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Kang DY, Bae SW, Jang KJ. Natural bioactive gallic acid shows potential anticancer effects by inhibiting the proliferation and invasiveness behavior in human embryonic carcinoma cells. Mol Med Rep 2025; 31:151. [PMID: 40211726 PMCID: PMC11997742 DOI: 10.3892/mmr.2025.13516] [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: 10/11/2024] [Accepted: 02/06/2025] [Indexed: 04/16/2025] Open
Abstract
Embryonic cancer stem cells (CSCs), referred to as self‑renewable cells, are commonly found in liquid and solid cancers and can also be attributed to tumor onset, resistance, expansion, recurrence and metastasis following treatment. Cancer therapy targeting CSCs using natural bioactive products is an optimal option for inhibiting cancer recurrence, thereby improving prognosis. Several natural compounds and extracts have been used to identify direct or indirect therapy effects that reduce the pathological activities of CSCs. Natural gallic acid (GA) is noted to have anticancer properties for oncogene expression, cycle arrest, apoptosis, angiogenesis, migration and metastasis in various cancers. The present study demonstrated that GA has various anticancer activities in NTERA‑2 and NCCIT human embryonic carcinoma cells. In two types of embryonic CSCs, GA effectively induced cell death via late apoptosis. Furthermore, GA showed the G0/G1 cell cycle arrest activity in embryonic CSCs by inducing the increase of p21, p27 and p53 expression and the decrease of CDK4, cyclin E and cyclin D1 expression. The present study showed that GA inhibited the expression levels of mRNA and protein for stem cell markers, such as SOX2, NANOG and OCT4, in NTERA‑2 and NCCIT cells. The induction of cellular and mitochondrial reactive oxygen species by GA also activated the cellular DNA damage response pathway by raising the phosphorylated‑BRCA1, ATM, Chk1, Chk2 and histone. Finally, GA inhibited CSCs invasion and migration by inhibiting the expression of matrix metalloproteinase by the downregulation of EGFR/JAK2/STAT5 signaling pathway. Thus, it is hypothesized that GA could be a potential inhibitor of cancer emergence by suppressing CSC properties.
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Affiliation(s)
- Dong Young Kang
- Department of Immunology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju. Chungcheong 27478, Republic of Korea
| | - Se Won Bae
- Department of Chemistry and Cosmetics, Jeju National University, Jeju, Jejudo 63243, Republic of Korea
| | - Kyoung-Jin Jang
- Department of Integrative Biological Sciences and Industry, College of Life Science, Sejong University, Seoul 05006, Republic of Korea
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Kereka KS, Mousavi SH, Alizadeh S, Ghaemmaghami L, Fakoorizad G, Motallebzadeh Khanmiri J. Up-Regulation of miR-625-5p Correlates with Suppressed Sox2, Increased Apoptosis, and Cell Cycle Arrest via The PI3K/AKT Signalling Pathway in Acute Myeloid Leukaemia. Int J Hematol Oncol Stem Cell Res 2024; 18:358-366. [PMID: 39703469 PMCID: PMC11652696 DOI: 10.18502/ijhoscr.v18i4.16760] [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: 04/25/2022] [Accepted: 08/10/2024] [Indexed: 12/21/2024] Open
Abstract
Background: Up-regulation of the microRNA-625 and abnormal expression of the Sox2 gene have been studied and seen in several tumors. Few reports have also shown the aberrant expression of miR-625 and Sox2 expression in various cancers. Several studies have also confirmed that phosphatidylinositol 3' -kinase /protein kinase B pathways regulate hematological malignancies, including Acute Myeloid Leukemia (AML). Thus, this study aimed to investigate the effects of mir-625 up-regulation on proliferation, apoptosis, and cell cycle by targeting the Sox2 gene via the downstream Akt signaling pathway and cell cycle regulators, such as p21, p27, and cyclin E in the KG-1 cell line. Materials and Methods: Cells obtained from the KG-1 cell line were cultured and transfected with plasmid DNA (miR-625) and scrambled as the control using the Lonza electroporation system. Flow cytometry was used to evaluate cell cycle, proliferation, and apoptosis. Relative gene expression was validated by qRT-PCR. All data were analyzed using graph pad prism 7.01 and REST 2009. Results: KG-1 cells transfected with the mir625-GFP construct showed decreased proliferation, increased apoptosis, and induced cell cycle arrest. Low levels of Sox2, p21, cyclin E, and up-regulation of p27 were confirmed and validated by qRT-PCR ( P < 0.05 ). Conclusion: MiR-625 can be a promising approach to aid in the treatment of AML. However, further studies are required in this field.
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Affiliation(s)
- Kangup Steven Kereka
- Department of Haematology and Blood Transfusion, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Hadi Mousavi
- Department of Haematology and Blood Transfusion, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Shaban Alizadeh
- Department of Haematology and Blood Transfusion, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ghasem Fakoorizad
- Department of Haematology and Blood Transfusion, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Jamal Motallebzadeh Khanmiri
- Department of Haematology and Blood Transfusion, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
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Hushmandi K, Saadat SH, Mirilavasani S, Daneshi S, Aref AR, Nabavi N, Raesi R, Taheriazam A, Hashemi M. The multifaceted role of SOX2 in breast and lung cancer dynamics. Pathol Res Pract 2024; 260:155386. [PMID: 38861919 DOI: 10.1016/j.prp.2024.155386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 05/09/2024] [Accepted: 05/31/2024] [Indexed: 06/13/2024]
Abstract
Breast and lung cancers are leading causes of death among patients, with their global mortality and morbidity rates increasing. Conventional treatments often prove inadequate due to resistance development. The alteration of molecular interactions may accelerate cancer progression and treatment resistance. SOX2, known for its abnormal expression in various human cancers, can either accelerate or impede cancer progression. This review focuses on examining the role of SOX2 in breast and lung cancer development. An imbalance in SOX2 expression can promote the growth and dissemination of these cancers. SOX2 can also block programmed cell death, affecting autophagy and other cell death mechanisms. It plays a significant role in cancer metastasis, mainly by regulating the epithelial-to-mesenchymal transition (EMT). Additionally, an imbalanced SOX2 expression can cause resistance to chemotherapy and radiation therapy in these cancers. Genetic and epigenetic factors may affect SOX2 levels. Pharmacologically targeting SOX2 could improve the effectiveness of breast and lung cancer treatments.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, the Islamic Republic of Iran.
| | - Seyed Hassan Saadat
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, the Islamic Republic of Iran
| | - Seyedalireza Mirilavasani
- Campus Venlo, Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, The Netherlands
| | - Salman Daneshi
- Department of Public Health,School of Health,Jiroft University of Medical Sciences,Jiroft, the Islamic Republic of Iran
| | - Amir Reza Aref
- Department of Translational Sciences, Xsphera Biosciences Inc. Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6 Canada
| | - Rasoul Raesi
- Department of Health Services Management, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran.; Department of Nursing, Torbat Jam Faculty of Medical Sciences, Torbat Jam, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, the Islamic Republic of Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, the Islamic Republic of Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, the Islamic Republic of Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, the Islamic Republic of Iran.
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Caerts D, Garmyn M, Güvenç C. A Narrative Review of the Role of Estrogen (Receptors) in Melanoma. Int J Mol Sci 2024; 25:6251. [PMID: 38892441 PMCID: PMC11173079 DOI: 10.3390/ijms25116251] [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: 04/30/2024] [Revised: 05/27/2024] [Accepted: 06/03/2024] [Indexed: 06/21/2024] Open
Abstract
In this narrative review, we attempt to provide an overview of the evidence regarding the role of estrogen (receptors) in cutaneous melanoma (CM). We reviewed 68 studies and 4 systematic reviews and meta-analyses published from 2002 up to and including 2022. The prevailing presence of estrogen receptor β (ERβ) instead of estrogen receptor α (ERα) in CM is notable, with ERβ potentially playing a protective role and being less frequently detected in progressive cases. While men with CM generally experience a less favorable prognosis, this distinction may become negligible with advancing age. The role of oral contraceptives (OC) and hormone replacement therapy (HRT) in CM remains controversial. However, recent studies tend to associate the use of these exogenous hormones with a heightened risk of CM, mostly only when using estrogen therapy and not in combination with progesterone. On the contrary, the majority of studies find no substantial influence of in vitro fertilization (IVF) treatment on CM risk. Reproductive factors, including younger age at first childbirth, higher parity, and shorter reproductive life, show conflicting evidence, with some studies suggesting a lower CM risk. We suggest an important role for estrogens in CM. More research is needed, but the integration of estrogens and targeting the estrogen receptors in melanoma therapy holds promise for future developments in the field.
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Affiliation(s)
| | | | - Canan Güvenç
- Department of Dermatology, University Hospitals Leuven, 3000 Leuven, Belgium; (D.C.); (M.G.)
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Gong Y, Li H. CDK7 in breast cancer: mechanisms of action and therapeutic potential. Cell Commun Signal 2024; 22:226. [PMID: 38605321 PMCID: PMC11010440 DOI: 10.1186/s12964-024-01577-y] [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: 11/07/2023] [Accepted: 03/19/2024] [Indexed: 04/13/2024] Open
Abstract
Cyclin-dependent kinase 7 (CDK7) serves as a pivotal regulator in orchestrating cellular cycle dynamics and gene transcriptional activity. Elevated expression levels of CDK7 have been ubiquitously documented across a spectrum of malignancies and have been concomitantly correlated with adverse clinical outcomes. This review delineates the biological roles of CDK7 and explicates the molecular pathways through which CDK7 exacerbates the oncogenic progression of breast cancer. Furthermore, we synthesize the extant literature to provide a comprehensive overview of the advancement of CDK7-specific small-molecule inhibitors, encapsulating both preclinical and clinical findings in breast cancer contexts. The accumulated evidence substantiates the conceptualization of CDK7 as a propitious therapeutic target in breast cancer management.
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Affiliation(s)
- Ying Gong
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Huiping Li
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
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6
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Cui W, Bai X, Bai Z, Chen F, Xu J, Bai W, Xi Y. Exploring the expression and clinical significance of the miR-140-3p-HOXA9 axis in colorectal cancer. J Cancer Res Clin Oncol 2024; 150:47. [PMID: 38285101 PMCID: PMC10824855 DOI: 10.1007/s00432-023-05592-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 12/22/2023] [Indexed: 01/30/2024]
Abstract
PURPOSE This study aims to investigate the expression patterns and clinical significance of miR-140-3p and homeobox A9 (HOXA9) in colorectal cancer (CRC) selected by bioinformatic study, while elucidating their potential interplay. METHODS The microRNA expression profiles of paired colorectal cancer and matched normal tissues were retrieved from the Gene Expression Omnibus Database. Differentially expressed microRNAs and microRNA candidates were filtered and subjected to further analysis. Clinicopathological data, along with paraffin-embedded samples of colorectal tumor tissues were collected to facilitate comprehensive analysis. Expression levels of miR-140-3p and HOXA9 were quantified using qRT-PCR and immunohistochemistry. Survival rates were determined using the Kaplan-Meier method, and the COX regression model was utilized to identify independent prognostic factors that impact the overall prognosis. RESULTS MiR-140-3p was significantly downregulated in colorectal tumors compared to normal tissue, and HOXA9 was identified as a previously unreported potential downstream target. HOXA9 expression was elevated in tumors compared to normal tissues. Reduced miR-140-3p expression was associated with lymph node metastasis, while high HOXA9 expression correlated with both lymph node metastasis and lympho-vascular invasion. Patients with low miR-140-3p and high HOXA9 expression had a poorer prognosis. HOXA9 was identified as an independent risk factor for CRC patient survival. CONCLUSION The miR-140-3p-HOXA9 signaling disruption is closely linked to lymph node metastasis and unfavorable prognosis in CRC. This axis shows promise as a clinical biomarker for predicting the CRC patient survival and a potential therapeutic target.
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Affiliation(s)
- Wei Cui
- Department of Pathology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, Shanxi, People's Republic of China
| | - Xueliang Bai
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, Shanxi, People's Republic of China
| | - Zhongyuan Bai
- First Clinical Medical School, Shanxi Medical University, Taiyuan, 030001, Shanxi, People's Republic of China
| | - Fengxin Chen
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, Shanxi, People's Republic of China
| | - Jing Xu
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, Shanxi, People's Republic of China
| | - Wenqi Bai
- Department of Colorectal Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, Shanxi, People's Republic of China.
| | - Yanfeng Xi
- Department of Pathology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, Shanxi, People's Republic of China.
