.); (Y.L.); (A.S.); (D.d.J.); (J.K.); (B.R.); (R.V.); (A.v.d.B.)
| | - Joost Kluiver
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (L.J.Y.M.Z.-S.); (Y.L.); (A.S.); (D.d.J.); (J.K.); (B.R.); (R.V.); (A.v.d.B.)
- Correspondence:
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7
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Li B, Zhang G, Wang Z, Yang Y, Wang C, Fang D, Liu K, Wang F, Mei Y. c-Myc-activated USP2-AS1 suppresses senescence and promotes tumor progression via stabilization of E2F1 mRNA. Cell Death Dis 2021; 12:1006. [PMID: 34707111 PMCID: PMC8551278 DOI: 10.1038/s41419-021-04330-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 10/11/2021] [Accepted: 10/14/2021] [Indexed: 12/16/2022]
Abstract
The c-Myc oncoprotein plays a prominent role in cancer initiation, progression, and maintenance. Long noncoding RNAs (lncRNAs) are recently emerging as critical regulators of the c-Myc signaling pathway. Here, we report the lncRNA USP2-AS1 as a direct transcriptional target of c-Myc. Functionally, USP2-AS1 inhibits cellular senescence and acts as an oncogenic molecule by inducing E2F1 expression. Mechanistically, USP2-AS1 associates with the RNA-binding protein G3BP1 and facilitates the interaction of G3BP1 to E2F1 3′-untranslated region, thereby leading to the stabilization of E2F1 messenger RNA. Furthermore, USP2-AS1 is shown as a mediator of the oncogenic function of c-Myc via the regulation of E2F1. Together, these findings suggest that USP2-AS1 is a negative regulator of cellular senescence and also implicates USP2-AS1 as an important player in mediating c-Myc function.
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Affiliation(s)
- Bingyan Li
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Guang Zhang
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhongyu Wang
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yang Yang
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Chenfeng Wang
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Debao Fang
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Kaiyue Liu
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Fang Wang
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
| | - Yide Mei
- The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. .,Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, Anhui, China.
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8
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Baruch E, Nizri-Megnaji T, Berkowitz O, Ginsberg D. A novel E2F1-regulated lncRNA, LAPAS1, is required for S phase progression and cell proliferation. Oncotarget 2021; 12:1072-1082. [PMID: 34084281 PMCID: PMC8169067 DOI: 10.18632/oncotarget.27962] [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: 12/10/2020] [Accepted: 05/03/2021] [Indexed: 11/25/2022] Open
Abstract
The transcription factor E2F1 induces both proliferation and apoptosis and is a critical downstream target of the tumor suppressor RB. Long non-coding RNAs (lncRNAs) are major regulators of many cellular processes, including cell cycle progression and cell proliferation. However, the mode of action as well as the transcriptional regulation of most lncRNAs are only beginning to be understood. Here, we report that a novel human lncRNA, LAPAS1, is an E2F1- regulated lncRNA that affects S phase progression. Inhibition of LAPAS1 expression increases percentage of S phase cells, and its silencing in synchronized cells delays their progression through S phase. In agreement with its suggested role in cell cycle progression, prolonged inhibition of LAPAS1 attenuates proliferation of human cancer cells. Our data demonstrate that LAPAS1 predominantly functions in trans to repress expression of Sphingolipid Transporter 2 (SPNS2). Importantly, knockdown of SPNS2 rescues the effect of LAPAS1 silencing on cell cycle and cell proliferation. Notably, low levels of LAPAS1 are associated with increased survival of kidney cancer patients. Summarily, we identify LAPAS1 as a novel E2F-regulated lncRNA that has a potential role in human cancer and regulates cell-cycle progression and cell proliferation, at least in part, via regulation of SPNS2.
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Affiliation(s)
- Esther Baruch
- The Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Ramat Gan, Israel
| | - Tali Nizri-Megnaji
- The Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Ramat Gan, Israel
| | - Oron Berkowitz
- The Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Ramat Gan, Israel.,Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Doron Ginsberg
- The Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Ramat Gan, Israel
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9
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Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol 2021; 22:96-118. [PMID: 33353982 PMCID: PMC7754182 DOI: 10.1038/s41580-020-00315-9] [Citation(s) in RCA: 2909] [Impact Index Per Article: 727.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/05/2020] [Indexed: 02/07/2023]
Abstract
Evidence accumulated over the past decade shows that long non-coding RNAs (lncRNAs) are widely expressed and have key roles in gene regulation. Recent studies have begun to unravel how the biogenesis of lncRNAs is distinct from that of mRNAs and is linked with their specific subcellular localizations and functions. Depending on their localization and their specific interactions with DNA, RNA and proteins, lncRNAs can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, alter the stability and translation of cytoplasmic mRNAs and interfere with signalling pathways. Many of these functions ultimately affect gene expression in diverse biological and physiopathological contexts, such as in neuronal disorders, immune responses and cancer. Tissue-specific and condition-specific expression patterns suggest that lncRNAs are potential biomarkers and provide a rationale to target them clinically. In this Review, we discuss the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications.
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Affiliation(s)
- Luisa Statello
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Chun-Jie Guo
- State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ling-Ling Chen
- State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
| | - Maite Huarte
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
- Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain.
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10
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Niu F, Dzikiewicz-Krawczyk A, Koerts J, de Jong D, Wijenberg L, Fernandez Hernandez M, Slezak-Prochazka I, Winkle M, Kooistra W, van der Sluis T, Rutgers B, Terpstra MM, Kok K, Kluiver J, van den Berg A. MiR-378a-3p Is Critical for Burkitt Lymphoma Cell Growth. Cancers (Basel) 2020; 12:E3546. [PMID: 33261009 PMCID: PMC7760147 DOI: 10.3390/cancers12123546] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/09/2020] [Accepted: 11/25/2020] [Indexed: 12/29/2022] Open
Abstract
MicroRNAs (miRNAs) are small RNA molecules with important gene regulatory roles in normal and pathophysiological cellular processes. Burkitt lymphoma (BL) is an MYC-driven lymphoma of germinal center B (GC-B) cell origin. To gain further knowledge on the role of miRNAs in the pathogenesis of BL, we performed small RNA sequencing in BL cell lines and normal GC-B cells. This revealed 26 miRNAs with significantly different expression levels. For five miRNAs, the differential expression pattern was confirmed in primary BL tissues compared to GC-B cells. MiR-378a-3p was upregulated in BL, and its inhibition reduced the growth of multiple BL cell lines. RNA immunoprecipitation of Argonaute 2 followed by microarray analysis (Ago2-RIP-Chip) upon inhibition and ectopic overexpression of miR-378a-3p revealed 63 and 20 putative miR-378a-3p targets, respectively. Effective targeting by miR-378a-3p was confirmed by luciferase reporter assays for MAX Network Transcriptional Repressor (MNT), Forkhead Box P1 (FOXP1), Interleukin 1 Receptor Associated Kinase 4 (IRAK4), and lncRNA Just Proximal To XIST (JPX), and by Western blot for IRAK4 and MNT. Overexpression of IRAK4 and MNT phenocopied the effect of miR-378a-3p inhibition. In summary, we identified miR-378a-3p as a miRNA with an oncogenic role in BL and identified IRAK4 and MNT as miR-378a-3p target genes that are involved in its growth regulatory role.
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Affiliation(s)
- Fubiao Niu
- Departments of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (F.N.); (J.K.); (D.d.J.); (L.W.); (M.F.H.); (M.W.); (W.K.); (T.v.d.S.); (B.R.); (J.K.)
| | | | - Jasper Koerts
- Departments of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (F.N.); (J.K.); (D.d.J.); (L.W.); (M.F.H.); (M.W.); (W.K.); (T.v.d.S.); (B.R.); (J.K.)
| | - Debora de Jong
- Departments of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (F.N.); (J.K.); (D.d.J.); (L.W.); (M.F.H.); (M.W.); (W.K.); (T.v.d.S.); (B.R.); (J.K.)
| | - Laura Wijenberg
- Departments of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (F.N.); (J.K.); (D.d.J.); (L.W.); (M.F.H.); (M.W.); (W.K.); (T.v.d.S.); (B.R.); (J.K.)
| | - Margot Fernandez Hernandez
- Departments of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (F.N.); (J.K.); (D.d.J.); (L.W.); (M.F.H.); (M.W.); (W.K.); (T.v.d.S.); (B.R.); (J.K.)
| | | | - Melanie Winkle
- Departments of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (F.N.); (J.K.); (D.d.J.); (L.W.); (M.F.H.); (M.W.); (W.K.); (T.v.d.S.); (B.R.); (J.K.)
| | - Wierd Kooistra
- Departments of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (F.N.); (J.K.); (D.d.J.); (L.W.); (M.F.H.); (M.W.); (W.K.); (T.v.d.S.); (B.R.); (J.K.)
| | - Tineke van der Sluis
- Departments of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (F.N.); (J.K.); (D.d.J.); (L.W.); (M.F.H.); (M.W.); (W.K.); (T.v.d.S.); (B.R.); (J.K.)
| | - Bea Rutgers
- Departments of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (F.N.); (J.K.); (D.d.J.); (L.W.); (M.F.H.); (M.W.); (W.K.); (T.v.d.S.); (B.R.); (J.K.)
| | - Miente Martijn Terpstra
- Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (M.M.T.); (K.K.)
| | - Klaas Kok
- Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (M.M.T.); (K.K.)
| | - Joost Kluiver
- Departments of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (F.N.); (J.K.); (D.d.J.); (L.W.); (M.F.H.); (M.W.); (W.K.); (T.v.d.S.); (B.R.); (J.K.)
| | - Anke van den Berg
- Departments of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands; (F.N.); (J.K.); (D.d.J.); (L.W.); (M.F.H.); (M.W.); (W.K.); (T.v.d.S.); (B.R.); (J.K.)
