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Kumari R, Banerjee S. Regulation of Different Types of Cell Death by Noncoding RNAs: Molecular Insights and Therapeutic Implications. ACS Pharmacol Transl Sci 2025; 8:1205-1226. [PMID: 40370994 PMCID: PMC12070317 DOI: 10.1021/acsptsci.4c00681] [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: 11/25/2024] [Revised: 04/23/2025] [Accepted: 04/24/2025] [Indexed: 05/16/2025]
Abstract
Noncoding RNAs (ncRNAs) are crucial regulatory molecules in various biological processes, despite not coding for proteins. ncRNAs are further divided into long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) based on the size of their nucleotides. These ncRNAs play crucial roles in transcriptional, post-transcriptional, and epigenetic regulation. The regulatory roles of noncoding RNAs, including lncRNAs, miRNAs, and circRNAs, are essential in various modalities of cellular death, such as apoptosis, ferroptosis, cuproptosis, pyroptosis, disulfidptosis, and necroptosis. These noncoding RNAs are integral to modulating gene expression and protein functionality during cellular death mechanisms. In apoptosis, lncRNAs, miRNAs, and circRNAs influence the transcription of apoptotic genes. In ferroptosis, these noncoding RNAs target genes and proteins involved in iron homeostasis and oxidative stress responses. For cuproptosis, noncoding RNAs regulate pathways associated with the accumulation of copper ions, leading to cellular death. During pyroptosis, noncoding RNAs modulate inflammatory mediators and caspases, affecting the proinflammatory cell death pathway. In necroptosis, noncoding RNAs oversee the formation and functionality of necrosomes, thereby influencing the balance between cellular survival and death. Disulfidptosis is a unique type of regulated cell death caused by the excessive formation of disulfide bonds within cells, leading to cytoskeletal collapse and oxidative stress, especially under glucose-limited conditions. This investigation highlights the complex mechanisms through which noncoding RNAs coordinate cellular death, emphasizing their therapeutic promise as potential targets, particularly in the domain of cancer treatment.
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Affiliation(s)
- Reshmi Kumari
- Department of Biotechnology, School
of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India
| | - Satarupa Banerjee
- Department of Biotechnology, School
of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India
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2
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Ma C, Yang X, Zhang L, Zhang J, Zhang Y, Hu X. BRCA1 regulates glucose and lipid metabolism in diabetes mellitus with metabolic dysfunction-associated steatotic liver disease via the PI3K/Akt signaling pathway. PLoS One 2025; 20:e0318696. [PMID: 40138287 PMCID: PMC11940781 DOI: 10.1371/journal.pone.0318696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 01/20/2025] [Indexed: 03/29/2025] Open
Abstract
PURPOSE This study mimics the metabolic environment of metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetic mellitus (DM) to investigate the function of BRCA1 in regulating glucose and lipid metabolism in hepatocytes under high glucose (HG) settings. METHODS MASLD and DM-related datasets (GSE89632, GSE95849) were screened for overlapping genes, Protein-Protein Interaction (PPI) network and enrichment analyses were performed. Then, quantitative real-time polymerase chain reaction (qRT-PCR), Western Blotting (WB), and enzymatic colorimetric assays to examine the expression changes of BRCA1 in mouse primary hepatocytes under HG conditions and the impact of the combined PI3K/Akt signaling pathway on key metabolic markers of gluconeogenesis and lipid metabolism. RESULTS Our study identified seven key overlapping genes (AURKA, BRCA1, ISG15, NUSAP1, OAS1, RSAD2, TLR7) between MASLD and DM. Experiments found that when BRCA1 was overexpressed in mouse primary hepatocytes, intracellular triglyceride content and lipid metabolism-related biomarkers (such as PEPCK, SREBP-1c, G6Pase, and FAS) were significantly increased in HG circumstances. However, the knockdown of BRCA1 reduced the expression of these indicators. Besides, we also observed that under HG conditions, the expression of proteins linked to the PI3K/Akt signaling pathway was negatively regulated by BRCA1 expression. Moreover, TG content and expression of lipid metabolism markers are also regulated by BRCA1 and PI3K/Akt pathway inhibitor Ly294002. CONCLUSION As a key regulator of hepatocyte metabolism under HG conditions, BRCA1 can participate in regulating glucose and lipid metabolism in mouse primary hepatocytes through the PI3K/AKT signaling pathway, which be able to become a possible remedy strategy for DM with MASLD.