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7
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Richard V, Nair MG, Jaikumar VS, Jones S, Prabhu JS, Kerin MJ. Cell State Transitions and Phenotypic Heterogeneity in Luminal Breast Cancer Implicating MicroRNAs as Potential Regulators. Int J Mol Sci 2023; 24:ijms24043497. [PMID: 36834918 PMCID: PMC9967449 DOI: 10.3390/ijms24043497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/12/2023] Open
Abstract
Luminal breast cancer subtypes respond poorly to endocrine and trastuzumab treatments due to cellular heterogeneity arising from the phenotype transitions, accounted for mainly by the loss of receptor expression. The origins of basal-like and human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer subtypes have been attributed to genetic and protein modifications in stem-like cells and luminal progenitor cell populations, respectively. The post-transcriptional regulation of protein expression is known to be influenced by microRNAs (miRNAs) that are deemed to be master regulators of several biological processes in breast tumorigenesis and progression. Our objective was to identify the fractions of luminal breast cancer cells that share stemness potentials and marker profiles and to elucidate the molecular regulatory mechanism that drives transitions between fractions, leading to receptor discordances. Established breast cancer cell lines of all prominent subtypes were screened for the expression of putative cancer stem cell (CSC) markers and drug transporter proteins using a side population (SP) assay. Flow-cytometry-sorted fractions of luminal cancer cells implanted in immunocompromised mice generated a pre-clinical estrogen receptor alpha (ERα+) animal model with multiple tumorigenic fractions displaying differential expression of drug transporters and hormone receptors. Despite an abundance of estrogen receptor 1 (ESR1) gene transcripts, few fractions transitioned to the triple-negative breast cancer (TNBC) phenotype with a visible loss of ER protein expression and a distinct microRNA expression profile that is reportedly enriched in breast CSCs. The translation of this study has the potential to provide novel therapeutic miRNA-based targets to counter the dreaded subtype transitions and the failure of antihormonal therapies in the luminal breast cancer subtype.
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Affiliation(s)
- Vinitha Richard
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, H91 V4AY Galway, Ireland
- Correspondence: (V.R.); (M.J.K.)
| | - Madhumathy G. Nair
- Division of Molecular Medicine, St. John’s Research Institute, Bangalore 560034, Karnataka, India
| | - Vishnu S. Jaikumar
- Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695585, Kerala, India
| | - Sara Jones
- Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695585, Kerala, India
| | - Jyothi S. Prabhu
- Division of Molecular Medicine, St. John’s Research Institute, Bangalore 560034, Karnataka, India
| | - Michael J. Kerin
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, H91 V4AY Galway, Ireland
- Correspondence: (V.R.); (M.J.K.)
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8
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Vishnubalaji R, Shaath H, Al-Alwan M, Abdelalim EM, Alajez NM. Reciprocal interplays between MicroRNAs and pluripotency transcription factors in dictating stemness features in human cancers. Semin Cancer Biol 2022; 87:1-16. [PMID: 36354097 DOI: 10.1016/j.semcancer.2022.10.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
The interplay between microRNAs (miRNAs) and pluripotency transcription factors (TFs) orchestrates the acquisition of cancer stem cell (CSC) features during the course of malignant transformation, rendering them essential cancer cell dependencies and therapeutic vulnerabilities. In this review, we discuss emerging themes in tumor heterogeneity, including the clonal evolution and the CSC models and their implications in resistance to cancer therapies, and then provide thorough coverage on the roles played by key TFs in maintaining normal and malignant stem cell pluripotency and plasticity. In addition, we discuss the reciprocal interactions between miRNAs and MYC, OCT4, NANOG, SOX2, and KLF4 pluripotency TFs and their contributions to tumorigenesis. We provide our view on the potential to interfere with key miRNA-TF networks through the use of RNA-based therapeutics as single agents or in combination with other therapeutic strategies, to abrogate the CSC state and render tumor cells more responsive to standard and targeted therapies.
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Affiliation(s)
- Radhakrishnan Vishnubalaji
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Hibah Shaath
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Monther Al-Alwan
- Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; College of Medicine, Al-Faisal University, Riyadh 11533, Saudi Arabia
| | - Essam M Abdelalim
- Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, PO Box 34110, Doha, Qatar; College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Nehad M Alajez
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar; College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
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9
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Lee J, Troike K, Fodor R, Lathia JD. Unexplored Functions of Sex Hormones in Glioblastoma Cancer Stem Cells. Endocrinology 2022; 163:bqac002. [PMID: 35023543 PMCID: PMC8807164 DOI: 10.1210/endocr/bqac002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Indexed: 01/14/2023]
Abstract
Biological sex impacts a wide array of molecular and cellular functions that impact organismal development and can influence disease trajectory in a variety of pathophysiological states. In nonreproductive cancers, epidemiological sex differences have been observed in a series of tumors, and recent work has identified previously unappreciated sex differences in molecular genetics and immune response. However, the extent of these sex differences in terms of drivers of tumor growth and therapeutic response is less clear. In glioblastoma (GBM), the most common primary malignant brain tumor, there is a male bias in incidence and outcome, and key genetic and epigenetic differences, as well as differences in immune response driven by immune-suppressive myeloid populations, have recently been revealed. GBM is a prototypic tumor in which cellular heterogeneity is driven by populations of therapeutically resistant cancer stem cells (CSCs) that underlie tumor growth and recurrence. There is emerging evidence that GBM CSCs may show a sex difference, with male tumor cells showing enhanced self-renewal, but how sex differences impact CSC function is not clear. In this mini-review, we focus on how sex hormones may impact CSCs in GBM and implications for other cancers with a pronounced CSC population. We also explore opportunities to leverage new models to better understand the contribution of sex hormones vs sex chromosomes to CSC function. With the rising interest in sex differences in cancer, there is an immediate need to understand the extent to which sex differences impact tumor growth, including effects on CSC function.
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Affiliation(s)
- Juyeun Lee
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic
| | - Katie Troike
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
| | - R’ay Fodor
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
| | - Justin D Lathia
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic
- Case Comprehensive Cancer Center
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10
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Dey A, Kundu M, Das S, Jena BC, Mandal M. Understanding the function and regulation of Sox2 for its therapeutic potential in breast cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188692. [PMID: 35122882 DOI: 10.1016/j.bbcan.2022.188692] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/11/2022] [Accepted: 01/28/2022] [Indexed: 12/12/2022]
Abstract
Sox family of transcriptional factors play essential functions in development and are implicated in multiple clinical disorders, including cancer. Sox2 being their most prominent member and performing a critical role in reprogramming differentiated adult cells to an embryonic phenotype is frequently upregulated in multiple cancers. High Sox2 levels are detected in breast tumor tissues and correlate with a worse prognosis. In addition, Sox2 expression is connected with resistance to conventional anticancer therapy. Together, it can be said that inhibiting Sox2 expression can reduce the malignant features associated with breast cancer, including invasion, migration, proliferation, stemness, and chemoresistance. This review highlights the critical roles played by the Sox gene family members in initiating or suppressing breast tumor development, while primarily focusing on Sox2 and its role in breast tumor initiation, maintenance, and progression, elucidates the probable mechanisms that control its activity, and puts forward potential therapeutic strategies to inhibit its expression.
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Affiliation(s)
- Ankita Dey
- Cancer Biology Lab, School of Medical Science and Technology, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur, West Bengal, India..
| | - Moumita Kundu
- Cancer Biology Lab, School of Medical Science and Technology, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur, West Bengal, India..
| | - Subhayan Das
- Cancer Biology Lab, School of Medical Science and Technology, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur, West Bengal, India..
| | - Bikash Chandra Jena
- Cancer Biology Lab, School of Medical Science and Technology, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur, West Bengal, India..
| | - Mahitosh Mandal
- Cancer Biology Lab, School of Medical Science and Technology, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur, West Bengal, India..
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11
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Ruiz-Manriquez LM, Ledesma Pacheco SJ, Medina-Gomez D, Uriostegui-Pena AG, Estrada-Meza C, Bandyopadhyay A, Pathak S, Banerjee A, Chakraborty S, Srivastava A, Paul S. A Brief Review on the Regulatory Roles of MicroRNAs in Cystic Diseases and Their Use as Potential Biomarkers. Genes (Basel) 2022; 13:genes13020191. [PMID: 35205236 PMCID: PMC8872411 DOI: 10.3390/genes13020191] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/16/2021] [Accepted: 12/20/2021] [Indexed: 02/04/2023] Open
Abstract
miRNAs are small endogenous conserved non-coding RNA molecules that regulate post-transcriptional gene expression through mRNA degradation or translational inhibition, modulating nearly 60% of human genes. Cystic diseases are characterized by the presence of abnormal fluid-filled sacs in the body, and though most cysts are benign, they can grow inside tumors and turn malignant. Recent evidence has revealed that the aberrant expression of a number of miRNAs present in extracellular fluids, including plasma or serum, urine, saliva, follicular fluid, and semen, contribute to different cystic pathologies. This review aims to describe the role of different miRNAs in three worldwide relevant cystic diseases: polycystic ovarian syndrome (PCOS), polycystic kidney disease (PKD), and pancreatic cyst tumors (PCTs), as well as their potential use as novel biomarkers.
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Affiliation(s)
- Luis M. Ruiz-Manriquez
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc. San Pablo, Queretaro 76130, Mexico; (L.M.R.-M.); (S.J.L.P.); (D.M.-G.); (A.G.U.-P.); (C.E.-M.)
| | - Schoenstatt Janin Ledesma Pacheco
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc. San Pablo, Queretaro 76130, Mexico; (L.M.R.-M.); (S.J.L.P.); (D.M.-G.); (A.G.U.-P.); (C.E.-M.)
| | - Daniel Medina-Gomez
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc. San Pablo, Queretaro 76130, Mexico; (L.M.R.-M.); (S.J.L.P.); (D.M.-G.); (A.G.U.-P.); (C.E.-M.)
| | - Andrea G. Uriostegui-Pena
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc. San Pablo, Queretaro 76130, Mexico; (L.M.R.-M.); (S.J.L.P.); (D.M.-G.); (A.G.U.-P.); (C.E.-M.)
| | - Carolina Estrada-Meza
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc. San Pablo, Queretaro 76130, Mexico; (L.M.R.-M.); (S.J.L.P.); (D.M.-G.); (A.G.U.-P.); (C.E.-M.)
| | - Anindya Bandyopadhyay
- C4 Rice Center, International Rice Research Institute, Manila 4031, Philippines;
- Synthetic Biology, Biofuel and Genome Editing R&D, Reliance Industries Ltd., Navi Mumbai 400701, India
| | - Surajit Pathak
- Department of Medical Biotechnology, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Faculty of Allied Health Sciences, Chennai 603103, India; (S.P.); (A.B.)
| | - Antara Banerjee
- Department of Medical Biotechnology, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Faculty of Allied Health Sciences, Chennai 603103, India; (S.P.); (A.B.)
| | - Samik Chakraborty
- Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
| | - Aashish Srivastava
- Department of Clinical Science, University of Bergen, 5021 Bergen, Norway;
| | - Sujay Paul
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc. San Pablo, Queretaro 76130, Mexico; (L.M.R.-M.); (S.J.L.P.); (D.M.-G.); (A.G.U.-P.); (C.E.-M.)
- Correspondence:
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12
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A Brief Review on the Regulatory Roles of MicroRNAs in Cystic Diseases and Their Use as Potential Biomarkers. Genes (Basel) 2022; 13:191. [PMID: 35205236 PMCID: PMC8872411 DOI: 10.3390/genes13020191&set/a 867452130+949943291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
miRNAs are small endogenous conserved non-coding RNA molecules that regulate post-transcriptional gene expression through mRNA degradation or translational inhibition, modulating nearly 60% of human genes. Cystic diseases are characterized by the presence of abnormal fluid-filled sacs in the body, and though most cysts are benign, they can grow inside tumors and turn malignant. Recent evidence has revealed that the aberrant expression of a number of miRNAs present in extracellular fluids, including plasma or serum, urine, saliva, follicular fluid, and semen, contribute to different cystic pathologies. This review aims to describe the role of different miRNAs in three worldwide relevant cystic diseases: polycystic ovarian syndrome (PCOS), polycystic kidney disease (PKD), and pancreatic cyst tumors (PCTs), as well as their potential use as novel biomarkers.