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11
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Arman K, Möröy T. Crosstalk Between MYC and lncRNAs in Hematological Malignancies. Front Oncol 2020; 10:579940. [PMID: 33134177 PMCID: PMC7579998 DOI: 10.3389/fonc.2020.579940] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/14/2020] [Indexed: 12/13/2022] Open
Abstract
The human genome project revealed the existence of many thousands of long non-coding RNAs (lncRNAs). These transcripts that are over 200 nucleotides long were soon recognized for their importance in regulating gene expression. However, their poor conservation among species and their still controversial annotation has limited their study to some extent. Moreover, a generally lower expression of lncRNAs as compared to protein coding genes and their enigmatic biochemical mechanisms have impeded progress in the understanding of their biological roles. It is, however, known that lncRNAs engage in various kinds of interactions and can form complexes with other RNAs, with genomic DNA or proteins rendering their functional regulatory network quite complex. It has emerged from recent studies that lncRNAs exert important roles in gene expression that affect many cellular processes underlying development, cellular differentiation, but also the pathogenesis of blood cancers like leukemia and lymphoma. A number of lncRNAs have been found to be regulated by several well-known transcription factors including Myelocytomatosis viral oncogene homolog (MYC). The c-MYC gene is known to be one of the most frequently deregulated oncogenes and a driver for many human cancers. The c-MYC gene is very frequently activated by chromosomal translocations in hematopoietic cancers most prominently in B- or T-cell lymphoma or leukemia and much is already known about its role as a DNA binding transcriptional regulator. Although the understanding of MYC's regulatory role controlling lncRNA expression and how MYC itself is controlled by lncRNA in blood cancers is still at the beginning, an intriguing picture emerges indicating that c-MYC may execute part of its oncogenic function through lncRNAs. Several studies have identified lncRNAs regulating c-MYC expression and c-MYC regulated lncRNAs in different blood cancers and have unveiled new mechanisms how these RNA molecules act. In this review, we give an overview of lncRNAs that have been recognized as critical in the context of activated c-MYC in leukemia and lymphoma, describe their mechanism of action and their effect on transcriptional reprogramming in cancer cells. Finally, we discuss possible ways how an interference with their molecular function could be exploited for new cancer therapies.
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Affiliation(s)
- Kaifee Arman
- Institut de recherches cliniques de Montréal, Montreal, QC, Canada.,Division of Experimental Medicine, McGill University, Montreal, QC, Canada
| | - Tarik Möröy
- Institut de recherches cliniques de Montréal, Montreal, QC, Canada.,Division of Experimental Medicine, McGill University, Montreal, QC, Canada.,Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montreal, QC, Canada
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12
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Chen Q, Shen H, Zhu X, Liu Y, Yang H, Chen H, Xiong S, Chi H, Xu W. A nuclear lncRNA Linc00839 as a Myc target to promote breast cancer chemoresistance via PI3K/AKT signaling pathway. Cancer Sci 2020; 111:3279-3291. [PMID: 32619088 PMCID: PMC7469761 DOI: 10.1111/cas.14555] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 06/18/2020] [Accepted: 06/23/2020] [Indexed: 12/16/2022] Open
Abstract
Chemoresistance has become a leading cause of mortality in breast cancer patients and is one of the major obstacles for improving the clinical outcome. Long noncoding RNAs play important roles in breast cancer tumorigenesis and chemoresistance. However, the involvement and regulation of lncRNAs in breast cancer chemoresistance are not completely understood. Here, we reported that Linc00839 was localized in the nucleus and upregulated in chemoresistant breast cancer cells and tissues, and high level of Linc00839 was associated with a poor prognosis. Knockdown of Linc00839 significantly suppressed proliferation, invasion, and migration, sensitized cells to paclitaxel in vitro and inhibited transplant tumor development in vivo. Mechanistically, we found that Myc could directly bind to the promoter region of Linc00839 and activate its transcription. Furthermore, Linc00839 overexpression increased the expression of Myc and the RNA‐binding protein Lin28B and activated the PI3K/AKT signaling pathway. We also discovered that Lin28B positively interacted with Linc00839 and was upregulated in breast cancer tissues. Taken together, for the first time, we showed that Linc00839 was activated by Myc and promoted proliferation and chemoresistance in breast cancer through binding with Lin28B. These findings provide new insight into the regulatory mechanism of Linc00839 and propose a Myc/Linc00839/Lin28B feedback loop that could be used as a novel therapeutic target for breast cancer.
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Affiliation(s)
- Qi Chen
- Department of Breast Diseases, Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China.,School of medicine, Jiangsu University, Zhenjiang, China
| | - Huiling Shen
- Department of Oncology, Affiliated People Hospital of Jiangsu University, Zhenjiang, China
| | - Xiaolan Zhu
- Central Laboratory, Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yueqin Liu
- Central Laboratory, Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Hui Yang
- Department of Breast Diseases, Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Hui Chen
- School of medicine, Jiangsu University, Zhenjiang, China
| | - Shangwan Xiong
- School of medicine, Jiangsu University, Zhenjiang, China
| | - Huamao Chi
- Department of Breast Diseases, Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Wenlin Xu
- Department of Breast Diseases, Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China.,School of medicine, Jiangsu University, Zhenjiang, China
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13
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Benetatos L, Benetatou A, Vartholomatos G. Long non-coding RNAs and MYC association in hematological malignancies. Ann Hematol 2020; 99:2231-2242. [PMID: 32621182 DOI: 10.1007/s00277-020-04166-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/29/2020] [Indexed: 12/19/2022]
Abstract
Long non-coding RNAs (lncRNAs) have an established role in cell biology. Among their functions is the regulation of hematopoiesis. They characterize the different stages of hematopoiesis in a more lineage-restricted expression pattern than coding mRNAs. They affect hematopoietic stem cell renewal, proliferation, and differentiation of committed progenitors by interacting with master regulators transcription factors. Among these transcription factors, MYC has a prominent role. Similar to MYC's transcriptional activation/amplification of protein coding genes, MYC also regulates lncRNAs' expression profile, while it is also regulated by lncRNAs. Both myeloid and lymphoid malignancies are prone to the association of MYC with lncRNAs. Such interaction inhibits apoptosis, enhances cell proliferation, deregulates metabolism, and promotes genomic instability and resistance to treatment. In this review, we discuss the recent findings that encompass the crosstalk between lncRNAs and describe the pathways that very probably have a pathogenetic role in both acute and chronic hematologic malignancies.
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Affiliation(s)
| | - Agapi Benetatou
- Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece
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14
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Niu F, Kazimierska M, Nolte IM, Terpstra MM, de Jong D, Koerts J, van der Sluis T, Rutgers B, O’Connell RM, Kok K, van den Berg A, Dzikiewicz-Krawczyk A, Kluiver J. The miR-26b-5p/KPNA2 Axis Is an Important Regulator of Burkitt Lymphoma Cell Growth. Cancers (Basel) 2020; 12:E1464. [PMID: 32512858 PMCID: PMC7352454 DOI: 10.3390/cancers12061464] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 05/29/2020] [Accepted: 05/31/2020] [Indexed: 12/26/2022] Open
Abstract
The expression of several microRNAs (miRNAs) is known to be changed in Burkitt lymphoma (BL), compared to its normal counterparts. Although for some miRNAs, a role in BL was demonstrated, for most of them, their function is unclear. In this study, we aimed to identify miRNAs that control BL cell growth. Two BL cell lines were infected with lentiviral pools containing either 58 miRNA inhibitors or 44 miRNA overexpression constructs. Eighteen constructs showed significant changes in abundance over time, indicating that they affected BL growth. The screening results were validated by individual green fluorescent protein (GFP) growth competition assays for fifteen of the eighteen constructs. For functional follow-up studies, we focused on miR-26b-5p, whose overexpression inhibited BL cell growth. Argonaute 2 RNA immunoprecipitation (Ago2-IP) in two BL cell lines revealed 47 potential target genes of miR-26b-5p. Overlapping the list of putative targets with genes showing a growth repression phenotype in a genome-wide CRISPR/Cas9 knockout screen, revealed eight genes. The top-5 candidates included EZH2, COPS2, KPNA2, MRPL15, and NOL12. EZH2 is a known target of miR-26b-5p, with oncogenic properties in BL. The relevance of the latter four targets was confirmed using sgRNAs targeting these genes in individual GFP growth competition assays. Luciferase reporter assay confirmed binding of miR-26b-5p to the predicted target site for KPNA2, but not to the other genes. In summary, we identified 18 miRNAs that affected BL cell growth in a loss- or gain-of-function screening. A tumor suppressor role was confirmed for miR-26b-5p, and this effect could at least in part be attributed to KPNA2, a known regulator of OCT4, c-jun, and MYC.
