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Rodríguez-Campuzano AG, Castelán F, Hernández-Kelly LC, Felder-Schmittbuhl MP, Ortega A. Yin Yang 1: Function, Mechanisms, and Glia. Neurochem Res 2025; 50:96. [PMID: 39904836 PMCID: PMC11794380 DOI: 10.1007/s11064-025-04345-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/21/2025] [Accepted: 01/22/2025] [Indexed: 02/06/2025]
Abstract
Yin Yang 1 is a ubiquitously expressed transcription factor that has been extensively studied given its particular dual transcriptional regulation. Yin Yang 1 is involved in various cellular processes like cell cycle progression, cell differentiation, DNA repair, cell survival and apoptosis among others. Its malfunction or alteration leads to disease and even to malignant transformation. This transcription factor is essential for the proper central nervous system development and function. The activity of Yin Yang 1 depends on its interacting partners, promoter environment and chromatin structure, however, its mechanistic activity is not completely understood. In this review, we briefly discuss the Yin Yang 1 structure, post-translational modifications, interactions, mechanistic functions and its participation in neurodevelopment. We also discuss its expression and critical involvement in the physiology and physiopathology of glial cells, summarizing the contribution of Yin Yang 1 on different aspects of cellular function.
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Affiliation(s)
- Ada G Rodríguez-Campuzano
- Departamento de Biología Celular y Fisiología, Unidad Foránea Tlaxcala, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Tlaxcala, Tlaxcala, Mexico
| | - Francisco Castelán
- Departamento de Biología Celular y Fisiología, Unidad Foránea Tlaxcala, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Tlaxcala, Tlaxcala, Mexico
| | - Luisa C Hernández-Kelly
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. IPN 2508, San Pedro Zacantenco, G.A. Madero, 07360, Ciudad de Mexico, Mexico
| | - Marie-Paule Felder-Schmittbuhl
- Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives (UPR 3212), Université de Strasbourg, Strasbourg, France
| | - Arturo Ortega
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. IPN 2508, San Pedro Zacantenco, G.A. Madero, 07360, Ciudad de Mexico, Mexico.
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2
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Merenstein A, Obeidat L, Zaravinos A, Bonavida B. The Role of YY1 in the Regulation of LAG-3 Expression in CD8 T Cells and Immune Evasion in Cancer: Therapeutic Implications. Cancers (Basel) 2024; 17:19. [PMID: 39796650 PMCID: PMC11718991 DOI: 10.3390/cancers17010019] [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: 11/06/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
The treatment of cancers with immunotherapies has yielded significant milestones in recent years. Amongst these immunotherapeutic strategies, the FDA has approved several checkpoint inhibitors (CPIs), primarily Anti-Programmed Death-1 (PD-1) and Programmed Death Ligand-1/2 (PDL-1/2) monoclonal antibodies, in the treatment of various cancers unresponsive to immune therapeutics. Such treatments resulted in significant clinical responses and the prolongation of survival in a subset of patients. However, not all patients responded to CPIs, due to various mechanisms of immune resistance. One such mechanism is that, in addition to PD-1 expression on CD8 T cells, other inhibitory receptors exist, such as Lymphocyte Activation Gene 3 (LAG-3), T cell Immunoglobulin Mucin 3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors might be active in the presence of the above approved CPIs. Clearly, it is clinically challenging to block all such inhibitory receptors simultaneously using conventional antibodies. To circumvent this difficulty, we sought to target a potential transcription factor that may be involved in the molecular regulation of more than one inhibitory receptor. The transcription factor Yin Yang1 (YY1) was found to regulate the expression of PD-1, LAG-3, and TIM3. Therefore, we hypothesized that targeting YY1 in CD8 T cells should inhibit the expression of these receptors and, thus, prevent the inactivation of the anti-tumor CD8 T cells by these receptors, by corresponding ligands to tumor cells. This strategy should result in the prevention of immune evasion, leading to the inhibition of tumor growth. In addition, this strategy will be particularly effective in a subset of cancer patients who were unresponsive to approved CPIs. In this review, we discuss the regulation of LAG-3 by YY1 as proof of principle for the potential use of targeting YY1 as an alternative therapeutic approach to preventing the immune evasion of cancer. We present findings on the molecular regulations of both YY1 and LAG-3 expressions, the direct regulation of LAG-3 by YY1, the various approaches to targeting YY1 to evade immune evasion, and their clinical challenges. We also present bioinformatic analyses demonstrating the overexpression of LAG-3, YY1, and PD-L1 in various cancers, their associations with immune infiltrates, and the fact that when LAG-3 is hypermethylated in its promoter region it correlates with a better overall survival. Hence, targeting YY1 in CD8 T cells will result in restoring the anti-tumor immune response and tumor regression. Notably, in addition to the beneficial effects of targeting YY1 in CD8 T cells to inhibit the expression of inhibitory receptors, we also suggest targeting YY1 overexpressed in the tumor cells, which will also inhibit PD-L1 expression and other YY1-associated pro-tumorigenic activities.
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Affiliation(s)
- Adam Merenstein
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA;
| | - Loiy Obeidat
- Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), 1516 Nicosia, Cyprus; (L.O.); (A.Z.)
- Department of Life Sciences, School of Sciences, European University Cyprus, 1516 Nicosia, Cyprus
| | - Apostolos Zaravinos
- Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), 1516 Nicosia, Cyprus; (L.O.); (A.Z.)
- Department of Life Sciences, School of Sciences, European University Cyprus, 1516 Nicosia, Cyprus
| | - Benjamin Bonavida
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA;
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Antonio-Andres G, Morales-Martinez M, Jimenez-Hernandez E, Huerta-Yepez S. The Role of PTEN in Chemoresistance Mediated by the HIF-1α/YY1 Axis in Pediatric Acute Lymphoblastic Leukemia. Int J Mol Sci 2024; 25:7767. [PMID: 39063014 PMCID: PMC11276810 DOI: 10.3390/ijms25147767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/26/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Current chemotherapy treatment regimens have improved survival rates to approximately 80%; however, resistance development remains the primary cause of treatment failure, affecting around 20% of cases. Some studies indicate that loss of the phosphatase and tensin homolog (PTEN) leads to deregulation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, increasing the expression of proteins involved in chemoresistance. PTEN loss results in deregulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces hypoxia-inducible factor 1-alpha (HIF-1α) expression in various cancers. Additionally, it triggers upregulation of the Yin Yang 1 (YY1) transcription factor, leading to chemoresistance mediated by glycoprotein p-170 (Gp-170). The aim of this study was to investigate the role of the PTEN/NF-κB axis in YY1 regulation via HIF-1α and its involvement in ALL. A PTEN inhibitor was administered in RS4;11 cells, followed by the evaluation of PTEN, NF-κB, HIF-1α, YY1, and Gp-170 expression, along with chemoresistance assessment. PTEN, HIF-1α, and YY1 expression levels were assessed in the peripheral blood mononuclear cells (PBMC) from pediatric ALL patients. The results reveal that the inhibition of PTEN activity significantly increases the expression of pAkt and NF-κB, which is consistent with the increase in the expression of HIF-1α and YY1 in RS4;11 cells. In turn, this inhibition increases the expression of the glycoprotein Gp-170, affecting doxorubicin accumulation in the cells treated with the inhibitor. Samples from pediatric ALL patients exhibit PTEN expression and higher HIF-1α and YY1 expression compared to controls. PTEN/Akt/NF-κB axis plays a critical role in the regulation of YY1 through HIF-1α, and this mechanism contributes to Gp-170-mediated chemoresistance in pediatric ALL.
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Affiliation(s)
- Gabriela Antonio-Andres
- Oncology Disease Research Unit, Children’s Hospital of Mexico, Federico Gomez, Mexico City 06720, Mexico;
| | - Mario Morales-Martinez
- Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA
- UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA
| | | | - Sara Huerta-Yepez
- Oncology Disease Research Unit, Children’s Hospital of Mexico, Federico Gomez, Mexico City 06720, Mexico;
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Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:97. [PMID: 38664391 PMCID: PMC11045871 DOI: 10.1038/s41392-024-01811-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/06/2024] [Accepted: 03/17/2024] [Indexed: 04/28/2024] Open
Abstract
Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.
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Affiliation(s)
- Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
| | - Sunil Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
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Mosca N, Pezzullo M, De Leo I, Truda A, Marchese G, Russo A, Potenza N. A Novel ceRNET Relying on the lncRNA JPX, miR-378a-3p, and Its mRNA Targets in Lung Cancer. Cancers (Basel) 2024; 16:1526. [PMID: 38672608 PMCID: PMC11049386 DOI: 10.3390/cancers16081526] [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: 03/30/2024] [Revised: 04/12/2024] [Accepted: 04/15/2024] [Indexed: 04/28/2024] Open
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Non-coding RNAs are emerging as critical players for the onset and progression of cancer. Analyses of three different datasets revealed that the lncRNA JPX was overexpressed in adenocarcinoma tissues in comparison to normal lungs, as expected for an oncogene. Intriguingly, the predicted binding miR-378a-3p showed a significant inverse correlation with JPX expression. The lncRNA/miRNA physical interaction was validated by reporter vectors. Then, the oncogenic activity of JPX, the tumor-suppressive role of miR-378a-3p, and the contribution of their functional interaction to cancer hallmarks were demonstrated using assays for cell proliferation, migration, invasion, and 3D-spheroid formation. Finally, molecular circuits were investigated by boosting the expression of both JPX and miR-378a-3p, singularly and in combination, demonstrating that JPX counteracted miR-378a-3p silencing activity toward its oncogenic targets GLUT1, NRP1, YY1, and Wnt5a. Overall, the data unveil a novel ceRNET (competing endogenous RNA network), wherein JPX acts as a ceRNA by binding to miR-378a-3p, thus reducing the miRNA silencing activity toward its downstream targets, and eliciting oncogenic pathways driving lung cancer. The knowledge of the network may pave the way to develop new diagnostic panels, and innovative RNA-targeted and RNA-based therapeutic strategies.
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Affiliation(s)
- Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (N.M.); (M.P.); (I.D.L.); (A.T.); (A.R.)
| | - Mariaceleste Pezzullo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (N.M.); (M.P.); (I.D.L.); (A.T.); (A.R.)
| | - Ilenia De Leo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (N.M.); (M.P.); (I.D.L.); (A.T.); (A.R.)
- Genomix4Life S.r.l., 84081 Baronissi, Italy;
| | - Anna Truda
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (N.M.); (M.P.); (I.D.L.); (A.T.); (A.R.)
- Genomix4Life S.r.l., 84081 Baronissi, Italy;
| | - Giovanna Marchese
- Genomix4Life S.r.l., 84081 Baronissi, Italy;
- Genome Research Center for Health—CRGS, 84081 Baronissi, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (N.M.); (M.P.); (I.D.L.); (A.T.); (A.R.)
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (N.M.); (M.P.); (I.D.L.); (A.T.); (A.R.)
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Dillen A, Bui I, Jung M, Agioti S, Zaravinos A, Bonavida B. Regulation of PD-L1 Expression by YY1 in Cancer: Therapeutic Efficacy of Targeting YY1. Cancers (Basel) 2024; 16:1237. [PMID: 38539569 PMCID: PMC10968822 DOI: 10.3390/cancers16061237] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/23/2024] [Accepted: 03/11/2024] [Indexed: 05/14/2025] Open
Abstract
During the last decade, we have witnessed several milestones in the treatment of various resistant cancers including immunotherapeutic strategies that have proven to be superior to conventional treatment options, such as chemotherapy and radiation. This approach utilizes the host's immune response, which is triggered by cancer cells expressing tumor-associated antigens or neoantigens. The responsive immune cytotoxic CD8+ T cells specifically target and kill tumor cells, leading to tumor regression and prolongation of survival in some cancers; however, some cancers may exhibit resistance due to the inactivation of anti-tumor CD8+ T cells. One mechanism by which the anti-tumor CD8+ T cells become dysfunctional is through the activation of the inhibitory receptor programmed death-1 (PD-1) by the corresponding tumor cells (or other cells in the tumor microenvironment (TME)) that express the programmed death ligand-1 (PD-L1). Hence, blocking the PD-1/PD-L1 interaction via specific monoclonal antibodies (mAbs) restores the CD8+ T cells' functions, leading to tumor regression. Accordingly, the Food and Drug Administration (FDA) has approved several checkpoint antibodies which act as immune checkpoint inhibitors. Their clinical use in various resistant cancers, such as metastatic melanoma and non-small-cell lung cancer (NSCLC), has shown significant clinical responses. We have investigated an alternative approach to prevent the expression of PD-L1 on tumor cells, through targeting the oncogenic transcription factor Yin Yang 1 (YY1), a known factor overexpressed in many cancers. We report the regulation of PD-L1 by YY1 at the transcriptional, post-transcriptional, and post-translational levels, resulting in the restoration of CD8+ T cells' anti-tumor functions. We have performed bioinformatic analyses to further explore the relationship between both YY1 and PD-L1 in cancer and to corroborate these findings. In addition to its regulation of PD-L1, YY1 has several other anti-cancer activities, such as the regulation of proliferation and cell viability, invasion, epithelial-mesenchymal transition (EMT), metastasis, and chemo-immuno-resistance. Thus, targeting YY1 will have a multitude of anti-tumor activities resulting in a significant obliteration of cancer oncogenic activities. Various strategies are proposed to selectively target YY1 in human cancers and present a promising novel therapeutic approach for treating unresponsive cancer phenotypes. These findings underscore the distinct regulatory roles of YY1 and PD-L1 (CD274) in cancer progression and therapeutic response.
