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Cortellesi E, Savini I, Veneziano M, Gambacurta A, Catani MV, Gasperi V. Decoding the Epigenome of Breast Cancer. Int J Mol Sci 2025; 26:2605. [PMID: 40141248 PMCID: PMC11942310 DOI: 10.3390/ijms26062605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/06/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Breast cancer (BC) is the most prevalent malignancy among women, characterized by extensive heterogeneity stemming from molecular and genetic alterations. This review explores the intricate epigenetic landscape of BC, highlighting the significant role of epigenetic modifications-particularly DNA methylation, histone modifications, and the influence of non-coding RNAs-in the initiation, progression, and prognosis of the disease. Epigenetic alterations drive crucial processes, including gene expression regulation, cell differentiation, and tumor microenvironment interactions, contributing to tumorigenesis and metastatic potential. Notably, aberrations in DNA methylation patterns, including global hypomethylation and hypermethylation of CpG islands, have been associated with distinct BC subtypes, with implications for early detection and risk assessment. Furthermore, histone modifications, such as acetylation and methylation, affect cancer cell plasticity and aggressiveness by profoundly influencing chromatin dynamics and gene transcription. Finally, non-coding RNAs contribute by modulating epigenetic machinery and gene expression. Despite advances in our knowledge, clinical application of epigenetic therapies in BC is still challenging, often yielding limited efficacy when used alone. However, combining epi-drugs with established treatments shows promise for enhancing therapeutic outcomes. This review underscores the importance of integrating epigenetic insights into personalized BC treatment strategies, emphasizing the potential of epigenetic biomarkers for improving diagnosis, prognosis, and therapeutic response in affected patients.
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Affiliation(s)
- Elisa Cortellesi
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Isabella Savini
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Matteo Veneziano
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Alessandra Gambacurta
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
- NAST Centre (Nanoscience & Nanotechnology & Innovative Instrumentation), Tor Vergata University of Rome, 00133 Rome, Italy
| | - Maria Valeria Catani
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
| | - Valeria Gasperi
- Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy; (E.C.); (I.S.); (M.V.); (A.G.); (M.V.C.)
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Amiri R, Nabi PN, Fazilat A, Roshani F, Nouhi Kararoudi A, Hemmati-Dinarvand M, Valilo M. Crosstalk between miRNAs and signaling pathways in the development of drug resistance in breast cancer. Horm Mol Biol Clin Investig 2024:hmbci-2024-0066. [PMID: 39665256 DOI: 10.1515/hmbci-2024-0066] [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: 10/24/2024] [Accepted: 11/28/2024] [Indexed: 12/13/2024]
Abstract
One of the biggest challenges of today's society is cancer, which imposes a significant financial, emotional and spiritual burden on human life. Breast cancer (BC) is one of the most common cancers that affects people in society, especially women, and due to advanced treatment strategies and primary prevention, it is still the second cause of cancer-related deaths in society. Various genetic and environmental factors are involved in the development of BC. MicroRNAs (miRNA)s are non-coding RNAs, that the degradation or inhibition of them plays an important role in the prevention or development of cancer by modulating many cellular pathways including apoptosis, drug resistance, and tumorigenesis. Drug resistance is one of the important defense mechanisms of cancer cells against anticancer drugs and is considered one of the main causes of cancer treatment failure. Different miRNAs, including mir-7, mir-21, mir-31, and mir-124 control different cell activities, including drug resistance, through different pathways, including PI3K/AKT/mTOR, TGF-β, STAT3, and NF-kB. Therefore, cell signaling pathways are one of the important factors that miRNAs control cellular activities. Hence, in this study, we decided to highlight an overview of the relationship between miRNAs and signaling pathways in the development of drug resistance in BC.
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Affiliation(s)
- Reza Amiri
- Nargund College of Pharmacy, Rajiv Gandhi University of Health Sciences, Bengaluru, Karnataka, India
| | | | - Ahmad Fazilat
- Department of Genetics, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Fatemeh Roshani
- Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - Alireza Nouhi Kararoudi
- Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, Rasht, Iran
| | - Mohsen Hemmati-Dinarvand
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Valilo
- Department of Biochemistry, 37555 Faculty of Medicine, Urmia University of Medical Sciences , Urmia, Iran
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Jia W, Wu Q, Shen M, Yu X, An S, Zhao L, Huang G, Liu J. PFKFB3 regulates breast cancer tumorigenesis and Fulvestrant sensitivity by affecting ERα stability. Cell Signal 2024; 119:111184. [PMID: 38640982 DOI: 10.1016/j.cellsig.2024.111184] [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: 02/12/2024] [Revised: 04/07/2024] [Accepted: 04/16/2024] [Indexed: 04/21/2024]
Abstract
Estrogen receptor alpha (ERα) is expressed in approximately 70% of breast cancer cases and determines the sensitivity and effectiveness of endocrine therapy. 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase3 (PFKFB3) is a glycolytic enzyme that is highly expressed in a great many human tumors, and recent studies have shown that it plays a significant role in improving drug sensitivity. However, the role of PFKFB3 in regulating ERα expression and the underlying mechanism remains unclear. Here, we find by using immunohistochemistry (IHC) that PFKFB3 is elevated in ER-positive breast cancer and high expression of PFKFB3 resulted in a worse prognosis. In vitro and in vivo experiments verify that PFKFB3 promotes ER-positive breast cancer cell proliferation. The overexpression of PFKFB3 promotes the estrogen-independent ER-positive breast cancer growth. In an estrogen-free condition, RNA-sequencing data from MCF7 cells treated with siPFKFB3 showed enrichment of the estrogen signaling pathway, and a luciferase assay demonstrated that knockdown of PFKFB3 inhibited the ERα transcriptional activity. Mechanistically, down-regulation of PFKFB3 promotes STUB1 binding to ERα, which accelerates ERα degradation by K48-based ubiquitin linkage. Finally, growth of ER-positive breast cancer cells in vivo was more potently inhibited by fulvestrant combined with the PFKFB3 inhibitor PFK158 than for each drug alone. In conclusion, these data suggest that PFKFB3 is identified as an adverse prognosis factor for ER-positive breast cancer and plays a previously unrecognized role in the regulation of ERα stability and activity. Our results further explores an effective approach to improve fulvestrant sensitivity through the early combination with a PFKFB3 inhibitor.
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Affiliation(s)
- Wenzhi Jia
- Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qianyun Wu
- Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mengqin Shen
- Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaofeng Yu
- Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuxian An
- Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Zhao
- Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Gang Huang
- Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianjun Liu
- Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Clinical Nuclear Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Molecular Imaging, Shanghai, China.
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4
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Kavishahi NN, Rezaee A, Jalalian S. The Impact of miRNAs on the Efficacy of Tamoxifen in Breast Cancer Treatment: A Systematic Review. Clin Breast Cancer 2024; 24:341-350. [PMID: 38413339 DOI: 10.1016/j.clbc.2024.01.015] [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: 09/08/2023] [Revised: 01/17/2024] [Accepted: 01/22/2024] [Indexed: 02/29/2024]
Abstract
Seventy percent of breast cancer patients have an active estrogen receptor. Tamoxifen interferes with estrogen's ability to bind to cancer cells. The most challenging aspect of tamoxifen, however, is that breast cancer cells become resistant to its effects. Some studies have shown that alterations in miRNA expression contribute significantly to drug resistance in breast cancer. Therefore, the present systematic review aims to investigate miRNAs that significantly influence the response to tamoxifen treatment. The present study follows the PRISMA instructions. The Web of Science, PubMed, and Scopus databases were searched to retrieve English articles. The searches were conducted up to September 11, 2022. The search strategy included the terms "Tamoxifen", "Breast Neoplasm", and "MicroRNA". The inclusion criteria of this study are English, original, and experimental studies investigating miRNAs that are effective in the treatment efficacy of tamoxifen. A total of 565 articles were retrieved. After screening, 75 studies met our inclusion criteria. This systematic review study examined 105 miRNAs, of which 44 have a positive effect, and 47 miRNAs inhibit tamoxifen function. Fourteen miRNAs have a controversial effect, ie, some studies show positive and negative effects. The study of miRNAs affecting tamoxifen function in breast cancer patients may facilitate the identification of individuals at higher risk of disease recurrence. Conversely, it can potentially utilize appropriate interventions to defeat drug resistance effectively.
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Affiliation(s)
- Nima Nikbin Kavishahi
- Department of Medical Genetics, Student Research Committee, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Aryan Rezaee
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Sara Jalalian
- Medical Doctor Student, Student Research Committee, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran.
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周 铎, 杨 德. [miRNA Is Involved in the Pathogenesis of Multiple Diseases by Targeting Osteoprotegerin]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2024; 55:777-782. [PMID: 38948285 PMCID: PMC11211783 DOI: 10.12182/20240560607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Indexed: 07/02/2024]
Abstract
As a member of the tumor necrosis factor receptor family, osteoprotegerin (OPG) is highly expressed in adults in the lung, heart, kidney, liver, spleen, thymus, prostate, ovary, small intestines, thyroid gland, lymph nodes, trachea, adrenal gland, the testis, and bone marrow. Together with the receptor activator of nuclear factor-κB (RANK) and the receptor activator of nuclear factor-κB ligand (RANKL), it forms the RANK/RANKL/OPG pathway, which plays an important role in the molecular mechanism of the development of various diseases. MicroRNAs (miRNAs) are a class of endogenous non-coding RNAs performing regulatory functions in eukaryotes, with a size of about 20-25 nucleotides. miRNA genes are transcribed into primary transcripts by RNA polymerase, bind to RNA-induced silencing complexes, identify target mRNAs through complementary base pairing, with a single miRNA being capable of targeting hundreds of mRNAs, and influence the expression of many genes through pathways involved in functional interactions. In recent years, a large number of studies have been done to explore the mechanism of action of miRNA in diseases through miRNA isolation, miRNA quantification, miRNA spectrum analysis, miRNA target detection, in vitro and in vivo regulation of miRNA levels, and other technologies. It was found that miRNA can play a key role in the pathogenesis of osteoporosis, rheumatoid arthritis, and other diseases by targeting OPG. The purpose of this review is to explore the interaction between miRNA and OPG in various diseases, and to propose new ideas for studying the mechanism of action of OPG in diseases.
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Affiliation(s)
- 铎 周
- 重庆医科大学附属口腔医院 牙体牙髓科 (重庆 401147)Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
- 口腔疾病与生物医学重庆市重点实验室 (重庆 401147)Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China
- 重庆市高校市级口腔生物医学工程重点实验室(重庆 401147)Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - 德琴 杨
- 重庆医科大学附属口腔医院 牙体牙髓科 (重庆 401147)Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
- 口腔疾病与生物医学重庆市重点实验室 (重庆 401147)Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China
- 重庆市高校市级口腔生物医学工程重点实验室(重庆 401147)Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
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Xiong S, Song K, Xiang H, Luo G. Dual-target inhibitors based on ERα: Novel therapeutic approaches for endocrine resistant breast cancer. Eur J Med Chem 2024; 270:116393. [PMID: 38588626 DOI: 10.1016/j.ejmech.2024.116393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 04/04/2024] [Accepted: 04/04/2024] [Indexed: 04/10/2024]
Abstract
Estrogen receptor alpha (ERα), a nuclear transcription factor, is a well-validated therapeutic target for more than 70% of all breast cancers (BCs). Antagonizing ERα either by selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs) forms the foundation of endocrine therapy and has achieved great success in the treatment of ERα positive (ERα+) BCs. Unfortunately, despite initial effectiveness, endocrine resistance eventually emerges in up to 30% of ERα+ BC patients and remains a significant medical challenge. Several mechanisms implicated in endocrine resistance have been extensively studied, including aberrantly activated growth factor receptors and downstream signaling pathways. Hence, the crosstalk between ERα and another oncogenic signaling has led to surge of interest to develop combination therapies and dual-target single agents. This review briefly introduces the synergisms between ERα and another anticancer target and summarizes the recent advances of ERα-based dual-targeting inhibitors from a medicinal chemistry perspective. Accordingly, their rational design strategies, structure-activity relationships (SARs) and biological activities are also dissected to provide some perspectives on future directions for ERα-based dual target drug discovery in BC therapy.