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Affiliation(s)
- Fubiao Niu
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands; (F.N.); (D.d.J.); (J.K.); (T.v.d.S.); (B.R.); (A.v.d.B.)
| | - Marta Kazimierska
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland;
| | - Ilja M. Nolte
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands;
| | - Miente Martijn Terpstra
- Department of Genetics, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands; (M.M.T.); (K.K.)
| | - Debora de Jong
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands; (F.N.); (D.d.J.); (J.K.); (T.v.d.S.); (B.R.); (A.v.d.B.)
| | - Jasper Koerts
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands; (F.N.); (D.d.J.); (J.K.); (T.v.d.S.); (B.R.); (A.v.d.B.)
| | - Tineke van der Sluis
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands; (F.N.); (D.d.J.); (J.K.); (T.v.d.S.); (B.R.); (A.v.d.B.)
| | - Bea Rutgers
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands; (F.N.); (D.d.J.); (J.K.); (T.v.d.S.); (B.R.); (A.v.d.B.)
| | - Ryan M. O’Connell
- Division of Microbiology and Immunology, Huntsman Cancer Institute, Department of Pathology at the University of Utah, Salt Lake City, UT 84112, USA.;
| | - Klaas Kok
- Department of Genetics, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands; (M.M.T.); (K.K.)
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands; (F.N.); (D.d.J.); (J.K.); (T.v.d.S.); (B.R.); (A.v.d.B.)
| | | | - Joost Kluiver
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands; (F.N.); (D.d.J.); (J.K.); (T.v.d.S.); (B.R.); (A.v.d.B.)
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15
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Chen S, Gu T, Lu Z, Qiu L, Xiao G, Zhu X, Li F, Yu H, Li G, Liu H. Roles of MYC-targeting long non-coding RNA MINCR in cell cycle regulation and apoptosis in non-small cell lung Cancer. Respir Res 2019; 20:202. [PMID: 31481083 PMCID: PMC6724276 DOI: 10.1186/s12931-019-1174-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 08/28/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death in the world, and has a relatively low survival rate. Long non-coding RNAs (lncRNAs) have been demonstrated to modulate cancer progression through a variety of molecular mechanisms. We sought to investigate the role and potential mechanism of MYC-induced long non-coding RNA (MINCR) in NSCLC. METHODS Expression levels of MINCR was first identified using The Cancer Genome Atlas (TCGA), further confirmed with specimens from 29 NSCLC patients and three cell lines using qRT-PCR. Overexpression and knockdown of MINCR were performed in NSCLC cell lines through MINCR overexpression vectors and synthesized siRNAs, respectively. The roles of MINCR in NSCLC cell lines, such as cell proliferation, cell cycle arrest, and apoptosis, were identified by MTT, flow cytometry, and Western blot. The modulation of MINCR-regulated genes, including c-Myc and its downstream effectors, as well as apoptosis-associated genes, was analyzed using Western blot. RESULTS MINCR expression was increased in NSCLC patients from TCGA datasets, and was also significantly increased in our collected specimens from NSCLC patients and NSCLC cell lines. Knocking down of MINCR greatly inhibited the growth of NSCLC cell lines PC9 and A549. In addition, silencing of MINCR induced cell cycle arrest and apoptosis. Furthermore, silencing of MINCR reduced the expression levels of oncogene c-Myc and its downstream cyclin A, cyclin D, CD4, and CDK2, as well as apoptosis-associated Bcl-2, while significantly increased the expression levels of cleaved PARP-1. In the meantime, overexpression of MINCR remarkably enhanced cell proliferation of PC9 cells and activated c-Myc and its downstream effectors. CONCLUSION MINCR exerted inhibitory effects on the cell cycle arrest and apoptosis of NSCLC cells by activating c-Myc and its downstream effectors, suggesting that this lncRNA could be used as a potential therapeutic target for the treatment of NSCLC.
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Affiliation(s)
- Shengjie Chen
- Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Tianyi Gu
- Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China.,School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu Province, China
| | - Ziwen Lu
- School of Pharmacy, Jiangsu University, Zhenjiang, 212013, Jiangsu Province, China
| | - Lipeng Qiu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, 212013, Jiangsu Province, China
| | - Guoliang Xiao
- Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China.,School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu Province, China
| | - Xiaozhong Zhu
- Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Feng Li
- Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Hui Yu
- Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Gang Li
- Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Hanqing Liu
- School of Pharmacy, Jiangsu University, Zhenjiang, 212013, Jiangsu Province, China.
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16
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A Cell's Fate: An Overview of the Molecular Biology and Genetics of Apoptosis. Int J Mol Sci 2019; 20:ijms20174133. [PMID: 31450613 PMCID: PMC6747454 DOI: 10.3390/ijms20174133] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 07/15/2019] [Accepted: 07/17/2019] [Indexed: 12/30/2022] Open
Abstract
Apoptosis is one of the main types of regulated cell death, a complex process that can be triggered by external or internal stimuli, which activate the extrinsic or the intrinsic pathway, respectively. Among various factors involved in apoptosis, several genes and their interactive networks are crucial regulators of the outcomes of each apoptotic phase. Furthermore, mitochondria are key players in determining the way by which cells will react to internal stress stimuli, thus being the main contributor of the intrinsic pathway, in addition to providing energy for the whole process. Other factors that have been reported as important players of this intricate molecular network are miRNAs, which regulate the genes involved in the apoptotic process. Imbalance in any of these mechanisms can lead to the development of several illnesses, hence, an overall understanding of these processes is essential for the comprehension of such situations. Although apoptosis has been widely studied, the current literature lacks an updated and more general overview on this subject. Therefore, here, we review and discuss the mechanisms of apoptosis, highlighting the roles of genes, miRNAs, and mitochondria involved in this type of cell death.
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17
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Long noncoding RNA EMS connects c-Myc to cell cycle control and tumorigenesis. Proc Natl Acad Sci U S A 2019; 116:14620-14629. [PMID: 31262817 DOI: 10.1073/pnas.1903432116] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Deregulated expression of c-Myc is an important molecular hallmark of cancer. The oncogenic function of c-Myc has been largely attributed to its intrinsic nature as a master transcription factor. Here, we report the long noncoding RNA (lncRNA) E2F1 messenger RNA (mRNA) stabilizing factor (EMS) as a direct c-Myc transcriptional target. EMS functions as an oncogenic molecule by promoting G1/S cell cycle progression. Mechanistically, EMS cooperates with the RNA binding protein RALY to stabilize E2F1 mRNA, and thereby increases E2F1 expression. Furthermore, EMS is able to connect c-Myc to cell cycle control and tumorigenesis via modulating E2F1 mRNA stability. Together, these findings reveal a previously unappreciated mechanism through which c-Myc induces E2F1 expression and also implicate EMS as an important player in the regulation of c-Myc function.
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18
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Zhao B, Chen Y, Hu S, Yang N, Wang M, Liu M, Li J, Xiao Y, Wu X. Systematic Analysis of Non-coding RNAs Involved in the Angora Rabbit ( Oryctolagus cuniculus) Hair Follicle Cycle by RNA Sequencing. Front Genet 2019; 10:407. [PMID: 31130985 PMCID: PMC6509560 DOI: 10.3389/fgene.2019.00407] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 04/12/2019] [Indexed: 12/12/2022] Open
Abstract
The hair follicle (HF) cycle is a complicated and dynamic process in mammals, associated with various signaling pathways and gene expression patterns. Non-coding RNAs (ncRNAs) are RNA molecules that are not translated into proteins but are involved in the regulation of various cellular and biological processes. This study explored the relationship between ncRNAs and the HF cycle by developing a synchronization model in Angora rabbits. Transcriptome analysis was performed to investigate ncRNAs and mRNAs associated with the various stages of the HF cycle. One hundred and eleven long non-coding RNAs (lncRNAs), 247 circular RNAs (circRNAs), 97 microRNAs (miRNAs), and 1,168 mRNAs were differentially expressed during the three HF growth stages. Quantitative real-time PCR was used to validate the ncRNA transcriptome analysis results. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses provided information on the possible roles of ncRNAs and mRNAs during the HF cycle. In addition, lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA ceRNA networks were constructed to investigate the underlying relationships between ncRNAs and mRNAs. LNC_002919 and novel_circ_0026326 were found to act as ceRNAs and participated in the regulation of the HF cycle as miR-320-3p sponges. This research comprehensively identified candidate regulatory ncRNAs during the HF cycle by transcriptome analysis, highlighting the possible association between ncRNAs and the regulation of hair growth. This study provides a basis for systematic further research and new insights on the regulation of the HF cycle.