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Affiliation(s)
- Ana Dillen
- Department of Microbiology, Immunology & Molecular Genetics, Jonsson Comprehensive Cancer, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; (A.D.); (I.B.)
| | - Indy Bui
- Department of Microbiology, Immunology & Molecular Genetics, Jonsson Comprehensive Cancer, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; (A.D.); (I.B.)
| | - Megan Jung
- Department of Microbiology, Immunology & Molecular Genetics, Jonsson Comprehensive Cancer, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; (A.D.); (I.B.)
| | - Stephanie Agioti
- Cancer Genetics, Genomic and Systems Biology Group, Basic and Translational Cancer Research Center (BTCRC), 1516 Nicosia, Cyprus (A.Z.)
| | - Apostolos Zaravinos
- Cancer Genetics, Genomic and Systems Biology Group, Basic and Translational Cancer Research Center (BTCRC), 1516 Nicosia, Cyprus (A.Z.)
- Department of Life Sciences, School of Sciences, European University Cyprus, 2404 Nicosia, Cyprus
| | - Benjamin Bonavida
- Department of Microbiology, Immunology & Molecular Genetics, Jonsson Comprehensive Cancer, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; (A.D.); (I.B.)
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Wu L, Zhou Z, Yu Y, Cheng C, Zhou S, Yan Y, Yu B, Zhang Y, Liu Z. Phosphorylation-dependent deubiquitinase OTUD3 regulates YY1 stability and promotes colorectal cancer progression. Cell Death Dis 2024; 15:137. [PMID: 38351178 PMCID: PMC10864350 DOI: 10.1038/s41419-024-06526-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 01/25/2024] [Accepted: 01/31/2024] [Indexed: 02/16/2024]
Abstract
Yin Yang 1 (YY1) is a key transcription factor that has been implicated in the development of several malignancies. The stability of YY1 is regulated by the ubiquitin-proteasome system. The role of deubiquitinases (DUBs) and their impact on YY1 remain to be fully elucidated. In this study, we screened for ubiquitin-specific proteases that interact with YY1, and identified OTUD3 as a DUB for YY1. Over-expressed OTUD3 inhibited YY1 degradation, thereby increasing YY1 protein levels, whereas OTUD3 knockdown or knockout promoted YY1 degradation, thereby decreasing the proliferation of colorectal cancer (CRC). Furthermore, PLK1 mediates OTUD3 S326 phosphorylation, which further enhances OTUD3 binding and deubiquitination of YY1. In CRC tissues, elevated the expression level of OTUD3 and YY1 were significantly associated with poor prognostic outcomes. These findings suggest that the OTUD3-YY1 pathway has therapeutic potential in CRC, and OTUD3 plays a critical role in regulating YY1.
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Affiliation(s)
- Liang Wu
- Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, 230001, China
| | - Zili Zhou
- Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000, Sichuan, China
| | - Yang Yu
- Department of Breast Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, Henan, China
- Microbiome Laboratory, People's Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Can Cheng
- Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, 230001, China
| | - Shuai Zhou
- Translational Research Institute, Henan Provincial and Zhengzhou City Key Laboratory of Non-coding RNA and Cancer Metabolism, Henan International Join Laboratory of Non-coding RNA and Metabolism in Cancer, Henan Provincial People's Hospital, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Yuan Yan
- Department of Breast Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, Henan, China
| | - Bofan Yu
- Department of Breast Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, Henan, China
| | - Yuwei Zhang
- Key Laboratory of Stem Cell Differentiation & Modification, School of Clinical Medicine, Henan University, Zhengzhou, 450000, China
| | - Zhengyi Liu
- Department of Breast Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, Henan, China.
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8
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Michas A, Michas V, Anagnostou E, Galanopoulos M, Tolia M, Tsoukalas N. The Clinical Significance of MicroRNAs in Colorectal Cancer Signaling Pathways: A Review. Glob Med Genet 2023; 10:315-323. [PMID: 38025193 PMCID: PMC10665125 DOI: 10.1055/s-0043-1777094] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023] Open
Abstract
Colorectal carcinoma (colon and rectum) is currently considered among the most prevalent malignancies of Western societies. The pathogenesis and etiological mechanisms underlying colorectal cancer (CRC) development remain complex and heterogeneous. The homeostasis and function of normal human intestinal cells is highly regulated by microRNAs. Therefore, it is not surprising that mutations and inactivation of these molecules appear to be linked with progression of colorectal tumors. Recent studies have reported significant alterations of microRNA expression in adenomas and CRCs compared with adjacent normal tissues. This observed deviation has been proposed to correlate with the progression and survival of disease as well as with choice of optimal treatment and drug resistance. MicroRNAs can adopt either oncogenic or tumor-suppressive roles during regulation of pathways that drive carcinogenesis. Typically, oncogenic microRNAs termed oncomirs, target and silence endogenous tumor-suppressor genes. On the other hand, tumor-suppressive microRNAs are critical in downregulating genes associated with cell growth and malignant capabilities. By extensively evaluating robust studies, we have emphasized and distinguished a discrete set of microRNAs that can modulate tumor progression by silencing specific driver genes crucial in signaling pathways including Wnt/b-catenin, epidermal growth factor receptor, P53, mismatch repair DNA repair, and transforming-growth factor beta.
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Affiliation(s)
- Athanasios Michas
- Department of Oncology, 401 General Military Hospital of Athens, Athens, Greece
| | - Vasileios Michas
- Department of Radiology, Achepa General Hospital Thessaloniki, Thessaloniki, Greece
| | - Evangelos Anagnostou
- Department of Neurosurgery, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | | | - Maria Tolia
- Department of Oncology, 401 General Military Hospital of Athens, Athens, Greece
| | - Nikolaos Tsoukalas
- Department of Oncology, 401 General Military Hospital of Athens, Athens, Greece
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9
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Liu R, Xu Z, Huang X, Xu B, Chen M. Yin Yang 1 promotes the neuroendocrine differentiation of prostate cancer cells via the non-canonical WNT pathway (FYN/STAT3). Clin Transl Med 2023; 13:e1422. [PMID: 37771187 PMCID: PMC10539684 DOI: 10.1002/ctm2.1422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 09/05/2023] [Accepted: 09/08/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND A growing number of studies have shown that Yin Yang 1 (YY1) promotes the development of multiple tumours. The purpose of the current study was to determine the mechanism by which YY1 mediates neuroendocrine differentiation of prostate cancer (NEPC) cells undergoing cellular plasticity. METHODS Using the Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases, we bioinformatically analyzed YY1 expression in prostate cancer (PCa). Aberrant YY1 expression was validated in different PCa tissues and cell lines via quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemistry. In vivo and in vitro functional assays verified the oncogenicity of YY1 in PCa. Further functional assays showed that ectopic expression of YY1 promoted cellular plasticity in PCa cells via epithelial-mesenchymal transition induction and neuroendocrine differentiation. RESULTS Androgen deprivation therapy induced a decrease in YY1 protein ubiquitination, enhanced its stability, and thus enhanced the transcriptional activity of FZD8. Castration enhanced FZD8 binding to Wnt9A and mediated cellular plasticity by activating the non-canonical Wnt (FZD8/FYN/STAT3) pathway. CONCLUSIONS We identified YY1 as a novel dysregulated transcription factor that plays an important role in NEPC progression in this study. We believe that an in-depth investigation of the mechanism underlying YY1-mediated disease may lead to improved NEPC therapies.
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Affiliation(s)
- Rui‐ji Liu
- Department of Urology, Sichuan Provincial People's Hospital, School of MedicineUniversity of Electronic Science and Technology of ChinaChengduChina
- Department of UrologyAffiliated Zhongda Hospital of Southeast UniversityNanjingChina
- Surgical Research Center, Institute of UrologySoutheast University Medical SchoolNanjingChina
| | - Zhi‐Peng Xu
- Department of UrologyAffiliated Zhongda Hospital of Southeast UniversityNanjingChina
- Surgical Research Center, Institute of UrologySoutheast University Medical SchoolNanjingChina
| | - Xiang Huang
- Department of Urology, Sichuan Provincial People's Hospital, School of MedicineUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Bin Xu
- Department of UrologyAffiliated Zhongda Hospital of Southeast UniversityNanjingChina
- Surgical Research Center, Institute of UrologySoutheast University Medical SchoolNanjingChina
| | - Ming Chen
- Department of UrologyAffiliated Zhongda Hospital of Southeast UniversityNanjingChina
- Surgical Research Center, Institute of UrologySoutheast University Medical SchoolNanjingChina
- Department of Urology, Nanjing Lishui District People's HospitalZhongda Hospital Lishui BranchSoutheast UniversityNanjingChina
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10
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Liu J, Zhao F, Chen LL, Su S. Dysregulation of circular RNAs in inflammation and cancers. FUNDAMENTAL RESEARCH 2023; 3:683-691. [PMID: 38933304 PMCID: PMC11197579 DOI: 10.1016/j.fmre.2023.04.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 02/24/2023] [Accepted: 04/19/2023] [Indexed: 06/28/2024] Open
Abstract
Emerging lines of evidence have shown that the production of the covalently closed single-stranded circular RNAs is not splicing errors, but rather a regulated process with distinct biogenesis and turnover. Circular RNAs are expressed in a cell type- and tissue-specific manner and often localize to specific subcellular regions or organelles for functions. The dysregulation of circular RNAs from birth to death is linked to the pathogenesis and progression of diverse diseases. This review outlines how aberrant circular RNA biogenesis, subcellular location, and degradation are linked to disease progression, focusing on metaflammation and cancers. We also discuss potential therapeutic strategies and obstacles in targeting such disease-related circular RNAs.
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Affiliation(s)
- Jiayu Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Fangqing Zhao
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310003, 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, Chinese Academy of Sciences, Shanghai 200031, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200092, China
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310003, China
| | - Shicheng Su
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
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11
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Tariq L, Arafah A, Sehar N, Ali A, Khan A, Rasool I, Rashid SM, Ahmad SB, Beigh S, Dar TUH, Rehman MU. Novel insights on perils and promises of miRNA in understanding colon cancer metastasis and progression. Med Oncol 2023; 40:282. [PMID: 37639075 DOI: 10.1007/s12032-023-02099-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/19/2023] [Indexed: 08/29/2023]
Abstract
Colorectal cancer (CRC) is the third highest frequent malignancy and ultimate critical source of cancer-associated mortality around the world. Regardless of latest advances in molecular and surgical targeted medicines that have increased remedial effects in CRC patients, the 5-year mortality rate for CRC patients remains dismally low. Evidence suggests that microRNAs (miRNAs) execute an essential part in the development and spread of CRC. The miRNAs are a type of short non-coding RNA that exhibited to control the appearance of tumor suppressor genes and oncogenes. miRNA expression profiling is already being utilized in clinical practice as analytical and prognostic biomarkers to evaluate cancer patients' tumor genesis, advancement, and counteraction to drugs. By modulating their target genes, dysregulated miRNAs are linked to malignant characteristics (e.g., improved proliferative and invasive capabilities, cell cycle aberration, evasion of apoptosis, and promotion of angiogenesis). This review presents an updated summary of circulatory miRNAs, tumor-suppressive and oncogenic miRNAs, and the potential reasons for dysregulated miRNAs in CRC. Further we will explore the critical role of miRNAs in CRC drug resistance.