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13
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A Brief Review on the Regulatory Roles of MicroRNAs in Cystic Diseases and Their Use as Potential Biomarkers. Genes (Basel) 2022. [DOI: 10.3390/genes13020191
expr 889616206 + 938882164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
miRNAs are small endogenous conserved non-coding RNA molecules that regulate post-transcriptional gene expression through mRNA degradation or translational inhibition, modulating nearly 60% of human genes. Cystic diseases are characterized by the presence of abnormal fluid-filled sacs in the body, and though most cysts are benign, they can grow inside tumors and turn malignant. Recent evidence has revealed that the aberrant expression of a number of miRNAs present in extracellular fluids, including plasma or serum, urine, saliva, follicular fluid, and semen, contribute to different cystic pathologies. This review aims to describe the role of different miRNAs in three worldwide relevant cystic diseases: polycystic ovarian syndrome (PCOS), polycystic kidney disease (PKD), and pancreatic cyst tumors (PCTs), as well as their potential use as novel biomarkers.
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14
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Wu HJ, Chu PY. Epigenetic Regulation of Breast Cancer Stem Cells Contributing to Carcinogenesis and Therapeutic Implications. Int J Mol Sci 2021; 22:ijms22158113. [PMID: 34360879 PMCID: PMC8348144 DOI: 10.3390/ijms22158113] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/23/2021] [Accepted: 07/27/2021] [Indexed: 12/15/2022] Open
Abstract
Globally, breast cancer has remained the most commonly diagnosed cancer and the leading cause of cancer death among women. Breast cancer is a highly heterogeneous and phenotypically diverse group of diseases, which require different selection of treatments. Breast cancer stem cells (BCSCs), a small subset of cancer cells with stem cell-like properties, play essential roles in breast cancer progression, recurrence, metastasis, chemoresistance and treatments. Epigenetics is defined as inheritable changes in gene expression without alteration in DNA sequence. Epigenetic regulation includes DNA methylation and demethylation, as well as histone modifications. Aberrant epigenetic regulation results in carcinogenesis. In this review, the mechanism of epigenetic regulation involved in carcinogenesis, therapeutic resistance and metastasis of BCSCs will be discussed, and finally, the therapies targeting these biomarkers will be presented.
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Affiliation(s)
- Hsing-Ju Wu
- Department of Biology, National Changhua University of Education, Changhua 500, Taiwan;
- Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan
- Department of Medical Research, Chang Bing Show Chwan Memorial Hospital, Lukang Town, Changhua 505, Taiwan
| | - Pei-Yi Chu
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
- Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
- Department of Health Food, Chung Chou University of Science and Technology, Changhua 510, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
- Correspondence: ; Tel.: +886-975611855; Fax: +886-47227116
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15
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Hafez HG, Mohareb RM, Salem SM, Matloub AA, Eskander EF, Ahmed HH. Molecular Mechanisms Underlying the Anti-Breast Cancer Stem Cell Activity of Pterocladia capillacea and Corallina officinalis Polysaccharides. Anticancer Agents Med Chem 2021; 22:1213-1225. [PMID: 34315394 DOI: 10.2174/1871520621666210727122756] [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: 02/01/2021] [Revised: 04/26/2021] [Accepted: 05/31/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE This study aimed to appraise the activity of Pterocladia capillacea and Corallina officinalis polysaccharides against breast cancer stem cells (BCSCs). P. capillacea and C. officinalis polysaccharides were characterized to be sulfated polysaccharide-protein complexes. METHODS Cytotoxicity of the polysaccharides against MDA-MB-231 and MCF-7 cell lines along with their impact on CD44+/CD24- and aldehyde dehydrogenase 1(ALDH1) positive BCSC population were determined. Their effect on gene expression of CSC markers, Wnt/β-catenin and Notch signaling pathways was evaluated. RESULTS P. capillacea and C. officinalis polysaccharides inhibited the growth of breast cancer cells and reduced BCSC subpopulation. P. capillacea polysaccharides significantly down-regulated OCT4, SOX2, ALDH1A3 and vimentin in MDA-MB-231 as well as in MCF-7 cells except for vimentin that was up-regulated in MCF-7 cells. C. officinalis polysaccharides exhibited similar effects except for OCT4 that was up-regulated in MDA-MB-231 cells. Significant suppression of Cyclin D1 gene expression was noted in MDA-MB-231 and MCF-7 cells treated with P. capillacea or C. officinalis polysaccharides. β-catenin and c-Myc genes were significantly down-regulated in MDA-MB-231 cells treated with C. officinalis and P. capillacea polysaccharides, respectively, while being up-regulated in MCF-7 cells treated with either of them. Additionally, P. capillacea and C. officinalis polysaccharides significantly down-regulated Hes1 gene in MCF-7 cells despite increasing Notch1 gene expression level. However, significant down-regulation of Notch1 gene was observed in MDA-MB-231 cells treated with P. capillacea polysaccharides. CONCLUSION Collectively, this study provides evidence for the effectiveness of P. capillacea and C. officinalis polysaccharides in targeting BCSCs through interfering with substantial signaling pathways contributing to their functionality.
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Affiliation(s)
- Hebatallah G Hafez
- Hormones Department, Medical Research Division, National Research Centre, Dokki, Giza, Egypt
| | - Rafat M Mohareb
- Chemistry Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Sohair M Salem
- Molecular Genetics and Enzymology Department, National Research Centre, Dokki, Giza, Egypt
| | - Azza A Matloub
- Department of Pharmacognosy, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza, Egypt
| | - Emad F Eskander
- Hormones Department, Medical Research Division, National Research Centre, Dokki, Giza, Egypt
| | - Hanaa H Ahmed
- Hormones Department, Medical Research Division, National Research Centre, Dokki, Giza, Egypt
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16
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Salinas-Jazmín N, Rosas-Cruz A, Velasco-Velázquez M. Reporter gene systems for the identification and characterization of cancer stem cells. World J Stem Cells 2021; 13:861-876. [PMID: 34367481 PMCID: PMC8316869 DOI: 10.4252/wjsc.v13.i7.861] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/19/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) are tumor cells that share functional characteristics with normal and embryonic stem cells. CSCs have increased tumor-initiating capacity and metastatic potential and lower sensitivity to chemo- and radiotherapy, with important roles in tumor progression and the response to therapy. Thus, a current goal of cancer research is to eliminate CSCs, necessitating an adequate phenotypic and functional characterization of CSCs. Strategies have been developed to identify, enrich, and track CSCs, many of which distinguish CSCs by evaluating the expression of surface markers, the initiation of specific signaling pathways, and the activation of master transcription factors that control stemness in normal cells. We review and discuss the use of reporter gene systems for identifying CSCs. Reporters that are under the control of aldehyde dehydrogenase 1A1, CD133, Notch, Nanog homeobox, Sex-determining region Y-box 2, and POU class 5 homeobox can be used to identify CSCs in many tumor types, track cells in real time, and screen for drugs. Thus, reporter gene systems, in combination with in vitro and in vivo functional assays, can assess changes in the CSCs pool. We present relevant examples of these systems in the evaluation of experimental CSCs-targeting therapeutics, demonstrating their value in CSCs research.
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Affiliation(s)
- Nohemí Salinas-Jazmín
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Arely Rosas-Cruz
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Marco Velasco-Velázquez
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
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17
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Abu-Halima M, Becker LS, Ayesh BM, Baus SL, Hamza A, Fischer U, Hammadeh M, Keller A, Meese E. Characterization of micro-RNA in women with different ovarian reserve. Sci Rep 2021; 11:13351. [PMID: 34172798 PMCID: PMC8233349 DOI: 10.1038/s41598-021-92901-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 06/08/2021] [Indexed: 12/11/2022] Open
Abstract
Women undergoing infertility treatment are routinely subjected to one or more tests of ovarian reserve. Therefore, an adequate assessment of the ovarian reserve is necessary for the treatment. In this study, we aimed to characterize the potential role of microRNAs (miRNAs) as biomarkers for women with different ovarian reserves. A total of 159 women were recruited in the study and classified according to their anti-Müllerian hormone (AMH) level into three groups: (1) low ovarian reserve (LAMH, n = 39), (2) normal ovarian reserve (NAMH, n = 80), and (3) high ovarian reserve (HAMH, n = 40). SurePrint Human miRNA array screening and reverse transcription-quantitative PCR (RT-qPCR) were respectively employed to screen and validate the miRNA abundance level in the three tested groups. Compared with NAMH, the abundance level of 34 and 98 miRNAs was found to be significantly altered in LAMH and HAMH, respectively. The abundance level of miRNAs was further validated by RT-qPCR in both, the screening samples as well as in an independent set of validation samples. The abundance levels of the validated miRNAs were significantly correlated with the AMH level. The best AUC value for the prediction of the increase and decrease in the AMH level was obtained for the miR-100-5p and miR-21-5p, respectively. The level of miRNAs abundance correlates with the level of AMH, which may serve as a tool for identifying women with a different ovarian reserve and may help to lay the ground for the development of novel diagnostic approaches.
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Affiliation(s)
- Masood Abu-Halima
- Institute of Human Genetics, Saarland University, 66421, Homburg, Saar, Germany.
| | - Lea Simone Becker
- Institute of Human Genetics, Saarland University, 66421, Homburg, Saar, Germany
| | - Basim M Ayesh
- Department of Laboratory Medical Sciences, Alaqsa University, Gaza, Palestine
| | - Simona Lucia Baus
- Department of Obstetrics and Gynecology, Saarland University, 66421, Homburg, Saar, Germany
| | - Amer Hamza
- Department of Obstetrics and Gynecology, Saarland University, 66421, Homburg, Saar, Germany.,Kantonspital Baden, Im Ergel 1, 5400, Baden, Switzerland
| | - Ulrike Fischer
- Institute of Human Genetics, Saarland University, 66421, Homburg, Saar, Germany
| | - Mohamad Hammadeh
- Department of Obstetrics and Gynecology, Saarland University, 66421, Homburg, Saar, Germany
| | - Andreas Keller
- Chair for Clinical Bioinformatics, Saarland University, 66123, Saarbruecken, Germany
| | - Eckart Meese
- Institute of Human Genetics, Saarland University, 66421, Homburg, Saar, Germany
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18
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Králíčková M, Vetvicka V, Fiala L, Laganà AS, Garzon S. The Search for Biomarkers in Endometriosis: a Long and Windy Road. Reprod Sci 2021; 29:1667-1673. [PMID: 34159571 DOI: 10.1007/s43032-021-00668-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 06/11/2021] [Indexed: 01/29/2023]
Abstract
Endometriosis is a complex and chronic estrogen-dependent disease, affecting a significant proportion of women of reproductive age. Despite the long interest and extensive research, the pathogenesis of the disease is still debated. Although available non-invasive diagnostic methods have adequate accuracy, an invasive approach by laparoscopy is often necessary to obtain histological confirmation. In this scenario, the search for an accurate, reliable, cost-effective, clinically applicable non-invasive biomarker plays a crucial role in a potentially early diagnosis and, in this way, shape the future management of the disease. Considering these elements, the current review aims to summarize the most significant and novel results about biomarkers for the diagnosis and follow-up of women affected by endometriosis.