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Affiliation(s)
- Bohao Zhao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Yang Chen
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Yangzhou University, Yangzhou, China
| | - Shuaishuai Hu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Naisu Yang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Manman Wang
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Yangzhou University, Yangzhou, China
| | - Ming Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Jiali Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Yeyi Xiao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Xinsheng Wu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Yangzhou University, Yangzhou, China
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19
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Li S, Zhang S, Chen J. c-Myc induced upregulation of long non-coding RNA SNHG16 enhances progression and carcinogenesis in oral squamous cell carcinoma. Cancer Gene Ther 2019; 26:400-410. [DOI: 10.1038/s41417-018-0072-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 11/09/2018] [Accepted: 11/17/2018] [Indexed: 12/18/2022]
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20
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Swier LJYM, Dzikiewicz‐Krawczyk A, Winkle M, van den Berg A, Kluiver J. Intricate crosstalk between MYC and non-coding RNAs regulates hallmarks of cancer. Mol Oncol 2019; 13:26-45. [PMID: 30451365 PMCID: PMC6322196 DOI: 10.1002/1878-0261.12409] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/10/2018] [Accepted: 10/23/2018] [Indexed: 01/17/2023] Open
Abstract
Myelocytomatosis viral oncogene homolog (MYC) plays an important role in the regulation of many cellular processes, and its expression is tightly regulated at the level of transcription, translation, protein stability, and activity. Despite this tight regulation, MYC is overexpressed in many cancers and contributes to multiple hallmarks of cancer. In recent years, it has become clear that noncoding RNAs add a crucial additional layer to the regulation of MYC and its downstream effects. So far, twenty-five microRNAs and eighteen long noncoding RNAs that regulate MYC have been identified. Thirty-three miRNAs and nineteen lncRNAs are downstream effectors of MYC that contribute to the broad oncogenic role of MYC, including its effects on diverse hallmarks of cancer. In this review, we give an overview of this extensive, multilayered noncoding RNA network that exists around MYC. Current data clearly show explicit roles of crosstalk between MYC and ncRNAs to allow tumorigenesis.
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Affiliation(s)
- Lotteke J. Y. M. Swier
- Department of Pathology and Medical BiologyUniversity of GroningenUniversity Medical Center GroningenThe Netherlands
| | | | - Melanie Winkle
- Department of Pathology and Medical BiologyUniversity of GroningenUniversity Medical Center GroningenThe Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical BiologyUniversity of GroningenUniversity Medical Center GroningenThe Netherlands
| | - Joost Kluiver
- Department of Pathology and Medical BiologyUniversity of GroningenUniversity Medical Center GroningenThe Netherlands
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21
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Dahl M, Kristensen LS, Grønbæk K. Long Non-Coding RNAs Guide the Fine-Tuning of Gene Regulation in B-Cell Development and Malignancy. Int J Mol Sci 2018; 19:E2475. [PMID: 30134619 PMCID: PMC6165225 DOI: 10.3390/ijms19092475] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 08/16/2018] [Accepted: 08/20/2018] [Indexed: 12/13/2022] Open
Abstract
With the introduction of next generation sequencing methods, such as RNA sequencing, it has become apparent that alterations in the non-coding regions of our genome are important in the development of cancer. Particularly interesting is the class of long non-coding RNAs (lncRNAs), including the recently described subclass of circular RNAs (circRNAs), which display tissue- and cell-type specific expression patterns and exert diverse regulatory functions in the cells. B-cells undergo complex and tightly regulated processes in order to develop from antigen naïve cells residing in the bone marrow to the highly diverse and competent effector cells circulating in peripheral blood. These processes include V(D)J recombination, rapid proliferation, somatic hypermutation and clonal selection, posing a risk of malignant transformation at each step. The aim of this review is to provide insight into how lncRNAs including circRNAs, participate in normal B-cell differentiation, and how deregulation of these molecules is involved in the development of B-cell malignancies. We describe the prognostic value and functional significance of specific deregulated lncRNAs in diseases such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Burkitt lymphoma and multiple myeloma, and we provide an overview of the current knowledge on the role of circRNAs in these diseases.
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MESH Headings
- B-Lymphocytes/immunology
- B-Lymphocytes/pathology
- Burkitt Lymphoma/genetics
- Burkitt Lymphoma/immunology
- Burkitt Lymphoma/pathology
- Cell Differentiation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Neoplastic
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Lymphoma, Follicular/genetics
- Lymphoma, Follicular/immunology
- Lymphoma, Follicular/pathology
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Mantle-Cell/genetics
- Lymphoma, Mantle-Cell/immunology
- Lymphoma, Mantle-Cell/pathology
- Multiple Myeloma/genetics
- Multiple Myeloma/immunology
- Multiple Myeloma/pathology
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
- RNA/genetics
- RNA/immunology
- RNA, Circular
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/immunology
- Signal Transduction
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Affiliation(s)
- Mette Dahl
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.
- Biotech Research and Innovation Centre, BRIC, Copenhagen University, DK-2100 Copenhagen, Denmark.
| | - Lasse Sommer Kristensen
- Department of Molecular Biology and Genetics (MBG), Aarhus University, DK-8000 Aarhus, Denmark.
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, DK-8000 Aarhus, Denmark.
| | - Kirsten Grønbæk
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.
- Biotech Research and Innovation Centre, BRIC, Copenhagen University, DK-2100 Copenhagen, Denmark.
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22
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Xia Y, Yan Z, Wan Y, Wei S, Bi Y, Zhao J, Liu J, Liao DJ, Huang H. Knockdown of long noncoding RNA GHET1 inhibits cell‑cycle progression and invasion of gastric cancer cells. Mol Med Rep 2018; 18:3375-3381. [PMID: 30066922 PMCID: PMC6102745 DOI: 10.3892/mmr.2018.9332] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 07/19/2018] [Indexed: 12/17/2022] Open
Abstract
GHET1 is an oncogenic long noncoding RNA (lncRNA) that promotes the proliferation and invasion of many malignant cell types. However, the function and underlying mechanisms of lncRNA GHET1 in gastric cancer are not fully understood. In this study, the expression of GHET1 was investigated in gastric cancer and it was determined whether GHET1 may potentially be used as a biomarker for the disease. The gastric cancer cell lines MGC‑803 and AGS were transfected with GHET1‑directed small interfering RNA (siRNA) and the changes in phenotype and cell‑cycle‑related molecules were assessed. The downregulation of GHET1 induced G0/G1‑phase arrest in gastric cancer cells and inhibited their proliferation, migration, and invasion. DNA synthesis and the expression of proliferating cell nuclear antigen (PCNA) decreased, which was consistent with the results of the CCK‑8 assay. The levels of specific cell‑cycle regulators were determined and the expression and activities of positive cell‑cycle regulators (cyclin D, CDK4, CDK6, cyclin E, CDK2) were reduced, whereas those of a negative regulator (P21) were increased in GHET1‑knockdown cells. Taken together, the present findings show that the downregulation of GHET1 not only inhibits the migration and invasion of gastric cancer cells, but also inhibits their proliferation, at least in part by upregulating P21 expression and downregulating cyclin and CDK expression to inhibit the G0/G1 to S phase transition. The present findings may provide a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Ying Xia
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Zhiqiang Yan
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Ying Wan
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Sixi Wei
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Ying Bi
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Juanjuan Zhao
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Juanjuan Liu
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Dezhong Joshua Liao
- Department of Pathology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Hai Huang
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
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23
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Amodio N, Raimondi L, Juli G, Stamato MA, Caracciolo D, Tagliaferri P, Tassone P. MALAT1: a druggable long non-coding RNA for targeted anti-cancer approaches. J Hematol Oncol 2018; 11:63. [PMID: 29739426 PMCID: PMC5941496 DOI: 10.1186/s13045-018-0606-4] [Citation(s) in RCA: 248] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 04/26/2018] [Indexed: 02/07/2023] Open
Abstract
The deeper understanding of non-coding RNAs has recently changed the dogma of molecular biology assuming protein-coding genes as unique functional biological effectors, while non-coding genes as junk material of doubtful significance. In the last decade, an exciting boom of experimental research has brought to light the pivotal biological functions of long non-coding RNAs (lncRNAs), representing more than the half of the whole non-coding transcriptome, along with their dysregulation in many diseases, including cancer.In this review, we summarize the emerging insights on lncRNA expression and functional role in cancer, focusing on the evolutionary conserved and abundantly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) that currently represents the best characterized lncRNA. Altogether, literature data indicate aberrant expression and dysregulated activity of MALAT1 in human malignancies and envision MALAT1 targeting as a novel treatment strategy against cancer.
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Affiliation(s)
- Nicola Amodio
- Department of Experimental and Clinical Medicine, Magna Graecia University, Viale Europa, 88100, Catanzaro, Italy.
| | - Lavinia Raimondi
- IRCSS Rizzoli Orthopedic Institute, Bologna, Italy
- Innovative Technology Platforms for Tissue Engineering, Theranostic and Oncology, Rizzoli Orthopedic Institute, Palermo, Italy
| | - Giada Juli
- Department of Experimental and Clinical Medicine, Magna Graecia University, Viale Europa, 88100, Catanzaro, Italy
| | - Maria Angelica Stamato
- Department of Experimental and Clinical Medicine, Magna Graecia University, Viale Europa, 88100, Catanzaro, Italy
| | - Daniele Caracciolo
- Department of Experimental and Clinical Medicine, Magna Graecia University, Viale Europa, 88100, Catanzaro, Italy
| | - Pierosandro Tagliaferri
- Department of Experimental and Clinical Medicine, Magna Graecia University, Viale Europa, 88100, Catanzaro, Italy
| | - Pierfrancesco Tassone
- Department of Experimental and Clinical Medicine, Magna Graecia University, Viale Europa, 88100, Catanzaro, Italy.