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Affiliation(s)
- Cui Ma
- Department of Endocrinology, The First People’s Hospital of Yuhang District, Hangzhou, Zhejiang, China
| | - Xiaodi Yang
- Department of Oncology, Minhang Branch, Zhongshan Hospital, Fudan University Shanghai, China, Key laboratory of whole-period monitoring and precise intervention of digestive cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai, China
| | - Liyin Zhang
- School of Sports Science and Engineering, East China University of Science and Technology, Shanghai, China
| | - Jie Zhang
- Department of pharmacy, The First People’s Hospital of Yuhang District, Hangzhou, Zhejiang, China
| | - Youyou Zhang
- Department of Oncology, Minhang Branch, Zhongshan Hospital, Fudan University Shanghai, China, Key laboratory of whole-period monitoring and precise intervention of digestive cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai, China
| | - Xiaofeng Hu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Mahendran G, Shangaradas AD, Romero-Moreno R, Wickramarachchige Dona N, Sarasija SHGS, Perera S, Silva GN. Unlocking the epigenetic code: new insights into triple-negative breast cancer. Front Oncol 2024; 14:1499950. [PMID: 39744000 PMCID: PMC11688480 DOI: 10.3389/fonc.2024.1499950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 11/19/2024] [Indexed: 01/04/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive and clinically challenging subtype of breast cancer, lacking the expression of estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. The absence of these receptors limits therapeutic options necessitating the exploration of novel treatment strategies. Epigenetic modifications, which include DNA methylation, histone modifications, and microRNA (miRNA) regulation, play a pivotal role in TNBC pathogenesis and represent promising therapeutic targets. This review delves into the therapeutic potential of epigenetic interventions in TNBC, with a focus on DNA methylation, histone modifications, and miRNA therapeutics. We examine the role of DNA methylation in gene silencing within TNBC and the development of DNA methylation inhibitors designed to reactivate silenced tumor suppressor genes. Histone modifications, through histone deacetylation and acetylation in particular, are critical in regulating gene expression. We explore the efficacy of histone deacetylase inhibitors (HDACi), which have shown promise in reversing aberrant histone deacetylation patterns, thereby restoring normal gene function, and suppressing tumor growth. Furthermore, the review highlights the dual role of miRNAs in TNBC as both oncogenes and tumor suppressors and discusses the therapeutic potential of miRNA mimics and inhibitors in modulating these regulatory molecules to inhibit cancer progression. By integrating these epigenetic therapies, we propose a multifaceted approach to target the underlying epigenetic mechanisms that drive TNBC progression. The synergistic use of DNA methylation inhibitors, HDACi, and the miRNA-based therapies offers a promising avenue for personalized treatment strategies, aiming to enhance the clinical outcome for patients with TNBC.
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Affiliation(s)
- Gowthami Mahendran
- Department of Chemistry, Faculty of Science, University of Colombo, Colombo, Sri Lanka
| | | | | | | | | | - Sumeth Perera
- Department of Biochemistry, Faculty of Medicine, Sabaragamuwa University of Sri Lanka, Ratnapura, Sri Lanka
| | - Gayathri N. Silva
- Department of Chemistry, Faculty of Science, University of Colombo, Colombo, Sri Lanka
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4
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Babadag S, Altundag-Erdogan Ö, Akkaya-Ulum YZ, Çelebi-Saltik B. Evaluation of Tumorigenic Properties of MDA-MB-231 Cancer Stem Cells Cocultured with Telocytes and Telocyte-Derived Mitochondria Following miR-146a Inhibition. DNA Cell Biol 2024; 43:341-352. [PMID: 38634821 DOI: 10.1089/dna.2024.0031] [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] [Indexed: 04/19/2024] Open
Abstract
Telocytes have some cytoplasmic extensions called telopodes, which are thought to play a role in mitochondrial transfer in intercellular communication. Besides, it is hypothesized that telocytes establish cell membrane-mediated connections with breast cancer cells in coculture and may contribute to the survival of neoplastic cell clusters together with other stromal cells. The aim of this study is to investigate the contribution of telocytes and telocyte-derived mitochondria, which have also been identified in breast tumors, to the tumor development of breast cancer stem cells (CSCs) via miR-146a-5p. The isolation/characterization of telocytes from bone marrow mononuclear cells and the isolation of mitochondria from these cells were performed, respectively. In the next step, CSCs were isolated from the MDA-MB-231 cell line and were characterized. Then, miR-146a-5p expressions of CSCs were inhibited by anti-miR-146a-5p. The epithelial-mesenchymal transition (EMT) was determined by evaluating changes in vimentin protein levels and was evaluated by analyzing BRCA1, P53, SOX2, E-cadherin, and N-cadherin gene expression changes. Our results showed that miR-146a promoted stemness and oncogenic properties in CSCs. EMT (N-cadherin, vimentin, E-cadherin) and tumorigenic markers (BRCA1, P53, SOX2) of CSCs decreased after miR-146a inhibition. Bone marrow-derived telocytes and mitochondria derived from telocytes favored the reduction of CSC aggressiveness following this inhibition.