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Affiliation(s)
- Lubna Tariq
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Azher Arafah
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Nouroz Sehar
- Centre for Translational and Clinical Research, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Aarif Ali
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, 45142, Jazan, Saudi Arabia
| | - Iyman Rasool
- Department of Pathology, Government Medical College (GMC-Srinagar), Karanagar, Srinagar, Jammu and Kashmir, 190006, India
| | - Shahzada Mudasir Rashid
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Sheikh Bilal Ahmad
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Saba Beigh
- Department of Public Health, Faculty of Applied Medical Science, Al Baha University, 65431, Al Baha, Saudi Arabia
| | - Tanveer Ul Hassan Dar
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Muneeb U Rehman
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia.
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12
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Jung M, Bui I, Bonavida B. Role of YY1 in the Regulation of Anti-Apoptotic Gene Products in Drug-Resistant Cancer Cells. Cancers (Basel) 2023; 15:4267. [PMID: 37686541 PMCID: PMC10486809 DOI: 10.3390/cancers15174267] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/21/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Cancer is a leading cause of death among the various diseases encountered in humans. Cancer is not a single entity and consists of numerous different types and subtypes that require various treatment regimens. In the last decade, several milestones in cancer treatments were accomplished, such as specific targeting agents or revitalizing the dormant anti-tumor immune response. These milestones have resulted in significant positive clinical responses as well as tumor regression and the prolongation of survival in subsets of cancer patients. Hence, in non-responding patients and non-responding relapsed patients, cancers develop intrinsic mechanisms of resistance to cell death via the overexpression of anti-apoptotic gene products. In parallel, the majority of resistant cancers have been reported to overexpress a transcription factor, Yin Yang 1 (YY1), which regulates the chemo-immuno-resistance of cancer cells to therapeutic anticancer cytotoxic agents. The relationship between the overexpression of YY1 and several anti-apoptotic gene products, such as B-cell lymphoma 2 protein (Bcl-2), B-cell lymphoma extra-large (Bcl-xL), myeloid cell leukemia 1 (Mcl-1) and survivin, is investigated in this paper. The findings demonstrate that these anti-apoptotic gene products are regulated, in part, by YY1 at the transcriptional, epigenetic, post-transcriptional and translational levels. While targeting each of the anti-apoptotic gene products individually has been examined and clinically tested for some, this targeting strategy is not effective due to compensation by other overexpressed anti-apoptotic gene products. In contrast, targeting YY1 directly, through small interfering RNAs (siRNAs), gene editing or small molecule inhibitors, can be therapeutically more effective and generalized in YY1-overexpressed resistant cancers.
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Affiliation(s)
| | | | - Benjamin Bonavida
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA
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13
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Hosea R, Hillary S, Wu S, Kasim V. Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions. Cancers (Basel) 2023; 15:3506. [PMID: 37444616 DOI: 10.3390/cancers15133506] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 06/28/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Cancer represents a significant and persistent global health burden, with its impact underscored by its prevalence and devastating consequences. Whereas numerous oncogenes could contribute to cancer development, a group of transcription factors (TFs) are overactive in the majority of tumors. Targeting these TFs may also combat the downstream oncogenes activated by the TFs, making them attractive potential targets for effective antitumor therapeutic strategy. One such TF is yin yang 1 (YY1), which plays crucial roles in the development and progression of various tumors. In preclinical studies, YY1 inhibition has shown efficacy in inhibiting tumor growth, promoting apoptosis, and sensitizing tumor cells to chemotherapy. Recent studies have also revealed the potential of combining YY1 inhibition with immunotherapy for enhanced antitumor effects. However, clinical translation of YY1-targeted therapy still faces challenges in drug specificity and delivery. This review provides an overview of YY1 biology, its role in tumor development and progression, as well as the strategies explored for YY1-targeted therapy, with a focus on their clinical implications, including those using small molecule inhibitors, RNA interference, and gene editing techniques. Finally, we discuss the challenges and current limitations of targeting YY1 and the need for further research in this area.
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Affiliation(s)
- Rendy Hosea
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Sharon Hillary
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Shourong Wu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China
| | - Vivi Kasim
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China
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14
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Iyer AS, Shaik MR, Raufman JP, Xie G. The Roles of Zinc Finger Proteins in Colorectal Cancer. Int J Mol Sci 2023; 24:10249. [PMID: 37373394 DOI: 10.3390/ijms241210249] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Despite colorectal cancer remaining a leading worldwide cause of cancer-related death, there remains a paucity of effective treatments for advanced disease. The molecular mechanisms underlying the development of colorectal cancer include altered cell signaling and cell cycle regulation that may result from epigenetic modifications of gene expression and function. Acting as important transcriptional regulators of normal biological processes, zinc finger proteins also play key roles in regulating the cellular mechanisms underlying colorectal neoplasia. These actions impact cell differentiation and proliferation, epithelial-mesenchymal transition, apoptosis, homeostasis, senescence, and maintenance of stemness. With the goal of highlighting promising points of therapeutic intervention, we review the oncogenic and tumor suppressor roles of zinc finger proteins with respect to colorectal cancer tumorigenesis and progression.
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Affiliation(s)
- Aishwarya S Iyer
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Mohammed Rifat Shaik
- Department of Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MD 21201, USA
| | - Jean-Pierre Raufman
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- VA Maryland Healthcare System, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Guofeng Xie
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- VA Maryland Healthcare System, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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15
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Li M, Wei J, Xue C, Zhou X, Chen S, Zheng L, Duan Y, Deng H, Xiong W, Tang F, Li G, Zhou M. Dissecting the roles and clinical potential of YY1 in the tumor microenvironment. Front Oncol 2023; 13:1122110. [PMID: 37081988 PMCID: PMC10110844 DOI: 10.3389/fonc.2023.1122110] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 03/13/2023] [Indexed: 04/07/2023] Open
Abstract
Yin-Yang 1 (YY1) is a member of the GLI-Kruppel family of zinc finger proteins and plays a vital dual biological role in cancer as an oncogene or a tumor suppressor during tumorigenesis and tumor progression. The tumor microenvironment (TME) is identified as the “soil” of tumor that has a critical role in both tumor growth and metastasis. Many studies have found that YY1 is closely related to the remodeling and regulation of the TME. Herein, we reviewed the expression pattern of YY1 in tumors and summarized the function and mechanism of YY1 in regulating tumor angiogenesis, immune and metabolism. In addition, we discussed the potential value of YY1 in tumor diagnosis and treatment and provided a novel molecular strategy for the clinical diagnosis and treatment of tumors.
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Affiliation(s)
- MengNa Li
- Key Laboratory of Carcinogenesis, National Health Commission, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - JianXia Wei
- Key Laboratory of Carcinogenesis, National Health Commission, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - ChangNing Xue
- Key Laboratory of Carcinogenesis, National Health Commission, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - XiangTing Zhou
- The First Clinical College of Changsha Medical University, Changsha, China
| | - ShiPeng Chen
- Key Laboratory of Carcinogenesis, National Health Commission, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - LeMei Zheng
- Key Laboratory of Carcinogenesis, National Health Commission, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - YuMei Duan
- Key Laboratory of Carcinogenesis, National Health Commission, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - HongYu Deng
- Key Laboratory of Carcinogenesis, National Health Commission, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, Central South University, Changsha, China
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Wei Xiong
- Key Laboratory of Carcinogenesis, National Health Commission, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - FaQing Tang
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - GuiYuan Li
- Key Laboratory of Carcinogenesis, National Health Commission, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Ming Zhou
- Key Laboratory of Carcinogenesis, National Health Commission, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- *Correspondence: Ming Zhou,
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16
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Gao Q, Wang S, Zhang Z. E3 ubiquitin ligase SMURF2 prevents colorectal cancer by reducing the stability of the YY1 protein and inhibiting the SENP1/c-myc axis. Gene Ther 2023; 30:51-63. [PMID: 34545207 DOI: 10.1038/s41434-021-00289-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 08/02/2021] [Accepted: 08/18/2021] [Indexed: 01/08/2023]
Abstract
Genetic association between E3 ubiquitin ligase SMURF2 and colorectal cancer (CRC) has been identified, while the mechanism remains undefined. Tumor-promoting gene YY1 represents a downstream factor of SMURF2. The study was designed to evaluate the effect of SMURF2 on the malignant phenotypes of CRC cells and the underlying mechanism. The expression pattern of SMURF2 and YY1 in CRC clinical tissues and cells was characterized by immunohistochemistry (IHC) and Western blot. Gain- and loss-of-function experiments were conducted to assess the effect of SMURF2 and YY1 on the behaviors of CRC cells. After bioinformatics analysis, the relationship between YY1 and SENP1 as well as between SENP1 and c-myc was determined by luciferase reporter and ChIP assays. Rescue experiments were performed to show their involvement during CRC progression. Finally, in vivo models of tumor growth were established for validation. SMURF2 was lowly expressed and YY1 was highly expressed in CRC tissues and cells. YY1 overexpression resulted in promotion of CRC cell proliferation, migration, and invasion, which could be reversed by SMURF2. Furthermore, SMURF2 could induce ubiquitination-mediated degradation of YY1, which bound to the SENP1 promoter and upregulated SENP1 expression, leading to enhancement of c-myc expression. The in vivo data revealed the suppressive role of SMURF2 gain-of-function in tumor growth through downregulation of YY1, SENP1, or c-myc. Altogether, our data demonstrate the antitumor activity of SMURF2 in CRC and the anti-tumor mechanism associated with degradation of YY1 and downregulation of SENP1/c-myc.
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Affiliation(s)
- Qianfu Gao
- Anorectal Department, Linyi People's Hospital, Linyi, 276003, PR China
| | - Shanchao Wang
- Anorectal Department, Linyi People's Hospital, Linyi, 276003, PR China
| | - Zeyan Zhang
- Anorectal Department, Linyi People's Hospital, Linyi, 276003, PR China.
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17
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Yari M, Soltani BM, Ghaemi Z, Omrani MD. EVADR ceRNA transcript variants upregulate WNT and PI3K signaling pathways in SW480 and HCT116 cells by sponging miR-7 and miR-29b. Biol Chem 2023; 404:71-83. [PMID: 36420528 DOI: 10.1515/hsz-2022-0246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 10/10/2022] [Indexed: 11/25/2022]
Abstract
Long noncoding RNAs are cancer regulators and EVADR-lncRNA is highly upregulated in colorectal cancer (CRC). Accordingly, we aimed to functionally characterize the EVADR in CRC-originated cells. Firstly, during the amplification of EVADR full-length cDNA (named EVADR-v1), a novel/shorter variant (EVADR-v2) was discovered. Then, RT-qPCR analysis confirmed that EVADR is upregulated in tumors, consistent with RNA-seq analysis. Interestingly, bioinformatics analysis and dual-luciferase assay verified that EVADR sponges miR-7 and miR-29b. When both EVADR-v1/-v2 variants were overexpressed in SW480/HCT116 cells, miR-7 and miR-29b target genes (involved in the WNT/PI3K signaling) were upregulated. Furthermore, EVADR-v1/-v2 overexpression resulted in elevated PI3K activity (verified by western blotting and RT-qPCR) and upregulation of WNT signaling (confirmed by western blotting, TopFlash assay, and RT-qPCR). Consistently, overexpression of EVADR-v1/-v2 variants was followed by increased cell cycle progression, viability and migration as well as reduced early/late apoptotic rate, and Bax/Bcl2 ratio of the CRC cells, detected by the cell cycle analysis, MTT, wound-healing, Annexin-V/PI, and RT-qPCR methods, respectively. Overall, we introduced two oncogenic transcript variants for EVADR that by sponging miR-7/miR-29b, upregulate WNT and PI3K signaling. Given the crucial role of these pathways in CRC, EVADR may present potential therapy use.