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24
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Gajbhiye R, McKinnon B, Mortlock S, Mueller M, Montgomery G. Genetic Variation at Chromosome 2q13 and Its Potential Influence on Endometriosis Susceptibility Through Effects on the IL-1 Family. Reprod Sci 2018; 25:1307-1317. [PMID: 29669463 DOI: 10.1177/1933719118768688] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Endometriosis is characterized by the growth of epithelial and stromal cells outside the uterine cavity. It has a complex etiology and affects ∼10% of reproductive age women. It is accompanied by a chronic inflammatory response with substantial evidence to indicate genetic susceptibility. The causal genes and their pathways leading to endometriosis, however, are still unknown. Recently, genomewide association studies on endometriosis identified 14 genomic risk loci in women of European and Japanese ancestry. It is becoming increasingly clear that these risk regions are intergenic and thus contribute to disease susceptibility through regulatory mechanisms, most likely mediated through regulation of genes within a restricted distance from the risk variants. One endometriosis risk locus has been detected at chromosome 2q13 within an inflammatory-rich region of gene transcripts and thus may play a role in the inflammation component of the disease. We carried out detailed analysis of the genomic region 250 kb on either side of sentinel SNP rs10167914 and identified 21 transcripts which contained 6 interleukin (IL)-1 family genes, 3 previously reported coding genes that have a relationship to inflammation, 4 novel coding, or pseudogenes, and 8 noncoding RNA transcripts. Through an extensive literature search, we examined the roles these genes and their resultant proteins play in endometriosis pathogenesis. The results suggest alteration in the expression the IL-1 family transcripts either alone or as a complex milieu could have a significant influence on endometriosis and should be prioritized for future study on the implications of inflammation on endometriotic lesions.
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Affiliation(s)
- Rahul Gajbhiye
- 1 Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD, Australia.,3 Department of Clinical Research, ICMR-National Institute for Research in Reproductive Health, Parel, Mumbai, Maharashtra, India
| | - Brett McKinnon
- 2 Department of Obstetrics and Gynaecology, Inselspital, Berne University Hospital, Bern, Switzerland
| | - Sally Mortlock
- 1 Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD, Australia
| | - Michael Mueller
- 2 Department of Obstetrics and Gynaecology, Inselspital, Berne University Hospital, Bern, Switzerland
| | - Grant Montgomery
- 1 Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD, Australia
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25
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Vučićević D, Gehre M, Dhamija S, Friis-Hansen L, Meierhofer D, Sauer S, Ørom UA. The long non-coding RNA PARROT is an upstream regulator of c-Myc and affects proliferation and translation. Oncotarget 2017; 7:33934-47. [PMID: 27129154 PMCID: PMC5085129 DOI: 10.18632/oncotarget.8985] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 04/16/2016] [Indexed: 12/26/2022] Open
Abstract
Long non-coding RNAs are important regulators of gene expression and signaling pathways. The expression of long ncRNAs is dysregulated in cancer and other diseases. The identification and characterization of long ncRNAs is often challenging due to their low expression level and localization to chromatin. Here, we identify a functional long ncRNA, PARROT (Proliferation Associated RNA and Regulator Of Translation) transcribed by RNA polymerase II and expressed at a relatively high level in a number of cell lines. The PARROT long ncRNA is associated with proliferation in both transformed and normal cell lines. We characterize the long ncRNA PARROT as an upstream regulator of c-Myc affecting cellular proliferation and translation using RNA sequencing and mass spectrometry following depletion of the long ncRNA. PARROT is repressed during senescence of human mammary epithelial cells and overexpressed in some cancers, suggesting an important association with proliferation through regulation of c-Myc. With this study, we add to the knowledge of cytoplasmic functional long ncRNAs and extent the long ncRNA-Myc regulatory network in transformed and normal cells.
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Affiliation(s)
- Dubravka Vučićević
- Max Planck Institute for Molecular Genetics, Berlin, Germany.,Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Maja Gehre
- Max Planck Institute for Molecular Genetics, Berlin, Germany.,EMBL, Heidelberg, Germany
| | - Sonam Dhamija
- Medizinische Hochschule Hannover Institute of Biochemistry, Hannover, Germany.,RNA Biology and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
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26
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Lu Y, Hu Z, Mangala LS, Stine ZE, Hu X, Jiang D, Xiang Y, Zhang Y, Pradeep S, Rodriguez-Aguayo C, Lopez-Berestein G, DeMarzo AM, Sood AK, Zhang L, Dang CV. MYC Targeted Long Noncoding RNA DANCR Promotes Cancer in Part by Reducing p21 Levels. Cancer Res 2017; 78:64-74. [PMID: 29180471 DOI: 10.1158/0008-5472.can-17-0815] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 09/20/2017] [Accepted: 11/03/2017] [Indexed: 01/10/2023]
Abstract
The MYC oncogene broadly promotes transcription mediated by all nuclear RNA polymerases, thereby acting as a positive modifier of global gene expression. Here, we report that MYC stimulates the transcription of DANCR, a long noncoding RNA (lncRNA) that is widely overexpressed in human cancer. We identified DANCR through its overexpression in a transgenic model of MYC-induced lymphoma, but found that it was broadly upregulated in many human cancer cell lines and cancers, including most notably in prostate and ovarian cancers. Mechanistic investigations indicated that DANCR limited the expression of cell-cycle inhibitor p21 (CDKN1A) and that the inhibitory effects of DANCR loss on cell proliferation could be partially rescued by p21 silencing. In a xenograft model of human ovarian cancer, a nanoparticle-mediated siRNA strategy to target DANCR in vivo was sufficient to strongly inhibit tumor growth. Our observations expand knowledge of how MYC drives cancer cell proliferation by identifying DANCR as a critical lncRNA widely overexpressed in human cancers.Significance: These findings expand knowledge of how MYC drives cancer cell proliferation by identifying an oncogenic long noncoding RNA that is widely overexpressed in human cancers. Cancer Res; 78(1); 64-74. ©2017 AACR.
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Affiliation(s)
- Yunqi Lu
- Abramson Family Cancer Research Institute, Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Zhongyi Hu
- Center for Research on Reproduction and Women's Health, and Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lingegowda S Mangala
- Department of Gynecologic Oncology, and Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zachary E Stine
- Abramson Family Cancer Research Institute, Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Xiaowen Hu
- Center for Research on Reproduction and Women's Health, and Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Dahai Jiang
- Department of Gynecologic Oncology, and Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yan Xiang
- Abramson Family Cancer Research Institute, Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Youyou Zhang
- Center for Research on Reproduction and Women's Health, and Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sunila Pradeep
- Department of Gynecologic Oncology, and Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cristian Rodriguez-Aguayo
- Department of Experimental Therapeutics, and Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, and Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Angelo M DeMarzo
- Departments of Pathology, Urology and Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Anil K Sood
- Department of Gynecologic Oncology, and Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Lin Zhang
- Center for Research on Reproduction and Women's Health, and Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Chi V Dang
- Abramson Family Cancer Research Institute, Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. .,Ludwig Institute for Cancer Research, New York, New York.,The Wistar Institute, Philadelphia, Pennsylvania
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27
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Emerging roles for long noncoding RNAs in B-cell development and malignancy. Crit Rev Oncol Hematol 2017; 120:77-85. [PMID: 29198340 DOI: 10.1016/j.critrevonc.2017.08.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Revised: 08/09/2017] [Accepted: 08/09/2017] [Indexed: 12/14/2022] Open
Abstract
Long noncoding (lnc)RNAs have emerged as essential mediators of cellular biology, differentiation and malignant transformation. LncRNAs have a broad range of possible functions at the transcriptional, posttranscriptional and protein level and their aberrant expression significantly contributes to the hallmarks of cancer cell biology. In addition, their high tissue- and cell-type specificity makes lncRNAs especially interesting as biomarkers, prognostic factors or specific therapeutic targets. Here, we review current knowledge on lncRNA expression changes during normal B-cell development, indicating essential functions in the differentiation process. In addition we address lncRNA deregulation in B-cell malignancies, the putative prognostic value of this as well as the molecular functions of multiple deregulated lncRNAs. Altogether, the discussed work indicates major roles for lncRNAs in normal and malignant B cells affecting oncogenic pathways as well as the response to common therapeutics.