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Affiliation(s)
- Shuangshuang Xiong
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Ke Song
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hua Xiang
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Guoshun Luo
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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7
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Eslaminejad T, Nematollahi-Mahani SN, Sargazi ML, Ansari M, Mirzaie V. Evaluating the effects of curcumin nano-chitosan on miR-221 and miR-222 expression and Wnt/β-catenin pathways in MCF-7, MDA-MB-231 and SKBR3 cell lines. Diagn Pathol 2024; 19:35. [PMID: 38365810 PMCID: PMC10870642 DOI: 10.1186/s13000-024-01468-3] [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: 01/11/2024] [Accepted: 02/12/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND Breast cancer is one of the most common diseases worldwide that affects women of reproductive age. miR-221 and miR-222 are two highly homogeneous microRNAs that play pivotal roles in many cellular processes and regulate the Wnt/β-catenin signaling pathway. Curcumin (CUR), a yellow polyphenolic compound, targets numerous signaling pathways relevant to cancer therapy. The main aim of this study was to compare the ability of chitosan curcumin nanoparticle (CC-CUR) formulation with the curcumin in modulating miR-221 and miR-222 expression through Wnt/β-catenin signaling pathway in MCF-7, MDA-MB-231 and SK-BR-3 breast cancer cell lines. METHOD Chitosan-cyclodextrin-tripolyphosphate containing curcumin nanoparticles (CC-CUR) were prepared. Cytotoxicity of the CUR and CC-CUR was evaluated. Experimental groups including CC-CUR, CUR and negative control were designed. The expression of miR-221 and miR-222 and Wnt/β-catenin pathway genes was measured. RESULTS The level of miR-221 and miR-222 and β-catenin genes decreased in MCF-7 and MDA-MB-231 cells and WIF1 gene increased in all cells in CC-CUR group. However, the results in SK-BR-3 cell line were unexpected; since miRs and WIF1 gene expressions were increased following CC-CUR administration and β-catenin decreased by administration of CUR. CONCLUSION Although the composite form of curcumin decreased the expression of miR-221 and miR-222 in MCF-7 and MDA cells, with significant decreasing of β-catenin and increasing of WIF1 gene in almost all three cell lines, we can conclude than this formulation exerts its effect mainly through the Wnt/β-catenin pathway. These preliminary findings may pave the way for the use of curcumin nanoparticles in the treatment of some known cancers.
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Affiliation(s)
- Touba Eslaminejad
- Department of Anatomy, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Marzieh Lotfian Sargazi
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mehdi Ansari
- Departments of Drug and Food Control, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Vida Mirzaie
- Department of Anatomy, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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8
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Muñoz JP, Pérez-Moreno P, Pérez Y, Calaf GM. The Role of MicroRNAs in Breast Cancer and the Challenges of Their Clinical Application. Diagnostics (Basel) 2023; 13:3072. [PMID: 37835815 PMCID: PMC10572677 DOI: 10.3390/diagnostics13193072] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/14/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
MicroRNAs (miRNAs) constitute a subclass of non-coding RNAs that exert substantial influence on gene-expression regulation. Their tightly controlled expression plays a pivotal role in various cellular processes, while their dysregulation has been implicated in numerous pathological conditions, including cancer. Among cancers affecting women, breast cancer (BC) is the most prevalent malignant tumor. Extensive investigations have demonstrated distinct expression patterns of miRNAs in normal and malignant breast cells. Consequently, these findings have prompted research efforts towards leveraging miRNAs as diagnostic tools and the development of therapeutic strategies. The aim of this review is to describe the role of miRNAs in BC. We discuss the identification of oncogenic, tumor suppressor and metastatic miRNAs among BC cells, and their impact on tumor progression. We describe the potential of miRNAs as diagnostic and prognostic biomarkers for BC, as well as their role as promising therapeutic targets. Finally, we evaluate the current use of artificial intelligence tools for miRNA analysis and the challenges faced by these new biomedical approaches in its clinical application. The insights presented in this review underscore the promising prospects of utilizing miRNAs as innovative diagnostic, prognostic, and therapeutic tools for the management of BC.
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Affiliation(s)
- Juan P. Muñoz
- Laboratorio de Bioquímica, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile
| | - Pablo Pérez-Moreno
- Programa de Comunicación Celular en Cáncer, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7780272, Chile
| | - Yasmín Pérez
- Laboratorio de Bioquímica, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile
| | - Gloria M. Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile
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Naderi Yeganeh P, Teo YY, Karagkouni D, Pita-Juárez Y, Morgan SL, Slack FJ, Vlachos IS, Hide WA. PanomiR: a systems biology framework for analysis of multi-pathway targeting by miRNAs. Brief Bioinform 2023; 24:bbad418. [PMID: 37985452 PMCID: PMC10661971 DOI: 10.1093/bib/bbad418] [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: 08/08/2023] [Revised: 10/16/2023] [Accepted: 10/20/2023] [Indexed: 11/22/2023] Open
Abstract
Charting microRNA (miRNA) regulation across pathways is key to characterizing their function. Yet, no method currently exists that can quantify how miRNAs regulate multiple interconnected pathways or prioritize them for their ability to regulate coordinate transcriptional programs. Existing methods primarily infer one-to-one relationships between miRNAs and pathways using differentially expressed genes. We introduce PanomiR, an in silico framework for studying the interplay of miRNAs and disease functions. PanomiR integrates gene expression, mRNA-miRNA interactions and known biological pathways to reveal coordinated multi-pathway targeting by miRNAs. PanomiR utilizes pathway-activity profiling approaches, a pathway co-expression network and network clustering algorithms to prioritize miRNAs that target broad-scale transcriptional disease phenotypes. It directly resolves differential regulation of pathways, irrespective of their differential gene expression, and captures co-activity to establish functional pathway groupings and the miRNAs that may regulate them. PanomiR uses a systems biology approach to provide broad but precise insights into miRNA-regulated functional programs. It is available at https://bioconductor.org/packages/PanomiR.
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Affiliation(s)
- Pourya Naderi Yeganeh
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA
| | - Yue Y Teo
- National University of Singapore, Singapore
- École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Dimitra Karagkouni
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Yered Pita-Juárez
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Sarah L Morgan
- Harvard Medical School, Boston, MA, USA
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Frank J Slack
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA
| | - Ioannis S Vlachos
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Winston A Hide
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA
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10
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Patellongi I, Amiruddin A, Massi MN, Islam AA, Pratama MY, Sutandyo N, Latar NH, Faruk M. Circulating miR-221/222 expression as microRNA biomarker predicting tamoxifen treatment outcome: a case-control study. Ann Med Surg (Lond) 2023; 85:3806-3815. [PMID: 37554919 PMCID: PMC10406100 DOI: 10.1097/ms9.0000000000001061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 07/02/2023] [Indexed: 08/10/2023] Open
Abstract
The high mortality rate in breast cancer (BC) patients is generally due to metastases resistant to systemic therapy. Two causes of systemic therapy resistance in BC patients are circulating miRNAs-221 and miR-222, leading to improved BC cell proliferation, survival, and reduced cell apoptosis. This study investigated the miRNA expression changes associated with cancer cell resistance to tamoxifen therapy and is expected to be clinically meaningful before providing endocrine therapy to luminal-type BC patients who express them. Methods This case-control research included individuals with the luminal subtype of BC who had received tamoxifen medication for around one year. Furthermore, the case group contained 15 individuals with local recurrence or metastases, while the control group comprised 19 patients without local recurrence or metastases. Plasma miR-221/222 quantification was performed with real-time PCR using transcript-specific primers. Results A significant difference was found in circulating miR-221 expression between cases and controls (P=0.005) but not in miR-222 expression (P=0.070). There were no significant differences between miR-221/222 expression, progesterone receptor, Ki67 protein levels, lymphovascular invasion, and stage. However, receiver operator characteristic curve analyses showed miR-221/222 expressions predictive of tamoxifen resistance (P=0.030) with a sensitivity of 60.00 and a specificity of 83.33%. Conclusion The use of circulating miR-221/222 expression can predict relapse as well as resistance to tamoxifen treatment in BC patients, and their testing is recommended for luminal subtype BC patients who will undergo tamoxifen therapy to determine their risk of tamoxifen resistance early, increasing treatment effectiveness.
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Affiliation(s)
| | | | | | | | | | - Noorwati Sutandyo
- Department of Medical Hematology-Oncology, Dharmais Hospital National Cancer Center, Jakarta, Indonesia
| | - Nani H.M. Latar
- Endocrine and Breast Surgery Unit, Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia
| | - Muhammad Faruk
- Department of Surgery, Faculty of Medicine, Universitas Hasanuddin, Makassar
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11
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He W, Demas DM, Shajahan-Haq AN, Baumann WT. Modeling breast cancer proliferation, drug synergies, and alternating therapies. iScience 2023; 26:106714. [PMID: 37234088 PMCID: PMC10206440 DOI: 10.1016/j.isci.2023.106714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 02/12/2023] [Accepted: 04/18/2023] [Indexed: 05/27/2023] Open
Abstract
Estrogen receptor positive (ER+) breast cancer is responsive to a number of targeted therapies used clinically. Unfortunately, the continuous application of targeted therapy often results in resistance, driving the consideration of combination and alternating therapies. Toward this end, we developed a mathematical model that can simulate various mono, combination, and alternating therapies for ER + breast cancer cells at different doses over long time scales. The model is used to look for optimal drug combinations and predicts a significant synergism between Cdk4/6 inhibitors in combination with the anti-estrogen fulvestrant, which may help explain the clinical success of adding Cdk4/6 inhibitors to anti-estrogen therapy. Furthermore, the model is used to optimize an alternating treatment protocol so it works as well as monotherapy while using less total drug dose.
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Affiliation(s)
- Wei He
- Program in Genetics, Bioinformatics, and Computational Biology, VT BIOTRANS, Virginia Tech, Blacksburg, VA 24061, USA
| | - Diane M. Demas
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Ayesha N. Shajahan-Haq
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - William T. Baumann
- Department of Electrical and Computer Engineering, Virginia Tech, Blacksburg, VA 24061, USA
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12
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Singh T, Kaushik M, Mishra LC, Behl C, Singh V, Tuli HS. Exosomal miRNAs as novel avenues for breast cancer treatment. Front Genet 2023; 14:1134779. [PMID: 37035739 PMCID: PMC10073516 DOI: 10.3389/fgene.2023.1134779] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/27/2023] [Indexed: 04/11/2023] Open
Abstract
Breast cancer is the most commonly diagnosed cancer and a leading cause of death in women worldwide. It is a heterogeneous disease, as shown by the gene expression profiles of breast cancer samples. It begins in milk-producing ducts, with a high degree of diversity between and within tumors, as well as among cancer-bearing individuals. The enhanced prevalence of breast cancer is influenced by various hormonal, lifestyle, and environmental factors, and very early onset of the disease correlates strongly with the risk of local and distant recurrence. Many subtypes are difficult to treat with conventional therapeutic modalities, and therefore, optimal management and early diagnosis are the first steps to minimizing the mortality linked with breast cancer. The use of newer methods of nanotechnology extends beyond the concept of synthesizing drug delivery mechanisms into the creation of new therapeutics, such as delivering chemotherapeutics with nanomaterial properties. Exosomes, a class of nanovesicles, are emerging as novel tools for deciphering the patient-specific proteins and biomarkers across different disease models, including breast cancer. In this review, we address the role of exosomal miRNA in breast cancer diagnosis and treatment.
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Affiliation(s)
- Tejveer Singh
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, India
| | - Mahesh Kaushik
- Radiation and Cancer Therapeutics Lab, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Lokesh Chandra Mishra
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, India
| | - Chesta Behl
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, India
| | - Vijay Singh
- Immunology and Infectious Disease Biology Lab, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Ambala, India
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13
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Treeck O, Haerteis S, Ortmann O. Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer. Cancers (Basel) 2023; 15:cancers15061632. [PMID: 36980520 PMCID: PMC10046587 DOI: 10.3390/cancers15061632] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/09/2023] Open
Abstract
The largest part of human DNA is transcribed into RNA that does not code for proteins. These non-coding RNAs (ncRNAs) are key regulators of protein-coding gene expression and have been shown to play important roles in health, disease and therapy response. Today, endocrine therapy of ERα-positive breast cancer (BC) is a successful treatment approach, but resistance to this therapy is a major clinical problem. Therefore, a deeper understanding of resistance mechanisms is important to overcome this resistance. An increasing amount of evidence demonstrate that ncRNAs affect the response to endocrine therapy. Thus, ncRNAs are considered versatile biomarkers to predict or monitor therapy response. In this review article, we intend to give a summary and update on the effects of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) on estrogen signaling in BC cells, this pathway being the target of endocrine therapy, and their role in therapy resistance. For this purpose, we reviewed articles on these topics listed in the PubMed database. Finally, we provide an assessment regarding the clinical use of these ncRNA types, particularly their circulating forms, as predictive BC biomarkers and their potential role as therapy targets to overcome endocrine resistance.