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Affiliation(s)
- Mohsen Yari
- Genetics Department, Faculty of Biological Sciences, Tarbiat Modares University, P. O. Box 14115-154, Tehran, Iran
| | - Bahram M Soltani
- Genetics Department, Faculty of Biological Sciences, Tarbiat Modares University, P. O. Box 14115-154, Tehran, Iran
| | - Zahra Ghaemi
- Genetics Department, Faculty of Biological Sciences, Tarbiat Modares University, P. O. Box 14115-154, Tehran, Iran
| | - Mir Davood Omrani
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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18
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Autophagy-Related ncRNAs in Pancreatic Cancer. Pharmaceuticals (Basel) 2022; 15:ph15121547. [PMID: 36558998 PMCID: PMC9785627 DOI: 10.3390/ph15121547] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 12/05/2022] [Accepted: 12/10/2022] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer (PC) is a malignancy accounting for only 3% of total cancers, but with a low 5-year relative survival rate. Approximately 80% of PC patients are diagnosed at a late stage when the disease has already spread from the primary site. Despite advances in PC treatment, there is an urgently needed for the identification of novel therapeutic strategies for PC, particularly for patients who cannot undergo classical surgery. Autophagy is an evolutionarily conserved process used by cells to adapt to metabolic stress via the degrading or recycling of damaged or unnecessary organelles and cellular components. This process is elevated in PC and, thus, it contributes to the onset, progression, and cancer cell resistance to chemotherapy in pancreatic tumors. Autophagy inhibition has been shown to lead to cancer regression and to increase the sensitivity of pancreatic cells to radiation and chemotherapy. Emerging studies have focused on the roles of non-coding RNAs (ncRNAs), such as miRNAs, long non-coding RNAs, and circular RNAs, in PC development and progression. Furthermore, ncRNAs have been reported as crucial regulators of many biological processes, including autophagy, suggesting that ncRNA-based autophagy targeting methods could be promising novel molecular approaches for specifically reducing autophagic flux, thus improving the management of PC patients. In this review, we briefly summarize the existing studies regarding the role and the regulatory mechanisms of autophagy-related ncRNAs in the context of this cancer.
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19
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Fan S, Xing J, Jiang Z, Zhang Z, Zhang H, Wang D, Tang D. Effects of Long Non-Coding RNAs Induced by the Gut Microbiome on Regulating the Development of Colorectal Cancer. Cancers (Basel) 2022; 14:5813. [PMID: 36497293 PMCID: PMC9735521 DOI: 10.3390/cancers14235813] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/16/2022] [Accepted: 11/19/2022] [Indexed: 11/29/2022] Open
Abstract
Although an imbalanced gut microbiome is closely associated with colorectal cancer (CRC), how the gut microbiome affects CRC is not known. Long non-coding RNAs (lncRNAs) can affect important cellular functions such as cell division, proliferation, and apoptosis. The abnormal expression of lncRNAs can promote CRC cell growth, proliferation, and metastasis, mediating the effects of the gut microbiome on CRC. Generally, the gut microbiome regulates the lncRNAs expression, which subsequently impacts the host transcriptome to change the expression of downstream target molecules, ultimately resulting in the development and progression of CRC. We focused on the important role of the microbiome in CRC and their effects on CRC-related lncRNAs. We also reviewed the impact of the two main pathogenic bacteria, Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, and metabolites of the gut microbiome, butyrate, and lipopolysaccharide, on lncRNAs. Finally, available therapies that target the gut microbiome and lncRNAs to prevent and treat CRC were proposed.
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Affiliation(s)
- Shiying Fan
- Clinical Medical College, Yangzhou University, Yangzhou 225000, China
| | - Juan Xing
- Clinical Medical College, Yangzhou University, Yangzhou 225000, China
| | - Zhengting Jiang
- Clinical Medical College, Yangzhou University, Yangzhou 225000, China
| | - Zhilin Zhang
- Clinical Medical College, Yangzhou University, Yangzhou 225000, China
| | - Huan Zhang
- Clinical Medical College, Yangzhou University, Yangzhou 225000, China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Northern Jiangsu People’s Hospital, Yangzhou University, Yangzhou 225000, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Northern Jiangsu People’s Hospital, Yangzhou University, Yangzhou 225000, China
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20
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Wei S, Hu W, Feng J, Geng Y. Promotion or remission: a role of noncoding RNAs in colorectal cancer resistance to anti-EGFR therapy. Cell Commun Signal 2022; 20:150. [PMID: 36131281 PMCID: PMC9490904 DOI: 10.1186/s12964-022-00960-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 08/16/2022] [Indexed: 11/10/2022] Open
Abstract
Anti-epidermal-growth-factor-receptor (EGFR) monoclonal antibodies (mAbs) are of great significance for RAS and BRAF wild-type metastatic colorectal cancer (mCRC) patients. However, the generation of primary and secondary resistance to anti-EGFR mAbs has become an important factor restricting its efficacy. Recent studies have revealed that non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are implicated in anti-EGFR antibodies resistance, affecting the sensitivity of CRC cells to Cetuximab and Panitumumab. This paper briefly reviewed the research advance of the expression, signaling network and functional mechanism of ncRNAs related to anti-EGFR mAbs resistance in CRC, as well as their relationship with clinical prognosis and the possibility of therapeutic targets. In addition, some ncRNAs that are involved in the regulation of signaling pathways or genes related to anti-EGFR resistance, but need to be further verified by resistance experiments were also included in this review, thereby providing more ideas and basis for ncRNAs as CRC prognostic markers and anti-EGFR therapy sensitizers. Video Abstract.
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Affiliation(s)
- Shanshan Wei
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jun Feng
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China
| | - Yiting Geng
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China.
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21
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Chen S, Wang Y, Li D, Wang H, Zhao X, Yang J, Chen L, Guo M, Zhao J, Chen C, Zhou Y, Liang G, Xu L. Mechanisms Controlling MicroRNA Expression in Tumor. Cells 2022; 11:cells11182852. [PMID: 36139427 PMCID: PMC9496884 DOI: 10.3390/cells11182852] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/06/2022] [Accepted: 09/09/2022] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are widely present in many organisms and regulate the expression of genes in various biological processes such as cell differentiation, metabolism, and development. Numerous studies have shown that miRNAs are abnormally expressed in tumor tissues and are closely associated with tumorigenesis. MiRNA-based cancer gene therapy has consistently shown promising anti-tumor effects and is recognized as a new field in cancer treatment. So far, some clinical trials involving the treatment of malignancies have been carried out; however, studies of miRNA-based cancer gene therapy are still proceeding slowly. Therefore, furthering our understanding of the regulatory mechanisms of miRNA can bring substantial benefits to the development of miRNA-based gene therapy or other combination therapies and the clinical outcome of patients with cancer. Recent studies have revealed that the aberrant expression of miRNA in tumors is associated with promoter sequence mutation, epigenetic alteration, aberrant RNA modification, etc., showing the complexity of aberrant expression mechanisms of miRNA in tumors. In this paper, we systematically summarized the regulation mechanisms of miRNA expression in tumors, with the aim of providing assistance in the subsequent elucidation of the role of miRNA in tumorigenesis and the development of new strategies for tumor prevention and treatment.
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Affiliation(s)
- Shipeng Chen
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Ya Wang
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Dongmei Li
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Hui Wang
- The Second Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Xu Zhao
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Jing Yang
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Longqing Chen
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Mengmeng Guo
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Juanjuan Zhao
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Chao Chen
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Ya Zhou
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Medical Physics, Zunyi Medical University, Zunyi 563000, China
- Correspondence: (Y.Z.); (G.L.); (L.X.)
| | - Guiyou Liang
- Department of Cardiovascular Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550031, China
- Department of Cardiovascular Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
- Correspondence: (Y.Z.); (G.L.); (L.X.)
| | - Lin Xu
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
- Correspondence: (Y.Z.); (G.L.); (L.X.)
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22
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Morales-Martínez M, Vega MI. Role of MicroRNA-7 (MiR-7) in Cancer Physiopathology. Int J Mol Sci 2022; 23:9091. [PMID: 36012357 PMCID: PMC9408913 DOI: 10.3390/ijms23169091] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/04/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
miRNAs are non-coding RNA sequences of approximately 22 nucleotides that interact with genes by inhibiting their translation through binding to their 3' or 5' UTR regions. Following their discovery, the role they play in the development of various pathologies, particularly cancer, has been studied. In this context, miR-7 is described as an important factor in the development of cancer because of its role as a tumor suppressor, regulating a large number of genes involved in the development and progression of cancer. Recent data support the function of miR-7 as a prognostic biomarker in cancer, and miR-7 has been proposed as a strategy in cancer therapy. In this work, the role of miR-7 in various types of cancer is reviewed, illustrating its regulation, direct targets, and effects, as well as its possible relationship to the clinical outcome of cancer patients.
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Affiliation(s)
- Mario Morales-Martínez
- Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, Mexico City 06720, Mexico
| | - Mario I. Vega
- Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, Mexico City 06720, Mexico
- Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA
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23
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Mao D, Zhang X, Wang Z, Xu G, Zhang Y. TMEM97 is transcriptionally activated by YY1 and promotes colorectal cancer progression via the GSK-3β/β-catenin signaling pathway. Hum Cell 2022; 35:1535-1546. [PMID: 35907137 DOI: 10.1007/s13577-022-00759-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/21/2022] [Indexed: 11/25/2022]
Abstract
Transmembrane protein 97 (TMEM97) is a conserved integral membrane protein highly expressed in various human cancers, including colorectal cancer (CRC), and it exhibits pro-tumor roles in breast cancer, gastric cancer, and glioma. However, whether TMEM97 participates in CRC progression is not fully understood. The expression of mRNA and protein was evaluated by real-time qPCR, western blotting, immunofluorescent, and immunohistochemical staining. TMEM97 functions in cell proliferation, apoptosis, migration, and invasion were assessed by CCK-8, flow cytometry, and transwell assays. The roles of TMEM97 in CRC cells in vivo was investigated using a subcutaneous xenograft model. The transcriptional regulation of TMEM97 was explored by luciferase reporter and ChIP assays. The silencing of TMEM97 inhibited migration and invasion of CRC cells in vitro and led to suppressed growth and enhanced apoptosis in CRC cells and xenografts, whereas overexpression of TMEM97 displayed opposite effects. Mechanistically, TMEM97 knockdown caused a reduction of the proliferating marker PCNA and an increase of pro-apoptotic proteins (cleaved caspase 8/3/7 and cleaved PARP) in CRC cells. TMEM97 also positively regulated the β-catenin signaling pathway in CRC cells and xenografts by modulating the phosphorylated-GSK-3β and active (non-phospho) β-catenin levels. Interestingly, YY1, a well-recognized oncogenic transcription factor, was identified to bind to the TMEM97 promoter and enhance its transcriptional activity, and silencing of TMEM97 abolished YY1-mediated pro-tumor effects on CRC cells. Our results suggest that TMEM97 is transcriptionally activated by YY1 and promotes CRC progression via the GSK-3β/β-catenin signaling pathway, providing that TMEM97 might be a novel therapeutic target for preventing CRC development.
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Affiliation(s)
- Dong Mao
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Jinzhou, Liaoning Province, China
| | - Xiaowei Zhang
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Jinzhou, Liaoning Province, China
| | - Zhaoping Wang
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Jinzhou, Liaoning Province, China
| | - Guannan Xu
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Jinzhou, Liaoning Province, China
| | - Yun Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinzhou Medical University, No. 2, The Fifth Section of Renmin Street, Jinzhou, Liaoning Province, China.
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24
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Tumor Cells-derived exosomal CircRNAs: Novel cancer drivers, molecular mechanisms, and clinical opportunities. Biochem Pharmacol 2022; 200:115038. [DOI: 10.1016/j.bcp.2022.115038] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 12/12/2022]
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25
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Sato N, Sakai N, Furukawa K, Takayashiki T, Kuboki S, Takano S, Ohira G, Matsubara H, Ohtsuka M. Yin Yang 1 regulates ITGAV and ITGB1, contributing to improved prognosis of colorectal cancer. Oncol Rep 2022; 47:87. [PMID: 35266011 PMCID: PMC8931837 DOI: 10.3892/or.2022.8298] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/14/2022] [Indexed: 11/05/2022] Open
Abstract
Yin Yang 1 (YY1) is a multifunctional transcription factor with critical roles in carcinogenesis and metastasis. However, its biological role and clinical impact in colorectal cancer (CRC) remain unclear. In the present study, the function and underlying molecular mechanisms of YY1 in CRC progression were investigated. The immunohistochemistry (IHC) of 143 CRC tissues revealed a significant correlation of low YY1 expression with aggressive clinicopathological features, increased metastasis and recurrence and poor patient survival. Multivariate analysis identified low YY1 expression as an independent poor prognostic factor. Subsequently, the IHC of 66 paired CRC primary tumor and liver metastasis tissues revealed that low YY1 expression in the primary CRC was significantly associated with multiple liver metastases, major hepatectomy, extrahepatic metastasis and poor prognosis. In vitro experiments revealed that YY1 knockdown promoted the migration and invasion of CRC cells. To examine the downstream genes of YY1, a cDNA microarray assay was conducted and the differentially expressed genes between the YY1‑knockdown and control cells were compared. Integrin alpha V (ITGAV) and integrin beta 1 (ITGB1) were identified as upregulated hub genes using gene enrichment analysis and protein‑protein interaction analyses. Western blotting and IHC confirmed YY1 expression to be negatively correlated with ITGAV and ITGB1 expression. In summary, it was revealed that YY1, as a tumor‑suppressor in CRC, contributes to the survival of patients with CRC. Low YY1 expression was associated with the poor prognosis of the patients with primary CRC and liver metastases. YY1 suppressed the expression of ITGAV and ITGB1, and this transcriptional regulation may lead to the suppression of CRC cell migration and invasion.