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Affiliation(s)
- Sena Babadag
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, Ankara, Turkey
- Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey
| | - Özlem Altundag-Erdogan
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, Ankara, Turkey
- Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey
| | - Yeliz Z Akkaya-Ulum
- Department of Medical Biology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Betül Çelebi-Saltik
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, Ankara, Turkey
- Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey
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Abdul Wahab MR, Palaniyandi T, Viswanathan S, Baskar G, Surendran H, Gangadharan SGD, Sugumaran A, Sivaji A, Kaliamoorthy S, Kumarasamy S. Biomarker-specific biosensors revolutionise breast cancer diagnosis. Clin Chim Acta 2024; 555:117792. [PMID: 38266968 DOI: 10.1016/j.cca.2024.117792] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/19/2024] [Accepted: 01/19/2024] [Indexed: 01/26/2024]
Abstract
Breast cancer is the most common cancer among women across the globe. In order to treat breast cancer successfully, it is crucial to conduct a comprehensive assessment of the condition during its initial stages. Although mammogram screening has long been a common method of breast cancer screening, high rates of type I error and type II error results as well as radiation exposure have always been of concern. The outgrowth cancer mortality rate is primarily due to delayed diagnosis, which occurs most frequently in a metastatic III or IV stage, resulting in a poor prognosis after therapy. Traditional detection techniques require identifying carcinogenic properties of cells, such as DNA or RNA alterations, conformational changes and overexpression of certain proteins, and cell shape, which are referred to as biomarkers or analytes. These procedures are complex, long-drawn-out, and expensive. Biosensors have recently acquired appeal as low-cost, simple, and super sensitive detection methods for analysis. The biosensor approach requires the existence of biomarkers in the sample. Thus, the development of novel molecular markers for diverse forms of cancer is a rising complementary affair. These biosensor devices offer two major advantages: (1) a tiny amount of blood collected from the patient is sufficient for analysis, and (2) it could help clinicians swiftly select and decide on the best therapy routine for the individual. This review will include updates on prospective cancer markers and biosensors in cancer diagnosis, as well as the associated detection limitations, with a focus on biosensor development for marker detection.
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Affiliation(s)
| | - Thirunavukkarasu Palaniyandi
- Department of Biotechnology, Dr. M.G.R. Educational and Research Institute, Chennai, India; Department of Anatomy, Biomedical Research Unit and Laboratory Animal Centre, Saveetha Dental College and Hospital, SIMATS, Saveetha University, Chennai, India.
| | - Sandhiya Viswanathan
- Department of Biotechnology, Dr. M.G.R. Educational and Research Institute, Chennai, India
| | - Gomathy Baskar
- Department of Biotechnology, Dr. M.G.R. Educational and Research Institute, Chennai, India
| | - Hemapreethi Surendran
- Department of Biotechnology, Dr. M.G.R. Educational and Research Institute, Chennai, India
| | - S G D Gangadharan
- Department of Medical Oncology, Madras Medical College, R. G. G. G. H., Chennai, Tamil Nadu, India
| | - Abimanyu Sugumaran
- Department of Pharmaceutical Sciences, Assam University, (A Central University), Silchar, Assam, India
| | - Asha Sivaji
- Department of Biochemistry, DKM College for Women, Vellore, India
| | - Senthilkumar Kaliamoorthy
- Department of Electronics and Communication Engineering, Dr. M.G.R Educational and Research Institute, Chennai, Tamil Nadu, India
| | - Saravanan Kumarasamy
- Department of Electrical and Electronics Engineering, Dr. M.G.R Educational and Research Institute, Chennai, Tamil Nadu, India
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Wen Z, Li Y, Zhao Z, Li R, Li X, Lu C, Sun C, Chen W, Ge Z, Ni L, Lai Y. A serum panel of three microRNAs may serve as possible biomarkers for kidney renal clear cell carcinoma. Cancer Cell Int 2024; 24:18. [PMID: 38191389 PMCID: PMC10773017 DOI: 10.1186/s12935-023-03187-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 12/21/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND Although non-invasive radiological techniques are widely applied in kidney renal clear cell carcinoma (KIRC) diagnosis, more than 50% of KIRCs are detected incidentally during the diagnostic procedures to identify renal cell carcinoma (RCC). Thus, sensitive and accurate KIRC diagnostic methods are required. Therefore, in this study, we aimed to identify KIRC-associated microRNAs (miRNAs). METHODS This three-phase study included 224 participants (112 each of patients with KIRC and healthy controls (NCs)). RT-qPCR was used to evaluate miRNA expression in KIRC and NC samples. Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were used to predict the usefulness of serum miRNAs in KIRC diagnosis. In addition, we performed survival and bioinformatics analyses. RESULTS We found that miR-1-3p, miR-129-5p, miR-146b-5p, miR-187-3p, and miR-200a-3p were significantly differentially expressed in patients with KIRC. A panel consisting of three miRNAs (miR-1-3p, miR-129-5p, and miR-146b-5p) had an AUC of 0.895, ranging from 0.848 to 0.942. In addition, using the GEPIA database, we found that the miRNAs were associated with CREB5. According to the survival analysis, miR-146b-5p overexpression was indicative of a poorer prognosis in patients with KIRC. CONCLUSIONS The identified three-miRNA panel could serve as a non-invasive indicator for KIRC and CREB5 as a potential target gene for KIRC treatment.