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Affiliation(s)
- Oliver Treeck
- Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany
- Correspondence:
| | - Silke Haerteis
- Institute for Molecular and Cellular Anatomy, University of Regensburg, 93053 Regensburg, Germany
| | - Olaf Ortmann
- Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany
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14
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Kim JY, Jung EJ, Kim JM, Son Y, Lee HS, Kwag SJ, Park JH, Cho JK, Kim HG, Park T, Jeong SH, Jeong CY, Ju YT. MiR‑221 and miR‑222 regulate cell cycle progression and affect chemosensitivity in breast cancer by targeting ANXA3. Exp Ther Med 2023; 25:127. [PMID: 36845963 PMCID: PMC9947582 DOI: 10.3892/etm.2023.11826] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 12/15/2022] [Indexed: 02/10/2023] Open
Abstract
Breast malignancy remains one of the most common causes of cancer-associated mortalities among women. MicroRNA (miR)-221 and miR-222 are homologous miRs and have a substantial impact on cancer progression. In the present study, the regulatory mechanisms of miR-221/222 and its target annexin A3 (ANXA3) in breast cancer cells were investigated. Breast tissue samples were collected to evaluate the expression patterns of miR-221/222 levels in breast cancer cell lines and cancer tissues according to clinical characteristics. The levels of miR-221/222 were increased or decreased in cancer cell lines compared with normal breast cell lines according to cell line subtype. Subsequently, the changes in the progression and invasion of breast cancer cells were investigated using cell proliferation, invasion assay, gap closure and colony formation assays. Western blotting of cell cycle proteins and flow cytometry were performed to evaluate the possible pathway of miR-221/222 and ANXA3 axis. Chemosensitivity tests were performed to explore the suitability of the miR-221/222 and ANXA3 axis as a therapeutic target in breast cancer. The expression levels of miR-221/222 were associated with aggressive characteristics of breast cancer subtypes. Cell transfection assay demonstrated the regulation of breast cancer proliferation and invasiveness by miR-221/222. MiR-221/222 directly targeted the 3'-untranslated region of ANXA3 and suppressed the expression of ANXA3 at the mRNA and protein levels. In addition, miR-221/222 negatively regulated cell proliferation and the cell cycle pathway in breast cancer cells by targeting ANXA3. In combination with adriamycin, downregulation of ANXA3 may sensitize adriamycin-induced cell death to induction of persistent G2/M and G0/G1 arrest. Decreased expression of ANXA3 through increased expression of miR-221/222 reduced breast cancer progression and increased the effectiveness of the chemotherapy drug. The present results indicated the miR-221/222 and ANXA3 axis to be a possible novel therapeutic target for the treatment of breast cancer.
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Affiliation(s)
- Ju-Yeon Kim
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Eun Jung Jung
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Gyeongsang 51472, Republic of Korea
| | - Jae-Myung Kim
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Youngsim Son
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Han Shine Lee
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Gyeongsang 51472, Republic of Korea
| | - Seung-Jin Kwag
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Ji-Ho Park
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Jin-Kyu Cho
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Han-Gil Kim
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Taejin Park
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Gyeongsang 51472, Republic of Korea
| | - Sang-Ho Jeong
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Gyeongsang 51472, Republic of Korea
| | - Chi-Young Jeong
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Young-Tae Ju
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
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15
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Liu Z, Wang M, Cheng A, Ou X, Mao S, Yang Q, Wu Y, Zhao XX, Huang J, Gao Q, Zhang S, Sun D, Tian B, Jia R, Chen S, Liu M, Zhu D. Gene regulation in animal miRNA biogenesis. Epigenomics 2022; 14:1197-1212. [PMID: 36382497 DOI: 10.2217/epi-2022-0214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
miRNAs are a class of noncoding RNAs of approximately 19-22 nucleotides that are widely found in animals, plants, bacteria and even viruses. Dysregulation of the expression profile of miRNAs is importantly linked to the development of diseases. Epigenetic modifications regulate gene expression and control cellular phenotypes. Although miRNAs are used as an epigenetic regulation tool, the biogenesis of miRNAs is also regulated by epigenetic events. Here the authors review the mechanisms and roles of epigenetic modification (DNA methylation, histone modifications), RNA modification and ncRNAs in the biogenesis of miRNAs, aiming to deepen the understanding of the miRNA biogenesis regulatory network.
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Affiliation(s)
- Zezheng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Xumin Ou
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Sai Mao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Qiao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Ying Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Xin-Xin Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Juan Huang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Qun Gao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Shaqiu Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Di Sun
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Bin Tian
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
| | - Dekang Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, People's Republic of China
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16
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Liu H, Zhao H, Sun Y. Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. Semin Cancer Biol 2022; 86:769-781. [PMID: 34799201 DOI: 10.1016/j.semcancer.2021.11.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 10/24/2021] [Accepted: 11/08/2021] [Indexed: 01/27/2023]
Abstract
The tumor microenvironment (TME) is a major contributor to cancer malignancy including development of therapeutic resistance, a process mediated in part through intercellular crosstalk. Besides diverse soluble factors responsible for pro-survival pathway activation, immune evasion and extracellular matrix (ECM) remodeling further promote cancer resistance. Importantly, therapy-induced senescence (TIS) of cells in the TME is frequently observed in anticancer regimens, an off-target effect that can generate profound impacts on disease progression. By conferring the resistance and fueling the repopulation of remaining cancerous cells, TIS is responsible for tumor relapse and distant metastasis in posttreatment stage. This pathological trajectory can be substantially driven by the pro-inflammatory feature of senescent cells, termed as the senescence-associated secretory phenotype (SASP). Targeting strategies to selectively and efficiently remove senescent cells before they exert non-autonomous but largely deleterious effects, are emerging as an effective solution to prevent drug resistance acquired from a treatment-remodeled TME. In this review, we summarize the TME composition and key activities that affect tissue homeostasis and support treatment resistance. Promising opportunities that allow TME-manipulation and senescent cell-targeting (senotherapy) are discussed, with translational pipelines to overcome therapeutic barriers in clinical oncology projected.
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Affiliation(s)
- Hanxin Liu
- Department of Pharmacology, Institute of Aging Medicine, Binzhou Medical University, Yantai, Shandong, 264003, China
| | - Huifang Zhao
- Department of Pharmacology, Institute of Aging Medicine, Binzhou Medical University, Yantai, Shandong, 264003, China
| | - Yu Sun
- Department of Pharmacology, Institute of Aging Medicine, Binzhou Medical University, Yantai, Shandong, 264003, China; CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; Department of Medicine and VAPSHCS, University of Washington, Seattle, WA, 98195, USA.
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17
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Wei W, Schon KR, Elgar G, Orioli A, Tanguy M, Giess A, Tischkowitz M, Caulfield MJ, Chinnery PF. Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes. Nature 2022; 611:105-114. [PMID: 36198798 PMCID: PMC9630118 DOI: 10.1038/s41586-022-05288-7] [Citation(s) in RCA: 101] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 08/29/2022] [Indexed: 02/02/2023]
Abstract
DNA transfer from cytoplasmic organelles to the cell nucleus is a legacy of the endosymbiotic event-the majority of nuclear-mitochondrial segments (NUMTs) are thought to be ancient, preceding human speciation1-3. Here we analyse whole-genome sequences from 66,083 people-including 12,509 people with cancer-and demonstrate the ongoing transfer of mitochondrial DNA into the nucleus, contributing to a complex NUMT landscape. More than 99% of individuals had at least one of 1,637 different NUMTs, with 1 in 8 individuals having an ultra-rare NUMT that is present in less than 0.1% of the population. More than 90% of the extant NUMTs that we evaluated inserted into the nuclear genome after humans diverged from apes. Once embedded, the sequences were no longer under the evolutionary constraint seen within the mitochondrion, and NUMT-specific mutations had a different mutational signature to mitochondrial DNA. De novo NUMTs were observed in the germline once in every 104 births and once in every 103 cancers. NUMTs preferentially involved non-coding mitochondrial DNA, linking transcription and replication to their origin, with nuclear insertion involving multiple mechanisms including double-strand break repair associated with PR domain zinc-finger protein 9 (PRDM9) binding. The frequency of tumour-specific NUMTs differed between cancers, including a probably causal insertion in a myxoid liposarcoma. We found evidence of selection against NUMTs on the basis of size and genomic location, shaping a highly heterogenous and dynamic human NUMT landscape.
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Affiliation(s)
- Wei Wei
- Department of Clinical Neuroscience, School of Clinical Medicine, University of Cambridge, Cambridge, UK
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
| | - Katherine R Schon
- Department of Clinical Neuroscience, School of Clinical Medicine, University of Cambridge, Cambridge, UK
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
- Academic Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | | | | | | | | | - Marc Tischkowitz
- Academic Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Mark J Caulfield
- William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Patrick F Chinnery
- Department of Clinical Neuroscience, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
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18
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Ismail A, El-Mahdy HA, Abulsoud AI, Sallam AAM, Eldeib MG, Elsakka EG, Zaki MB, Doghish AS. Beneficial and detrimental aspects of miRNAs as chief players in breast cancer: A comprehensive review. Int J Biol Macromol 2022; 224:1541-1565. [DOI: 10.1016/j.ijbiomac.2022.10.241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/12/2022] [Accepted: 10/24/2022] [Indexed: 11/05/2022]
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19
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Ozyurt R, Ozpolat B. Molecular Mechanisms of Anti-Estrogen Therapy Resistance and Novel Targeted Therapies. Cancers (Basel) 2022; 14:5206. [PMID: 36358625 PMCID: PMC9655708 DOI: 10.3390/cancers14215206] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/05/2022] [Accepted: 10/20/2022] [Indexed: 07/29/2023] Open
Abstract
Breast cancer (BC) is the most commonly diagnosed cancer in women, constituting one-third of all cancers in women, and it is the second leading cause of cancer-related deaths in the United States. Anti-estrogen therapies, such as selective estrogen receptor modulators, significantly improve survival in estrogen receptor-positive (ER+) BC patients, which represents about 70% of cases. However, about 60% of patients inevitably experience intrinsic or acquired resistance to anti-estrogen therapies, representing a major clinical problem that leads to relapse, metastasis, and patient deaths. The resistance mechanisms involve mutations of the direct targets of anti-estrogen therapies, compensatory survival pathways, as well as alterations in the expression of non-coding RNAs (e.g., microRNA) that regulate the activity of survival and signaling pathways. Although cyclin-dependent kinase 4/6 and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors have significantly improved survival, the efficacy of these therapies alone and in combination with anti-estrogen therapy for advanced ER+ BC, are not curative in advanced and metastatic disease. Therefore, understanding the molecular mechanisms causing treatment resistance is critical for developing highly effective therapies and improving patient survival. This review focuses on the key mechanisms that contribute to anti-estrogen therapy resistance and potential new treatment strategies alone and in combination with anti-estrogen drugs to improve the survival of BC patients.
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Affiliation(s)
- Rumeysa Ozyurt
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Houston Methodist Research Institute, Department of Nanomedicine, 6670 Bertner Ave, Houston, TX 77030, USA
| | - Bulent Ozpolat
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Houston Methodist Research Institute, Department of Nanomedicine, 6670 Bertner Ave, Houston, TX 77030, USA
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20
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Cai Y, Zhou Y, Li Z, Xia P, ChenFu X, Shi A, Zhang J, Yu P. Non-coding RNAs in necroptosis, pyroptosis, and ferroptosis in cardiovascular diseases. Front Cardiovasc Med 2022; 9:909716. [PMID: 35990979 PMCID: PMC9386081 DOI: 10.3389/fcvm.2022.909716] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/04/2022] [Indexed: 11/18/2022] Open
Abstract
Accumulating evidence has proved that non-coding RNAs (ncRNAs) play a critical role in the genetic programming and gene regulation of cardiovascular diseases (CVDs). Cardiovascular disease morbidity and mortality are rising and have become a primary public health issue that requires immediate resolution through effective intervention. Numerous studies have revealed that new types of cell death, such as pyroptosis, necroptosis, and ferroptosis, play critical cellular roles in CVD progression. It is worth noting that ncRNAs are critical novel regulators of cardiovascular risk factors and cell functions by mediating pyroptosis, necroptosis, and ferroptosis. Thus, ncRNAs can be regarded as promising therapeutic targets for treating and diagnosing cardiovascular diseases. Recently, there has been a surge of interest in the mediation of ncRNAs on three types of cell death in regulating tissue homeostasis and pathophysiological conditions in CVDs. Although our understanding of ncRNAs remains in its infancy, the studies reviewed here may provide important new insights into how ncRNAs interact with CVDs. This review summarizes what is known about the functions of ncRNAs in modulating cell death-associated CVDs and their role in CVDs, as well as their current limitations and future prospects.