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Affiliation(s)
- Nami Sato
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan
| | - Nozomu Sakai
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan
| | - Gaku Ohira
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan
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26
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Sharma AR, Bhattacharya M, Bhakta S, Saha A, Lee SS, Chakraborty C. Recent research progress on circular RNAs: Biogenesis, properties, functions, and therapeutic potential. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 25:355-371. [PMID: 34484862 PMCID: PMC8399087 DOI: 10.1016/j.omtn.2021.05.022] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Circular RNAs (circRNAs), an emerging family member of RNAs, have gained importance in research due to their new functional roles in cellular physiology and disease progression. circRNAs are usually available in a wide range of cells and have shown tissue-specific expression as well as developmental specific expression. circRNAs are characterized by structural stability, conservation, and high abundance in the cell. In this review, we discuss the different models of biogenesis. The properties of circRNAs such as localization, structure and conserved pattern, stability, and expression specificity are also been illustrated. Furthermore, we discuss the biological functions of circRNAs such as microRNA (miRNA) sponging, cell cycle regulation, cell-to-cell communication, transcription regulation, translational regulation, disease diagnosis, and therapeutic potential. Finally, we discuss the recent research progress and future perspective of circRNAs. This review provides an understanding of potential diagnostic markers and the therapeutic potential of circRNAs, which are emerging daily.
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Affiliation(s)
- Ashish Ranjan Sharma
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon-si 24252, Gangwon-do, Republic of Korea
| | - Manojit Bhattacharya
- Department of Zoology, Fakir Mohan University, Vyasa Vihar, Balasore 756020, Odisha, India
| | - Swarnav Bhakta
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Barasat-Barrackpore Road, Jagannathpur, Kolkata, West Bengal 700126, India
| | - Abinit Saha
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Barasat-Barrackpore Road, Jagannathpur, Kolkata, West Bengal 700126, India
| | - Sang-Soo Lee
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon-si 24252, Gangwon-do, Republic of Korea
| | - Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Barasat-Barrackpore Road, Jagannathpur, Kolkata, West Bengal 700126, India
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27
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Yang M, Zhu L, Zhu L, Xu D, Yuan Y. Role of a Rare Variant in APC Gene Promoter 1B Region in Classic Familial Adenomatous Polyposis. Digestion 2021; 102:527-533. [PMID: 32702694 DOI: 10.1159/000509234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/09/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Familial adenomatous polyposis (FAP) is most commonly caused by germline variants in the adenomatous polyposis coli (APC) gene. Although definite pathogenic variants could be detected in the majority of individuals with FAP, there are still numerous variant-negative FAP patients. METHOD We utilized a 139-gene next-generation sequencing (NGS) panel and multiplex ligation-dependent probe amplification (MLPA) to detect pathogenic variants in FAP patients and found a variant-negative pedigree. Through whole-exome sequencing (WES), we identified a point variant in the noncoding region in the APC gene. Finally, we used Sanger sequencing to analyze its pedigree cosegregation and a dual-luciferase reporter (DLR) assay to assess its function. RESULTS With the exception of 2 variants of undetermined significance (VUS), WES showed no pathogenic or likely pathogenic variants. After performing MLPA, the pedigree was still variant-negative. Interestingly, through WES, a point variant c.-190G>A located in the promoter 1B region of the APC gene was identified in 3 affected individuals. Moreover, a variant carrier was found during screening of the family with Sanger sequencing. Through the DLR assay, we further confirmed that the variant c.-190G>A caused significant suppression of downstream transcription of APC. CONCLUSIONS The variant (c.-190G>A) in the APC promoter 1B region is able to cause FAP with a classic phenotype, but this kind of variant in the noncoding region could be missed by conventional genetic testing. Thus, utilizing sequencing technologies covering a larger area can help us to further explore the pathogenesis in variant-negative FAP cases.
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Affiliation(s)
- Mengyuan Yang
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lila Zhu
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lizhen Zhu
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dong Xu
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, .,Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China,
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28
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Jafarzadeh M, Soltani BM. MiRNA-Wnt signaling regulatory network in colorectal cancer. J Biochem Mol Toxicol 2021; 35:e22883. [PMID: 34382723 DOI: 10.1002/jbt.22883] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 08/02/2021] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) is one of the common malignancies worldwide and the Wnt signaling pathway is recognized as the main disrupted pathway in this malignancy. MicroRNAs (miRNAs) are recognized to contribute to the pathogenesis of CRC by triggering or impeding the Wnt signaling pathway. In addition, transcriptional regulation of miRNAs by canonical Wnt signaling also participates in CRC cell progression. In this review, we present comprehensive literature of the existing data on the interaction of miRNAs and Wnt signaling that could be useful in future studies in the field of CRC management.
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Affiliation(s)
- Meisam Jafarzadeh
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Bahram M Soltani
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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29
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Matly A, Quinn JA, McMillan DC, Park JH, Edwards J. The relationship between β-catenin and patient survival in colorectal cancer systematic review and meta-analysis. Crit Rev Oncol Hematol 2021; 163:103337. [PMID: 33992802 DOI: 10.1016/j.critrevonc.2021.103337] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/23/2021] [Accepted: 03/31/2021] [Indexed: 01/11/2023] Open
Abstract
β-catenin is a key component of Wnt signalling, which plays a crucial role in CRC progression. Therefore, a meta-analysis was performed to assess the prognostic value of β-catenin expression in CRC patients. PubMed and Web of Science were searched for relevant publications referring to the association between β-catenin expression and outcome of CRC patients. Review Manager version 5.4 was employed to analysis data from 28 eligible studies (containing 5475 patients). Of these, 6 provided data on DFS, 6 provided data on CSS and 18 reports provided data on OS. High nuclear β-catenin expression was significantly associated with poorer DFS, CSS and OS in patients with CRC whereas, low membranous β-catenin expression was associated to poor OS. In conclusion, β-catenin has prognostic value and potential as a biomarker to stratify patients with CRC. However, further work with high quantity tissue cohorts and patient data is required to confirm this conclusion.
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Affiliation(s)
- Amna Matly
- Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
| | - Jean A Quinn
- Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
| | - Donald C McMillan
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Alexandria Parade, Glasgow, G31 2ER, United Kingdom.
| | - James H Park
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Alexandria Parade, Glasgow, G31 2ER, United Kingdom.
| | - Joanne Edwards
- Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
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30
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Korać P, Antica M, Matulić M. MiR-7 in Cancer Development. Biomedicines 2021; 9:325. [PMID: 33806891 PMCID: PMC8004586 DOI: 10.3390/biomedicines9030325] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/20/2021] [Accepted: 03/22/2021] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNA involved in the regulation of specific mRNA translation. They participate in cellular signaling circuits and can act as oncogenes in tumor development, so-called oncomirs, as well as tumor suppressors. miR-7 is an ancient miRNA involved in the fine-tuning of several signaling pathways, acting mainly as tumor suppressor. Through downregulation of PI3K and MAPK pathways, its dominant role is the suppression of proliferation and survival, stimulation of apoptosis and inhibition of migration. Besides these functions, it has numerous additional roles in the differentiation process of different cell types, protection from stress and chromatin remodulation. One of the most investigated tissues is the brain, where its downregulation is linked with glioblastoma cell proliferation. Its deregulation is found also in other tumor types, such as in liver, lung and pancreas. In some types of lung and oral carcinoma, it can act as oncomir. miR-7 roles in cell fate determination and maintenance of cell homeostasis are still to be discovered, as well as the possibilities of its use as a specific biotherapeutic.
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Affiliation(s)
- Petra Korać
- Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102, 10000 Zagreb, Croatia;
| | - Mariastefania Antica
- Division of Molecular Biology, Rudjer Bosković Institute, Bijenička 54, 10000 Zagreb, Croatia;
| | - Maja Matulić
- Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102, 10000 Zagreb, Croatia;
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31
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Abstract
Accumulating evidence strongly indicates that the presence of cancer stem cells (CSCs) leads to the emergence of worse clinical scenarios, such as chemo- and radiotherapy resistance, metastasis, and cancer recurrence. CSCs are a highly tumorigenic population characterized by self-renewal capacity and differentiation potential. Thus, CSCs establish a hierarchical intratumor organization that enables tumor adaptation to evade the immune response and resist anticancer therapy. YY1 functions as a transcription factor, RNA-binding protein, and 3D chromatin regulator. Thus, YY1 has multiple effects and regulates several molecular processes. Emerging evidence indicates that the development of lethal YY1-mediated cancer phenotypes is associated with the presence of or enrichment in cancer stem-like cells. Therefore, it is necessary to investigate whether and to what extent YY1 regulates the CSC phenotype. Since CSCs mirror the phenotypic behavior of stem cells, we initially describe the roles played by YY1 in embryonic and adult stem cells. Next, we scrutinize evidence supporting the contributions of YY1 in CSCs from a number of various cancer types. Finally, we identify new areas for further investigation into the YY1-CSCs axis, including the participation of YY1 in the CSC niche.
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32
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Guo J, Tong J, Zheng J. Circular RNAs: A Promising Biomarker for Endometrial Cancer. Cancer Manag Res 2021; 13:1651-1665. [PMID: 33633465 PMCID: PMC7901565 DOI: 10.2147/cmar.s290975] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 01/19/2021] [Indexed: 01/06/2023] Open
Abstract
Endometrial cancer (EC) is one of the most common malignant tumors of the female reproductive tract. EC patients have high morbidity and mortality rates and remain an important cause of cancer-related morbidity and mortality worldwide. More and more studies have shown that a large number of non-coding RNAs (such as microRNAs and long non-coding RNAs) are associated with the occurrence of diseases. Circular RNAs (circRNAs) is an endogenous non-coding RNA. It has a unique covalent structure. Many studies in recent years have found circRNAs differential expression in a variety of tumor tissues compared to matched normal tissues. In endometrial carcinoma, there also are multiple circRNAs differentially expressed and therefore circRNAs perhaps can be used as a diagnostic and prognosis biomarkers of EC. In this review, we described the biogenesis, function and characteristics of circRNAs, and the circRNAs with potential influence and clinical significance on the development of EC were summarized. Adenocarcinoma is the most common form of EC, so this review focuses on endometrioid adenocarcinoma.
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Affiliation(s)
- Jialu Guo
- Department of the Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310008, People's Republic of China.,Department of Obstetrics and Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, Zhejiang Province, 310008, People's Republic of China
| | - Jinyi Tong
- Department of the Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310008, People's Republic of China.,Department of Obstetrics and Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, Zhejiang Province, 310008, People's Republic of China
| | - Jianfeng Zheng
- Department of Obstetrics and Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, Zhejiang Province, 310008, People's Republic of China.,Department of Obstetrics and Gynecology, Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, Zhejiang Province, 310008, People's Republic of China
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33
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Morales-Martinez M, Vega MI. Participation of different miRNAs in the regulation of YY1: Their role in pathogenesis, chemoresistance, and therapeutic implication in hematologic malignancies. YY1 IN THE CONTROL OF THE PATHOGENESIS AND DRUG RESISTANCE OF CANCER 2021:171-198. [DOI: 10.1016/b978-0-12-821909-6.00010-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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Kim H, Bang S, Jee S, Park S, Kim Y, Park H, Jang K, Paik SS. Loss of YY1 expression predicts unfavorable prognosis in stage III colorectal cancer. INDIAN J PATHOL MICR 2021; 64:S78-S84. [PMID: 34135143 DOI: 10.4103/ijpm.ijpm_96_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background Yin Yang 1 (YY1), the multifunctional transcription factor, has recently been assigned biological properties related to human malignancies. YY1 can facilitate both tumor suppression and tumor growth. The conflicting role of YY1 in human malignancies is not yet fully explained. Objective In this study, we determined the clinicopathologic significance and prognostic role of YY1 in stage III colorectal cancer (CRC). Materials and Methods YY1 expression was evaluated immunohistochemically in tissue microarray from 345 CRCs. YY1 expression was scored by the proportion of tumor cells with nuclear staining into 4 scores (0, none; 1+, ≤10%; 2+, 10 to ≤25%; 3+, >25%). A score of 0 and 1 were considered as loss of expression. Results Loss of YY1 expression was observed in 49 (14.2%) out of 345 CRCs and was associated with larger tumor size (P = 0.004), tumor deposit (P = 0.008), and higher pathologic tumor (pT) stage (P = 0.004). In stage III group, loss of YY1 expression was associated with larger tumor size (P = 0.027) and tumor deposit (P = 0.011). Kaplan-Meier survival curves revealed no significant difference between patients with YY1 loss and patients with intact YY1 in both cancer-specific survival and recurrence-free survival (P = 0.330 and P = 0.470, respectively). In American Joint Committee on Cancer (AJCC) stage subgroup, loss of YY1 expression was associated with poor recurrence-free survival in AJCC stage III CRC (P = 0.038). Conclusion Loss of YY1 expression was significantly associated with aggressive phenotypes and poor patient outcome in AJCC stage III CRC.