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Affiliation(s)
- Milena Králíčková
- Department of Histology and Embryology, Faculty of Medicine, Charles University, Pilsen, Czech Republic.,Department of Obstetrics and Gynecology, University Hospital, Faculty of Medicine, Charles University, Pilsen, Czech Republic.,Biomedical Centre, Faculty of Medicine in Plzen, Charles University, Pilsen, Czech Republic
| | - Vaclav Vetvicka
- Department of Pathology, University of Louisville, Louisville, KY, USA
| | - Luděk Fiala
- Institute of Sexology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Antonio Simone Laganà
- Department of Obstetrics and Gynecology, "Filippo Del Ponte" Hospital, University of Insubria, Piazza Biroldi 1, 21100, Varese, Italy.
| | - Simone Garzon
- Department of Obstetrics and Gynecology, "Filippo Del Ponte" Hospital, University of Insubria, Piazza Biroldi 1, 21100, Varese, Italy.,Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, Verona, Italy
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19
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Cao J, Wu D, Wu G, Wang Y, Ren T, Wang Y, Lv Y, Sun W, Wang J, Qian C, He L, Yang K, Li H, Gu H. USP35, regulated by estrogen and AKT, promotes breast tumorigenesis by stabilizing and enhancing transcriptional activity of estrogen receptor α. Cell Death Dis 2021; 12:619. [PMID: 34131114 PMCID: PMC8206120 DOI: 10.1038/s41419-021-03904-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 06/04/2021] [Accepted: 06/07/2021] [Indexed: 12/15/2022]
Abstract
Although endocrine therapies targeting estrogen receptor α (ERα) are effective in managing ER positive (+) breast cancer, many patients have primary resistance or develop resistance to endocrine therapies. In addition, ER+ breast cancer with PIK3CA activating mutations and 11q13-14 amplification have poor survival with unclear mechanism. We uncovered that higher expression of deubiquitinase USP35, located in 11q14.1, was associated with ER+ breast cancer and poor survival. Estrogen enhanced USP35 protein levels by downregulating USP35-targeting miRNA-140-3p and miRNA-26a-5p. USP35 promoted the growth of ER+ breast cancer in vitro and in vivo, and reduced the sensitivity of ER+ breast cancer cells to endocrine therapies such as tamoxifen and fulvestrant. Mechanistically, USP35 enhanced ERα stability by interacting and deubiquitinating ERα, and transcriptional activity of ERα by interacting with ERα in DNA regions containing estrogen response element. In addition, AKT, a key effector of PI3K, phosphorylated USP35 at Serine613, which promoted USP35 nuclear translocation, ERα transcriptional activity, and the growth of ER+ breast cancer cells. Our data indicate that USP35 and ERα form a positive feedback loop in promoting the growth of ER+ breast cancer. USP35 may be a treatment target for ER+ breast cancer with endocrine resistance or with PIK3CA mutations or hyperactivation of the PI3K pathway.
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Affiliation(s)
- Jiawei Cao
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Du Wu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Guang Wu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Yaqi Wang
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Tianhao Ren
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Yang Wang
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Yingshuai Lv
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Wei Sun
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Jieyi Wang
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Changrui Qian
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Licai He
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Kaiyan Yang
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Hongzhi Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
| | - Haihua Gu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
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20
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García-Venzor A, Mandujano-Tinoco EA, Ruiz-Silvestre A, Sánchez JM, Lizarraga F, Zampedri C, Melendez-Zajgla J, Maldonado V. lncMat2B regulated by severe hypoxia induces cisplatin resistance by increasing DNA damage repair and tumor-initiating population in breast cancer cells. Carcinogenesis 2021; 41:1485-1497. [PMID: 32710610 DOI: 10.1093/carcin/bgaa078] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 07/14/2020] [Accepted: 07/22/2020] [Indexed: 12/15/2022] Open
Abstract
Multicellular tumor spheroids (MCTSs) constitute a three-dimensional culture system that recapitulates the in vivo tumor microenvironment. Tumor cells cultured as MCTSs present antineoplastic resistance due to the effect of microenvironmental signals acting upon them. In this work, we evaluated the biological function of a new microenvironment-regulated long non-coding RNA, lncMat2B, in breast cancer. In MCTSs, the expression of lncMat2B presented an increase and a zonal heterogeneity, as it was expressed principally in quiescent cells of hypoxic regions of the MCTSs. As expected, functional assays supported the role of severe hypoxia in the regulation of lncMat2B. Moreover, gain- and loss-of-function assays using a transcriptional silencing CRISPR/Cas9 system and gBlock revealed that lncMAT2B regulates the tumor-initiating phenotype. Interestingly, lncMat2B is overexpressed in a cisplatin-resistant MCF-7 cell line, and its ectopic expression in wild type MCF-7 cells increased survival to cisplatin exposure by reducing DNA damage and reactive oxygen species accumulation. lncMAT2B is a possible link between severe hypoxia, tumor-initiating phenotype and drug resistance in breast cancer cells.
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Affiliation(s)
| | - Edna Ayerim Mandujano-Tinoco
- Basic Research, Instituto Nacional de Medicina Genómica, CDMX, México, México.,Tejido Conjuntivo, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra, CDMX, México, México
| | | | - José Manuel Sánchez
- Basic Research, Instituto Nacional de Medicina Genómica, CDMX, México, México
| | - Floria Lizarraga
- Basic Research, Instituto Nacional de Medicina Genómica, CDMX, México, México
| | - Cecilia Zampedri
- Basic Research, Instituto Nacional de Medicina Genómica, CDMX, México, México
| | | | - Vilma Maldonado
- Basic Research, Instituto Nacional de Medicina Genómica, CDMX, México, México
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21
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Lv L, Shi Y, Wu J, Li G. Nanosized Drug Delivery Systems for Breast Cancer Stem Cell Targeting. Int J Nanomedicine 2021; 16:1487-1508. [PMID: 33654398 PMCID: PMC7914063 DOI: 10.2147/ijn.s282110] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 02/10/2021] [Indexed: 01/15/2023] Open
Abstract
Breast cancer stem cells (BCSCs), also known as breast cancer initiating cells, are reported to be responsible for the initiation, progression, therapeutic resistance, and relapse of breast cancer. Conventional therapeutic agents mainly kill the bulk of breast tumor cells and fail to eliminate BCSCs, even enhancing the fraction of BCSCs in breast tumors sometimes. Therefore, it is essential to develop specific and effective methods of eliminating BCSCs that will enhance the efficacy of killing breast tumor cells and thereby, increase the survival rates and quality of life of breast cancer patients. Despite the availability of an increasing number of anti-BCSC agents, their clinical translations are hindered by many issues, such as instability, low bioavailability, and off-target effects. Nanosized drug delivery systems (NDDSs) have the potential to overcome the drawbacks of anti-BCSC agents by providing site-specific delivery and enhancing of the stability and bioavailability of the delivered agents. In this review, we first briefly introduce the strategies and agents used against BCSCs and then highlight the mechanism of action and therapeutic efficacy of several state-of-the-art NDDSs that can be used to treat breast cancer by eliminating BCSCs.
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Affiliation(s)
- Li Lv
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, People's Republic of China
| | - Yonghui Shi
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, People's Republic of China.,Department of Pharmacy, Zengcheng District People's Hospital of Guangzhou, Guangzhou, 511300, Guangdong, People's Republic of China
| | - Junyan Wu
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, People's Republic of China
| | - Guocheng Li
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, People's Republic of China
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22
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Effects of miRNA-140 on the Growth and Clinical Prognosis of SMMC-7721 Hepatocellular Carcinoma Cell Line. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6638915. [PMID: 33628799 PMCID: PMC7884124 DOI: 10.1155/2021/6638915] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/27/2020] [Accepted: 01/07/2021] [Indexed: 12/15/2022]
Abstract
Background A growing number of studies have suggested that microRNAs exert an essential role in the development and occurrence of multiple tumours and act as crucial regulators in various biological processes. However, the expression and function of miRNA-140 in hepatocellular carcinoma (HCC) cells are not yet adequately identified and manifested. Methods The expression of miRNA-140 was determined in HCC tissues and adjacent nontumour tissues by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier survival analysis and Cox regression analysis were performed to explore the correlation between miRNA-140 expression level and the survival rate of patients with HCC. Additionally, overexpression experiments were conducted to investigate the biological role of miRNA-140 in HCC cells. Bioinformatics was used to predict the related target genes and pathways of miRNA-140. Results QRT-PCR results signified that the expression level of miRNA-140 in HCC was lower than that of adjacent normal tissues (P < 0.0001). Compared with the control group, the SMMC-7721 HCC cells in the miRNA-140 mimic group had a decrease in proliferation, migration, and invasion (P < 0.05), whereas those in the miRNA-140 inhibitor group had an increase in proliferation, migration, and invasion (P < 0.05). Cell cycle arrest occurred in the G0/1 phase. Prognosis analysis showed that the expression level of miRNA-140 was not related to the prognosis of HCC. Furthermore, the Kaplan-Meier test revealed that patients with lower miRNA-140 expression levels in liver cancer tissue had significantly shorter disease-free survival (DFS, P = 0.004) and overall survival (OS) times (P = 0.010) after hepatectomy. Cox regression analysis further indicated that miRNA-140 was an independent risk factor that may affect the DFS (P = 0.004) and OS times (P = 0.014) of patients after hepatectomy. Our results suggested that miRNA-140 might be a crucial regulator involved in the HCC progression and is thus considered a potential prognostic biomarker and therapeutic target for HCC.
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23
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Zheng Q, Zhang M, Zhou F, Zhang L, Meng X. The Breast Cancer Stem Cells Traits and Drug Resistance. Front Pharmacol 2021; 11:599965. [PMID: 33584277 PMCID: PMC7876385 DOI: 10.3389/fphar.2020.599965] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/17/2020] [Indexed: 12/13/2022] Open
Abstract
Drug resistance is a major challenge in breast cancer (BC) treatment at present. Accumulating studies indicate that breast cancer stem cells (BCSCs) are responsible for the BC drugs resistance, causing relapse and metastasis in BC patients. Thus, BCSCs elimination could reverse drug resistance and improve drug efficacy to benefit BC patients. Consequently, mastering the knowledge on the proliferation, resistance mechanisms, and separation of BCSCs in BC therapy is extremely helpful for BCSCs-targeted therapeutic strategies. Herein, we summarize the principal BCSCs surface markers and signaling pathways, and list the BCSCs-related drug resistance mechanisms in chemotherapy (CT), endocrine therapy (ET), and targeted therapy (TT), and display therapeutic strategies for targeting BCSCs to reverse drug resistance in BC. Even more importantly, more attention should be paid to studies on BCSC-targeted strategies to overcome the drug resistant dilemma of clinical therapies in the future.
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Affiliation(s)
- Qinghui Zheng
- Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Mengdi Zhang
- MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Fangfang Zhou
- Institutes of Biology and Medical Science, Soochow University, Suzhou, China
| | - Long Zhang
- MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Xuli Meng
- Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China
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24
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Porter L, McCaughan F. SOX2 and squamous cancers. Semin Cancer Biol 2020; 67:154-167. [PMID: 32905832 DOI: 10.1016/j.semcancer.2020.05.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 11/10/2019] [Accepted: 05/09/2020] [Indexed: 12/20/2022]
Abstract
SOX2 is a pleiotropic nuclear transcription factor with major roles in stem cell biology and in development. Over the last 10 years SOX2 has also been implicated as a lineage-specific oncogene, notably in squamous carcinomas but also neurological tumours, particularly glioblastoma. Squamous carcinomas (SQCs) comprise a common group of malignancies for which there are no targeted therapeutic interventions. In this article we review the molecular epidemiological and laboratory evidence linking SOX2 with squamous carcinogenesis, explore in detail the multifaceted impact of SOX2 in SQC, describe areas of uncertainty and highlight areas for potential future research.
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Affiliation(s)
- Linsey Porter
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge, CB2 0QQ, United Kingdom
| | - Frank McCaughan
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge, CB2 0QQ, United Kingdom.
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25
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Wang Y, Chen J, Wang X, Wang K. miR-140-3p inhibits bladder cancer cell proliferation and invasion by targeting FOXQ1. Aging (Albany NY) 2020; 12:20366-20379. [PMID: 33098639 PMCID: PMC7655201 DOI: 10.18632/aging.103828] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 07/07/2020] [Indexed: 12/14/2022]
Abstract
Upregulation of the forkhead box protein Q1 (FOXQ1) promotes bladder cancer (BCa) cell growth and metastasis. Factors affecting FOXQ1 expression at the post-transcriptional level have not yet been identified. We performed cell proliferation, cell invasion, and tumorigenesis experiments to characterize the relationship between FOXQ1 and miR-140-3p. We found that FOXQ1 was significantly upregulated and miR-140-3p was significantly downregulated in BCa tissues. We also identified an inverse correlation between miR-140-3p and FOXQ1 expression in BCa tissues. Overexpression of miR-140-3p reduced FOXQ1 expression, suppressing BCa cell proliferation and invasion. A luciferase assay confirmed that miR-140-3p bound to the 3’-UTR of FOXQ1 mRNA and decreased its expression. In addition, we used a mouse xenograft model to demonstrate that miR-140-3p suppressed tumor cell growth in vivo. Our findings suggest that miR-140-3p suppresses BCa cell proliferation and invasion by directly decreasing FOXQ1 expression.