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Affiliation(s)
- Yuxi Cai
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yiwen Zhou
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhangwang Li
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Panpan Xia
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Metabolism and Endocrinology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
- Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, China
- Branch of National Clinical Research Center for Metabolic Diseases, Nanchang, China
| | - Xinxi ChenFu
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Metabolism and Endocrinology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
- Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, China
- Branch of National Clinical Research Center for Metabolic Diseases, Nanchang, China
| | - Ao Shi
- School of Medicine, University of Nicosia, Nicosia, Cyprus
- School of Medicine, St. George University of London, London, United Kingdom
| | - Jing Zhang
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jing Zhang
| | - Peng Yu
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Metabolism and Endocrinology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
- Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, China
- *Correspondence: Peng Yu
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Predictors of fulvestrant long-term benefit in hormone receptor-positive/HER2 negative advanced breast cancer. Sci Rep 2022; 12:12789. [PMID: 35896637 PMCID: PMC9329443 DOI: 10.1038/s41598-022-16409-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/11/2022] [Indexed: 11/08/2022] Open
Abstract
We retrospectively investigated in women treated with fulvestrant for HR+/HER2 negative advanced breast cancer clinical, pathological and molecular features associated with long-term benefit from treatment defined as being progression-free at 18 months. Specifically, we analyzed on formalin-fixed paraffin-embedded tumor samples ESR1 and PI3KCA mutations and miRNAs profiles. 59 patients were evaluable (median age of 67 years, range 32-92). 18-month PFS rate was 27%; the lack of visceral metastases significantly predicted the likelihood of being progression-free at 18 months, while PI3KCA mutations, found in 36% of patients, were not associated with 18-month PFS. As of miRNAs, miR-549a, miR-644a, miR-16-5p were negatively while let-7c-5p was positively associated with 18-month PFS. In addition, miR-520d-3p and miR-548g-3p values were significantly lower while miR-603, miR-181a-5p and miR-199a-miR-199b-3p values were significantly higher in patients achieving 18-month PFS. In silico analysis of targets modulated by these two latter groups of miRNAs show that in patients achieving 18-month PFS the Hippo and Wnt signaling pathways were predicted to be upregulated while endocrine resistance was potentially repressed by miR-603, miR-181a-5p and miR-199a-miR-199b-3p. Our results provide additional clues on the molecular mechanisms involved in fulvestrant activity and resistance. Underlying pathways should be further elucidated and confirmed in larger cohorts.
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22
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Saha T, Lukong KE. Breast Cancer Stem-Like Cells in Drug Resistance: A Review of Mechanisms and Novel Therapeutic Strategies to Overcome Drug Resistance. Front Oncol 2022; 12:856974. [PMID: 35392236 PMCID: PMC8979779 DOI: 10.3389/fonc.2022.856974] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most frequent type of malignancy in women worldwide, and drug resistance to the available systemic therapies remains a major challenge. At the molecular level, breast cancer is heterogeneous, where the cancer-initiating stem-like cells (bCSCs) comprise a small yet distinct population of cells within the tumor microenvironment (TME) that can differentiate into cells of multiple lineages, displaying varying degrees of cellular differentiation, enhanced metastatic potential, invasiveness, and resistance to radio- and chemotherapy. Based on the expression of estrogen and progesterone hormone receptors, expression of human epidermal growth factor receptor 2 (HER2), and/or BRCA mutations, the breast cancer molecular subtypes are identified as TNBC, HER2 enriched, luminal A, and luminal B. Management of breast cancer primarily involves resection of the tumor, followed by radiotherapy, and systemic therapies including endocrine therapies for hormone-responsive breast cancers; HER2-targeted therapy for HER2-enriched breast cancers; chemotherapy and poly (ADP-ribose) polymerase inhibitors for TNBC, and the recent development of immunotherapy. However, the complex crosstalk between the malignant cells and stromal cells in the breast TME, rewiring of the many different signaling networks, and bCSC-mediated processes, all contribute to overall drug resistance in breast cancer. However, strategically targeting bCSCs to reverse chemoresistance and increase drug sensitivity is an underexplored stream in breast cancer research. The recent identification of dysregulated miRNAs/ncRNAs/mRNAs signatures in bCSCs and their crosstalk with many cellular signaling pathways has uncovered promising molecular leads to be used as potential therapeutic targets in drug-resistant situations. Moreover, therapies that can induce alternate forms of regulated cell death including ferroptosis, pyroptosis, and immunotherapy; drugs targeting bCSC metabolism; and nanoparticle therapy are the upcoming approaches to target the bCSCs overcome drug resistance. Thus, individualizing treatment strategies will eliminate the minimal residual disease, resulting in better pathological and complete response in drug-resistant scenarios. This review summarizes basic understanding of breast cancer subtypes, concept of bCSCs, molecular basis of drug resistance, dysregulated miRNAs/ncRNAs patterns in bCSCs, and future perspective of developing anticancer therapeutics to address breast cancer drug resistance.
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Affiliation(s)
- Taniya Saha
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Kiven Erique Lukong
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
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23
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Feng X, Zhang L, Feng W, Zhang C, Jin T, Li J, Guo J. miR-221 promotes keratinocyte proliferation and migration by targeting SOCS7 and is regulated by YB-1. J Cell Mol Med 2022; 26:2299-2311. [PMID: 35201663 PMCID: PMC8995440 DOI: 10.1111/jcmm.17250] [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: 06/15/2021] [Revised: 01/26/2022] [Accepted: 01/31/2022] [Indexed: 11/28/2022] Open
Abstract
Proliferation and migration of keratinocytes are vital processes for the successful epithelization specifically after wounding. MiR‐221 has been identified to play a potential role in promoting wound regeneration by inducing blood vessel formation. However, little is known about the role of miR‐221 in the keratinocyte proliferation and migration during wound healing. An in vivo mice wound‐healing model was generated; the expression levels of miR‐221 were assessed by qRT‐PCR and fluorescence in situ hybridization. Initially, we found that miR‐221 was upregulated in the proliferative phase of wound healing. Further, in an in vivo wound‐healing mice model, targeted delivery of miR‐221 mimics accelerated wound healing. Contrastingly, inhibition of miR‐221 delayed healing. Additionally, we observed that overexpression of miR‐221 promoted cell proliferation and migration, while inhibition of miR‐221 had the opposite effects. Moreover, we identified SOCS7 as a direct target of miR‐221 in keratinocytes and overexpression of SOCS7 reversed the effects of miR‐221 in HaCaT keratinocytes. Finally, we identified that YB‐1 regulates the expression of miR‐221 in HaCaT keratinocytes. Overall, our experiments suggest that miR‐221 is regulated by YB‐1 in HaCaT keratinocytes and acts on SOCS7, thereby playing an important role in HaCaT keratinocyte proliferation and migration during wound healing.
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Affiliation(s)
- Xiao Feng
- Department of Plastic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Lei Zhang
- Department of Plastic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Wei Feng
- Department of Plastic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Ce Zhang
- Department of Plastic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Tingting Jin
- Department of Plastic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Jingyu Li
- Department of Plastic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Jincai Guo
- Department of Plastic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
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24
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Zhao Y, Wang X, Liu Y, Wang HY, Xiang J. The effects of estrogen on targeted cancer therapy drugs. Pharmacol Res 2022; 177:106131. [DOI: 10.1016/j.phrs.2022.106131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/29/2022] [Accepted: 02/10/2022] [Indexed: 10/19/2022]
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25
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Alam M, Ali S, Ashraf GM, Bilgrami AL, Yadav DK, Hassan MI. Epigallocatechin 3-gallate: From green tea to cancer therapeutics. Food Chem 2022; 379:132135. [PMID: 35063850 DOI: 10.1016/j.foodchem.2022.132135] [Citation(s) in RCA: 133] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/22/2021] [Accepted: 01/09/2022] [Indexed: 12/13/2022]
Abstract
Epigallocatechin 3-gallate (EGCG) possesses various biological functions, including anti-cancer and anti-inflammatory properties. EGCG is an abundant polyphenolic component originating from green tea extract that has exhibited versatile bioactivities in combating several cancers. This review highlights the pharmacological features of EGCG and its therapeutic implications in cancer and other metabolic diseases. It modulates numerous signaling pathways, regulating cells' undesired survival and proliferation, thus imparting strong tumor chemopreventive and therapeutic effects. EGCG initiates cell death through the intrinsic pathway and causes inhibition of EGFR, STAT3, and ERK pathways in several cancers. EGCG alters and inhibits ERK1/2, NF-κB, and Akt-mediated signaling, altering the Bcl-2 family proteins ratio and activating caspases in tumor cells. This review focuses on anti-cancer, anti-oxidant, anti-inflammatory, anti-angiogenesis, and apoptotic effects of EGCG. We further highlighted the potential of EGCG in different types of cancer, emphasizing clinical trials formulations that further improve our understanding of the therapeutic management of cancer and inflammatory diseases.
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Affiliation(s)
- Manzar Alam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Sabeeha Ali
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Anwar L Bilgrami
- Deanship of Scientific Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Dharmendra Kumar Yadav
- College of Pharmacy, Gachon University of Medicine and Science, Hambakmoeiro, Yeonsu-gu, Incheon City 21924, South Korea.
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.
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26
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Xia S, Lin Q. Estrogen Receptor Bio-Activities Determine Clinical Endocrine Treatment Options in Estrogen Receptor-Positive Breast Cancer. Technol Cancer Res Treat 2022; 21:15330338221090351. [PMID: 35450488 PMCID: PMC9036337 DOI: 10.1177/15330338221090351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
In estrogen receptor positive (ER+) breast cancer therapy, estrogen receptors (ERs) are the major targeting molecules. ER-targeted therapy has provided clinical benefits for approximately 70% of all breast cancer patients through targeting the ERα subtype. In recent years, mechanisms underlying breast cancer occurrence and progression have been extensively studied and largely clarified. The PI3K/AKT/mTOR pathway, microRNA regulation, and other ER downstream signaling pathways are found to be the effective therapeutic targets in ER+ BC therapy. A number of the ER+ (ER+) breast cancer biomarkers have been established for diagnosis and prognosis. The ESR1 gene mutations that lead to endocrine therapy resistance in ER+ breast cancer had been identified. Mutations in the ligand-binding domain of ERα which encoded by ESR1 gene occur in most cases. The targeted drugs combined with endocrine therapy have been developed to improve the therapeutic efficacy of ER+ breast cancer, particularly the endocrine therapy resistance ER+ breast cancer. The combination therapy has been demonstrated to be superior to monotherapy in overall clinical evaluation. In this review, we focus on recent progress in studies on ERs and related clinical applications for targeted therapy and provide a perspective view for therapy of ER+ breast cancer.
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Affiliation(s)
- Song Xia
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Qiong Lin
- School of Medicine, Jiangsu University, Zhenjiang, China
- Qiong Lin, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China.
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27
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Amiruddin A, Massi MN, Islam AA, Patellongi I, Pratama MY, Sutandyo N, Natzir R, Hatta M, Md Latar NH, Wahid S. microRNA-221 and tamoxifen resistance in luminal-subtype breast cancer patients: A case-control study. Ann Med Surg (Lond) 2022; 73:103092. [PMID: 35079352 PMCID: PMC8767262 DOI: 10.1016/j.amsu.2021.103092] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/18/2021] [Accepted: 11/20/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Around 70% of breast cancers (BCs) are estrogen receptor-α (ERα)-positive. Adjuvant endocrine therapy is used to reduce estrogen levels and inhibit signal transduction through the ER. The anti-estrogen drugs that are most commonly used in endocrine therapy belong to the selective ER modulator (SERM) class and include tamoxifen. Although it has been used for three decades in cases of early-stage and ERα-positive BC, resistance to tamoxifen is a common problem. microRNAs (miRNAs) have a potential role in demonstrating BC resistance to tamoxifen therapy. Hence, there is a need to investigate the expression of miRNA-221 (miR-221) in luminal-subtype BC patients receiving tamoxifen therapy. METHODS This case-control study investigated luminal-subtype BC patients who had undergone endocrine therapy for at least 1 year. The case group comprised patients with local or metastatic recurrence, and the control group comprised patients without local or metastatic recurrence. RESULTS There was a significant difference in miR-221 expression (p = 0.005) between the case and control groups. There were no significant differences between the groups that were positive and negative for the progesterone receptor (PR) (p = 0.25), had high and low marker of proliferation Ki-67 levels (p = 0.60), were positive and negative for lymphovascular invasion (p = 0.14), and had stage 2 and stage 3 cancer (p = 0.25). CONCLUSION miR-221 expression was higher in tamoxifen-resistant BC cases. miR-221 is a potential biomarker of tamoxifen resistance.