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Affiliation(s)
- Hyunsung Kim
- Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea
| | - Seongsik Bang
- Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea
| | - Seungyun Jee
- Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea
| | - Seongeon Park
- Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea
| | - Yeseul Kim
- Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea
| | - Hosub Park
- Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea
| | - Kiseok Jang
- Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea
| | - Seung Sam Paik
- Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea
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Massaro C, Safadeh E, Sgueglia G, Stunnenberg HG, Altucci L, Dell’Aversana C. MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance. Cells 2020; 10:cells10010039. [PMID: 33396628 PMCID: PMC7823834 DOI: 10.3390/cells10010039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 12/26/2020] [Accepted: 12/28/2020] [Indexed: 12/17/2022] Open
Abstract
Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.
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Affiliation(s)
- Crescenzo Massaro
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
| | - Elham Safadeh
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
| | - Giulia Sgueglia
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
| | | | - Lucia Altucci
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
- Correspondence: (L.A.); (C.D.); Tel.: +39-081-566-7564 (L.A.); +39-081-566-7566 (C.D.)
| | - Carmela Dell’Aversana
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
- Institute of Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS)-National Research Council (CNR), Via Sergio Pansini 5, 80131 Naples, Italy
- Correspondence: (L.A.); (C.D.); Tel.: +39-081-566-7564 (L.A.); +39-081-566-7566 (C.D.)
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36
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Aggarwal N, Yadav J, Thakur K, Bibban R, Chhokar A, Tripathi T, Bhat A, Singh T, Jadli M, Singh U, Kashyap MK, Bharti AC. Human Papillomavirus Infection in Head and Neck Squamous Cell Carcinomas: Transcriptional Triggers and Changed Disease Patterns. Front Cell Infect Microbiol 2020. [PMID: 33344262 DOI: 10.3389/fcimb.2020.537650,] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers. Collectively, HNSCC ranks sixth in incidence rate worldwide. Apart from classical risk factors like tobacco and alcohol, infection of human papillomavirus (HPV) is emerging as a discrete risk factor for HNSCC. HPV-positive HNSCC represent a distinct group of diseases that differ in their clinical presentation. These lesions are well-differentiated, occur at an early age, and have better prognosis. Epidemiological studies have demonstrated a specific increase in the proportions of the HPV-positive HNSCC. HPV-positive and HPV-negative HNSCC lesions display different disease progression and clinical response. For tumorigenic-transformation, HPV essentially requires a permissive cellular environment and host cell factors for induction of viral transcription. As the spectrum of host factors is independent of HPV infection at the time of viral entry, presumably entry of HPV only selects host cells that are permissive to establishment of HPV infection. Growing evidence suggest that HPV plays a more active role in a subset of HNSCC, where they are transcriptionally-active. A variety of factors provide a favorable environment for HPV to become transcriptionally-active. The most notable are the set of transcription factors that have direct binding sites on the viral genome. As HPV does not have its own transcription machinery, it is fully dependent on host transcription factors to complete the life cycle. Here, we review and evaluate the current evidence on level of a subset of host transcription factors that influence viral genome, directly or indirectly, in HNSCC. Since many of these transcription factors can independently promote carcinogenesis, the composition of HPV permissive transcription factors in a tumor can serve as a surrogate marker of a separate molecularly-distinct class of HNSCC lesions including those cases, where HPV could not get a chance to infect but may manifest better prognosis.
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Affiliation(s)
- Nikita Aggarwal
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Joni Yadav
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Kulbhushan Thakur
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Rakhi Bibban
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Arun Chhokar
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Anjali Bhat
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tejveer Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Mohit Jadli
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Ujala Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Manoj K Kashyap
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.,Amity Medical School, Stem Cell Institute, Amity University Haryana, Amity Education Valley Panchgaon, Gurugram, India
| | - Alok C Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
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37
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Aggarwal N, Yadav J, Thakur K, Bibban R, Chhokar A, Tripathi T, Bhat A, Singh T, Jadli M, Singh U, Kashyap MK, Bharti AC. Human Papillomavirus Infection in Head and Neck Squamous Cell Carcinomas: Transcriptional Triggers and Changed Disease Patterns. Front Cell Infect Microbiol 2020; 10:537650. [PMID: 33344262 PMCID: PMC7738612 DOI: 10.3389/fcimb.2020.537650] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 11/02/2020] [Indexed: 02/05/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers. Collectively, HNSCC ranks sixth in incidence rate worldwide. Apart from classical risk factors like tobacco and alcohol, infection of human papillomavirus (HPV) is emerging as a discrete risk factor for HNSCC. HPV-positive HNSCC represent a distinct group of diseases that differ in their clinical presentation. These lesions are well-differentiated, occur at an early age, and have better prognosis. Epidemiological studies have demonstrated a specific increase in the proportions of the HPV-positive HNSCC. HPV-positive and HPV-negative HNSCC lesions display different disease progression and clinical response. For tumorigenic-transformation, HPV essentially requires a permissive cellular environment and host cell factors for induction of viral transcription. As the spectrum of host factors is independent of HPV infection at the time of viral entry, presumably entry of HPV only selects host cells that are permissive to establishment of HPV infection. Growing evidence suggest that HPV plays a more active role in a subset of HNSCC, where they are transcriptionally-active. A variety of factors provide a favorable environment for HPV to become transcriptionally-active. The most notable are the set of transcription factors that have direct binding sites on the viral genome. As HPV does not have its own transcription machinery, it is fully dependent on host transcription factors to complete the life cycle. Here, we review and evaluate the current evidence on level of a subset of host transcription factors that influence viral genome, directly or indirectly, in HNSCC. Since many of these transcription factors can independently promote carcinogenesis, the composition of HPV permissive transcription factors in a tumor can serve as a surrogate marker of a separate molecularly-distinct class of HNSCC lesions including those cases, where HPV could not get a chance to infect but may manifest better prognosis.
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Affiliation(s)
- Nikita Aggarwal
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Joni Yadav
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Kulbhushan Thakur
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Rakhi Bibban
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Arun Chhokar
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Anjali Bhat
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tejveer Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Mohit Jadli
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Ujala Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Manoj K. Kashyap
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
- Amity Medical School, Stem Cell Institute, Amity University Haryana, Amity Education Valley Panchgaon, Gurugram, India
| | - Alok C. Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
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38
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Landry-Truchon K, Houde N, Lhuillier M, Charron L, Hadchouel A, Delacourt C, Foulkes WD, Galmiche-Rolland L, Jeannotte L. Deletion of Yy1 in mouse lung epithelium unveils molecular mechanisms governing pleuropulmonary blastoma pathogenesis. Dis Model Mech 2020; 13:dmm045989. [PMID: 33158935 PMCID: PMC7790197 DOI: 10.1242/dmm.045989] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 10/21/2020] [Indexed: 12/11/2022] Open
Abstract
Pleuropulmonary blastoma (PPB) is a very rare pediatric lung disease. It can progress from abnormal epithelial cysts to an aggressive sarcoma with poor survival. PPB is difficult to diagnose as it can be confounded with other cystic lung disorders, such as congenital pulmonary airway malformation (CPAM). PPB is associated with mutations in DICER1 that perturb the microRNA (miRNA) profile in lung. How DICER1 and miRNAs act during PPB pathogenesis remains unsolved. Lung epithelial deletion of the Yin Yang1 (Yy1) gene in mice causes a phenotype mimicking the cystic form of PPB and affects the expression of key regulators of lung development. Similar changes in expression were observed in PPB but not in CPAM lung biopsies, revealing a distinctive PPB molecular signature. Deregulation of molecules promoting epithelial-mesenchymal transition (EMT) was detected in PPB specimens, suggesting that EMT might participate in tumor progression. Changes in miRNA expression also occurred in PPB lung biopsies. miR-125a-3p, a candidate to regulate YY1 expression and lung branching, was abnormally highly expressed in PPB samples. Together, these findings support the concept that reduced expression of YY1, due to the abnormal miRNA profile resulting from DICER1 mutations, contributes to PPB development via its impact on the expression of key lung developmental genes.This article has an associated First Person interview with the joint first authors of the paper.
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Affiliation(s)
- Kim Landry-Truchon
- Centre de recherche sur le cancer de l'Université Laval, Centre de recherche du CHU de Québec-Université Laval (Oncology Axis), Québec, Canada G1R 3S3
| | - Nicolas Houde
- Centre de recherche sur le cancer de l'Université Laval, Centre de recherche du CHU de Québec-Université Laval (Oncology Axis), Québec, Canada G1R 3S3
| | - Mickaël Lhuillier
- Inserm U1151, Institut Necker-Enfants Malades, Université de Paris, 75743 Paris, Cedex15, France
| | - Louis Charron
- Centre de recherche sur le cancer de l'Université Laval, Centre de recherche du CHU de Québec-Université Laval (Oncology Axis), Québec, Canada G1R 3S3
| | - Alice Hadchouel
- Inserm U1151, Institut Necker-Enfants Malades, Université de Paris, 75743 Paris, Cedex15, France
- AP-HP, Hôpital Necker-Enfants Malades, 75743 Paris, Cedex15, France
| | - Christophe Delacourt
- Inserm U1151, Institut Necker-Enfants Malades, Université de Paris, 75743 Paris, Cedex15, France
- AP-HP, Hôpital Necker-Enfants Malades, 75743 Paris, Cedex15, France
| | - William D Foulkes
- Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montréal, Canada H3T 1E2
| | | | - Lucie Jeannotte
- Centre de recherche sur le cancer de l'Université Laval, Centre de recherche du CHU de Québec-Université Laval (Oncology Axis), Québec, Canada G1R 3S3
- Department of Molecular Biology, Medical Biochemistry & Pathology, Université Laval, Québec, Canada G1V 0A6
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39
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Shi Y, He R, Yang Y, He Y, Shao K, Zhan L, Wei B. Circular RNAs: Novel biomarkers for cervical, ovarian and endometrial cancer (Review). Oncol Rep 2020; 44:1787-1798. [PMID: 33000238 PMCID: PMC7551080 DOI: 10.3892/or.2020.7780] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 08/24/2020] [Indexed: 12/24/2022] Open
Abstract
Cervical, ovarian and endometrial cancer are the three most common types of malignant tumor and the leading causes of cancer‑associated death in women. Tumor debulking surgery followed by platinum and paclitaxel chemotherapy is the current treatment regime of choice. However, as a result of late diagnosis and chemoresistance, the survival rates of patients with advanced gynecological cancers remains unsatisfactory. Circular RNAs (circRNAs) are stable noncoding RNAs that are present in a wide variety of tissue and cell types. With the enhancement of RNA sequencing methods, increasing numbers of circRNAs have been identified, and their functions are gradually being revealed. In recent years, circRNAs have received increasing attention for their regulatory roles in cervical, ovarian and endometrial cancer. The aim of the present review was to summarize the possible mechanisms of recently identified circRNAs; we hypothesize that a novel diagnostic and therapeutic biomarker may be identified to prolong the survival time of patients with gynecological malignancies.