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28
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Gasri-Plotnitsky L, Ovadia A, Shamalov K, Nizri-Megnaji T, Meir S, Zurer I, Cohen CJ, Ginsberg D. A novel lncRNA, GASL1, inhibits cell proliferation and restricts E2F1 activity. Oncotarget 2017; 8:23775-23786. [PMID: 28423601 PMCID: PMC5410343 DOI: 10.18632/oncotarget.15864] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 02/10/2017] [Indexed: 01/23/2023] Open
Abstract
The human genome encodes thousands of unique long non-coding RNAs (lncRNAs), many of which are emerging as critical regulators of cell fate. However, their functions as well as their transcriptional regulation are only partially understood. The E2F1 transcription factor induces both proliferation and apoptosis, and is a critical downstream target of the tumor suppressor, RB. Here, we provide evidence that a novel lncRNA named GASL1 is transcriptionally regulated by E2F1; GASL1 levels are elevated upon activation of exogenous E2F1 or endogenous E2Fs. Inhibition of GASL1 expression induced cell cycle progression, and in particular, G1 exit. Moreover, GASL1 silencing enhanced cell proliferation, while, conversely, its ectopic expression inhibited proliferation. Knockdown of GASL1 also enhanced E2F1-induced apoptosis, suggesting the existence of an E2F/GASL1 negative feedback loop. In agreement with this notion, silencing of GASL1 led to increased levels of phosphorylated pRB and loss of Rb impaired the effect of GASL1 silencing on G1 exit. Importantly, xenograft experiments demonstrated that GASL1 deletion enhances tumor growth. Moreover, low levels of GASL1 are associated with decreased survival of liver cancer patients. Taken together, our data identify GASL1 as a novel lncRNA regulator of cell cycle progression and cell proliferation with a potential role in cancer.
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Affiliation(s)
- Lital Gasri-Plotnitsky
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
| | - Aviv Ovadia
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
| | - Katerina Shamalov
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
| | - Tali Nizri-Megnaji
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
| | - Shimrit Meir
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
| | - Irit Zurer
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
| | - Cyrille J Cohen
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
| | - Doron Ginsberg
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
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29
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De Paepe B, Lefever S, Mestdagh P. How long noncoding RNAs enforce their will on mitochondrial activity: regulation of mitochondrial respiration, reactive oxygen species production, apoptosis, and metabolic reprogramming in cancer. Curr Genet 2017; 64:163-172. [PMID: 28879612 DOI: 10.1007/s00294-017-0744-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 08/17/2017] [Accepted: 08/31/2017] [Indexed: 12/13/2022]
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30
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lncRNAs and MYC: An Intricate Relationship. Int J Mol Sci 2017; 18:ijms18071497. [PMID: 28704924 PMCID: PMC5535987 DOI: 10.3390/ijms18071497] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 07/05/2017] [Accepted: 07/11/2017] [Indexed: 01/27/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are emerging as important regulators of gene expression networks, acting either at the transcriptional level, by influencing histone modifications, or at the post-transcriptional level, by controlling mRNA stability and translation. Among the gene expression networks known to influence the process of oncogenic transformation, the one controlled by the proto-oncogene MYC is one of the most frequently deregulated in cancer. In B-cell lymphomas, the MYC gene is subject to chromosomal rearrangements that result in MYC overexpression. In many other cancers, the region surrounding MYC is subject to gene amplification. MYC expression is also controlled at the level of protein and mRNA stability. Neoplastic lesions affecting MYC expression are responsible for a drastic change in the number and the type of genes that are transcriptionally controlled by MYC, depending on differential promoter affinities. Transcriptome profiling of tumor samples has shown that several lncRNAs can be found differentially regulated by MYC in different cancer types and many of them can influence cancer cell viability and proliferation. At the same time, lncRNAs have been shown to be able to control the expression of MYC itself, both at transcriptional and post-transcriptional levels. Given that targeting the MYC-dependent transcriptional program has the potential to reach broad anticancer activity, molecular dissection of the complex regulatory mechanisms governing MYC expression will be crucial in the future for the identification of novel therapeutic strategies.
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31
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Brodie S, Lee HK, Jiang W, Cazacu S, Xiang C, Poisson LM, Datta I, Kalkanis S, Ginsberg D, Brodie C. The novel long non-coding RNA TALNEC2, regulates tumor cell growth and the stemness and radiation response of glioma stem cells. Oncotarget 2017; 8:31785-31801. [PMID: 28423669 PMCID: PMC5458248 DOI: 10.18632/oncotarget.15991] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 02/06/2017] [Indexed: 12/21/2022] Open
Abstract
Despite advances in novel therapeutic approaches for the treatment of glioblastoma (GBM), the median survival of 12-14 months has not changed significantly. Therefore, there is an imperative need to identify molecular mechanisms that play a role in patient survival. Here, we analyzed the expression and functions of a novel lncRNA, TALNEC2 that was identified using RNA seq of E2F1-regulated lncRNAs. TALNEC2 was localized to the cytosol and its expression was E2F1-regulated and cell-cycle dependent. TALNEC2 was highly expressed in GBM with poor prognosis, in GBM specimens derived from short-term survivors and in glioma cells and glioma stem cells (GSCs). Silencing of TALNEC2 inhibited cell proliferation and arrested the cells in the G1\S phase of the cell cycle in various cancer cell lines. In addition, silencing of TALNEC2 decreased the self-renewal and mesenchymal transformation of GSCs, increased sensitivity of these cells to radiation and prolonged survival of mice bearing GSC-derived xenografts. Using miRNA array analysis, we identified specific miRNAs that were altered in the silenced cells that were associated with cell-cycle progression, proliferation and mesenchymal transformation. Two of the downregulated miRNAs, miR-21 and miR-191, mediated some of TALNEC2 effects on the stemness and mesenchymal transformation of GSCs. In conclusion, we identified a novel E2F1-regulated lncRNA that is highly expressed in GBM and in tumors from patients of short-term survival. The expression of TALNEC2 is associated with the increased tumorigenic potential of GSCs and their resistance to radiation. We conclude that TALNEC2 is an attractive therapeutic target for the treatment of GBM.
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Affiliation(s)
- Shlomit Brodie
- Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
| | - Hae Kyung Lee
- Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Detroit, MI, USA
| | - Wei Jiang
- Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Detroit, MI, USA
| | - Simona Cazacu
- Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Detroit, MI, USA
| | - Cunli Xiang
- Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Detroit, MI, USA
| | - Laila M Poisson
- Department of Public Health Sciences, Center for Bioinformatics, Henry Ford Hospital, Detroit, MI, USA
| | - Indrani Datta
- Department of Public Health Sciences, Center for Bioinformatics, Henry Ford Hospital, Detroit, MI, USA
| | - Steve Kalkanis
- Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Detroit, MI, USA
| | - Doron Ginsberg
- Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
| | - Chaya Brodie
- Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
- Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Detroit, MI, USA
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32
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Nobili L, Ronchetti D, Taiana E, Neri A. Long non-coding RNAs in B-cell malignancies: a comprehensive overview. Oncotarget 2017; 8:60605-60623. [PMID: 28947998 PMCID: PMC5601166 DOI: 10.18632/oncotarget.17303] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 03/16/2017] [Indexed: 01/06/2023] Open
Abstract
B-cell malignancies constitute a large part of hematological neoplasias. They represent a heterogeneous group of diseases, including Hodgkin's lymphoma, most non-Hodgkin's lymphomas (NHL), some leukemias and myelomas. B-cell malignancies reflect defined stages of normal B-cell differentiation and this represents the major basis for their classification. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts longer than 200 nucleotides, for which many recent studies have demonstrated a function in regulating gene expression, cell biology and carcinogenesis. Deregulated expression levels of lncRNAs have been observed in various types of cancers including hematological malignancies. The involvement of lncRNAs in cancer initiation and progression and their attractive features both as biomarker and for therapeutic research are becoming increasingly evident. In this review, we summarize the recent literature to highlight the status of the knowledge of lncRNAs role in normal B-cell development and in the pathogenesis of B-cell tumors.
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Affiliation(s)
- Lucia Nobili
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Hematology, Fondazione Cà Granda IRCCS Policlinico, Milano, Italy
| | - Domenica Ronchetti
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Hematology, Fondazione Cà Granda IRCCS Policlinico, Milano, Italy
| | - Elisa Taiana
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Hematology, Fondazione Cà Granda IRCCS Policlinico, Milano, Italy
| | - Antonino Neri
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Hematology, Fondazione Cà Granda IRCCS Policlinico, Milano, Italy
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33
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Dzikiewicz-Krawczyk A, Kok K, Slezak-Prochazka I, Robertus JL, Bruining J, Tayari MM, Rutgers B, de Jong D, Koerts J, Seitz A, Li J, Tillema B, Guikema JE, Nolte IM, Diepstra A, Visser L, Kluiver J, van den Berg A. ZDHHC11 and ZDHHC11B are critical novel components of the oncogenic MYC-miR-150-MYB network in Burkitt lymphoma. Leukemia 2017; 31:1470-1473. [PMID: 28331227 DOI: 10.1038/leu.2017.94] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- A Dzikiewicz-Krawczyk
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,lnstitute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - K Kok
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - I Slezak-Prochazka
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Biosystems Group, Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland
| | - J-L Robertus
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - J Bruining
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - M M Tayari
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - B Rutgers
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - D de Jong
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - J Koerts
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - A Seitz
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - J Li
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - B Tillema
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - J E Guikema
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - I M Nolte
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - A Diepstra
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - L Visser
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - J Kluiver
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - A van den Berg
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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34
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Teteloshvili N, Smigielska-Czepiel K, Yuan Y, Seitz A, de Jong D, Rutgers B, Jellema P, van der Lei RJ, Slezak-Prochazka I, Brouwer E, Boots AMH, Kroesen BJ, van den Berg A, Kluiver J. Argonaute 2 immunoprecipitation revealed large tumor suppressor kinase 1 as a novel proapoptotic target of miR-21 in T cells. FEBS J 2017; 284:555-567. [PMID: 28075055 DOI: 10.1111/febs.14011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 12/09/2016] [Accepted: 01/09/2017] [Indexed: 01/13/2023]
Abstract
MicroRNA (miR)-21 is an important suppressor of T-cell apoptosis that is also overexpressed in many types of cancers. The exact mechanisms underlying the antiapoptotic effects of miR-21 are not well understood. In this study, we used the Jurkat T-cell line as a model to identify apoptosis-associated miR-21 target genes. We showed that expression of miR-21 rapidly increases upon αCD3/αCD28 activation of Jurkat cells. Inhibition of miR-21 reduced cell growth which could be explained by an increase in apoptosis. MicroRNA target gene identification by AGO2 RNA-immunoprecipitation followed by gene expression microarray (RIP-Chip) resulted in the identification of 72 predicted miR-21 target genes that were at least twofold enriched in the AGO2-IP fraction of miR-21 overexpressing cells. Of these, 71 were at least twofold more enriched in the AGO2-IP fraction of miR-21 overexpressing cells as compared to AGO2-IP fraction of control cells. The target gene for which the AGO2-IP enrichment was most prominently increased upon miR-21 overexpression was the proapoptotic protein LATS1. Luciferase reporter assays and western blot analysis confirmed targeting of LATS1 by miR-21. qRT-PCR analysis in primary T cells showed an inverse expression pattern between LATS1 transcript levels and miR-21 upon T-cell stimulation. Finally, LATS1 knockdown partially rescued the miR-21 inhibition-induced impaired cell growth. Collectively, these data identify LATS1 as a miR-21 target important for the antiapoptotic function of miR-21 in T cells and likely also in many types of cancer.