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Affiliation(s)
- Alfiah Amiruddin
- Doctoral Program of Biomedical Sciences, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Muhammad Nassrum Massi
- Department of Microbiology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Andi Asadul Islam
- Department of Neurosurgery, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Ilhamjaya Patellongi
- Department of Physiology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Muhammad Yogi Pratama
- Department of Pathology Anatomy, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Noorwati Sutandyo
- Department of Medical Hematology-Oncology, Dharmais Hospital National Cancer Center, Jakarta, Indonesia
| | - Rosdiana Natzir
- Department of Biochemistry, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | - Mochammad Hatta
- Department of Microbiology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Nani Harlina Md Latar
- Endocrine and Breast Surgery Unit, Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Syarifuddin Wahid
- Department of Pathology Anatomy, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
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28
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Crosstalk between non-coding RNAs expression profile, drug resistance and immune response in breast cancer. Pharmacol Res 2021; 176:106041. [PMID: 34952200 DOI: 10.1016/j.phrs.2021.106041] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/15/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022]
Abstract
Drug resistance is one of the most critical challenges facing researchers in treating breast cancer. Despite numerous treatments for breast cancer, including conventional chemical drugs, monoclonal antibodies, and immunotherapeutic drugs known as immune checkpoint inhibitors (ICI), many patients resist various approaches. In recent years, the relationship between gene expression profiles and drug resistance phenotypes has attracted much attention. Non-coding RNAs (ncRNAs) are regulatory molecules that have been shown to regulate gene expression and cell transcriptome. Two categories, microRNAs and long non-coding RNAs have been more considered and studied among these ncRNAs. Studying the role of different ncRNAs in chemical drug resistance and ICI resistance together can be beneficial in selecting more effective treatments for breast cancer. Changing the expression and action mechanism of these regulatory molecules on drug resistance phenotypes is the main topic of this review article.
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29
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Escher TE, Dandawate P, Sayed A, Hagan CR, Anant S, Lewis-Wambi J. Enhanced IFNα Signaling Promotes Ligand-Independent Activation of ERα to Promote Aromatase Inhibitor Resistance in Breast Cancer. Cancers (Basel) 2021; 13:5130. [PMID: 34680281 PMCID: PMC8534010 DOI: 10.3390/cancers13205130] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/06/2021] [Accepted: 10/11/2021] [Indexed: 01/07/2023] Open
Abstract
Aromatase inhibitors (AIs) reduce estrogen levels up to 98% as the standard practice to treat postmenopausal women with estrogen receptor-positive (ER+) breast cancer. However, approximately 30% of ER+ breast cancers develop resistance to treatment. Enhanced interferon-alpha (IFNα) signaling is upregulated in breast cancers resistant to AIs, which drives expression of a key regulator of survival, interferon-induced transmembrane protein 1 (IFITM1). However, how upregulated IFNα signaling mediates AI resistance is unknown. In this study, we utilized MCF-7:5C cells, a breast cancer cell model of AI resistance, and demonstrate that these cells exhibit enhanced IFNα signaling and ligand-independent activation of the estrogen receptor (ERα). Experiments demonstrated that STAT1, the mediator of intracellular signaling for IFNα, can interact directly with ERα. Notably, inhibition of IFNα signaling significantly reduced ERα protein expression and ER-regulated genes. In addition, loss of ERα suppressed IFITM1 expression, which was associated with cell death. Notably, chromatin immunoprecipitation experiments validated that both ERα and STAT1 associate with ERE sequences in the IFITM1 promoter. Overall, hyperactivation of IFNα signaling enhances ligand-independent activation of ERα, which promotes ER-regulated, and interferon stimulated gene expression to promote survival in AI-resistant breast cancer cells.
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Affiliation(s)
- Taylor E. Escher
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
| | - Prasad Dandawate
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
- The University of Kansas Cancer Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Afreen Sayed
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
| | - Christy R. Hagan
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
- The University of Kansas Cancer Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
- The University of Kansas Cancer Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Joan Lewis-Wambi
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; (T.E.E.); (P.D.); (A.S.); (C.R.H.); (S.A.)
- The University of Kansas Cancer Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
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30
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Shi D, Zhang Y, Mao T, Liu D, Liu W, Luo B. MiR-BART2-3p targets Unc-51-like kinase 1 and inhibits cell autophagy and migration in Epstein-Barr virus-associated gastric cancer. Virus Res 2021; 305:198567. [PMID: 34555439 DOI: 10.1016/j.virusres.2021.198567] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/01/2021] [Accepted: 09/07/2021] [Indexed: 12/29/2022]
Abstract
ULK1 (Unc-51-like kinase 1) is an evolutionarily conserved serine/threonine kinase that plays a central role in the regulation of autophagy. ULK1 is associated with prognosis for metastasis and survival in several tumors. However, its relationship with Epstein-Barr virus (EBV) has not been studied. We found that the expression of ULK1 in EBV-associated gastric cancer cells was lower than that in EBV-negative gastric cancer cells. Further, a luciferase reporter gene assay showed that miR-BART2-3p directly targets ULK1. EBV-miR-BART2-3p attenuated endogenous protein expression levels of some autophagy-related genes. MiR-BART2-3p could thus be involved in the regulation of autophagy. Most important, our research indicates that miR-BART2-3p targets ULK1, resulting in downregulation of epithelial-mesenchymal transformation (EMT) -associated marker proteins and reducing EMT and cell migration. Our study shows that modulation of ULK1 is the likely mechanism by which miR-BART2-3p participates in the regulation of autophagy and cancer cell migration.
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Affiliation(s)
- Duo Shi
- Department of Pathogeny Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Yan Zhang
- Department of Pathogeny Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China; Department of Clinical Laboratory, Zibo Central Hospital, ZiBo, 255000, China
| | - Tao Mao
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Dandan Liu
- Department of Pathogeny Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Wen Liu
- Department of Pathogeny Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Bing Luo
- Department of Pathogeny Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
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31
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Dittmer J. Nuclear Mechanisms Involved in Endocrine Resistance. Front Oncol 2021; 11:736597. [PMID: 34604071 PMCID: PMC8480308 DOI: 10.3389/fonc.2021.736597] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/26/2021] [Indexed: 12/27/2022] Open
Abstract
Endocrine therapy is a standard treatment offered to patients with ERα (estrogen receptor α)-positive breast cancer. In endocrine therapy, ERα is either directly targeted by anti-estrogens or indirectly by aromatase inhibitors which cause estrogen deficiency. Resistance to these drugs (endocrine resistance) compromises the efficiency of this treatment and requires additional measures. Endocrine resistance is often caused by deregulation of the PI3K/AKT/mTOR pathway and/or cyclin-dependent kinase 4 and 6 activities allowing inhibitors of these factors to be used clinically to counteract endocrine resistance. The nuclear mechanisms involved in endocrine resistance are beginning to emerge. Exploring these mechanisms may reveal additional druggable targets, which could help to further improve patients' outcome in an endocrine resistance setting. This review intends to summarize our current knowledge on the nuclear mechanisms linked to endocrine resistance.
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Affiliation(s)
- Jürgen Dittmer
- Clinic for Gynecology, Martin Luther University Halle-Wittenberg, Halle, Germany
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32
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Andrikopoulou A, Shalit A, Zografos E, Koutsoukos K, Korakiti AM, Liontos M, Dimopoulos MA, Zagouri F. MicroRNAs as Potential Predictors of Response to CDK4/6 Inhibitor Treatment. Cancers (Basel) 2021; 13:cancers13164114. [PMID: 34439268 PMCID: PMC8391635 DOI: 10.3390/cancers13164114] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/07/2021] [Accepted: 08/11/2021] [Indexed: 01/07/2023] Open
Abstract
Simple Summary MicroRNAs are endogenous non-coding 20–22 nucleotide long RNAs that play a fundamental role in the post-transcriptional control of gene expression. Consequently, microRNAs are involved in multiple biological processes of cancer and could be used as biomarkers with prognostic and predictive significance. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become a mainstay of treatment for patients with advanced hormone receptor-positive (HR) breast cancer. Despite the initial high response rates, approximately 10% of patients demonstrate primary resistance to CDK4/6 inhibitors while acquired resistance is almost inevitable. Considering the fundamental role of miRNAs in tumorigenesis, we aimed to explore the potential involvement of microRNAs in response to CDK4/6 inhibition in solid tumors. A number of microRNAs were shown to confer resistance or sensitivity to CDK4/6 inhibitors in preclinical studies, although this remains to be proved in human studies. Abstract Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as novel treatment options in the management of advanced or metastatic breast cancer. MicroRNAs are endogenous non-coding 19–22-nucleotide-long RNAs that regulate gene expression in development and tumorigenesis. Herein, we systematically review all microRNAs associated with response to CDK4/6 inhibitors in solid tumors and hematological malignancies. Eligible articles were identified by a search of the MEDLINE and ClinicalTrials.gov databases for the period up to1 January 2021; the algorithm consisted of a predefined combination of the words “microRNAs”, “cancer” and “CDK 4/6 inhibitors”. Overall, 15 studies were retrieved. Six microRNAs (miR-126, miR-326, miR3613-3p, miR-29b-3p, miR-497 and miR-17-92) were associated with sensitivity to CDK4/6 inhibitors. Conversely, six microRNAs (miR-193b, miR-432-5p, miR-200a, miR-223, Let-7a and miR-21) conferred resistance to treatment with CDK4/6 inhibitors. An additional number of microRNAs (miR-124a, miR9, miR200b and miR-106b) were shown to mediate cellular response to CDK4/6 inhibitors without affecting sensitivity to treatment. Collectively, our review provides evidence that microRNAs could serve as predictive biomarkers for treatment with CDK4/6 inhibitors. Moreover, microRNA-targeted therapy could potentially maximize sensitivity to CDK4/6 inhibition.
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Affiliation(s)
- Angeliki Andrikopoulou
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, 11528 Athens, Greece; (A.A.); (E.Z.); (K.K.); (A.-M.K.); (M.L.); (M.-A.D.)
| | - Almog Shalit
- Medical School, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece;
| | - Eleni Zografos
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, 11528 Athens, Greece; (A.A.); (E.Z.); (K.K.); (A.-M.K.); (M.L.); (M.-A.D.)
| | - Konstantinos Koutsoukos
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, 11528 Athens, Greece; (A.A.); (E.Z.); (K.K.); (A.-M.K.); (M.L.); (M.-A.D.)
| | - Anna-Maria Korakiti
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, 11528 Athens, Greece; (A.A.); (E.Z.); (K.K.); (A.-M.K.); (M.L.); (M.-A.D.)
| | - Michalis Liontos
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, 11528 Athens, Greece; (A.A.); (E.Z.); (K.K.); (A.-M.K.); (M.L.); (M.-A.D.)
| | - Meletios-Athanasios Dimopoulos
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, 11528 Athens, Greece; (A.A.); (E.Z.); (K.K.); (A.-M.K.); (M.L.); (M.-A.D.)
| | - Flora Zagouri
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, 11528 Athens, Greece; (A.A.); (E.Z.); (K.K.); (A.-M.K.); (M.L.); (M.-A.D.)
- Correspondence: ; Tel.: +30-21-0338-1554; Fax: +30-21-3216-2511
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Chien TJ. A review of the endocrine resistance in hormone-positive breast cancer. Am J Cancer Res 2021; 11:3813-3831. [PMID: 34522451 PMCID: PMC8414389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/25/2021] [Indexed: 06/13/2023] Open
Abstract
Hormone-positive breast cancer (BC) is a unique heterogeneous disease with a favorable prognosis compared to other types of breast cancer. As tumor biology influences the prognosis and clinical treatment, a deep understanding of how the molecular mechanisms regulate hormone sensitivity or resistance is critical in improving the efficacy and overcoming the endocrine resistance. This article comprehensively reviews the endocrine resistance in hormone-positive BC from a molecular and genetic perspective, encompassing the updated treatment and developing direction. This review includes the mechanisms of hormone resistance, which vary from epigenetic changes, crosstalk between signaling networks, cell cycle aberrance, and even change in the tumor microenvironment (TME) or stem cell. These mechanisms may contribute to treatment resistance. Current targeted therapy for hormone-resistant tumors includes PI3K/AKT/mTOR and cdk4/6 inhibitors. Several relevant pathways, biomarkers, and predictor genes have also been identified. Immunotherapy so far has a relatively less crucial role in hormone-positive than in triple-negative BC. Furthermore, the methodology to identify the PDL1 is not standardized. In a molecule and gene study, next-generation sequencing with circulating tumor DNA (ctDNA) has recently appeared as a sensitive and minimally invasive tool worth investigating.