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Affiliation(s)
- Yuchuan Shi
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Runhua He
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Yu Yang
- Cardiology Department, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Yu He
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Kang Shao
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Lei Zhan
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Bing Wei
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
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40
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Morales-Martinez M, Vega GG, Neri N, Nambo MJ, Alvarado I, Cuadra I, Duran-Padilla MA, Huerta-Yepez S, Vega MI. MicroRNA-7 Regulates Migration and Chemoresistance in Non-Hodgkin Lymphoma Cells Through Regulation of KLF4 and YY1. Front Oncol 2020; 10:588893. [PMID: 33194748 PMCID: PMC7654286 DOI: 10.3389/fonc.2020.588893] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/02/2020] [Indexed: 12/12/2022] Open
Abstract
The discovery and description of the role of microRNAs has become very important, specifically due to their participation in the regulation of proteins and transcription factors involved in the development of cancer. microRNA-7 (miR-7) has been described as a negative regulator of several proteins involved in cancer, such as YY1 and KLF4. We have recently reported that YY1 and KLF4 play a role in non-Hodgkin lymphoma (NHL) and that the expression of KLF4 is regulated by YY1. Therefore, in this study we analyzed the role of miR-7 in NHL through the negative regulation of YY1 and KLF4. qRT-PCR showed that there is an inverse expression of miR-7 in relation to the expression of YY1 and KLF4 in B-NHL cell lines. The possible regulation of YY1 and KLF4 by miR-7 was analyzed using the constitutive expression or inhibition of miR-7, as well as using reporter plasmids containing the 3 'UTR region of YY1 or KLF4. The role of miR-7 in NHL, through the negative regulation of YY1 and KLF4 was determined by chemoresistance and migration assays. We corroborated our results in cell lines, in a TMA from NHL patients including DLBCL and follicular lymphoma subtypes, in where we analyzed miR-7 by ISH and YY1 and KLF4 using IHC. All tumors expressing miR-7 showed a negative correlation with YY1 and KLF4 expression. In addition, expression of miR-7 was analyzed using the GEO Database; miR-7 downregulated expression was associated with pour overall-survival. Our results show for the first time that miR-7 is implicate in the cell migration and chemoresistance in NHL, through the negative regulation of YY1 and KLF4. That also support the evidence that YY1 and KLF4 can be a potential therapeutic target in NHL.
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Affiliation(s)
- Mario Morales-Martinez
- Molecular Signal Pathway in Cancer Laboratory, Unidad de Investigación Medica en Enfermedades Oncologicas (UIMEO), Oncology Hospital, Siglo XXI National Medical Center, Instituto Méxicano del Seguro Social (IMSS), Mexico City, Mexico
- Unidad de Posgrado, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Gabriel G. Vega
- Molecular Signal Pathway in Cancer Laboratory, Unidad de Investigación Medica en Enfermedades Oncologicas (UIMEO), Oncology Hospital, Siglo XXI National Medical Center, Instituto Méxicano del Seguro Social (IMSS), Mexico City, Mexico
- Unidad de Posgrado, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Natividad Neri
- Department of Hematology, Oncology Hospital, National Medical Center, IMSS, Mexico City, Mexico
| | - M. J Nambo
- Department of Hematology, Oncology Hospital, National Medical Center, IMSS, Mexico City, Mexico
| | - Isabel Alvarado
- Servicio de Anatomía Patológica, Hospital de Oncología, Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - Ivonne Cuadra
- Servicio de Anatomía Patológica, Hospital de Oncología, Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - M. A. Duran-Padilla
- Servicio de Patología, Hospital General de México “Eduardo Liceaga”, Facultad de Medicina de la UNAM, Mexico City, Mexico
| | - Sara Huerta-Yepez
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez S.S.A, Mexico City, Mexico
| | - Mario I. Vega
- Molecular Signal Pathway in Cancer Laboratory, Unidad de Investigación Medica en Enfermedades Oncologicas (UIMEO), Oncology Hospital, Siglo XXI National Medical Center, Instituto Méxicano del Seguro Social (IMSS), Mexico City, Mexico
- Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, CA, United States
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Han S, Zhang T, Kusumanchi P, Huda N, Jiang Y, Liangpunsakul S, Yang Z. Role of microRNA-7 in liver diseases: a comprehensive review of the mechanisms and therapeutic applications. J Investig Med 2020; 68:1208-1216. [PMID: 32843369 PMCID: PMC9303053 DOI: 10.1136/jim-2020-001420] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/21/2020] [Indexed: 12/14/2022]
Abstract
MicroRNA-7 (miR-7) is a small non-coding RNA, which plays critical roles in regulating gene expression of multiple key cellular processes. MiR-7 exhibits a tissue-specific pattern of expression, with abundant levels found in the brain, spleen, and pancreas. Although it is expressed at lower levels in other tissues, including the liver, miR-7 is involved in both the development of organs and biological functions of cells. In this review, we focus on the mechanisms by which miR-7 controls cell growth, proliferation, invasion, metastasis, metabolism, and inflammation. We also summarize the specific roles of miR-7 in liver diseases. MiR-7 is considered as a tumor suppressor miRNA in hepatocellular carcinoma and is involved in the pathogenesis of hepatic steatosis and hepatitis. Future studies to further define miR-7 functions and its mechanism in association with other types of liver diseases should be explored. An improved understanding from these studies will provide us a useful perspective leading to mechanism-based intervention by targeting miR-7 for the treatment of liver diseases.
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Affiliation(s)
- Sen Han
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, Beijing, China
| | - Ting Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Praveen Kusumanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nazmul Huda
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Yanchao Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
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42
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Li L, Li Y, Timothy Sembiring Meliala I, Kasim V, Wu S. Biological roles of Yin Yang 2: Its implications in physiological and pathological events. J Cell Mol Med 2020; 24:12886-12899. [PMID: 32969187 PMCID: PMC7754051 DOI: 10.1111/jcmm.15919] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 09/07/2020] [Accepted: 09/08/2020] [Indexed: 12/15/2022] Open
Abstract
Yin yang 2 (YY2) is a multifunctional zinc finger protein that belongs to the yin yang (YY) family. YY2 has dual function in regulating gene expression, as it could act either as a transcriptional activator or as a repressor of its target genes. YY2 could regulate genes that have been previously identified as targets of yin yang 1 (YY1), another member of the YY family, by binding to their common binding sequences. However, recent studies revealed that YY2 also has its own specific binding sequences, leading to its particular biological functions distinct from those of YY1. Furthermore, they have different levels or even opposite regulatory effects on common target genes, suggesting the importance of balanced YY1 and YY2 regulations in maintaining proper cellular homeostasis and biological functions. Recent studies revealed that YY2 plays crucial roles in maintaining stemness and regulating differentiation potential of embryonic stem cells, as well as in the development of the brain, nervous and cardiovascular systems. YY2 expression is also closely related to diseases, as it could act as a tumour suppressor gene that regulates tumour cell proliferation and metastasis. Moreover, YY2 is also involved in immune regulation and immune surveillance. Herein, we summarize recent perspectives regarding the regulatory functions of YY2, as well as its biological functions and relation with diseases.
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Affiliation(s)
- Lang Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China
| | - Yanjun Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China
| | - Ian Timothy Sembiring Meliala
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China
| | - Vivi Kasim
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China.,State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing, China
| | - Shourong Wu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China.,State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing, China
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Xu G, Yang H, Liu M, Niu J, Chen W, Tan X, Sun L. lncRNA TINCR facilities bladder cancer progression via regulating miR‑7 and mTOR. Mol Med Rep 2020; 22:4243-4253. [PMID: 33000269 PMCID: PMC7533511 DOI: 10.3892/mmr.2020.11530] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 03/26/2020] [Indexed: 12/25/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) have been implicated in various human malignancies, but the molecular mechanism of lncRNA TINCR ubiquitin domain containing (TINCR) in bladder cancer remains unclear. The present study found that the expression of TINCR was significantly increased in bladder cancer tissues and cell lines, when compared with that in adjacent normal tissues and normal urinary tract epithelial cell line SV-HUC-1, respectively. Moreover, the high expression of TINCR was associated with tumor metastasis and advanced tumor, node, metastasis stage, as well as reduced overall survival rates of patients with bladder cancer. Further investigation revealed that microRNA (miR)-7 was negatively mediated by TINCR in bladder cancer cells. Silencing of TINCR expression significantly increased miR-7 expression and reduced bladder cancer cell proliferation, migration and invasion, while knockdown of miR-7 expression reversed the inhibitory effects of TINCR downregulation on bladder cancer cells. mTOR was then identified as a target gene of miR-7 in bladder cancer, and it was demonstrated that overexpression of mTOR reversed the inhibitory effects of miR-7 on bladder cancer cells. In conclusion, this study suggests that TINCR/miR-7/mTOR signaling may be a potential therapeutic target for bladder cancer.
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Affiliation(s)
- Guoying Xu
- Department of Urology Surgery, Shengli Hospital of Shengli Petroleum Administration, Dongying, Shandong 257055, P.R. China
| | - Honglan Yang
- Department of Oncology, Dongying People's Hospital, Dongying, Shandong 257091, P.R. China
| | - Meichun Liu
- Clinical Laboratory, Shengli Hospital of Shengli Petroleum Administration, Dongying, Shandong 257055, P.R. China
| | - Jintao Niu
- Department of Urology Surgery, Shengli Hospital of Shengli Petroleum Administration, Dongying, Shandong 257055, P.R. China
| | - Weidong Chen
- Shengli Hospital of Shengli Petroleum Administration, Dongying, Shandong 257055, P.R. China
| | - Xiaojing Tan
- Department of Oncology, Dongying People's Hospital, Dongying, Shandong 257091, P.R. China
| | - Li Sun
- Shengli Hospital of Shengli Petroleum Administration, Dongying, Shandong 257055, P.R. China
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Vivarelli S, Falzone L, Ligresti G, Candido S, Garozzo A, Magro GG, Bonavida B, Libra M. Role of the Transcription Factor Yin Yang 1 and Its Selectively Identified Target Survivin in High-Grade B-Cells Non-Hodgkin Lymphomas: Potential Diagnostic and Therapeutic Targets. Int J Mol Sci 2020; 21:ijms21176446. [PMID: 32899428 PMCID: PMC7504013 DOI: 10.3390/ijms21176446] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/21/2020] [Accepted: 09/02/2020] [Indexed: 12/19/2022] Open
Abstract
B-cell non-Hodgkin lymphomas (B-NHLs) are often characterized by the development of resistance to chemotherapeutic drugs and/or relapse. During drug-induced apoptosis, Yin Yang 1 (YY1) transcription factor might modulate the expression of apoptotic regulators genes. The present study was aimed to: (1) examine the potential oncogenic role of YY1 in reversing drug resistance in B-NHLs; and (2) identify YY1 transcriptional target(s) that regulate the apoptotic pathway in B-NHLs. Predictive analyses coupled with database-deposited data suggested that YY1 binds the promoter of the BIRC5/survivin anti-apoptotic gene. Gene Expression Omnibus (GEO) analyses of several B-NHL repositories revealed a conserved positive correlation between YY1 and survivin, both highly expressed, especially in aggressive B-NHLs. Further validation experiments performed in Raji Burkitt’s lymphomas cells, demonstrated that YY1 silencing was associated with survivin downregulation and sensitized the cells to apoptosis. Overall, our results revealed that: (1) YY1 and survivin are positively correlated and overexpressed in B-NHLs, especially in BLs; (2) YY1 strongly binds to the survivin promoter, hence survivin may be suggested as YY1 transcriptional target; (3) YY1 silencing sensitizes Raji cells to drug-induced apoptosis via downregulation of survivin; (4) both YY1 and survivin are potential diagnostic markers and therapeutic targets for the treatment of resistant/relapsed B-NHLs.
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Affiliation(s)
- Silvia Vivarelli
- Laboratory of Translational Oncology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.V.); (G.L.); (S.C.)
| | - Luca Falzone
- Epidemiology Unit, IRCCS Istituto Nazionale Tumori ‘Fondazione G. Pascale’, 80131 Naples, Italy;
| | - Giovanni Ligresti
- Laboratory of Translational Oncology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.V.); (G.L.); (S.C.)
| | - Saverio Candido
- Laboratory of Translational Oncology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.V.); (G.L.); (S.C.)
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy; (A.G.); (G.G.M.)
| | - Adriana Garozzo
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy; (A.G.); (G.G.M.)
- Laboratory of Virology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | - Gaetano Giuseppe Magro
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy; (A.G.); (G.G.M.)
- Department of Medical and Surgical Sciences and Advanced Technology “G.F. Ingrassia”, University of Catania, 95123 Catania, Sicily, Italy
| | - Benjamin Bonavida
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
| | - Massimo Libra
- Laboratory of Translational Oncology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.V.); (G.L.); (S.C.)
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy; (A.G.); (G.G.M.)