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Affiliation(s)
- Nato Teteloshvili
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands.,Groningen Research initiative on healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, The Netherlands
| | - Katarzyna Smigielska-Czepiel
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands.,Groningen Research initiative on healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, The Netherlands
| | - Ye Yuan
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands.,Institute of Clinical Pharmacology of the Second Affiliated Hospital, Harbin Medical University, Heilongjiang Province, China
| | - Annika Seitz
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Debora de Jong
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Bea Rutgers
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Pytrick Jellema
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Roelof Jan van der Lei
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Izabella Slezak-Prochazka
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Elisabeth Brouwer
- Groningen Research initiative on healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, The Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Annemieke M H Boots
- Groningen Research initiative on healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, The Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Bart-Jan Kroesen
- Groningen Research initiative on healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, The Netherlands.,Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands.,Groningen Research initiative on healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, The Netherlands
| | - Joost Kluiver
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
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35
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Molecular mechanisms of long noncoding RNAs on gastric cancer. Oncotarget 2017; 7:8601-12. [PMID: 26788991 PMCID: PMC4890990 DOI: 10.18632/oncotarget.6926] [Citation(s) in RCA: 238] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 01/13/2016] [Indexed: 12/14/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. Aberrant expression of lncRNAs has been found associated with gastric cancer, one of the most malignant tumors. By complementary base pairing with mRNAs or forming complexes with RNA binding proteins (RBPs), some lncRNAs including GHET1, MALAT1, and TINCR may mediate mRNA stability and splicing. Other lncRNAs, such as BC032469, GAPLINC, and HOTAIR, participate in the competing endogenous RNA (ceRNA) network. Under certain circumstances, ANRIL, GACAT3, H19, MEG3, and TUSC7 exhibit their biological roles by associating with microRNAs (miRNAs). By recruiting histone-modifying complexes, ANRIL, FENDRR, H19, HOTAIR, MALAT1, and PVT1 may inhibit the transcription of target genes in cis or trans. Through these mechanisms, lncRNAs form RNA-dsDNA triplex. CCAT1, GAPLINC, GAS5, H19, MEG3, and TUSC7 play oncogenic or tumor suppressor roles by correlated with tumor suppressor P53 or onco-protein c-Myc, respectively. In conclusion, interaction with DNA, RNA and proteins is involved in lncRNAs' participation in gastric tumorigenesis and development.
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36
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Slezak-Prochazka I, Kluiver J, de Jong D, Smigielska-Czepiel K, Kortman G, Winkle M, Rutgers B, Koerts J, Visser L, Diepstra A, Kroesen BJ, van den Berg A. Inhibition of the miR-155 target NIAM phenocopies the growth promoting effect of miR-155 in B-cell lymphoma. Oncotarget 2016; 7:2391-400. [PMID: 26497687 PMCID: PMC4823043 DOI: 10.18632/oncotarget.6165] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 10/04/2015] [Indexed: 11/25/2022] Open
Abstract
Several studies have indicated an important role for miR-155 in the pathogenesis of B-cell lymphoma. Highly elevated levels of miR-155 were indeed observed in most B-cell lymphomas with the exception of Burkitt lymphoma (BL). However, the molecular mechanisms that underlie the oncogenic role of miR-155 in B-cell lymphoma are not well understood. To identify the miR-155 targets relevant for B-cell lymphoma, we performed RNA immunoprecipitation of Argonaute 2 in Hodgkin lymphoma (HL) cells upon miR-155 inhibition and in BL cells upon ectopic expression of miR-155. We identified 54 miR-155-specific target genes in BL cells and confirmed miR-155 targeting of DET1, NIAM, TRIM32, HOMEZ, PSIP1 and JARID2. Five of these targets are also regulated by endogenous miR-155 in HL cells. Both overexpression of miR-155 and inhibition of expression of the novel miR-155 target gene NIAM increased proliferation of BL cells. In primary B-cell lymphoma NIAM-positive cases have significant lower levels of miR-155 as compared to NIAM-negative cases, suggesting that NIAM is also regulated by miR-155 in primary B-cell lymphoma. Thus, our data indicate an oncogenic role for miR-155 in B-cell lymphoma which involves targeting the tumor suppressor NIAM.
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Affiliation(s)
- Izabella Slezak-Prochazka
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Biosystems Group, Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland
| | - Joost Kluiver
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Debora de Jong
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Katarzyna Smigielska-Czepiel
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Gertrud Kortman
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Melanie Winkle
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bea Rutgers
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jasper Koerts
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Lydia Visser
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Arjan Diepstra
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bart-Jan Kroesen
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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37
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Sipos F, Firneisz G, Műzes G. Therapeutic aspects of c-MYC signaling in inflammatory and cancerous colonic diseases. World J Gastroenterol 2016; 22:7938-7950. [PMID: 27672289 PMCID: PMC5028808 DOI: 10.3748/wjg.v22.i35.7938] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 08/04/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
Colonic inflammation is required to heal infections, wounds, and maintain tissue homeostasis. As the seventh hallmark of cancer, however, it may affect all phases of tumor development, including tumor initiation, promotion, invasion and metastatic dissemination, and also evasion immune surveillance. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability, and, further, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Both sporadical and colitis-associated colorectal carcinogenesis are multi-step, complex processes arising from the uncontrolled proliferation and spreading of malignantly transformed cell clones with the obvious ability to evade the host's protective immunity. In cells upon DNA damage several proto-oncogenes, including c-MYC are activated in parelell with the inactivation of tumor suppressor genes. The target genes of the c-MYC protein participate in different cellular functions, including cell cycle, survival, protein synthesis, cell adhesion, and micro-RNA expression. The transcriptional program regulated by c-MYC is context dependent, therefore the final cellular response to elevated c-MYC levels may range from increased proliferation to augmented apoptosis. Considering physiological intestinal homeostasis, c-MYC displays a fundamental role in the regulation of cell proliferation and crypt cell number. However, c-MYC gene is frequently deregulated in inflammation, and overexpressed in both sporadic and colitis-associated colon adenocarcinomas. Recent results demonstrated that endogenous c-MYC is essential for efficient induction of p53-dependent apoptosis following DNA damage, but c-MYC function is also involved in and regulated by autophagy-related mechanisms, while its expression is affected by DNA-methylation, or histone acetylation. Molecules directly targeting c-MYC, or agents acting on other genes involved in the c-MYC pathway could be selected for combined regiments. However, due to its context-dependent cellular function, it is clinically essential to consider which cytotoxic drugs are used in combination with c-MYC targeted agents in various tissues. Increasing our knowledge about MYC-dependent pathways might provide direction to novel anti-inflammatory and colorectal cancer therapies.
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38
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Bida O, Gidoni M, Ideses D, Efroni S, Ginsberg D. A novel mitosis-associated lncRNA, MA-linc1, is required for cell cycle progression and sensitizes cancer cells to Paclitaxel. Oncotarget 2016; 6:27880-90. [PMID: 26337085 PMCID: PMC4695032 DOI: 10.18632/oncotarget.4944] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 07/31/2015] [Indexed: 11/25/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are major regulators of many cellular processes including cell cycle progression and tumorigenesis. In this study, we identify a novel lncRNA, MA-linc1, and reveal its effects on cell cycle progression and cancer growth. Inhibition of MA-linc1 expression alters cell cycle distribution, leading to a decrease in the number of G1 cells and a concomitant increase in all other stages of the cell cycle, and in particular G2/M, suggesting its involvement in the regulation of M phase. Accordingly, knock down of MA-linc1 inhibits M phase exit upon release from a mitotic block. We further demonstrate that MA-linc1 predominantly functions in cis to repress expression of its neighboring gene, Purα, which is often deleted in human cancers and whose ectopic expression inhibits cell cycle progression. Knock down of Purα partially rescues the MA-linc1 dependent inhibition of M phase exit. In agreement with its suggested role in M phase, inhibition of MA-linc1 enhances apoptotic cell death induced by the antimitotic drug, Paclitaxel and this enhancement of apoptosis is rescued by Purα knockdown. Furthermore, high levels of MA-linc1 are associated with reduced survival in human breast and lung cancer patients. Taken together, our data identify MA-linc1 as a novel lncRNA regulator of cell cycle and demonstrate its potential role in cancer progression and treatment.