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Affiliation(s)
- Tsai-Ju Chien
- Division of Hemato-Oncology, Department of Internal Medicine, Branch of Zhong-Zhou, Taipei City HospitalTaipei, Taiwan
- Division of Hemato-Oncology, Department of Internal Medicine, Branch of Jen-Ai, Taipei City HospitalTaipei, Taiwan
- Institute of Traditional Medicine, National Yang-Ming Chiao Tung UniversityTaipei, Taiwan
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Mahmoudian-Sani MR, Asadi-Samani M. Modulation of MicroRNAs by Euphorbia Microsciadia Boiss in MDA-MB-231 Cell Line: New Possibilities in Breast Cancer Therapy. Recent Pat Anticancer Drug Discov 2021; 15:174-184. [PMID: 32603285 DOI: 10.2174/1574892815666200630102944] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 04/16/2020] [Accepted: 06/29/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND A large number of Euphorbia species have been evaluated for anticancer effects; however, their anticancer mechanisms have not been established up to now. OBJECTIVE The present study aimed to evaluate the effects of Euphorbia microsciadia (E. microsciadia) Boiss on the modulation of micro (mi) RNAs in MDA-MB-231 cell line. METHODS As the first step, the inhibitory concentration of hydroalcoholic extract of E. microsciadia on MDA-MB-231 cells was examined using the MTT assay, bypassing 24 and 48h from seeding. The real-time quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) was also utilized to determine Let-7, miR-15, miR-16, miR-29, miR-151, miR-155, miR-21, miR-146b, miR-181b, miR-221, miR-222, miR-21, and miR-146b expressions in MDA-MB-231 cells, by passing 24 and 48h from treating with the extract of E. microsciadia. RESULTS The results reveal the cytotoxic effects of E. microsciadia on MDA-MB-231 cell line in a dose-dependent manner. The half maximal Inhibitory Concentrations (IC50) were also equal to 275 and 240μg/ml for E. microsciadia, by passing 24 and 48h from the treatment, respectively. Furthermore, it was confirmed that, E. microsciadia had augmented the expression levels of Let-7, miR-15, miR-16, miR-29, and miR-34a, which lead to an increase in apoptosis. CONCLUSION E. microsciadia could modulate some miRNAs involved in cell cycle arrest and apoptosis in MDA-MB-231 cell line. Accordingly, targeting miRNAs by E. microsciadia can open some newer avenues for breast cancer therapy.
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Affiliation(s)
- Mohammad-Reza Mahmoudian-Sani
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Majid Asadi-Samani
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Petrović N, Nakashidze I, Nedeljković M. Breast Cancer Response to Therapy: Can microRNAs Lead the Way? J Mammary Gland Biol Neoplasia 2021; 26:157-178. [PMID: 33479880 DOI: 10.1007/s10911-021-09478-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 01/17/2021] [Indexed: 12/23/2022] Open
Abstract
Breast cancer (BC) is a leading cause of death among women with malignant diseases. The selection of adequate therapies for highly invasive and metastatic BCs still represents a major challenge. Novel combinatorial therapeutic approaches are urgently required to enhance the efficiency of BC treatment. Recently, microRNAs (miRNAs) emerged as key regulators of the complex mechanisms that govern BC therapeutic resistance and susceptibility. In the present review we aim to critically examine how miRNAs influence BC response to therapies, or how to use miRNAs as a basis for new therapeutic approaches. We summarized recent findings in this rapidly evolving field, emphasizing the challenges still ahead for the successful implementation of miRNAs into BC treatment while providing insights for future BC management.The goal of this review was to propose miRNAs, that might simultaneously improve the efficacy of all four therapies that are the backbone of current BC management (radio-, chemo-, targeted, and hormone therapy). Among the described miRNAs, miR-21 and miR-16 emerged as the most promising, closely followed by miR-205, miR-451, miR-182, and miRNAs from the let-7 family. miR-21 inhibition might be the best choice for future improvement of invasive BC treatment.New therapeutic strategies of miRNA-based agents alongside current standard treatment modalities could greatly benefit BC patients. This review represents a guideline on how to navigate this elaborate puzzle.
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Affiliation(s)
- Nina Petrović
- Laboratory for Radiobiology and Molecular Genetics, Department of Health and Environment, "VINČA" Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovića Alasa 12-14, 11001, Belgrade, Serbia.
- Department for Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia.
| | - Irina Nakashidze
- Department of Biology, Natural Science and Health Care, Batumi Shota Rustaveli State University, Ninoshvili str. 35, 6010, Batumi, Georgia
| | - Milica Nedeljković
- Department for Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia
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Dimitrakopoulos FI, Kottorou A, Tzezou A. Endocrine resistance and epigenetic reprogramming in estrogen receptor positive breast cancer. Cancer Lett 2021; 517:55-65. [PMID: 34077785 DOI: 10.1016/j.canlet.2021.05.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/08/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023]
Abstract
Despite the enormous advances during the last three decades, breast cancer continues to be the most frequent type of cancer as well as one of the most frequent cancer-related causes of death in women. Therapeutic management of patients with hormone receptor-positive breast cancer becomes very often a challenge, since de novo or acquired resistance deprives a significant percentage of the patients from the clinical benefit of the well-tolerated hormone therapy. Several molecular mechanisms are implicated in resistance to endocrine therapy, including changes in hormone receptor signaling, activation of parallel signaling pathways, modifications of cell cycle regulators, activation of different transcription factors as well as changes in stem cells activity. In addition, a growing number of studies supports the pivotal role of epigenetic changes not only in the initiation and progression of breast cancer, but also in resistance to endocrine therapy. These changes refer to DNA methylation, histone post-translational modifications as well as to ncRNAs alterations. In this review, we provide an overview of epigenetic mechanisms underlying the endocrine resistance focusing exclusively on breast cancer patients.
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Affiliation(s)
- Foteinos-Ioannis Dimitrakopoulos
- Molecular Oncology Laboratory, Medical School of Patras, University of Patras, 26500, Patras, Greece; Division of Oncology, University Hospital of Patras, 26500, Patras, Greece
| | - Anastasia Kottorou
- Molecular Oncology Laboratory, Medical School of Patras, University of Patras, 26500, Patras, Greece; Division of Oncology, University Hospital of Patras, 26500, Patras, Greece
| | - Aspasia Tzezou
- Laboratory of Biology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41500, Larissa, Greece; Laboratory of Cytogenetics and Molecular Genetics, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41500, Larissa, Greece.
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Kim S, Bai Y, Fan Z, Diergaarde B, Tseng GC, Park HJ. The microRNA target site landscape is a novel molecular feature associating alternative polyadenylation with immune evasion activity in breast cancer. Brief Bioinform 2021; 22:bbaa191. [PMID: 32844230 PMCID: PMC8138879 DOI: 10.1093/bib/bbaa191] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/10/2020] [Accepted: 07/28/2020] [Indexed: 12/14/2022] Open
Abstract
Alternative polyadenylation (APA) in breast tumor samples results in the removal/addition of cis-regulatory elements such as microRNA (miRNA) target sites in the 3'-untranslated region (3'-UTRs) of genes. Although previous computational APA studies focused on a subset of genes strongly affected by APA (APA genes), we identify miRNAs of which widespread APA events collectively increase or decrease the number of target sites [probabilistic inference of microRNA target site modification through APA (PRIMATA-APA)]. Using PRIMATA-APA on the cancer genome atlas (TCGA) breast cancer data, we found that the global APA events change the number of the target sites of particular microRNAs [target sites modified miRNA (tamoMiRNA)] enriched for cancer development and treatments. We also found that when knockdown (KD) of NUDT21 in HeLa cells induces a different set of widespread 3'-UTR shortening than TCGA breast cancer data, it changes the target sites of the common tamoMiRNAs. Since the NUDT21 KD experiment previously demonstrated the tumorigenic role of APA events in a miRNA dependent fashion, this result suggests that the APA-initiated tumorigenesis is attributable to the miRNA target site changes, not the APA events themselves. Further, we found that the miRNA target site changes identify tumor cell proliferation and immune cell infiltration to the tumor microenvironment better than the miRNA expression levels or the APA events themselves. Altogether, our computational analyses provide a proof-of-concept demonstration that the miRNA target site information indicates the effect of global APA events with a potential as predictive biomarker.
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Affiliation(s)
- Soyeon Kim
- Department of Pediatrics, University of Pittsburgh Medical Center and in Division of Pulmonary Medicine, Children’s Hospital of Pittsburgh of UPMC
| | - YuLong Bai
- Department of Human Genetics in the Graduate School of Public Health, University of Pittsburgh
| | - Zhenjiang Fan
- Department of Computer Science, University of Pittsburgh
| | - Brenda Diergaarde
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh
| | - George C Tseng
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh
| | - Hyun Jung Park
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh
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MicroRNAs and Long Noncoding RNAs as Novel Therapeutic Targets in Estrogen Receptor-Positive Breast and Ovarian Cancers. Int J Mol Sci 2021; 22:ijms22084072. [PMID: 33920789 PMCID: PMC8071157 DOI: 10.3390/ijms22084072] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/11/2021] [Accepted: 04/12/2021] [Indexed: 01/27/2023] Open
Abstract
Aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane have shown to prevent metastasis and angiogenesis in estrogen receptor (ER)-positive breast and ovarian tumors. They function primarily by reducing estrogen production in ER-positive post-menopausal breast and ovarian cancer patients. Unfortunately, current AI-based therapies often have detrimental side-effects, along with acquired resistance, with increased cancer recurrence. Thus, there is an urgent need to identify novel AIs with fewer side effects and improved therapeutic efficacies. In this regard, we and others have recently suggested noncoding RNAs (ncRNAs), specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), as potential molecular targets for utilization in modulating cancer hallmarks and overcoming drug resistance in several cancers, including ER-positive breast and ovarian cancer. Herein, we describe the disruptive functions of several miRNAs and lncRNAs seen in dysregulated cancer metabolism, with a focus on the gene encoding for aromatase (CYP19A1 gene) and estrogen synthesis as a novel therapeutic approach for treating ER-positive breast and ovarian cancers. Furthermore, we discuss the oncogenic and tumor-suppressive roles of several miRNAs (oncogenic miRNAs: MIR125b, MIR155, MIR221/222, MIR128, MIR2052HG, and MIR224; tumor-suppressive miRNAs: Lethal-7f, MIR27B, MIR378, and MIR98) and an oncogenic lncRNA (MIR2052HG) in aromatase-dependent cancers via transcriptional regulation of the CYP19A1 gene. Additionally, we discuss the potential effects of dysregulated miRNAs and lncRNAs on the regulation of critical oncogenic molecules, such as signal transducer, and activator of transcription 3, β-catenin, and integrins. The overall goal of this review is to stimulate further research in this area and to facilitate the development of ncRNA-based approaches for more efficacious treatments of ER-positive breast and ovarian cancer patients, with a slight emphasis on associated treatment–delivery mechanisms.
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Tang LB, Ma SX, Chen ZH, Huang QY, Wu LY, Wang Y, Zhao RC, Xiong LX. Exosomal microRNAs: Pleiotropic Impacts on Breast Cancer Metastasis and Their Clinical Perspectives. BIOLOGY 2021; 10:biology10040307. [PMID: 33917233 PMCID: PMC8067993 DOI: 10.3390/biology10040307] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/28/2021] [Accepted: 04/03/2021] [Indexed: 01/07/2023]
Abstract
As a major threat factor for female health, breast cancer (BC) has garnered a lot of attention for its malignancy and diverse molecules participating in its carcinogenesis process. Among these complex carcinogenesis processes, cell proliferation, epithelial-to-mesenchymal transition (EMT), mesenchymal-to-epithelial transition (MET), and angiogenesis are the major causes for the occurrence of metastasis and chemoresistance which account for cancer malignancy. MicroRNAs packaged and secreted in exosomes are termed "exosomal microRNAs (miRNAs)". Nowadays, more researches have uncovered the roles of exosomal miRNAs played in BC metastasis. In this review, we recapitulated the dual actions of exosomal miRNAs exerted in the aggressiveness of BC by influencing migration, invasion, and distant metastasis. Next, we presented how exosomal miRNAs modify angiogenesis and stemness maintenance. Clinically, several exosomal miRNAs can govern the transformation between drug sensitivity and chemoresistance. Since the balance of the number and type of exosomal miRNAs is disturbed in pathological conditions, they are able to serve as instructive biomarkers for BC diagnosis and prognosis. More efforts are needed to connect the theoretical studies and clinical traits together. This review provides an outline of the pleiotropic impacts of exosomal miRNAs on BC metastasis and their clinical implications, paving the way for future personalized drugs.