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Affiliation(s)
- Yuan Wang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Junwen Chen
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xia Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Kefeng Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
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26
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Chen B, Ye P, Chen Y, Liu T, Cha JH, Yan X, Yang WH. Involvement of the Estrogen and Progesterone Axis in Cancer Stemness: Elucidating Molecular Mechanisms and Clinical Significance. Front Oncol 2020; 10:1657. [PMID: 33014829 PMCID: PMC7498570 DOI: 10.3389/fonc.2020.01657] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 07/28/2020] [Indexed: 12/21/2022] Open
Abstract
Estrogen and progesterone regulate the growth and development of human tissues, including the reproductive system and breasts, through estrogen and progesterone receptors, respectively. These receptors are also important indicators for the clinical prognosis of breast cancer and various reproductive cancers. Many studies have reported that cancer stem cells (CSCs) play a key role in tumor initiation, progression, metastasis, and recurrence. Although the role of estrogen and progesterone in human organs and various cancers has been studied, the molecular mechanisms underlying the action of these hormones on CSCs remain unclear. Therefore, further elucidation of the effects of estrogen and progesterone on CSCs should provide a new direction for developing pertinent therapies. In this review, we summarize the current knowledge on the estrogen and progesterone axis involved in cancer stemness and discuss potential therapeutic strategies to inhibit CSCs by targeting relevant pathways.
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Affiliation(s)
- Bi Chen
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Peng Ye
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Yeh Chen
- Institute of New Drug Development, China Medical University, Taichung, Taiwan
| | - Tong Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.,The Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin, China
| | - Jong-Ho Cha
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, South Korea
| | - Xiuwen Yan
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Wen-Hao Yang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
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27
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Shi S, Li H. Overexpressed microRNA-140 inhibits pulmonary fibrosis in interstitial lung disease via the Wnt signaling pathway by downregulating osteoglycin. Am J Physiol Cell Physiol 2020; 319:C895-C905. [PMID: 32755451 DOI: 10.1152/ajpcell.00479.2019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Interstitial lung disease (ILD) comprises of a group of diffuse parenchymal lung disorders that are strongly associated with substantial morbidity and mortality. Previous studies have highlighted the therapeutic significance of microRNAs (miRNAs) in the treatment of ILD. Thus this study aims to investigate the mechanism by which miR-140 affects ILD through the regulation of osteoglycin (OGN)-Wnt signaling pathway. Gene expression microarray analysis was performed to screen ILD-related differentially expressed genes and miRNAs that regulated OGN. The targeting relationship between miR-140 and OGN was verified. Ectopic expression and knockdown experiments were performed in lung fibroblasts to explore the potential mechanism of action of miR-140 in ILD. The expression of miR-140, OGN, as well as Wnt- and pulmonary fibrosis-related factors, was determined by RT-qPCR and Western blot analysis. In addition, cell viability and apoptosis were examined. OGN was found to be negatively regulated by miR-140. The ectopic expression of miR-140 and OGN silencing resulted in increased lung fibroblast apoptosis and Wnt3a expression, along with reduced proliferation and pulmonary fibrosis. Our results also revealed that miR-140 decreased OGN, thereby activating the Wnt signaling pathway, which was observed to further affect the expression of genes associated with the progression of pulmonary fibrosis in mouse fibroblasts. In conclusion, the key findings from our study suggest that overexpressed miR-140 suppresses ILD development via the Wnt signaling pathway by downregulating OGN, which could potentially be used as a therapeutic target for ILD.
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Affiliation(s)
- Songtao Shi
- Department of Chest Surgery, Linyi People's Hospital, Linyi, People's Republic of China
| | - Hongli Li
- Operation Room, Linyi People's Hospital, Linyi, People's Republic of China
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28
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Functional characterization of SOX2 as an anticancer target. Signal Transduct Target Ther 2020; 5:135. [PMID: 32728033 PMCID: PMC7391717 DOI: 10.1038/s41392-020-00242-3] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/01/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023] Open
Abstract
SOX2 is a well-characterized pluripotent factor that is essential for stem cell self-renewal, reprogramming, and homeostasis. The cellular levels of SOX2 are precisely regulated by a complicated network at the levels of transcription, post-transcription, and post-translation. In many types of human cancer, SOX2 is dysregulated due to gene amplification and protein overexpression. SOX2 overexpression is associated with poor survival of cancer patients. Mechanistically, SOX2 promotes proliferation, survival, invasion/metastasis, cancer stemness, and drug resistance. SOX2 is, therefore, an attractive anticancer target. However, little progress has been made in the efforts to discover SOX2 inhibitors, largely due to undruggable nature of SOX2 as a transcription factor. In this review, we first briefly introduced SOX2 as a transcription factor, its domain structure, normal physiological functions, and its involvement in human cancers. We next discussed its role in embryonic development and stem cell-renewal. We then mainly focused on three aspects of SOX2: (a) the regulatory mechanisms of SOX2, including how SOX2 level is regulated, and how SOX2 cross-talks with multiple signaling pathways to control growth and survival; (b) the role of SOX2 in tumorigenesis and drug resistance; and (c) current drug discovery efforts on targeting SOX2, and the future perspectives to discover specific SOX2 inhibitors for effective cancer therapy.
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Sammarco A, Finesso G, Zanetti R, Ferro S, Rasotto R, Caliari D, Goldschmidt MH, Orvieto E, Castagnaro M, Cavicchioli L, Zappulli V. Biphasic Feline Mammary Carcinomas Including Carcinoma and Malignant Myoepithelioma. Vet Pathol 2020; 57:377-387. [PMID: 32100640 DOI: 10.1177/0300985820908792] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Feline mammary tumors are usually malignant and aggressive carcinomas. Most cases are simple monophasic carcinomas (1 epithelial population), and additional phenotyping is usually not needed. In this study, we describe 10 malignant mammary tumors from 9 female cats that had unusual histomorphology: they appeared biphasic, with 2 distinct cell populations. Initially, they were morphologically diagnosed as either carcinosarcoma (1/10) or malignant pleomorphic tumor (9/10) of the mammary gland, as the latter did not match any previously described histological subtype. Immunohistochemistry (IHC) was performed for pancytokeratin, cytokeratins 8 and 18, cytokeratin 14, cytokeratins 5 and 6, vimentin, p63, calponin, alpha-smooth muscle actin, Ki-67, ERBB2, estrogen receptor alpha, and progesterone receptor. In 7 of 10 cases, the biphasic nature was confirmed and, on the basis of the IHC results, they were classified as carcinoma and malignant myoepithelioma (4/10), ductal carcinoma (1/10), and carcinosarcoma (2/10). The other 3 of 10 cases were monophasic based on IHC. In the cases of carcinoma and malignant myoepithelioma, the malignant myoepithelial cells were 100% positive for vimentin (4/4) and variably positive for p63, calponin, and cytokeratins (4/4). These findings show that, although rare, biphasic mammary carcinomas do occur in cats. In dogs and humans, tumors composed of malignant epithelial and myoepithelial cells have a less aggressive behavior than certain simple carcinomas, and therefore, their identification might also be clinically significant in the cat.
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Affiliation(s)
- Alessandro Sammarco
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell'Università, Legnaro, Padua, Italy
| | - Giovanni Finesso
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell'Università, Legnaro, Padua, Italy
- National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Rossella Zanetti
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell'Università, Legnaro, Padua, Italy
| | - Silvia Ferro
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell'Università, Legnaro, Padua, Italy
| | | | | | - Michael H Goldschmidt
- Laboratory of Pathology and Toxicology, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA
| | - Enrico Orvieto
- Pathology Department ULSS5 Polesana, Viale Tre Martiri, Rovigo, Italy
| | - Massimo Castagnaro
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell'Università, Legnaro, Padua, Italy
| | - Laura Cavicchioli
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell'Università, Legnaro, Padua, Italy
| | - Valentina Zappulli
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell'Università, Legnaro, Padua, Italy
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30
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Vaidya M, Sugaya K. Differential sequences and single nucleotide polymorphism of exosomal SOX2 DNA in cancer. PLoS One 2020; 15:e0229309. [PMID: 32092088 PMCID: PMC7039433 DOI: 10.1371/journal.pone.0229309] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 02/03/2020] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common form of brain cancer, with an average life expectancy of fewer than two years post-diagnosis. We have previously reported that cancer cell originated exosomes, including GBM, have NANOG and NANOGP8 DNA associated with them. The exosomal NANOG DNA has certain differences as compared to its normal counterpart that are of immense importance as a potential cancer biomarker. NANOG has been demonstrated to play an essential role in the maintenance of embryonic stem cells, and its pseudogene, NANOGP8, is suggested to promote the cancer stem cell phenotype. Similarly, SOX2 is another stemness gene highly expressed in cancer stem cells with an intimate involvement in GBM progression and metastasis as well as promotion of tumorigenicity in Neuroblastoma (NB). Since exosomes are critical in intercellular communication with a role in dissipating hallmark biomolecules responsible for cancer, we conducted a detailed analysis of the association of the SOX2 gene with exosomes whose sequence modulations with further research and appropriate sample size can help to identify diagnostic markers for cancer. We have detected SOX2 DNA associated with exosomes and have identified some of the SNPs and nucleotide variations in the sequences from a GBM and SH-SY5Y sample. Although a further systematic investigation of exosomal DNA from GBM and NB patient's blood is needed, finding of SOX2 DNA in exosomes in the current study may have value in clinical research. SOX2 is known to be misregulated in cancer cells by changes in miRNA function, such as SNPs in the binding sites. Our finding of cancer-specific SNPs in exosomal SOX2 DNA sequence may reflect those changes in the cancer stem cells as well as cancer cells. A series of our study on embryonic stem cell gene analysis in exosomal DNA may lead to a minimally invasive exosome-based diagnosis, and give us a key in understanding the mechanisms of cancer formation, progression, and metastasis.
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Affiliation(s)
- Manjusha Vaidya
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America
| | - Kiminobu Sugaya
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America
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31
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Yang F, Chen S, He S, Huo Q, Hu Y, Xie N. YB-1 interplays with ERα to regulate the stemness and differentiation of ER-positive breast cancer stem cells. Theranostics 2020; 10:3816-3832. [PMID: 32206124 PMCID: PMC7069074 DOI: 10.7150/thno.41014] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 01/21/2020] [Indexed: 02/06/2023] Open
Abstract
Background: Some stemness-associated transcription factors consistently play essential roles in the maintenance of pluripotency or induce the differentiation of cancer stem cells (CSCs). However, the regulatory mechanism of CSC stemness mediated by transcription factors has not been extensively explored. Here, we show that two transcription factors (YB-1 and ERα), which are simultaneously highly expressed in estrogen receptor (ER)-positive CSCs, interact with each other to regulate the stemness and differentiation of ER-positive CSCs. Methods: The expression of YB-1 was examined in ER-positive CSCs and patient specimens. Western blot, real-time PCR, cell viability analysis, tumorsphere formation assay and subcutaneous tumorigenesis assays were used to study the stemness functions of YB-1 and ERα in CSCs. The relationship between YB-1 and ERα in cells was studied by promoter activity analysis, the electrophoretic mobility shift assay (EMSA) and the Co-IP assay. The mechanisms and functional significance of YB-1 in the sensitivity of CSCs to tamoxifen were further investigated with both in vitro and in vivo models. Results: YB-1 was aberrantly upregulated in the cancerous tissue of ER-positive breast cancer patients and in CSCs. Knockdown of YB-1 in ER-positive CSCs significantly inhibited cell stemness and induced differentiation, and the expression of YB-1 could be regulated by estrogen signaling and ERα in ER-positive breast CSCs. The Co-IP results showed that YB-1 interacted directly with ERα specifically in ER-positive non-CSCs and that YB-1 induced ERα degradation by ubiquitination via direct interaction in differentiated cells. Cell differentiation induced by FBS could inhibit YB-1 phosphorylation and promote YB-1 protein transfer from the nucleus to the cytoplasm. Moreover, cell differentiation induced by targeting inhibited the expression of YB-1 in ER-positive CSCs, which increased the sensitivity of cells to tamoxifen in vitro and in vivo. Conclusion: The ERα/YB-1 axis has an important role in the regulation of ER-positive breast cancer stemness. The dephosphorylation of YB-1 and the interaction between YB-1 and ERα may be the switch that initiates the differentiation of ER-positive CSCs. Targeting YB-1 to sensitize ER-positive CSCs to antiestrogen therapy might represent a new therapeutic strategy that warrants further exploration.