- Correspondence: ; Tel.: +39-095-478-1271
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Fathizadeh H, Hallajzadeh J, Asemi Z. Circular RNAs as diagnostic biomarker in pancreatic cancer. Pathol Res Pract 2020; 216:153075. [PMID: 32825948 DOI: 10.1016/j.prp.2020.153075] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 05/31/2020] [Accepted: 06/17/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is one of the causes of death in the world. Unfortunately, common imaging technologies did not succeed in identifying this disease, and because of the absence of sensitive and specific biomarkers, it is not possible to screen and diagnose the disease. Therefore, this disease is usually diagnosed when patient is at an advanced stage of cancer and has lost the chance of surgery, and routine treatments such as radiotherapy and chemotherapy are not very effective. For this reason, the discovery of new biomarkers to overcome the diagnostic and therapeutic problems of pancreatic cancer is essential. Recently, circular RNAs (circRNAs) have been introduced as a group of noncoding RNAs that can play the role of critical regulators in various human diseases including cancer. A lot of studies revealed that circRNAs can have diverse roles in various cancers, including breast, colorectal, lung, renal, gastric, and hepatocellular carcinoma. The results of these researches have demonstrated that change in circRNAs expression levels in the tumor cells affects carcinogenesis, the stages of progression and metastasis of cancer through various mechanisms. Given that several studies have tested the role of circRNAs in pancreatic cancer, we decided to review the mechanisms proposed in these studies to conclude and summarize the work done in this regard.
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Affiliation(s)
- Hadis Fathizadeh
- Department of Microbiology, Kashan University of Medical Sciences, Kashan, Iran.
| | - Jamal Hallajzadeh
- Department of Biochemistry and Nutrition, Research Center for Evidence-Based Health Management, Maragheh University of Medical Sciences, Maragheh, Iran.
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Pan CM, Chan KH, Chen CH, Jan CI, Liu MC, Lin CM, Cho DY, Tsai WC, Chu YT, Cheng CH, Chuang HY, Chiu SC. MicroRNA-7 targets T-Box 2 to inhibit epithelial-mesenchymal transition and invasiveness in glioblastoma multiforme. Cancer Lett 2020; 493:133-142. [PMID: 32861705 DOI: 10.1016/j.canlet.2020.08.024] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 08/11/2020] [Accepted: 08/20/2020] [Indexed: 12/12/2022]
Abstract
The dysregulation of microRNA expression in cancer has been associated with the epithelial-mesenchymal transition (EMT) that triggers invasive ability and increases therapeutic resistance. Here, we determined the microRNA expression profile of seven tumor tissues from patients with glioblastoma multiforme (GBM) by use of microRNA array analysis. We discovered that microRNA-7 (miR-7) is consistently downregulated in all tumor samples. Using the microRNA.org algorithm, the T-box 2 gene (TBX2) was identified as a candidate gene targeted by miR-7. In contrast to miR-7, TBX2 had an increased expression in GBM tumors and was linked to poor prognosis. We confirmed that TBX2 mRNA and protein production are significantly repressed by overexpressing miR-7 in GBM cells in vitro. The reporter assay showed that miR-7 significantly represses the signal from luciferase with the 3' UTR of TBX2. Furthermore, TBX2 overexpression decreased E-cadherin expression and increased Vimentin expression, causing an increasing number of invaded cells in the invasion assay, as well as pulmonary metastasis in vivo. Our findings demonstrated that overexpression of TBX2 in GBM tumors via the downregulation of miR-7 leads to EMT induction and increased cell invasion.
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Affiliation(s)
- Chih-Ming Pan
- Translational Cell Therapy Center, China Medical University Hospital, Taichung, 40447, Taiwan
| | - Kai-Hsiang Chan
- Cell Therapy Center, An Nan Hospital, China Medical University, Tainan, 70967, Taiwan; Department of Radiation Oncology, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, 70967, Taiwan
| | - Chao-Hsuan Chen
- Department of Neurosurgery, Neuropsychiatric Center, China Medical University Hospital, Taichung, 40447, Taiwan
| | - Chia-Ing Jan
- Translational Cell Therapy Center, China Medical University Hospital, Taichung, 40447, Taiwan; Division of Molecular Pathology, Department of Pathology, China Medical University and Hospital, Taichung, 40447, Taiwan; Department of Medicine, China Medical University, Taichung, 40447, Taiwan; Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA
| | - Ming-Chao Liu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan
| | - Chien-Min Lin
- Taipei Neuroscience Institute, Taipei Medical University, Taipei, 11031, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Division of Neurosurgery, Department of Surgery, Taipei Medical University-Shuang Ho Hospital, New Taipei City, 23561, Taiwan
| | - Der-Yang Cho
- Translational Cell Therapy Center, China Medical University Hospital, Taichung, 40447, Taiwan; Department of Neurosurgery, Neuropsychiatric Center, China Medical University Hospital, Taichung, 40447, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan; Drug Development Center, China Medical University, Taichung, 40402, Taiwan
| | - Wan-Chen Tsai
- Translational Cell Therapy Center, China Medical University Hospital, Taichung, 40447, Taiwan
| | - Yen-Tse Chu
- Department of Neurosurgery, An Nan Hospital, China Medical University, Tainan, 70967, Taiwan
| | - Cheng-Hsin Cheng
- Department of Neurosurgery, An Nan Hospital, China Medical University, Tainan, 70967, Taiwan
| | - Hao-Yu Chuang
- Cell Therapy Center, An Nan Hospital, China Medical University, Tainan, 70967, Taiwan; Department of Neurosurgery, An Nan Hospital, China Medical University, Tainan, 70967, Taiwan; Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin County, 65152, Taiwan.
| | - Shao-Chih Chiu
- Translational Cell Therapy Center, China Medical University Hospital, Taichung, 40447, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan; Drug Development Center, China Medical University, Taichung, 40402, Taiwan.
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Identification of Tumorigenic and Prognostic Biomarkers in Colorectal Cancer Based on microRNA Expression Profiles. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7136049. [PMID: 32802869 PMCID: PMC7424406 DOI: 10.1155/2020/7136049] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 07/24/2020] [Indexed: 12/11/2022]
Abstract
Objective Although noncoding RNAs, especially the microRNAs, have been found to play key roles in CRC development in intestinal tissue, the specific mechanism of these microRNAs has not been fully understood. Methods GEO and TCGA database were used to explore the microRNA expression profiles of normal mucosa, adenoma, and carcinoma. And the differential expression genes were selected. Computationally, we built the SVM model and multivariable Cox regression model to evaluate the performance of tumorigenic microRNAs in discriminating the adenomas from normal tissues and risk prediction. Results In this study, we identified 20 miRNA biomarkers dysregulated in the colon adenomas. The functional enrichment analysis showed that MAPK activity and MAPK cascade were highly enriched by these tumorigenic microRNAs. We also investigated the target genes of the tumorigenic microRNAs. Eleven genes, including PIGF, TPI1, KLF4, RARS, PCBP2, EIF5A, HK2, RAVER2, HMGN1, MAPK6, and NDUFA2, were identified to be frequently targeted by the tumorigenic microRNAs. The high AUC value and distinct overall survival rates between the two risk groups suggested that these tumorigenic microRNAs had the potential of diagnostic and prognostic value in CRC. Conclusions The present study revealed possible mechanisms and pathways that may contribute to tumorigenesis of CRC, which could not only be used as CRC early detection biomarkers, but also be useful for tumorigenesis mechanism studies.
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Gajda E, Godlewska M, Mariak Z, Nazaruk E, Gawel D. Combinatory Treatment with miR-7-5p and Drug-Loaded Cubosomes Effectively Impairs Cancer Cells. Int J Mol Sci 2020; 21:E5039. [PMID: 32708846 PMCID: PMC7404280 DOI: 10.3390/ijms21145039] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/14/2020] [Accepted: 07/15/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Multidrug resistance (MDR) is an emerging problem in the treatment of cancer. Therefore, there is a necessity for novel strategies that would sensitize tumor cells to the administered chemotherapeutics. One of the innovative approaches in fighting drug-resistant tumors is the treatment of cancer with microRNA (miRNA), or the use of cubosomes (lipid nanoparticles) loaded with drugs. Here, we present a study on a novel approach, which combines both tools. METHODS Cubosomes loaded with miR-7-5p and chemotherapeutics were developed. The effects of drug- and miRNA-loaded vehicles on glioma- (A172, T98G), papillary thyroid- (TPC-1) and cervical carcinoma-derived (HeLa) cells were analyzed using molecular biology techniques, including quantitative real-time PCR, MTS-based cell proliferation test, flow cytometry and spheroids formation assay. RESULTS The obtained data indicate that miR-7-5p increases the sensitivity of the tested cells to the drug, and that nanoparticles loaded with both miRNA and the drug produce a greater anti-tumor effect in comparison to the free drug treatment. It was found that an increased level of apoptosis in the drug/miRNA co-treated cells is accompanied by an alternation in the expression of the genes encoding for key MDR proteins of the ABC family. CONCLUSIONS Overall, co-administration of miR-7-5p with a chemotherapeutic can be considered a promising strategy, leading to reduced MDR and the induction of apoptosis in cancer cells.
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Affiliation(s)
- Ewa Gajda
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland;
| | - Marlena Godlewska
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland;
| | - Zenon Mariak
- Department of Neurosurgery, Medical University of Bialystok, M. Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland;
| | - Ewa Nazaruk
- Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland;
| | - Damian Gawel
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland;
- Department of Immunohematology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland
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Eshghifar N, Badrlou E, Pouresmaeili F. The roles of miRNAs' clinical efficiencies in the colorectal cancer pathobiology: A review article. Hum Antibodies 2020; 28:273-285. [PMID: 32623393 DOI: 10.3233/hab-200417] [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] [Indexed: 12/30/2022]
Abstract
MiRNAs (microRNAs) are defined as micro directors and regulators of gene expression. Since altered miRNA expression is signified in the pathobiology of diverse cancers such as colorectal cancers (CRCs), these molecules are described as therapeutic targets, either. Manipulation of miRNAs could lead to further therapy for chemo and radio-resistant CRCs. The usage of microRNAs has indicated prominent promise in the prognosis and diagnosis of CRC, because of their unique expression pattern associated with cancer types and malignancies. Nowadays, many researchers are analyzing the correlation between miRNA polymorphisms and cancer risk. With continuous incompatibility in colorectal cancer (CRC) miRNAs expression data, it is critical to move toward the content of a "pre-laboratory" analysis to speed up efficient accuracy medicine and translational study. Pathway study for the highest expressed miRNAs- regulated target genes resulted in the identification of a considerable number of genes associated with CRC pathway including PI3K, TGFβ, and APC. In this review, we aimed to collect fruitful information about miRNAs and their potential roles in CRC, and provide a meta-analysis of the most frequently studied miRNAs in association with the disease.
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Affiliation(s)
- Nahal Eshghifar
- Department of Molecular and Cellular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elham Badrlou
- Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farkhondeh Pouresmaeili
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Nei Endonuclease VIII-Like1 (NEIL1) Inhibits Apoptosis of Human Colorectal Cancer Cells. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5053975. [PMID: 32685496 PMCID: PMC7336199 DOI: 10.1155/2020/5053975] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/13/2020] [Indexed: 12/25/2022]
Abstract
The study is aimed at investigating the role of Nei endonuclease VIII-like1 (NEIL1) in the pathogenesis of colorectal cancer (CRC). The human CRC (HCT116 and SW480) cells were subjected to the siRNA silencing and recombinant plasmid overexpression of NEIL1. Transfection of siNEIL1 significantly inhibited the cell growth. It also increased the Bax expression levels, while it decreased the Bcl-2 expression levels in human CRC cells, leading the Bax/Bcl-2 balance toward apoptosis. Moreover, the apoptosis was promoted through the caspase-9 signaling pathway. One the other hand, high expression of NEIL1 promoted the cell viability and reduced the apoptosis, inducing the balance of Bax/Bcl-2 in the human colon cancer cells to be antiapoptotic. In addition, the caspase-9 signaling pathway inhibited apoptosis, contrary to the results obtained by downregulating NEIL1 expression. Furthermore, NEIL1 was negatively regulated by miR-7-5p, indicating that miR-7-5p inhibited the NEIL1 expression after transcription. Overexpression of miR-7-5p reversed the effects of NEIL1 on these CRC cells. In conclusion, NEIL1 promotes the proliferation of CRC cells, which is regulated negatively by miR-7-5p. These findings suggest that NEIL1 is a potential therapeutic target for CRC.
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