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Affiliation(s)
- Li-Bo Tang
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China;
| | - Shu-Xin Ma
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330006, China;
| | - Zhuo-Hui Chen
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China;
| | - Qi-Yuan Huang
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China;
| | - Long-Yuan Wu
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- First Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Yi Wang
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
| | - Rui-Chen Zhao
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330006, China;
| | - Li-Xia Xiong
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang 330006, China
- Correspondence: ; Tel.: +86-791-8636-0556
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Galvão-Lima LJ, Morais AHF, Valentim RAM, Barreto EJSS. miRNAs as biomarkers for early cancer detection and their application in the development of new diagnostic tools. Biomed Eng Online 2021; 20:21. [PMID: 33593374 PMCID: PMC7885381 DOI: 10.1186/s12938-021-00857-9] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 02/05/2021] [Indexed: 02/06/2023] Open
Abstract
Over the last decades, microRNAs (miRNAs) have emerged as important molecules associated with the regulation of gene expression in humans and other organisms, expanding the strategies available to diagnose and handle several diseases. This paper presents a systematic review of literature of miRNAs related to cancer development and explores the main techniques used to quantify these molecules and their limitations as screening strategy. The bibliographic research was conducted using the online databases, PubMed, Google Scholar, Web of Science, and Science Direct searching the terms "microRNA detection", "miRNA detection", "miRNA and prostate cancer", "miRNA and cervical cancer", "miRNA and cervix cancer", "miRNA and breast cancer", and "miRNA and early cancer diagnosis". Along the systematic review over 26,000 published papers were reported, and 252 papers were returned after applying the inclusion and exclusion criteria, which were considered during this review. The aim of this study is to identify potential miRNAs related to cancer development that may be useful for early cancer diagnosis, notably in the breast, prostate, and cervical cancers. In addition, we suggest a preliminary top 20 miRNA panel according to their relevance during the respective cancer development. Considering the progressive number of new cancer cases every year worldwide, the development of new diagnostic tools is critical to refine the accuracy of screening tests, improving the life expectancy and allowing a better prognosis for the affected patients.
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Affiliation(s)
- Leonardo J. Galvão-Lima
- Advanced Nucleus of Technological Innovation (NAVI), Federal Institute of Rio Grande do Norte (IFRN), Avenue Senador Salgado Filho 1559, Natal, RN 59015-000 Brazil
| | - Antonio H. F. Morais
- Advanced Nucleus of Technological Innovation (NAVI), Federal Institute of Rio Grande do Norte (IFRN), Avenue Senador Salgado Filho 1559, Natal, RN 59015-000 Brazil
| | - Ricardo A. M. Valentim
- Laboratory of Technological Innovation in Health (LAIS), Hospital Universitário Onofre Lopes (HUOL), Federal University of Rio Grande do Norte (UFRN), Campus Lagoa Nova, Natal, RN Brazil
| | - Elio J. S. S. Barreto
- Division of Oncology and Hematology, Hospital Universitário Onofre Lopes (HUOL), Federal University of Rio Grande do Norte (UFRN), Campus Lagoa Nova, Natal, RN Brazil
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Abstract
Despite the decline in death rate from breast cancer and recent advances in targeted therapies and combinations for the treatment of metastatic disease, metastatic breast cancer remains the second leading cause of cancer-associated death in U.S. women. The invasion-metastasis cascade involves a number of steps and multitudes of proteins and signaling molecules. The pathways include invasion, intravasation, circulation, extravasation, infiltration into a distant site to form a metastatic niche, and micrometastasis formation in a new environment. Each of these processes is regulated by changes in gene expression. Noncoding RNAs including microRNAs (miRNAs) are involved in breast cancer tumorigenesis, progression, and metastasis by post-transcriptional regulation of target gene expression. miRNAs can stimulate oncogenesis (oncomiRs), inhibit tumor growth (tumor suppressors or miRsupps), and regulate gene targets in metastasis (metastamiRs). The goal of this review is to summarize some of the key miRNAs that regulate genes and pathways involved in metastatic breast cancer with an emphasis on estrogen receptor α (ERα+) breast cancer. We reviewed the identity, regulation, human breast tumor expression, and reported prognostic significance of miRNAs that have been documented to directly target key genes in pathways, including epithelial-to-mesenchymal transition (EMT) contributing to the metastatic cascade. We critically evaluated the evidence for metastamiRs and their targets and miRNA regulation of metastasis suppressor genes in breast cancer progression and metastasis. It is clear that our understanding of miRNA regulation of targets in metastasis is incomplete.
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Affiliation(s)
- Belinda J Petri
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Carolyn M Klinge
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
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Wu Y, Li Q, Zhang R, Dai X, Chen W, Xing D. Circulating microRNAs: Biomarkers of disease. Clin Chim Acta 2021; 516:46-54. [PMID: 33485903 DOI: 10.1016/j.cca.2021.01.008] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 02/07/2023]
Abstract
MicroRNAs are a class of endogenous noncoding single-stranded RNA molecules with approximately 20-24 nucleotides and are associated with a broad range of biological processes. Researchers found that microRNAs are abundant in tissues, and more importantly, there are also trace circulating microRNAs that exist in biological fluids. In recent years, circulating microRNAs had emerged as promising diagnostic and prognostic biomarkers for the noninvasive detection of diseases with high specificity and sensitivity. More importantly, specific microRNA expression signatures reflect not only the existence of early-stage diseases but also the dynamic development of advanced-stage diseases, disease prognosis prediction, and drug resistance. To date, an increasing number of potential miRNA biomarkers have been reported, but their practical application prospects are still unclear. Therefore, microRNAs, as potential diagnostic and prognostic biomarkers in a variety of diseases, need to be updated, as they are of great importance in the diagnosis, prognosis and prediction of therapeutic responses. In this review, we summary our current understanding of microRNAs as potential biomarkers in the major diseases (e.g., cancers and cardio-cerebrovascular diseases), which provide the basis for the design of diagnosis and treatment plan and the improvement of the cure rate.
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Affiliation(s)
- Yudong Wu
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Qingdao Cancer Institute, Qingdao University, Qingdao 266071, China
| | - Qian Li
- Qingdao Cancer Institute, Qingdao University, Qingdao 266071, China
| | - Renshuai Zhang
- Qingdao Cancer Institute, Qingdao University, Qingdao 266071, China
| | - Xiaoli Dai
- Qingdao Cancer Institute, Qingdao University, Qingdao 266071, China
| | - Wujun Chen
- Qingdao Cancer Institute, Qingdao University, Qingdao 266071, China.
| | - Dongming Xing
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Qingdao Cancer Institute, Qingdao University, Qingdao 266071, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
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Li C, Zhao J, Sun W. microRNA-222-Mediated VHL Downregulation Facilitates Retinoblastoma Chemoresistance by Increasing HIF1α Expression. Invest Ophthalmol Vis Sci 2021; 61:9. [PMID: 32756923 PMCID: PMC7441340 DOI: 10.1167/iovs.61.10.9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Purpose Retinoblastoma (RB) is the most common primary intraocular tumor in children. Chemoresistance is the major obstacle for treatment of these tumors. This study aims to determine whether or not downregulating microRNA-222 (miR-222) could serve as a potential therapeutic target for preventing chemoresistance in RB treatment. Methods Differentially expressed miR-222 in RB samples and its downstream target genes were predicted using bioinformatics methods. The expression of miR-222 was altered by mimic or inhibitor to examine its role in RB cell in response to the chemotherapeutic agent vincristine (VCR). Further bioinformatic analysis predicted involvement of the stability of hypoxia-inducible factor 1α (HIF1α) protein in regulation of the von Hippel–Lindau (VHL) tumor suppressor, followed by characterization of the effect of VHL on the ubiquitin–proteasome degradation of HIF1α. Next, VHL or HIF1α was overexpressed to determine their effects on RB cell activities after VCR treatment. In vivo assays were performed on nude mice to further verify the in vitro results. Results miR-222 is highly expressed in RB tissues and cells and was found to facilitate resistance of RB cells to VCR. Of note, miR-222 specifically bound to and negatively regulated VHL. VHL could inhibit the stability of HIF1α and promote the degradation of ubiquitin–proteasome, thus reducing HIF1α expression to attenuate VCR resistance in RB cells. Moreover, inhibition of miR-222 in combination with VCR suppressed tumor formation in nude mice. Conclusions miR-222 promotes the expression of HIF1α by targeting VHL, thus accelerating the resistance of RB cells to the chemotherapeutic agent VCR.
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Affiliation(s)
- Chunzhi Li
- Department of Pharmacy, Linyi People's Hospital, Linyi, China
| | - Jun Zhao
- Department of Ophthalmology, Linyi People's Hospital, Linyi, China
| | - Weiying Sun
- Department of Pharmacy, Linyi People's Hospital, Linyi, China
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Anastasov N, Hirmer E, Klenner M, Ott J, Falkenberg N, Bao X, Mutschelknaus L, Moertl S, Combs S, Atkinson MJ, Schmid T. MEK1 Inhibitor Combined with Irradiation Reduces Migration of Breast Cancer Cells Including miR-221 and ZEB1 EMT Marker Expression. Cancers (Basel) 2020; 12:cancers12123760. [PMID: 33327491 PMCID: PMC7764972 DOI: 10.3390/cancers12123760] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/02/2020] [Accepted: 12/09/2020] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Combined chemotherapy and radiotherapy are an effective treatment for invasive breast cancer. However, some studies suggest that such interventions may increase the risk of metastasis. Cell metastatic behavior is highly dependent on RAS-RAF-MEK pathway and its downstream target activation, including miR-221 overexpression and epithelial-to-mesenchymal transition (EMT). By using MEK1 inhibitor (TAK-733) in combination with radiation therapy for breast cancer cells, significant decrease in migration capacity, including reduction of miR-221 and EMT (ZEB1) marker expression was observed. miR-221 holds great potential as therapeutic biomarker and target for new drug developments, however more insight into efficiency of miR-221 inhibition needs to be followed in the future. Abstract The miR-221 expression is dependent on the oncogenic RAS-RAF-MEK pathway activation and influences epithelial-to-mesenchymal transition (EMT). The Cancer Genome Atlas (TCGA) database analysis showed high gene significance for ZEB1 with EMT module analysis and miR-221 overexpression within the triple-negative breast cancer (TNBC) and HER2+ subgroups when compared to luminal A/B subgroups. EMT marker expression analysis after MEK1 (TAK-733) inhibitor treatment and irradiation was combined with miR-221 and ZEB1 expression analysis. The interaction of miR-221 overexpression with irradiation and its influence on migration, proliferation, colony formation and subsequent EMT target activation were investigated. The results revealed that MEK1 inhibitor treatment combined with irradiation could decrease the migratory potential of breast cancer cells including reduction of miR-221 and corresponding downstream ZEB1 (EMT) marker expression. The clonogenic survival assays revealed that miR-221 overexpressing SKBR3 cells were more radioresistant when compared to the control. Remarkably, the effect of miR-221 overexpression on migration in highly proliferative and highly HER2-positive SKBR3 cells remained constant even upon 8 Gy irradiation. Further, in naturally miR-221-overexpressing MDA-MB-231 cells, the proliferation and migration significantly decrease after miR-221 knockdown. This leads to the assumption that radiation alone is not reducing migration capacity of miR-221-overexpressing cells and that additional factors play an important role in this context. The miR-221/ZEB1 activity is efficiently targeted upon MEK1 inhibitor (TAK-733) treatment and when combined with irradiation treatment, significant reduction in migration of breast cancer cells was shown.
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Affiliation(s)
- Nataša Anastasov
- Institute of Radiation Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (E.H.); (M.K.); (J.O.); (X.B.); (L.M.); (S.M.); (M.J.A.)
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Correspondence: ; Tel.: +49-893-187-3798; Fax: +49-893-187-3017
| | - Elisabeth Hirmer
- Institute of Radiation Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (E.H.); (M.K.); (J.O.); (X.B.); (L.M.); (S.M.); (M.J.A.)
- Institute of Radiation Medicine, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (S.C.); (T.S.)
| | - Marbod Klenner
- Institute of Radiation Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (E.H.); (M.K.); (J.O.); (X.B.); (L.M.); (S.M.); (M.J.A.)
| | - Jessica Ott
- Institute of Radiation Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (E.H.); (M.K.); (J.O.); (X.B.); (L.M.); (S.M.); (M.J.A.)