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Affiliation(s)
- Fan Yang
- Biobank, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, People's Republic of China
- Shenzhen institute of advanced technology, Chinese academy of sciences, Shenzhen 518035, People's Republic of China
| | - Siqi Chen
- Biobank, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, People's Republic of China
| | - Shengnan He
- Biobank, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, People's Republic of China
| | - Qin Huo
- Biobank, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, People's Republic of China
| | - Ye Hu
- Biobank, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, People's Republic of China
| | - Ni Xie
- Biobank, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, People's Republic of China
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Sp N, Kang DY, Jo ES, Rugamba A, Kim WS, Park YM, Hwang DY, Yoo JS, Liu Q, Jang KJ, Yang YM. Tannic Acid Promotes TRAIL-Induced Extrinsic Apoptosis by Regulating Mitochondrial ROS in Human Embryonic Carcinoma Cells. Cells 2020; 9:E282. [PMID: 31979292 PMCID: PMC7072125 DOI: 10.3390/cells9020282] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 01/17/2020] [Accepted: 01/22/2020] [Indexed: 12/12/2022] Open
Abstract
: Human embryonic carcinoma (EC; NCCIT) cells have self-renewal ability and pluripotency. Cancer stem cell markers are highly expressed in NCCIT cells, imparting them with the pluripotent nature to differentiate into other cancer types, including breast cancer. As one of the main cancer stem cell pathways, Wnt/β-catenin is also overexpressed in NCCIT cells. Thus, inhibition of these pathways defines the ability of a drug to target cancer stem cells. Tannic acid (TA) is a natural polyphenol present in foods, fruits, and vegetables that has anti-cancer activity. Through Western blotting and PCR, we demonstrate that TA inhibits cancer stem cell markers and the Wnt/β-catenin signaling pathway in NCCIT cells and through a fluorescence-activated cell sorting analysis we demonstrated that TA induces sub-G1 cell cycle arrest and apoptosis. The mechanism underlying this is the induction of mitochondrial reactive oxygen species (ROS) (mROS), which then induce the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated extrinsic apoptosis pathway instead of intrinsic mitochondrial apoptosis pathway. Moreover, ribonucleic acid sequencing data with TA in NCCIT cells show an elevation in TRAIL-induced extrinsic apoptosis, which we confirm by Western blotting and real-time PCR. The induction of human TRAIL also proves that TA can induce extrinsic apoptosis in NCCIT cells by regulating mROS.
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Affiliation(s)
- Nipin Sp
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Dong Young Kang
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Eun Seong Jo
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Alexis Rugamba
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Wan Seop Kim
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Yeong-Min Park
- Department of Immunology, School of Medicine, Konkuk University, Chungju 27478, Korea;
| | - Dae-Yong Hwang
- Department of Surgery, School of Medicine, Konkuk University, Seoul 05029, Korea;
| | - Ji-Seung Yoo
- Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-0808, Japan;
| | - Qing Liu
- Jilin Green food Engineering Research Institute, Changchun 130000, Jilin, China;
| | - Kyoung-Jin Jang
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Young Mok Yang
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
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MicroRNAs Contribute to Breast Cancer Invasiveness. Cells 2019; 8:cells8111361. [PMID: 31683635 PMCID: PMC6912645 DOI: 10.3390/cells8111361] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/25/2019] [Accepted: 10/28/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer statistics in 2018 highlight an 8.6 million incidence in female cancers, and 4.2 million cancer deaths globally. Moreover, breast cancer is the most frequent malignancy in females and twenty percent of these develop metastasis. This provides only a small chance for successful therapy, and identification of new molecular markers for the diagnosis and prognostic prediction of metastatic disease and development of innovative therapeutic molecules are therefore urgently required. Differentially expressed microRNAs (miRNAs) in cancers cause multiple changes in the expression of the tumorigenesis-promoting genes which have mostly been investigated in breast cancers. Herein, we summarize recent data on breast cancer-specific miRNA expression profiles and their participation in regulating invasive processes, in association with changes in cytoskeletal structure, cell-cell adhesion junctions, cancer cell-extracellular matrix interactions, tumor microenvironments, epithelial-to-mesenchymal transitions and cancer cell stem abilities. We then focused on the epigenetic regulation of individual miRNAs and their modified interactions with other regulatory genes, and reviewed the function of miRNA isoforms and exosome-mediated miRNA transfer in cancer invasiveness. Although research into miRNA’s function in cancer is still ongoing, results herein contribute to improved metastatic cancer management.
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34
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Giovannelli P, Di Donato M, Galasso G, Di Zazzo E, Medici N, Bilancio A, Migliaccio A, Castoria G. Breast cancer stem cells: The role of sex steroid receptors. World J Stem Cells 2019; 11:594-603. [PMID: 31616537 PMCID: PMC6789191 DOI: 10.4252/wjsc.v11.i9.594] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 05/06/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023] Open
Abstract
Breast cancer (BC) is the most common cancer among women, and current available therapies often have high success rates. Nevertheless, BC might acquire drug resistance and sometimes relapse. Current knowledge about the most aggressive forms of BC points to the role of specific cells with stem properties located within BC, the so-called “BC stem cells” (BCSCs). The role of BCSCs in cancer formation, growth, invasiveness, therapy resistance and tumor recurrence is becoming increasingly clear. The growth and metastatic properties of BCSCs are regulated by different pathways, which are only partially known. Sex steroid receptors (SSRs), which are involved in BC etiology and progression, promote BCSC proliferation, dedifferentiation and migration. However, in the literature, there is incomplete information about their roles. Particularly, there are contrasting conclusions about the expression and role of the classical BC hormonal biomarkers, such as estrogen receptor alpha (ERα), together with scant, albeit promising information concerning ER beta (ERβ) and androgen receptor (AR) properties that control different transduction pathways in BCSCs. In this review, we will discuss the role that SRs expressed in BCSCs play to BC progression and recurrence and how these findings have opened new therapeutic possibilities.
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Affiliation(s)
- Pia Giovannelli
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Marzia Di Donato
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Giovanni Galasso
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Erika Di Zazzo
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Nicola Medici
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Antonio Bilancio
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Antimo Migliaccio
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Gabriella Castoria
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
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Mehta GA, Khanna P, Gatza ML. Emerging Role of SOX Proteins in Breast Cancer Development and Maintenance. J Mammary Gland Biol Neoplasia 2019; 24:213-230. [PMID: 31069617 PMCID: PMC6790170 DOI: 10.1007/s10911-019-09430-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 04/21/2019] [Indexed: 12/26/2022] Open
Abstract
The SOX genes encode a family of more than 20 transcription factors that are critical regulators of embryogenesis and developmental processes and, when aberrantly expressed, have been shown to contribute to tumor development and progression in both an oncogenic and tumor suppressive role. Increasing evidence demonstrates that the SOX proteins play essential roles in multiple cellular processes that mediate or contribute to oncogenic transformation and tumor progression. In the context of breast cancer, SOX proteins function both as oncogenes and tumor suppressors and have been shown to be associated with tumor stage and grade and poor prognosis. Experimental evidence demonstrates that a subset of SOX proteins regulate critical aspects of breast cancer biology including cancer stemness and multiple signaling pathways leading to altered cell proliferation, survival, and tumor development; EMT, cell migration and metastasis; as well as other tumor associated characteristics. This review will summarize the role of SOX family members as important mediators of tumorigenesis in breast cancer, with an emphasis on the triple negative or basal-like subtype of breast cancer, as well as examine the therapeutic potential of these genes and their downstream targets.
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Affiliation(s)
- Gaurav A Mehta
- Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, CINJ 4558, New Brunswick, NJ, 08903, USA
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Pooja Khanna
- Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, CINJ 4558, New Brunswick, NJ, 08903, USA
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Michael L Gatza
- Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, CINJ 4558, New Brunswick, NJ, 08903, USA.
- Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
- Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
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MicroRNA-140 impedes DNA repair by targeting FEN1 and enhances chemotherapeutic response in breast cancer. Oncogene 2019; 39:234-247. [PMID: 31471584 DOI: 10.1038/s41388-019-0986-0] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 05/29/2019] [Accepted: 06/15/2019] [Indexed: 01/18/2023]
Abstract
An increased DNA repair capacity is associated with drug resistance and limits the efficacy of chemotherapy in breast cancers. Flap endonuclease 1 (FEN1) participates in various DNA repair pathways and contributes to cancer progression and drug resistance in chemotherapy. Inhibition of FEN1 serves as a potent strategy for cancer therapy. Here, we demonstrate that microRNA-140 (miR-140) inhibits FEN1 expression via directly binding to its 3' untranslated region, leading to impaired DNA repair and repressed breast cancer progression. Overexpression of miR-140 sensitizes breast cancer cells to chemotherapeutic agents and overcomes drug resistance in breast cancer. Notably, ectopic expression of FEN1 abates the effects of miR-140 on DNA damage and the chemotherapy response in breast cancer cells. Furthermore, the transcription factor/repressor Ying Yang 1 (YY1) directly binds to the miR-140 promoter and activates miR-140 expression, which is attenuated in doxorubicin resistance. Our results demonstrate that miR-140 acts as a tumor suppressor in breast cancer by inhibiting FEN1 to repress DNA damage repair and reveal miR-140 to be a new anti-tumorigenesis factor for adjunctive breast cancer therapy. This novel mechanism will enhance the treatment effect of chemotherapy in breast cancer.
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MicroRNA-140-5p inhibits cell proliferation, migration and promotes cell apoptosis in gastric cancer through the negative regulation of THY1-mediated Notch signaling. Biosci Rep 2019; 39:BSR20181434. [PMID: 31123165 PMCID: PMC6646234 DOI: 10.1042/bsr20181434] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 05/16/2019] [Accepted: 05/21/2019] [Indexed: 01/20/2023] Open
Abstract
Studies have highlighted the importance of microRNAs (miRs) in the development of various cancers, including gastric cancer (GC), a commonly occurring malignancy, accompanied by high recurrence and metastasis rate. The aim of the current study was to investigate the role of miR-140-5p in GC. Microarray expression profiles were initially employed to screen the differentially expressed gene related to GC, and the miR regulating the gene was predicted accordingly. The data obtained indicated that thymus cell antigen 1 (THY1) was differentially expressed in GC and confirmed to be a target gene of miR-140-5p. Poorly expressed miR-140-5p and highly expressed THY1 were observed in the GC tissues. SGC-7901 cells were treated with miR-140-5p mimic/inhibitor, siRNA against THY1 and siRNA against Notch1 in order to determine their regulatory roles in GC cell activities. The relationship of miR-140-5p, THY1 and the Notch signaling pathway was subsequently identified. Moreover, cell proliferation, migration, invasion and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), wound-healing, transwell assay and flow cytometry, respectively. The overexpression of miR-140-5p and silencing of THY1 resulted in a diminished expression of the Notch signaling pathway-related proteins, as well as inhibited proliferation, migration and invasion of GC cells, enhanced expression of pro-apoptotic proteins in addition to elevated apoptosis rate. Taken together, the present study suggests that miR-140-5p directly targets and negatively regulates THY1 expression and inhibits activation of the Notch signaling pathway, whereby the up-regulation of miR-140-5p inhibits development of GC, highlighting the promise of miR-140-5p as a potential target for GC treatment.
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Moghbeli M. Genetic and molecular biology of breast cancer among Iranian patients. J Transl Med 2019; 17:218. [PMID: 31286981 PMCID: PMC6615213 DOI: 10.1186/s12967-019-1968-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 07/04/2019] [Indexed: 02/07/2023] Open
Abstract
Abstract Background, Breast cancer (BC) is one of the leading causes of cancer related deaths in Iran. This high ratio of mortality had a rising trend during the recent years which is probably associated with late diagnosis. Main body Therefore it is critical to define a unique panel of genetic markers for the early detection among our population. In present review we summarized all of the reported significant genetic markers among Iranian BC patients for the first time, which are categorized based on their cellular functions. Conclusions This review paves the way of introducing a unique ethnic specific panel of diagnostic markers among Iranian BC patients. Indeed, this review can also clarify the genetic and molecular bases of BC progression among Iranians.
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Affiliation(s)
- Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Chen B, Xu P, Wang J, Zhang C. The role of MiRNA in polycystic ovary syndrome (PCOS). Gene 2019; 706:91-96. [PMID: 31054362 DOI: 10.1016/j.gene.2019.04.082] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 04/30/2019] [Indexed: 12/31/2022]
Abstract
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in reproductive-aged women. Clinical manifestations include hyperandrogenism, chronic anovulation, polycystic ovaries and being frequently accompanied by insulin resistance (IR) and obesity. MicroRNAs (miRNAs) are short non-coding RNAs which are involved in the regulation of gene expression at the post-transcriptional level. Altered miRNAs levels have been showed to be associated with a variety of diseases including diabetes, endometriosis and cancer. In recent years, more and more evidence suggests abnormal expression of miRNAs are detected in granulosa cells, theca cells, adipose tissue, follicular fluid, serum and peripheral blood leukocytes of women with PCOS and display vital role in the occurrence and development of PCOS. This will shed light on new strategies for the diagnosis and treatment of this syndrome. In this paper, we will review the recent research on miRNAs with respect to PCOS.