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Affiliation(s)
- Zhenyu Wen
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, People's Republic of China
- Shantou University Medical College, Shantou, 515063, Guangdong, China
| | - Yingqi Li
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, People's Republic of China
- Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Zhengping Zhao
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, People's Republic of China
| | - Rongkang Li
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, People's Republic of China
- Anhui Medical University, Hefei, 230032, Anhui, China
| | - Xinji Li
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, People's Republic of China
- Shantou University Medical College, Shantou, 515063, Guangdong, China
| | - Chong Lu
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, People's Republic of China
- Anhui Medical University, Hefei, 230032, Anhui, China
| | - Chen Sun
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, People's Republic of China
- Anhui Medical University, Hefei, 230032, Anhui, China
| | - Wenkang Chen
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, People's Republic of China
- Shantou University Medical College, Shantou, 515063, Guangdong, China
| | - Zhenjian Ge
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, People's Republic of China
- Shantou University Medical College, Shantou, 515063, Guangdong, China
| | - Liangchao Ni
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, People's Republic of China.
| | - Yongqing Lai
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, People's Republic of China.
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Abd ELhafeez AS, Ghanem HM, Swellam M, Taha AM. Involvement of FAM170B-AS1, hsa-miR-1202, and hsa-miR-146a-5p in breast cancer. Cancer Biomark 2024; 39:313-333. [PMID: 38250762 PMCID: PMC11091646 DOI: 10.3233/cbm-230396] [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: 09/09/2023] [Accepted: 12/01/2023] [Indexed: 01/23/2024]
Abstract
BACKGROUND FAM170B-AS1 is usually expressed low in all organs except for testicular tissues. No study was performed to explore its role in breast cancer (BC). Contradictory results were reported about hsa-miR-1202 and hsa-miR-146a-5p in BC. OBJECTIVE The present study aimed to explore the involvement of FAM170B-AS1 in BC using bioinformatics predictive tools, followed by a practical validation besides exploring the impact of hsa-miR-1202 and hsa-miR-146a-5p in BC. METHODS This study enrolled 96 female patients with BC, 30 patients with benign breast diseases (BBD), and 25 control subjects. The expressions of circulating FAM170B-AS1, hsa-miR-1202, and hsa-miR-146a-5p were quantified using qRT-PCR. These ncRNAs' associations, predictive, and diagnostic roles in BC were statistically tested. The underlying miRNA/mRNA targets of FAM170B-AS1 in BC were bioinformatically predicted followed by confirmation based on the GEPIA and TCGA databases. RESULTS The expression of FAM170B-AS1 was upregulated in sera of BC patients and hsa-miR-1202 was upregulated in sera of BBD and BC patients while that of hsa-miR-146a-5p was downregulated in BC. These FAM170B-AS1 was significantly associated with BC when compared to BBD. FAM170B-AS1 and hsa-miR-1202 were statistically associated with the BC's stage, grade, and LN metastasis. FAM170B-AS1 and hsa-miR-146a-5p gave the highest specificity and sensitivity for BC. KRAS and EGFR were predicted to be targeted by FAM170B-AS1 through interaction with hsa-miR-143-3p and hsa-miR-7-5p, respectively. Based on the TCGA database, cancer patients having mutations in FAM170B show good overall survival. CONCLUSIONS The present study reported that for the first time, FAM170B-AS1 may be a potential risk factor, predictive, and diagnostic marker for BC. In addition, FAM170B-AS1 might be involved in BC by interacting with hsa-miR-143-3p/KRAS and hsa-miR-7-5p/EGFR through enhancement or repression that may present a new therapeutic option for BC.
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Affiliation(s)
| | - Hala Mostafa Ghanem
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Menha Swellam
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Dokki, Giza, Egypt
- High Throughput Molecular and Genetic laboratory, Central Laboratories Network and the Centers of Excellence, National Research Centre, Dokki, Giza, Egypt
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Chatterjee P, Karn R, Isaac AE, Ray S. Unveiling the vulnerabilities of synthetic lethality in triple-negative breast cancer. Clin Transl Oncol 2023; 25:3057-3072. [PMID: 37079210 DOI: 10.1007/s12094-023-03191-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 04/04/2023] [Indexed: 04/21/2023]
Abstract
Triple-negative breast cancer (TNBC) is the most invasive molecular subtype of breast cancer (BC), accounting for about nearly 15% of all BC cases reported annually. The absence of the three major BC hormone receptors, Estrogen (ER), Progesterone (PR), and Human Epidermal Growth Factor 2 (HER2) receptor, accounts for the characteristic "Triple negative" phraseology. The absence of these marked receptors makes this cancer insensitive to classical endocrine therapeutic approaches. Hence, the available treatment options remain solemnly limited to only conventional realms of chemotherapy and radiation therapy. Moreover, these therapeutic regimes are often accompanied by numerous treatment side-effects that account for early distant metastasis, relapse, and shorter overall survival in TNBC patients. The rigorous ongoing research in the field of clinical oncology has identified certain gene-based selective tumor-targeting susceptibilities, which are known to account for the molecular fallacies and mutation-based genetic alterations that develop the progression of TNBC. One such promising approach is synthetic lethality, which identifies novel drug targets of cancer, from undruggable oncogenes or tumor-suppressor genes, which cannot be otherwise clasped by the conventional approaches of mutational analysis. Herein, a holistic scientific review is presented, to undermine the mechanisms of synthetic lethal (SL) interactions in TNBC, the epigenetic crosstalks encountered, the role of Poly (ADP-ribose) polymerase inhibitors (PARPi) in inducing SL interactions, and the limitations faced by the lethal interactors. Thus, the future predicament of synthetic lethal interactions in the advancement of modern translational TNBC research is assessed with specific emphasis on patient-specific personalized medicine.