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Affiliation(s)
- Or Bida
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
| | - Moriah Gidoni
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
| | - Diana Ideses
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
| | - Sol Efroni
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
| | - Doron Ginsberg
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel
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39
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Zhang P, Cao L, Fan P, Mei Y, Wu M. LncRNA-MIF, a c-Myc-activated long non-coding RNA, suppresses glycolysis by promoting Fbxw7-mediated c-Myc degradation. EMBO Rep 2016; 17:1204-20. [PMID: 27317567 PMCID: PMC4967955 DOI: 10.15252/embr.201642067] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 05/17/2016] [Accepted: 05/23/2016] [Indexed: 01/26/2023] Open
Abstract
The c-Myc proto-oncogene is activated in more than half of all human cancers. However, the precise regulation of c-Myc protein stability is unknown. Here, we show that the lncRNA-MIF (c-Myc inhibitory factor), a c-Myc-induced long non-coding RNA, is a competing endogenous RNA for miR-586 and attenuates the inhibitory effect of miR-586 on Fbxw7, an E3 ligase for c-Myc, leading to increased Fbxw7 expression and subsequent c-Myc degradation. Our data reveal the existence of a feedback loop between c-Myc and lncRNA-MIF, through which c-Myc protein stability is finely controlled. Additionally, we show that the lncRNA-MIF inhibits aerobic glycolysis and tumorigenesis by suppressing c-Myc and miR-586.
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Affiliation(s)
- Pengfei Zhang
- CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science & Technology of China, Hefei, Anhui, China
| | - Limian Cao
- CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science & Technology of China, Hefei, Anhui, China
| | - Pingsheng Fan
- Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yide Mei
- CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science & Technology of China, Hefei, Anhui, China
| | - Mian Wu
- CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science & Technology of China, Hefei, Anhui, China
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40
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Tayari MM, Winkle M, Kortman G, Sietzema J, de Jong D, Terpstra M, Mestdagh P, Kroese FGM, Visser L, Diepstra A, Kok K, van den Berg A, Kluiver J. Long Noncoding RNA Expression Profiling in Normal B-Cell Subsets and Hodgkin Lymphoma Reveals Hodgkin and Reed-Sternberg Cell-Specific Long Noncoding RNAs. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:2462-72. [PMID: 27423697 DOI: 10.1016/j.ajpath.2016.05.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 05/13/2016] [Accepted: 05/18/2016] [Indexed: 12/22/2022]
Abstract
Hodgkin lymphoma (HL) is a malignancy of germinal center (GC) B-cell origin. To explore the role of long noncoding RNAs (lncRNAs) in HL, we studied lncRNA expression patterns in normal B-cell subsets, HL cell lines, and tissues. Naive and memory B cells showed a highly similar lncRNA expression pattern, distinct from GC-B cells. Significant differential expression between HL and normal GC-B cells was observed for 475 lncRNA loci. For two validated lncRNAs, an enhanced expression was observed in HL, diffuse large B-cell lymphoma, and lymphoblastoid cell lines. For a third lncRNA, increased expression levels were observed in HL and part of Burkitt lymphoma cell lines. RNA fluorescence in situ hybridization on primary HL tissues revealed a tumor cell-specific expression pattern for all three lncRNAs. A potential cis-regulatory role was observed for 107 differentially expressed lncRNA-mRNA pairs localizing within a 60-kb region. Consistent with a cis-acting role, we showed a preferential nuclear localization for two selected candidates. Thus, we showed dynamic lncRNA expression changes during the transit of normal B cells through the GC reaction and widely deregulated lncRNA expression patterns in HL. Three lncRNAs showed a tumor cell-specific expression pattern in HL tissues and might therefore be of value as a biomarker.
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Affiliation(s)
- Mina Masoumeh Tayari
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Melanie Winkle
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Gertrud Kortman
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jantine Sietzema
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Debora de Jong
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Martijn Terpstra
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Pieter Mestdagh
- Center for Medical Genetics, Ghent University, Ghent, Belgium
| | - Frans G M Kroese
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Lydia Visser
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Arjan Diepstra
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Klaas Kok
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Joost Kluiver
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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Kim T, Cui R, Jeon YJ, Fadda P, Alder H, Croce CM. MYC-repressed long noncoding RNAs antagonize MYC-induced cell proliferation and cell cycle progression. Oncotarget 2016; 6:18780-9. [PMID: 26003165 PMCID: PMC4662455 DOI: 10.18632/oncotarget.3909] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 04/28/2015] [Indexed: 01/01/2023] Open
Abstract
The transcription factor MYC is a proto-oncogene regulating cell proliferation, cell cycle, apoptosis and metabolism. The recent identification of MYC-regulated long noncoding RNAs (lncRNAs) expands our knowledge of the role of lncRNAs in MYC functions. Here, we identify MYC-repressed lncRNAs named MYCLo-4, -5 and -6 by comparing 3 categories of lncRNAs (downregulated in highly MYC-expressing colorectal cancer, up-regulated by MYC knockdown in HCT116, upregulated by MYC knockdown in RKO). The MYC-repressed MYCLos are implicated in MYC-modulated cell proliferation through cell cycle regulation. By screening cell cycle-related genes regulated by MYC and the MYC-repressed MYCLos, we identified the MYC-repressed gene GADD45A as a target gene of the MYC-repressed MYCLos such as MYCLo-4 and MYCLo-6.
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Affiliation(s)
- Taewan Kim
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ri Cui
- Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Young-Jun Jeon
- Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Paolo Fadda
- Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Hansjuerg Alder
- Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Carlo M Croce
- Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
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Abstract
It is increasingly evident that many of the genomic mutations in cancer reside inside regions that do not encode proteins. However, these regions are often transcribed into long noncoding RNAs (lncRNAs). The recent application of next-generation sequencing to a growing number of cancer transcriptomes has indeed revealed thousands of lncRNAs whose aberrant expression is associated with different cancer types. Among the few that have been functionally characterized, several have been linked to malignant transformation. Notably, these lncRNAs have key roles in gene regulation and thus affect various aspects of cellular homeostasis, including proliferation, survival, migration or genomic stability. This review aims to summarize current knowledge of lncRNAs from the cancer perspective. It discusses the strategies that led to the identification of cancer-related lncRNAs and the methodologies and challenges involving the study of these molecules, as well as the imminent applications of these findings to the clinic.
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43
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Reply to Hart et al.: MINCR and MYC: More than expression correlation. Proc Natl Acad Sci U S A 2016; 113:E498. [PMID: 26811501 DOI: 10.1073/pnas.1520413113] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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44
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Abstract
Long non-coding RNAs (lncRNAs) are a class of RNA molecules that are changing how researchers view eukaryotic gene regulation. Once considered to be non-functional products of low-level aberrant transcription from non-coding regions of the genome, lncRNAs are now viewed as important epigenetic regulators and several lncRNAs have now been demonstrated to be critical players in the development and/or maintenance of cancer. Similarly, the emerging variety of interactions between lncRNAs and MYC, a well-known oncogenic transcription factor linked to most types of cancer, have caught the attention of many biomedical researchers. Investigations exploring the dynamic interactions between lncRNAs and MYC, referred to as the lncRNA-MYC network, have proven to be especially complex. Genome-wide studies have shown that MYC transcriptionally regulates many lncRNA genes. Conversely, recent reports identified lncRNAs that regulate MYC expression both at the transcriptional and post-transcriptional levels. These findings are of particular interest because they suggest roles of lncRNAs as regulators of MYC oncogenic functions and the possibility that targeting lncRNAs could represent a novel avenue to cancer treatment. Here, we briefly review the current understanding of how lncRNAs regulate chromatin structure and gene transcription, and then focus on the new developments in the emerging field exploring the lncRNA-MYC network in cancer.
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Affiliation(s)
- Michael J. Hamilton
- Department of Biochemistry, University of California, Riverside, CA 92521, USA
| | - Matthew D. Young
- Department of Biochemistry, University of California, Riverside, CA 92521, USA
| | - Silvia Sauer
- Department of Biochemistry, University of California, Riverside, CA 92521, USA
| | - Ernest Martinez
- Department of Biochemistry, University of California, Riverside, CA 92521, USA
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45
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MINCR is a MYC-induced lncRNA able to modulate MYC's transcriptional network in Burkitt lymphoma cells. Proc Natl Acad Sci U S A 2015; 112:E5261-70. [PMID: 26351698 DOI: 10.1073/pnas.1505753112] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.
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