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Affiliation(s)
- Baiqi Chen
- School of Public Health, Nanchang University, Nanchang, Jiangxi 330006, People's Republic of China
| | - Ping Xu
- Second Clinical College, Nanchang University, Nanchang, Jiangxi 330006, People's Republic of China
| | - Jing Wang
- Department of Microbiology, Nanchang University, Nanchang, Jiangxi 330006, People's Republic of China
| | - Chunping Zhang
- Department of Cell Biology, School of Medicine, Nanchang University, Nanchang, Jiangxi 330006, China.
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Ha J, Park C, Park S. PMAMCA: prediction of microRNA-disease association utilizing a matrix completion approach. BMC SYSTEMS BIOLOGY 2019; 13:33. [PMID: 30894171 PMCID: PMC6425656 DOI: 10.1186/s12918-019-0700-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 01/29/2019] [Indexed: 01/29/2023]
Abstract
Background Numerous experimental results have indicated that microRNAs (miRNAs) play a vital role in biological processes, as well as outbreaks of diseases at the molecular level. Despite their important role in biological processes, knowledge regarding specific functions of miRNAs in the development of human diseases is very limited. While attempting to solve this problem, many computational approaches have been proposed and attracted significant attention. However, most previous approaches suffer from the common problem of being inapplicable to new diseases without any known miRNA-disease associations. Results This paper proposes a novel method for inferring disease-miRNA associations utilizing a machine learning technique called matrix factorization, which is widely used in recommendation systems. In recommendation systems, the goal is to predict rating scores that a user might assign to specific items. By replacing users with miRNAs and items with diseases, we can efficiently predict miRNA-disease associations without seed miRNAs. As a result, our proposed model, called prediction of microRNA-disease association utilizing a matrix completion approach, achieves excellent performance compared to previous approaches with a reliable AUC value of 0.882 by implementing five-fold cross validation. Conclusions To the best of our knowledge, the proposed method applies the matrix completion technique to infer miRNA-disease associations and overcome the seed-miRNA problem negatively affects existing computational models. Electronic supplementary material The online version of this article (10.1186/s12918-019-0700-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jihwan Ha
- Department of Computer Science, Yonsei University, 134 Sinchon-dong, Seodaemun-gu, Seoul, South Korea
| | - Chihyun Park
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, 9211 Euclid Ave., Cleveland, OH, 44106, USA
| | - Sanghyun Park
- Department of Computer Science, Yonsei University, 134 Sinchon-dong, Seodaemun-gu, Seoul, South Korea.
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Sun T, Song Y, Yu H, Luo X. Identification of lncRNA TRPM2-AS/miR-140-3p/PYCR1 axis's proliferates and anti-apoptotic effect on breast cancer using co-expression network analysis. Cancer Biol Ther 2019; 20:760-773. [PMID: 30810442 PMCID: PMC6605980 DOI: 10.1080/15384047.2018.1564563] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 11/09/2018] [Accepted: 12/25/2018] [Indexed: 12/12/2022] Open
Abstract
Breast cancer (BC) is one of the most common malignancies occurring in women worldwide. Weighted gene co-expression network analysis (WGCNA) has not been widely utilized in uncovering the biomarkers which played pivotal roles in BC treatment. This study aimed to verify the proliferative and anti-apoptotic effect of lncRNA TRPM2-AS/miR-140-3p/PYCR1 axis on BC based on WGCNA. WGCNA was applied for determining hub genes using gene expression data gained from breast cancer and adjacent tissues which were downloaded from the Cancer Genome Atlas (TCGA) database. The correlative curves showed the correlation between OS/DFS of BC patients and TRPM2-AS expression or PYCR1 expression based on the data of survival rate of BC patients obtained from the TCGA database. QRT-PCR was employed in detecting the expression levels of TRPM2-AS, miR-140-3p and PYCR1, and western blot analysis was adopted for determination of protein expression level of PYCR1. Dual luciferase assay was applied to verify the targeting relationship between TRPM2-AS and miR-140-3p, as well as miR-140-3p and PYCR1. The roles of TRPM2-AS, miR-140-3p, and PYCR1 in proliferation, migration, and apoptosis of BC cell were identified by CCK-8 assay, cell migration assay and flow cytometry. Hub genes were also gained from WGCNA test. The prognostic study showed a significant negative correlation between the high expression of PYCR1 and TRPM2-AS and the BC survival. QRT-PCR demonstrated that PYCR1 and TRPM2-AS were both overexpressed, while miR-140-3p was greatly down-regulated in BC cell. In addition, it was validated by dual luciferase assay that miR-140-3p directly targeted both TRPM2-AS and PYCR1. Furthermore, down-regulation of TRPM2-AS and PYCR1 inhibited proliferation yet promoted apoptosis of BC cell, and up-regulation of miR-140-3p in BC cell showed the same tendency. Taken together, TRPM2-AS could promote proliferation and inhibit apoptosis of BC cell through TRPM2-AS/miR-140-3p/PYCR1 axis.
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Affiliation(s)
- Tong Sun
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yan Song
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Hong Yu
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xiao Luo
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
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Li F, Yoshizawa JM, Kim KM, Kanjanapangka J, Grogan TR, Wang X, Elashoff DE, Ishikawa S, Chia D, Liao W, Akin D, Yan X, Lee MS, Choi R, Kim SM, Kang SY, Bae JM, Sohn TS, Lee JH, Choi MG, Min BH, Lee JH, Kim JJ, Kim Y, Kim S, Wong DTW. Discovery and Validation of Salivary Extracellular RNA Biomarkers for Noninvasive Detection of Gastric Cancer. Clin Chem 2018; 64:1513-1521. [PMID: 30097497 DOI: 10.1373/clinchem.2018.290569] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 07/03/2018] [Indexed: 01/28/2023]
Abstract
BACKGROUND Biomarkers are needed for noninvasive early detection of gastric cancer (GC). We investigated salivary extracellular RNA (exRNA) biomarkers as potential clinical evaluation tools for GC. METHODS Unstimulated whole saliva samples were prospectively collected from 294 individuals (163 GC and 131 non-GC patients) who underwent endoscopic evaluation at the Samsung Medical Center in Korea. Salivary transcriptomes of 63 GC and 31 non-GC patients were profiled, and mRNA biomarker candidates were verified with reverse transcription quantitative real-time PCR (RT-qPCR). In parallel, microRNA (miRNA) biomarkers were profiled and verified with saliva samples from 10 GC and 10 non-GC patients. Candidate biomarkers were validated with RT-qPCR in an independent cohort of 100/100 saliva samples from GC and non-GC patients. Validated individual markers were configured into a best performance panel. RESULTS We identified 30 mRNA and 15 miRNA candidates whose expression pattern associated with the presence of GC. Among them, 12 mRNA and 6 miRNA candidates were verified with the discovery cohort by RT-qPCR and further validated with the independent cohort (n = 200). The configured biomarker panel consisted of 3 mRNAs (SPINK7, PPL, and SEMA4B) and 2 miRNAs (MIR140-5p and MIR301a), which were all significantly down-regulated in the GC group, and yielded an area under the ROC curve (AUC) of 0.81 (95% CI, 0.72-0.89). When combined with demographic factors, the AUC of the biomarker panel reached 0.87 (95% CI, 0.80-0.93). CONCLUSIONS We have discovered and validated a panel of salivary exRNA biomarkers with credible clinical performance for the detection of GC. Our study demonstrates the potential utility of salivary exRNA biomarkers in screening and risk assessment for GC.
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Affiliation(s)
- Feng Li
- Institute of Diagnostic in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China.,School of Dentistry, University of California, Los Angeles, CA
| | | | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | | | - Tristan R Grogan
- Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - Xiaoyan Wang
- Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - David E Elashoff
- Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - Shigeo Ishikawa
- School of Dentistry, University of California, Los Angeles, CA
| | - David Chia
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - Wei Liao
- School of Dentistry, University of California, Los Angeles, CA
| | - David Akin
- School of Dentistry, University of California, Los Angeles, CA
| | - Xinmin Yan
- School of Dentistry, University of California, Los Angeles, CA
| | - Min-Sun Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Rayun Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Su-Mi Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - So-Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jae-Moon Bae
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Tae-Sung Sohn
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jun-Ho Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Min-Gew Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Byung-Hoon Min
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jun-Haeng Lee
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jae J Kim
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yong Kim
- School of Dentistry, University of California, Los Angeles, CA;
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea;
| | - David T W Wong
- School of Dentistry, University of California, Los Angeles, CA;
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Zeng H, Wang L, Wang J, Chen T, Li H, Zhang K, Chen J, Zhen S, Tuluhong D, Li J, Wang S. microRNA-129-5p suppresses Adriamycin resistance in breast cancer by targeting SOX2. Arch Biochem Biophys 2018; 651:52-60. [PMID: 29802821 DOI: 10.1016/j.abb.2018.05.018] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 05/18/2018] [Accepted: 05/22/2018] [Indexed: 12/11/2022]
Abstract
Adriamycin resistance is closely related to therapeutic efficacy in breast cancer patients and their prognosis. Increasing evidence has suggested that miRNA functions in Adriamycin resistance in various types of cancer. microRNA-129-5p (miR-129-5p) has been considered a tumor-suppressive miRNA in several cancers, but its potential role in Adriamycin resistance in breast cancer has not been fully elucidate. By qRT-PCR assay, we revealed that the expression of miR-129-5p was significantly decreased in breast cancer tissues and Adriamycin-resistant breast cancer cells (MDA-MB-231/ADR, MCF-7/ADR). CCK-8, colony formation, wound healing, Transwell invasion, and flow cytometric profiles were examined to determine the influence of miR-129-5p on Adriamycin-resistant breast cancer in vitro. The upregulation of miR-129-5p decreased the IC50 concentration of Adriamycin and invasion and promoted the apoptosis of MDA-MB-231/ADR cells in the presence of Adriamycin, whereas the upregulation of Sex-Determining Region Y-Box 2 (SOX2) reversed these effects. A luciferase reporter assay confirmed the binding of miR-129-5p to the 3'UTR of SOX2. Collectively, it was suggested that miR-129-5p suppresses Adriamycin resistance in breast cancer by directly targeting SOX2.
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Affiliation(s)
- Huijuan Zeng
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, PR China
| | - Lulu Wang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, PR China
| | - Jingjie Wang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, PR China
| | - Tao Chen
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, PR China
| | - Hanjun Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, PR China
| | - Kai Zhang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, PR China
| | - Jing Chen
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, PR China
| | - Shuang Zhen
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, PR China
| | - Dilihumaer Tuluhong
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, PR China
| | - Jieshou Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, PR China.
| | - Shaohua Wang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, PR China.
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Su Y, Xiong J, Hu J, Wei X, Zhang X, Rao L. MicroRNA-140-5p targets insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) to suppress cervical cancer growth and metastasis. Oncotarget 2018; 7:68397-68411. [PMID: 27588393 PMCID: PMC5356564 DOI: 10.18632/oncotarget.11722] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 08/22/2016] [Indexed: 01/30/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that play important roles in carcinogenesis and tumor progression. Previous studies have revealed that MicroRNA-140-5p (miR-140-5p) was abnormally expressed in several cancers. However, its function and possible mechanism in cervical cancer (CC) remains unknown. In this study, the data mining results showed that miR-140-5p was down-regulated in CC specimens and the down-regulation of miR-140-5p was associated with CC poor prognosis. These observations prompted us to further investigate the roles and mechanisms of miR-140-5p in human CC pathogenesis. We found that the over-expression/inhibition of miR-140-5p significantly decreased/increased cell proliferation, migration, and invasion in CC cells in vitro. Meanwhile, the results from in vivo assays showed that the over-expression of miR-140-5p induced significantly suppression of tumor growth and metastasis in nude mice. Furthermore, Insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) was identified as a direct target of miR-140-5p, and both gain-of-function and loss-of-function assays revealed that IGF2BP1 is also a functional target of miR-140-5p. Taken together, our findings suggested a novel miR-140-5p-IGF2BP1 regulatory circuit for CC pathogenesis, and miR-140-5p may be a potential target for CC therapy.