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Affiliation(s)
| | - Rohit Karn
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Arnold Emerson Isaac
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Smita Ray
- Department of Botany, Bethune College, Kolkata, West Bengal, 700006, India.
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Petrović N, Essack M, Šami A, Perry G, Gojobori T, Isenović ER, Bajić VP. MicroRNA networks linked with BRCA1/2, PTEN, and common genes for Alzheimer's disease and breast cancer share highly enriched pathways that may unravel targets for the AD/BC comorbidity treatment. Comput Biol Chem 2023; 106:107925. [PMID: 37487248 DOI: 10.1016/j.compbiolchem.2023.107925] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 06/29/2023] [Accepted: 07/13/2023] [Indexed: 07/26/2023]
Abstract
MicroRNAs (miRNAs) are involved in the regulation of various cellular processes including pathological conditions. MiRNA networks have been extensively researched in age-related degenerative diseases, such as cancer, Alzheimer's disease (AD), and heart failure. Thus, miRNA has been studied from different approaches, in vivo, in vitro, and in silico including miRNA networks. Networks linking diverse biomedical entities unveil information not readily observable by other means. This work focuses on biological networks related to Breast cancer susceptibility 1 (BRCA1) in AD and breast cancer (BC). Using various bioinformatics approaches, we identified subnetworks common to AD and BC that suggest they are linked. According to our results, miR-107 was identified as a potentially good candidate for both AD and BC treatment (targeting BRCA1/2 and PTEN in both diseases), accompanied by miR-146a and miR-17. The analysis also confirmed the involvement of the miR-17-92 cluster, and miR-124-3p, and highlighted the importance of poorly researched miRNAs such as mir-6785 mir-6127, mir-6870, or miR-8485. After filtering the in silico analysis results, we found 49 miRNA molecules that modulate the expression of at least five genes common to both BC and AD. Those 49 miRNAs regulate the expression of 122 genes in AD and 93 genes in BC, from which 26 genes are common genes for AD and BC involved in neuron differentiation and genesis, cell differentiation and migration, regulation of cell cycle, and cancer development. Additionally, the highly enriched pathway was associated with diabetic complications, pointing out possible interplay among molecules underlying BC, AD, and diabetes pathology.
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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
| | - Magbubah Essack
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center, Computer (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia
| | - Ahmad Šami
- Cellular and Molecular Radiation Oncology Laboratory, Department of Radiation Oncology, Universitatsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - George Perry
- Department of Biology, The University of Texas at San Antonio, San Antonio, TX, USA
| | - Takashi Gojobori
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center, Computer (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia
| | - Esma R Isenović
- 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
| | - Vladan P Bajić
- 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.
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Kuthethur R, Jerome MS, Subbannayya Y, Chakrabarty S. An integrated analysis of microRNAs regulating DNA damage response in triple-negative breast cancer. Breast Cancer 2023; 30:832-844. [PMID: 37344703 PMCID: PMC10404216 DOI: 10.1007/s12282-023-01477-y] [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: 01/07/2023] [Accepted: 06/09/2023] [Indexed: 06/23/2023]
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive phenotype and limited treatment options for the patients. Many TNBC patients show an inherent defect in the DNA repair capacity primarily by acquiring germline mutations in BRCA1 and BRCA2 genes leading to Homologous Recombination Deficiency (HRD). Epigenetic modifications such as BRCA1 promoter methylation and miRNA expression targeting DNA repair pathway genes have contributed to the HRD phenotype in TNBC. Hence, we aimed to identify microRNAs that are associated with HRD status in the TCGA-BRCA project. MATERIALS AND METHODS We implemented a miRNA prediction strategy for identifying miRNAs targeting HR pathway genes using an in silico predicted and experimentally validated list from published literature for their association with genomic instability and factors affecting HRD. In silico analysis was performed to study miRNA expression patterns regulated by DNA methylation and TMB status in the TNBC patients from TCGA-BRCA project. Finally, we analysed selected miRNA expression with immune cell infiltration pattern in the TNBC patient cohort. RESULTS Our study identified miRNAs associated with HRD, tumour mutation burden (TMB), and immune cell infiltration. Identified miRNA signatures were associated with the miR-17 ~ 92 cluster, miR-106b ~ 25 cluster, and miR-200b ~ 429 cluster. Pathway analysis of selected miRNAs suggested their association with altered immune cell infiltration in TNBC. CONCLUSION Our study identified 6 'HRD associated miRNAs' such as miR-106b, miR-93, miR-17, miR-20a, miR-200b, and miR-429 as novel miRNA-based signatures associated with HR deficiency in TNBC.