- Institute of Radiation Medicine, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (S.C.); (T.S.)
| | - Natalie Falkenberg
- Institute of Pathology, Technical University of Munich (TUM), 81675 Munich, Germany;
- Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of Munich (TUM), 81675 Munich, Germany
| | - Xuanwen Bao
- Institute of Radiation Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (E.H.); (M.K.); (J.O.); (X.B.); (L.M.); (S.M.); (M.J.A.)
| | - Lisa Mutschelknaus
- Institute of Radiation Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (E.H.); (M.K.); (J.O.); (X.B.); (L.M.); (S.M.); (M.J.A.)
| | - Simone Moertl
- Institute of Radiation Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (E.H.); (M.K.); (J.O.); (X.B.); (L.M.); (S.M.); (M.J.A.)
- Federal Office of Radiation Protection, 85764 Oberschleissheim, Germany
| | - Stephanie Combs
- Institute of Radiation Medicine, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (S.C.); (T.S.)
- Department of Radiation Oncology, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany
| | - Michael J. Atkinson
- Institute of Radiation Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (E.H.); (M.K.); (J.O.); (X.B.); (L.M.); (S.M.); (M.J.A.)
- Radiation Biology, Technical University of Munich, 81675 Munich, Germany
| | - Thomas Schmid
- Institute of Radiation Medicine, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; (S.C.); (T.S.)
- Department of Radiation Oncology, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany
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Kandettu A, Radhakrishnan R, Chakrabarty S, Sriharikrishnaa S, Kabekkodu SP. The emerging role of miRNA clusters in breast cancer progression. Biochim Biophys Acta Rev Cancer 2020; 1874:188413. [PMID: 32827583 DOI: 10.1016/j.bbcan.2020.188413] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/01/2020] [Accepted: 08/11/2020] [Indexed: 02/07/2023]
Abstract
Micro RNAs (miRNAs) are small non-coding RNAs that are essential for regulation of gene expression of the target genes. Large number of miRNAs are organized into defined units known as miRNA clusters (MCs). The MCs consist of two or more than two miRNA encoding genes driven by a single promoter, transcribed together in the same orientation, that are not separated from each other by a transcription unit. Aberrant miRNA clusters expression is reported in breast cancer (BC), exhibiting both pro-tumorogenic and anti-tumorigenic role. Altered MCs expression facilitates to breast carcinogenesis by promoting the breast cells to acquire the various hallmarks of the cancer. Since miRNA clusters contain multiple miRNA encoding genes, targeting cluster may be more attractive than targeting individual miRNAs. Besides targeting dysregulated miRNA clusters in BC, studies have focused on the mechanism of action, and its contribution to the progression of the BC. The present review provides a comprehensive overview of dysregulated miRNA clusters and its role in the acquisition of cancer hallmarks in BC. More specifically, we have presented the regulation, differential expression, classification, targets, mechanism of action, and signaling pathways of miRNA clusters in BC. Additionally, we have also discussed the potential utility of the miRNA cluster as a diagnostic and prognostic indicator in BC.
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Affiliation(s)
- Amoolya Kandettu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India
| | - Raghu Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - S Sriharikrishnaa
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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Protective Effects of Epigallocatechin Gallate (EGCG) on Endometrial, Breast, and Ovarian Cancers. Biomolecules 2020; 10:biom10111481. [PMID: 33113766 PMCID: PMC7694163 DOI: 10.3390/biom10111481] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 02/07/2023] Open
Abstract
Green tea and its major bioactive component, (-)-epigallocatechin gallate (EGCG), possess diverse biological properties, particularly antiproliferation, antimetastasis, and apoptosis induction. Many studies have widely investigated the anticancer and synergistic effects of EGCG due to the side effects of conventional cytotoxic agents. This review summarizes recent knowledge of underlying mechanisms of EGCG on protective roles for endometrial, breast, and ovarian cancers based on both in vitro and in vivo animal studies. EGCG has the ability to regulate many pathways, including the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), inhibition of nuclear factor-κB (NF-κB), and protection against epithelial-mesenchymal transition (EMT). EGCG has also been found to interact with DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), which affect epigenetic modifications. Finally, the action of EGCG may exert a suppressive effect on gynecological cancers and have beneficial effects on auxiliary therapies for known drugs. Thus, future clinical intervention studies with EGCG will be necessary to more and clear evidence for the benefit to these cancers.
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Tan G, Jiang L, Li G, Bai K. ESTAT3 Inhibitor AG-490 Inhibits the Growth of Prostate Cancer by miR-503-5p Both In Vivo and In Vitro. Technol Cancer Res Treat 2020; 19:1533033820948062. [PMID: 33063634 PMCID: PMC7580129 DOI: 10.1177/1533033820948062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Objective: To explore the effect and the related mechanism of STAT3 inhibitor AG-490 on inhibiting the proliferation of prostate cancer cells. Methods: PC3 cells and DU145 cells were cultured stably and treated with AG-490 to detect the changes in the activity of PC3 cells and DU145 cells. Thirty 6-8 weeks male BALB/c nude mouse were randomly divided into a control group, a DMSO group, and an AG-490 group to detect differences in various indexes . Results: The overexpression of miR-503-5p depends on the activation of STAT3. After treatment with AG-490, The proliferation and invasion of PC3 cells and DU145 cells and the expression of miR-503-5p were all reduced. Luciferase reporter assay demonstrated that the target proteins of miR-503-5p include PDCD4, TIMP-3, and PTEN. After treatment with AG-490, the expression of PDCD4, TIMP-3, and PTEN in cells was significantly up-regulated. IL-6-induced overexpression of miR-503-5p and restored the expression of STAT3, demonstrating the correlation between STAT3 and miR-503-5p. AG-490 can inhibit tumor growth and induce tumor cell apoptosis in the PC3 BALB/c nude mouse xenograft model. Western blotting and immunohistochemical staining showed that the expression levels of STAT3, Ki67, Bcl-2 and MMP-2 in the AG-490 group were significantly reduced, and the expression of PDCD4, TIMP-3 and PTEN increased. Conclusion: AG-490 can inhibit the growth of prostate cancer cells in a miR-503-5p-dependent manner by targeting STAT3. AG-490 is expected to become a new candidate drug for the treatment of prostate cancer.
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Affiliation(s)
- Guangxing Tan
- Wuxi Hospital of Traditional Chinese Medicine, Wuxi, People Republic of China
| | - Lin Jiang
- Wuxi Hospital of Traditional Chinese Medicine, Wuxi, People Republic of China
| | - Gangqin Li
- Wuxi Hospital of Traditional Chinese Medicine, Wuxi, People Republic of China
| | - Kuan Bai
- Wuxi Hospital of Traditional Chinese Medicine, Wuxi, People Republic of China
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Kudela E, Samec M, Koklesova L, Liskova A, Kubatka P, Kozubik E, Rokos T, Pribulova T, Gabonova E, Smolar M, Biringer K. miRNA Expression Profiles in Luminal A Breast Cancer-Implications in Biology, Prognosis, and Prediction of Response to Hormonal Treatment. Int J Mol Sci 2020; 21:ijms21207691. [PMID: 33080858 PMCID: PMC7589921 DOI: 10.3390/ijms21207691] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/25/2020] [Accepted: 10/15/2020] [Indexed: 12/12/2022] Open
Abstract
Breast cancer, which is the most common malignancy in women, does not form a uniform nosological unit but represents a group of malignant diseases with specific clinical, histopathological, and molecular characteristics. The increasing knowledge of the complex pathophysiological web of processes connected with breast cancercarcinogenesis allows the development of predictive and prognostic gene expressionand molecular classification systems with improved risk assessment, which could be used for individualized treatment. In our review article, we present the up-to-date knowledge about the role of miRNAs and their prognostic and predictive value in luminal A breast cancer. Indeed, an altered expression profile of miRNAs can distinguish not only between cancer and healthy samples, but they can classify specific molecular subtypes of breast cancer including HER2, Luminal A, Luminal B, and TNBC. Early identification and classification of breast cancer subtypes using miRNA expression profilescharacterize a promising approach in the field of personalized medicine. A detection of sensitive and specific biomarkers to distinguish between healthy and early breast cancer patients can be achieved by an evaluation of the different expression of several miRNAs. Consequently, miRNAs represent a potential as good diagnostic, prognostic, predictive, and therapeutic biomarkers for patients with luminal A in the early stage of BC.
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Affiliation(s)
- Erik Kudela
- Department of Obstetrics and Gynecology, Martin University Hospital and Jessenius Faculty of Medicine in Martin, Comenius University of Bratislava, 03601 Martin, Slovakia; (M.S.); (L.K.); (A.L.); (E.K.); (T.R.); (T.P.); (K.B.)
- Correspondence: ; Tel.: +421-9-0230-0017
| | - Marek Samec
- Department of Obstetrics and Gynecology, Martin University Hospital and Jessenius Faculty of Medicine in Martin, Comenius University of Bratislava, 03601 Martin, Slovakia; (M.S.); (L.K.); (A.L.); (E.K.); (T.R.); (T.P.); (K.B.)
| | - Lenka Koklesova
- Department of Obstetrics and Gynecology, Martin University Hospital and Jessenius Faculty of Medicine in Martin, Comenius University of Bratislava, 03601 Martin, Slovakia; (M.S.); (L.K.); (A.L.); (E.K.); (T.R.); (T.P.); (K.B.)
| | - Alena Liskova
- Department of Obstetrics and Gynecology, Martin University Hospital and Jessenius Faculty of Medicine in Martin, Comenius University of Bratislava, 03601 Martin, Slovakia; (M.S.); (L.K.); (A.L.); (E.K.); (T.R.); (T.P.); (K.B.)
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Erik Kozubik
- Department of Obstetrics and Gynecology, Martin University Hospital and Jessenius Faculty of Medicine in Martin, Comenius University of Bratislava, 03601 Martin, Slovakia; (M.S.); (L.K.); (A.L.); (E.K.); (T.R.); (T.P.); (K.B.)
| | - Tomas Rokos
- Department of Obstetrics and Gynecology, Martin University Hospital and Jessenius Faculty of Medicine in Martin, Comenius University of Bratislava, 03601 Martin, Slovakia; (M.S.); (L.K.); (A.L.); (E.K.); (T.R.); (T.P.); (K.B.)
| | - Terezia Pribulova
- Department of Obstetrics and Gynecology, Martin University Hospital and Jessenius Faculty of Medicine in Martin, Comenius University of Bratislava, 03601 Martin, Slovakia; (M.S.); (L.K.); (A.L.); (E.K.); (T.R.); (T.P.); (K.B.)
| | - Eva Gabonova
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia; (E.G.); (M.S.)
| | - Marek Smolar
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia; (E.G.); (M.S.)
| | - Kamil Biringer
- Department of Obstetrics and Gynecology, Martin University Hospital and Jessenius Faculty of Medicine in Martin, Comenius University of Bratislava, 03601 Martin, Slovakia; (M.S.); (L.K.); (A.L.); (E.K.); (T.R.); (T.P.); (K.B.)
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50
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Dobre EG, Dinescu S, Costache M. Connecting the Missing Dots: ncRNAs as Critical Regulators of Therapeutic Susceptibility in Breast Cancer. Cancers (Basel) 2020; 12:E2698. [PMID: 32967267 PMCID: PMC7565380 DOI: 10.3390/cancers12092698] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/10/2020] [Accepted: 09/14/2020] [Indexed: 12/24/2022] Open
Abstract
Whether acquired or de novo, drug resistance remains a significant hurdle in achieving therapeutic success in breast cancer (BC). Thus, there is an urge to find reliable biomarkers that will help in predicting the therapeutic response. Stable and easily accessible molecules such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are regarded as valuable prognostic biomarkers and therapeutic targets since they act as crucial regulators of the various mechanisms involved in BC drug resistance. Here, we reviewed the current literature on ncRNAs as mediators of resistance to systemic therapies in BC. Interestingly, upon integrating data results from individual studies, we concluded that miR-221, miR-222, miR-451, Urothelial Carcinoma Associated 1 (UCA1), and Growth arrest-specific 5 (GAS5) are strong candidates as prognostic biomarkers and therapeutic targets since they are regulating multiple drug resistance phenotypes in BC. However, further research around their clinical implications is needed to validate and integrate them into therapeutic applications. Therefore, we believe that our review may provide relevant evidence for the selection of novel therapeutic targets and prognostic biomarkers for BC and will serve as a foundation for future translational research in the field.
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Affiliation(s)
- Elena-Georgiana Dobre
- AMS Genetic Lab, 030882 Bucharest, Romania;
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania;
| | - Sorina Dinescu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania;
- The Research Institute of the University of Bucharest, 050095 Bucharest, Romania
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania;
- The Research Institute of the University of Bucharest, 050095 Bucharest, Romania
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