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Affiliation(s)
- Yanlin Su
- Department of Obstetrics and Gynecology, Changsha Central Hospital, Changsha, China
| | - Jie Xiong
- Department of Epidemiology and Health Statistcs, XiangYa School of Public Health, Central South University, Changsha, China
| | - Jinyue Hu
- Medical Research Center, Changsha Central Hospital, Changsha, China
| | - Xin Wei
- Department of Obstetrics and Gynecology, Changsha Central Hospital, Changsha, China
| | - Xuelian Zhang
- Department of Obstetrics and Gynecology, Changsha Central Hospital, Changsha, China
| | - Lijuan Rao
- Department of Obstetrics and Gynecology, Changsha Central Hospital, Changsha, China
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Heydari N, Nikbakhsh N, Sadeghi F, Farnoush N, Khafri S, Bastami M, Parsian H. Overexpression of serum MicroRNA-140-3p in premenopausal women with newly diagnosed breast cancer. Gene 2018; 655:25-29. [PMID: 29474861 DOI: 10.1016/j.gene.2018.02.032] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 01/16/2018] [Accepted: 02/12/2018] [Indexed: 12/21/2022]
Abstract
AIMS The purpose of the present study was to evaluate microRNA-140-3p expression level in breast cancer patients in comparison to healthy controls. PATIENTS & METHODS Serum microRNA-140-3p level was quantified by realtime quantitative reverse transcription PCR in 40 women with breast cancer and 40 healthy subjects. RESULTS Serum microRNA-140-3p level in patients compared to healthy subjects was significantly up-regulated (P = 0.01). MicroRNA-140-3p had a good diagnostic accuracy for discrimination of the two groups (AUC = 0.667; sensitivity = 70%; specificity = 50%). Serum microRNA-140-3p level was overexpressed in premenopausal patients who were ≤48 years old. ROC curve showed a similar pattern again (AUC = 0.690; sensitivity = 73%; specificity = 50%). CONCLUSIONS microRNA-140-3p has the potential for detection of breast cancer, especially in premenopausal and in ≤48 years old women.
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Affiliation(s)
- Nadia Heydari
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Novin Nikbakhsh
- Cancer Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Farzin Sadeghi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Nazila Farnoush
- Department of Surgery, Babol University of Medical Sciences, Babol, Iran
| | - Soraya Khafri
- Department of Epidemiology, Babol University of Medical Sciences, Babol, Iran
| | - Milad Bastami
- Department of Medical Genetics, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Parsian
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
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Li X, Li P, Liu C, Ren Y, Tang X, Wang K, He J. Sinomenine hydrochloride inhibits breast cancer metastasis by attenuating inflammation-related epithelial-mesenchymal transition and cancer stemness. Oncotarget 2017; 8:13560-13574. [PMID: 28088791 PMCID: PMC5355120 DOI: 10.18632/oncotarget.14593] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 01/03/2017] [Indexed: 12/21/2022] Open
Abstract
Sinomenine hydrochloride (SH) has been investigated for its anti-tumor growth effect. We have previously reported that SH inhibited breast cancer cell proliferation via MAPKs signaling. However, whether SH could inhibit tumor metastasis has not been fully explored. In this study, we found that SH suppressed the metastasis potential of breast cancer cells. The wound healing and transwell assays showed that SH inhibited the migration and invasion ability of both 4T1 and MDA-MB-231 breast cancer cells. The orthotopic mouse model of 4T1 and the experimental mouse model of MDA-MB-231-luc (MDA-MB-231 cell line expressing firefly luciferase) demonstrated that SH treatment inhibited breast cancer metastasis by inhibiting epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) properties without obvious hepatotoxicity and renal toxicity. We also found that SH decreased spleen volume and weight in both mouse models, especially in the 4T1 mouse model. IL-6, a strong inflammatory factor causing EMT, was remarkably reduced. Overall, this anti-metastasis effect of SH could be possibly caused by attenuating inflammatory reaction, which led to inhibition of EMT and CSC characteristics of breast cancer cells. This study, together with our previous one, provides more evidence of SH as a potential drug for breast cancer therapy.
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Affiliation(s)
- Xiao Li
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Pingping Li
- Translational Medical Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Chao Liu
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Yu Ren
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Xiaojiang Tang
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Ke Wang
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Jianjun He
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
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47
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Fan X, Chen W, Fu Z, Zeng L, Yin Y, Yuan H. MicroRNAs, a subpopulation of regulators, are involved in breast cancer progression through regulating breast cancer stem cells. Oncol Lett 2017; 14:5069-5076. [PMID: 29142594 DOI: 10.3892/ol.2017.6867] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Accepted: 05/18/2017] [Indexed: 12/11/2022] Open
Abstract
Cancer stem cells (CSCs; also known as tumor-initiating cells) are essential effectors of tumor progression due to their self-renewal capacity, differentiation potential, tumorigenic ability and resistance to chemotherapy, all of which contribute to cancer relapse, metastasis and a poor prognosis. Breast cancer stem cells (BCSCs) have been identified to be involved in the processes of BC initiation, growth and recurrence. MicroRNAs (miRNAs) are a class of non-coding small RNAs of 19-23 nucleotides in length that regulate gene expression at the post-transcriptional level through various mechanisms, and serve critical roles in cancer progression. miRNAs have been demonstrated to elicit effects on BCSCs characteristics via the targeting of oncogenes or tumor suppressor genes. The present study focused on the effect of miRNAs on BCSC, including BCSC formation, self-renewal and differentiation, by which miRNAs may inhibit BCSC invasion and metastasis, modulate clonogenicity and tumorigenicity of BCSCs as well as regulate chemotherapy resistance to BC. Through an improved understanding of the association between BCSCs and miRNAs, a novel and safer therapeutic target for BC may be identified.
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Affiliation(s)
- Xuemei Fan
- Nanjing Maternity and Child Health Medical Institute, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210004, P.R. China
| | - Wei Chen
- Department of Head and Neck Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Ziyi Fu
- Nanjing Maternity and Child Health Medical Institute, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210004, P.R. China
| | - Lihua Zeng
- Nanjing Maternity and Child Health Medical Institute, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210004, P.R. China
| | - Yongmei Yin
- Department of Oncology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hongyan Yuan
- Nanjing Maternity and Child Health Medical Institute, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210004, P.R. China.,Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
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48
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Hu Y, Li Y, Wu C, Zhou L, Han X, Wang Q, Xie X, Zhou Y, Du Z. MicroRNA-140-5p inhibits cell proliferation and invasion by regulating VEGFA/MMP2 signaling in glioma. Tumour Biol 2017; 39:1010428317697558. [PMID: 28443475 DOI: 10.1177/1010428317697558] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Glioma is the most common primary malignant tumor of the central nervous system, which results in both a poor prognosis and outcome because of the aggressive progression of disease, growth and resistance to surgery, chemotherapy, and radiotherapy. MiR-140-5p is a small, non-coding single-stranded RNA molecule, which was previously studied in the settings of human tongue cancer, hepatocellular carcinoma, and colorectal cancer. However, detailed data that formally demonstrate the contribution of miR-140-5p to glioma development are missing. Similarly, relatively little is known about the relationship of miR-140-5p, vascular endothelial growth factor A, and matrix metalloproteinase-2 in glioma progression. In this study, we found that miR-140-5p expression was significantly decreased in glioma tissues and in the glioma cell-lines U87 and U251 as compared with non-cancerous brain tissues by quantitative real-time polymerase chain reaction. In addition, miR-140-5p inhibited glioma cell proliferation and invasion and promoted glioma cell apoptosis both in vivo and in vitro. Interestingly, while the expression levels of miR-140-5p were higher in glioma cells, the messenger RNA or protein expression levels of vascular endothelial growth factor A and matrix metalloproteinase-2 were lower in glioma cells as determined by quantitative real-time polymerase chain reaction, western blot assay, and immunohistochemistry. By contrast, downregulation in the expression levels of miR-140-5p augmented the messenger RNA and protein expression levels of both vascular endothelial growth factor A and matrix metalloproteinase-2. These findings suggested that miR-140-5p inhibited glioma proliferation and invasion by regulating the vascular endothelial growth factor A/matrix metalloproteinase-2 signaling pathway both in vitro and in vivo.
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Affiliation(s)
- Yuan Hu
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Yanyan Li
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Chun Wu
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Liang Zhou
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Xiaoxiao Han
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Qingyue Wang
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Xueshun Xie
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Youxin Zhou
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Ziwei Du
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
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49
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Cao Y, Wu T, Li D, Hu J, Lu H. MicroRNA‑336 directly targets Sox‑2 in osteosarcoma to inhibit tumorigenesis. Mol Med Rep 2017; 15:4217-4224. [PMID: 28440454 DOI: 10.3892/mmr.2017.6493] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 02/02/2017] [Indexed: 11/06/2022] Open
Abstract
Previous evidence has suggested that microRNAs (miRNAs or miRs), which belong to a class of non‑coding RNAs, shape cellular processes by regulating gene expression. Abnormal expression of miRNAs has been associated with tumorigenesis in multiple cancers. However, the function of miR‑336 in osteosarcoma (OS) remains unknown. The experimental procedures used in the present study included flow cytometry, reverse transcription‑quantitative polymerase chain reaction, luciferase reporter assay, invasion assay, western blot analysis and in vivo implantation. The results of the present study demonstrated that miR‑336 may serve as a tumor suppressor in OS. Downregulation of miR‑336 was observed in human OS specimens as well as OS cell lines. In addition, a significant negative correlation between sex determining region Y‑box 2 (Sox‑2) expression and miR‑336 was demonstrated. miR‑336 was confirmed to target the 3'‑untranslated region of Sox‑2 to inhibit proliferation, migration and invasion of OS cells. Consistently, restoration of Sox‑2 expression counteracted the effect of miR‑336, and recovered the tumorigenic potential of OS cells. The present study established a novel association between miR‑336 and Sox‑2 in OS. This relationship between miR‑336 and Sox‑2 may lead to improved knowledge concerning OS progression and sheds light on potential novel therapeutic interventions for OS treatment.
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Affiliation(s)
- Yong Cao
- Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Tianding Wu
- Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Dongzhe Li
- Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Jianzhong Hu
- Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Hongbin Lu
- Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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50
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Guo D, Ye Y, Qi J, Tan X, Zhang Y, Ma Y, Li Y. Age and sex differences in microRNAs expression during the process of thymus aging. Acta Biochim Biophys Sin (Shanghai) 2017; 49:409-419. [PMID: 28369179 DOI: 10.1093/abbs/gmx029] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Indexed: 12/18/2022] Open
Abstract
The gender-biased thymus involution and the importance of microRNAs (miRNAs, miRs) expression in modulating the thymus development have been reported in many studies. However, how males and females differ in so many ways in thymus involution remains unclear. To address this question, we investigated the miRNA expression profiles in both untreated 3- and 12-month-old female and male mice thymuses. The results showed that 7 and 18 miRNAs were defined as the sex- and age-specific miRNAs, respectively. The expression of miR-181c-5p, miR-20b-5p, miR-98b-5p, miR-329-3p, miR-341-5p, and miR-2137 showed significant age-difference in mice thymus by quantitative polymerase chain reaction. High expression levels of miR-2137 were detected in mice thymic epithelial cells and gradually increased during the process of thymus aging. MiR-27b-3p and miR-378a-3p of the female-biased miRNAs were confirmed as the sex- and estrogen-responsive miRNAs in mice thymus in vivo. Their potential target genes and the pathway were identified by the online software. Possible regulation roles of sex- and age-specific miRNA expression during the process of thymus aging were discussed. Our results suggested that these miRNAs may be potential biomarkers for the study of sex- and age-specific thymus aging and involution.
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Affiliation(s)
- Dongguang Guo
- Department of Basic Veterinary Medicine, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Yaqiong Ye
- Department of Basic Veterinary Medicine, School of Life Science and Engineering, Foshan University, Foshan 528000, China
| | - Junjie Qi
- Department of Basic Veterinary Medicine, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Xiaotong Tan
- Department of Basic Veterinary Medicine, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Yuan Zhang
- Department of Basic Veterinary Medicine, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Yongjiang Ma
- Department of Basic Veterinary Medicine, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Yugu Li
- Department of Basic Veterinary Medicine, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
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