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Affiliation(s)
- Raviprasad Kuthethur
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Maria Sona Jerome
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Yashwanth Subbannayya
- Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491, Trondheim, Norway
- School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH, UK
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
- Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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11
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Chamandi G, El-Hajjar L, El Kurdi A, Le Bras M, Nasr R, Lehmann-Che J. ER Negative Breast Cancer and miRNA: There Is More to Decipher Than What the Pathologist Can See! Biomedicines 2023; 11:2300. [PMID: 37626796 PMCID: PMC10452617 DOI: 10.3390/biomedicines11082300] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/03/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Breast cancer (BC), the most prevalent cancer in women, is a heterogenous disease. Despite advancements in BC diagnosis, prognosis, and therapeutics, survival rates have drastically decreased in the metastatic setting. Therefore, BC still remains a medical challenge. The evolution of high-throughput technology has highlighted gaps in the classification system of BCs. Of particular interest is the notorious triple negative BC, which was recounted as being heterogenous itself and it overlaps with distinct subtypes, namely molecular apocrine (MA) and luminal androgen (LAR) BCs. These subtypes are, even today, still misdiagnosed and poorly treated. As such, researchers and clinicians have been looking for ways through which to refine BC classification in order to properly understand the initiation, development, progression, and the responses to the treatment of BCs. One tool is biomarkers and, specifically, microRNA (miRNA), which are highly reported as associated with BC carcinogenesis. In this review, the diverse roles of miRNA in estrogen receptor negative (ER-) and androgen receptor positive (AR+) BC are depicted. While highlighting their oncogenic and tumor suppressor functions in tumor progression, we will discuss their diagnostic, prognostic, and predictive biomarker potentials, as well as their drug sensitivity/resistance activity. The association of several miRNAs in the KEGG-reported pathways that are related to ER-BC carcinogenesis is presented. The identification and verification of accurate miRNA panels is a cornerstone for tackling BC classification setbacks, as is also the deciphering of the carcinogenesis regulators of ER - AR + BC.
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Affiliation(s)
- Ghada Chamandi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, 11-0236 Beirut, Lebanon; (G.C.); (L.E.-H.)
- Pathophysiology of Breast Cancer Team, INSERM U976, Immunologie Humaine, Pathophysiologie, Immunothérapie (HIPI), Université Paris Cité, 75010 Paris, France;
| | - Layal El-Hajjar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, 11-0236 Beirut, Lebanon; (G.C.); (L.E.-H.)
- Office of Basic/Translational Research and Graduate Studies, Faculty of Medicine, American University of Beirut, 11-0236 Beirut, Lebanon
| | - Abdallah El Kurdi
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, 11-0236 Beirut, Lebanon;
| | - Morgane Le Bras
- Pathophysiology of Breast Cancer Team, INSERM U976, Immunologie Humaine, Pathophysiologie, Immunothérapie (HIPI), Université Paris Cité, 75010 Paris, France;
| | - Rihab Nasr
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, 11-0236 Beirut, Lebanon; (G.C.); (L.E.-H.)
| | - Jacqueline Lehmann-Che
- Pathophysiology of Breast Cancer Team, INSERM U976, Immunologie Humaine, Pathophysiologie, Immunothérapie (HIPI), Université Paris Cité, 75010 Paris, France;
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12
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Panoutsopoulou K, Liu Y, Avgeris M, Dreyer T, Dorn J, Magdolen V, Scorilas A. Repression of miR-146a in predicting poor treatment outcome in triple-negative breast cancer. Clin Biochem 2023; 114:43-51. [PMID: 36502883 DOI: 10.1016/j.clinbiochem.2022.12.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 11/17/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022]
Abstract
OBJECTIVES In the era of precision medicine, the highly aggressive and heterogenous triple-negative breast cancer (TNBC) is still characterized by limited options to support personalized prognosis and guide therapeutic interventions. Thereafter, the aim of the present study has been the thorough evaluation of miR-146a as a novel molecular indicator of TNBC prognosis and treatment outcome, utilizing four independent TNBC cohorts. DESIGN & METHODS miR-146a levels were clinically evaluated in our screening (n = 122) and three external validation TNBC cohorts (de Rinaldis et al. 2013, n = 114; Jézéquel et al. 2015, n = 107; TCGA, n = 180). Analysis of miR-146a and validated gene targets was performed in Jézéquel et al. and TCGA validation cohorts. Patients' survival, recurrence and metastasis were determined as clinical endpoints for the survival analysis. Internal validation was performed by bootstrap analysis and clinical net benefit was evaluated by decision curve analysis. RESULTS Reduction of miR-146a is strongly associated with patients' poor survival and can predict post-treatment disease early-recurrence, independently of tumor size, lymph node status, histological grade and patients' age. The analysis of the external validation cohorts corroborated the unfavorable nature of miR-146a repression regarding patients' survival and, strikingly, unveiled the ability of miR-146a to predict TNBC metastasis. Combined assessment of miR-146a levels and lymph node status resulted in superior risk-stratification of TNBC patients and higher clinical benefit regarding disease prognosis and post-treatment outcome. Ultimately, miR-146a was negatively associated with EGFR and SOX2 expression in TNBC. CONCLUSIONS miR-146a evaluation could ameliorate personalized prognosis and support precision medicine decisions in TNBC.
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Affiliation(s)
- Konstantina Panoutsopoulou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Yueyang Liu
- Clinical Research Unit, Department of Obstetrics and Gynecology, School of Medicine, Technical University of Munich, Munich, Germany; Department of Gynecology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Margaritis Avgeris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece; Laboratory of Clinical Biochemistry-Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Tobias Dreyer
- Clinical Research Unit, Department of Obstetrics and Gynecology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Julia Dorn
- Clinical Research Unit, Department of Obstetrics and Gynecology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Viktor Magdolen
- Clinical Research Unit, Department of Obstetrics and Gynecology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
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13
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Khazaei-Poul Y, Mirmotalebisohi SA, Zali H, Molavi Z, Mohammadi-Yeganeh S. Identification of miR-3182 and miR-3143 target genes involved in the cell cycle as a novel approach in TNBC treatment: A systems biology approach. Chem Biol Drug Des 2023; 101:662-677. [PMID: 36310371 DOI: 10.1111/cbdd.14167] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 10/15/2022] [Accepted: 10/24/2022] [Indexed: 02/04/2023]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis, lacking therapeutic targets. miRNAs play crucial roles in TNBC through regulating various mechanisms, including cellular growth and proliferation. This study aims to identify critical target genes of two novel miRNAs (miR-3143 and miR-3182) involved in the cell cycle of TNBC as possible therapeutic targets and investigates their regulatory and therapeutic roles through a systems biology approach and in vitro experiment. Datasets related to the TNBC cell line (MDA-MB-231) were screened and retrieved, and Gene regulatory networks were constructed. Significant regulatory motifs were detected and analyzed using the FANMOD and Cytoscape analyzer, and the clusters and seeds were identified using the MCODE. Functional enrichment analysis was also performed using DAVID and STRING. The most critical genes were determined using the analysis of GRN motifs and PPI clusters. The essential genes involved in the cell cycle were selected and verified using the bc-GenExMiner v4.7. We overexpressed miR-3143 and miR-3182 in the MDA-MB-231 cell line using human umbilical cord mesenchymal stem cell (HUCMSC)-miRNA loaded exosomes, and the expression of the critical target genes was investigated using RT-qPCR. We identified eight critical genes as potential therapeutic targets. Their expression decreased by overexpression of miR-3143 and miR-3182 in RT-qPCR. The identified critical genes have probably significant roles in the pathogenesis of TNBC through the cell cycle. We suggest that the overexpression of miR-3143 and miR-3182 could be a new therapeutic candidate in TNBC and is worth more investigation.
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Affiliation(s)
- Yalda Khazaei-Poul
- Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Amir Mirmotalebisohi
- Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hakimeh Zali
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Molavi
- Proteomics Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Samira Mohammadi-Yeganeh
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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14
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Deb S, Chakrabarti A, Fox SB. Prognostic and Predictive Biomarkers in Familial Breast Cancer. Cancers (Basel) 2023; 15:cancers15041346. [PMID: 36831687 PMCID: PMC9953970 DOI: 10.3390/cancers15041346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/06/2023] [Accepted: 02/15/2023] [Indexed: 02/23/2023] Open
Abstract
Large numbers of breast cancers arise within a familial context, either with known inherited germline mutations largely within DNA repair genes, or with a strong family history of breast and/or ovarian cancer, with unknown genetic underlying mechanisms. These cancers appear to be different to sporadic cases, with earlier age of onset, increased multifocality and with association with specific breast cancer histological and phenotypic subtypes. Furthermore, tumours showing homologous recombination deficiency, due to loss of BRCA1, BRCA2, PALB2 and CHEK2 function, have been shown to be especially sensitive to platinum-based chemotherapeutics and PARP inhibition. While there is extensive research and data accrued on risk stratification and genetic predisposition, there are few data pertaining to relevant prognostic and predictive biomarkers within this breast cancer subgroup. The following is a review of such biomarkers in male and female familial breast cancer, although the data for the former are particularly sparse.
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Affiliation(s)
- Siddhartha Deb
- Anatpath, Gardenvale, VIC 3185, Australia
- Monash Health Pathology, Clayton, VIC 3168, Australia
- Correspondence:
| | | | - Stephen B. Fox
- Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, University of Mebourne, Melbourne, VIC 3101, Australia
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15
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Dos Santos JS, Bonafé GA, Lourenço GJ, Ortega MM. Evaluating Single-Nucleotide Variants in MicroRNA Targeting Sites and Mature MicroRNA In Vitro Cell Culture by Luciferase Reporter Gene Assays. Methods Mol Biol 2023; 2595:185-201. [PMID: 36441463 DOI: 10.1007/978-1-0716-2823-2_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
MicroRNAs (miRs) are small non-coding RNAs of 21-24 nucleotides in length that modulate gene expression by targeting the untranslated region (UTR) of mRNA. Single-nucleotide variants (SNVs) in primary miRs (pri-miRs), precursor miRs (pre-miRs), promoters of pri-miRs, and seed regions can affect miR stability or processing, may influence mature miR expression, and can affect target gene identification, respectively. The present protocol tests the binding and activity of miRs on 3'-UTR target sequences based on the expression of luciferase as a reporter gene fused to the UTR sequence in the presence of plasmids containing pre-miR of interest to test in vitro cell culture assay.
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Affiliation(s)
- Jéssica Silva Dos Santos
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista, São Paulo, Brazil
| | - Gabriel Alves Bonafé
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista, São Paulo, Brazil
| | - Gustavo Jacob Lourenço
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Manoela Marques Ortega
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista, São Paulo, Brazil.
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16
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Matis S, Grazia Recchia A, Colombo M, Cardillo M, Fabbi M, Todoerti K, Bossio S, Fabris S, Cancila V, Massara R, Reverberi D, Emionite L, Cilli M, Cerruti G, Salvi S, Bet P, Pigozzi S, Fiocca R, Ibatici A, Angelucci E, Gentile M, Monti P, Menichini P, Fronza G, Torricelli F, Ciarrocchi A, Neri A, Fais F, Tripodo C, Morabito F, Ferrarini M, Cutrona G. MiR-146b-5p regulates IL-23 receptor complex expression in chronic lymphocytic leukemia cells. Blood Adv 2022; 6:5593-5612. [PMID: 35819446 PMCID: PMC9647700 DOI: 10.1182/bloodadvances.2021005726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 06/30/2022] [Indexed: 11/20/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) cells express the interleukin-23 receptor (IL-23R) chain, but the expression of the complementary IL-12Rβ1 chain requires cell stimulation via surface CD40 molecules (and not via the B-cell receptor [BCR]). This stimulation induces the expression of a heterodimeric functional IL-23R complex and the secretion of IL-23, initiating an autocrine loop that drives leukemic cell expansion. Based on the observation in 224 untreated Binet stage A patients that the cases with the lowest miR-146b-5p concentrations had the shortest time to first treatment (TTFT), we hypothesized that miR-146b-5p could negatively regulate IL-12Rβ1 side chain expression and clonal expansion. Indeed, miR-146b-5p significantly bound to the 3'-UTR region of the IL-12Rβ1 mRNA in an in vitro luciferase assay. Downregulation of miR-146b-5p with specific miRNA inhibitors in vitro led to the upregulation of the IL-12Rβ1 side chain and expression of a functional IL-23R complex similar to that observed after stimulation of the CLL cell through the surface CD40 molecules. Expression of miR-146b-5p with miRNA mimics in vitro inhibited the expression of the IL-23R complex after stimulation with CD40L. Administration of a miR-146b-5p mimic to NSG mice, successfully engrafted with CLL cells, caused tumor shrinkage, with a reduction of leukemic nodules and of IL-12Rβ1-positive CLL cells in the spleen. Our findings indicate that IL-12Rβ1 expression, a crucial checkpoint for the functioning of the IL-23 and IL-23R complex loop, is under the control of miR-146b-5p, which may represent a potential target for therapy since it contributes to the CLL pathogenesis. This trial is registered at www.clinicaltrials.gov as NCT00917540.
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Affiliation(s)
- Serena Matis
- Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Anna Grazia Recchia
- Hematology Unit AO of Cosenza, Cosenza, Italy
- Biothecnology Research Unit, AO, Cosenza, Italy
| | - Monica Colombo
- Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Martina Cardillo
- Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Marina Fabbi
- Biotherapy Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Katia Todoerti
- Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Sabrina Bossio
- Hematology Unit AO of Cosenza, Cosenza, Italy
- Biothecnology Research Unit, AO, Cosenza, Italy
| | - Sonia Fabris
- Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Valeria Cancila
- Tumor Immunology Unit, Department of Health Sciences, University of Palermo School of Medicine, Palermo, Italy
| | - Rosanna Massara
- Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Daniele Reverberi
- Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Laura Emionite
- Animal Facility, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Michele Cilli
- Animal Facility, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Giannamaria Cerruti
- Molecular Diagnostic Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Sandra Salvi
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Paola Bet
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Simona Pigozzi
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
| | - Roberto Fiocca
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
| | - Adalberto Ibatici
- Hematology Unit and Transplant Center, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Emanuele Angelucci
- Hematology Unit and Transplant Center, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Massimo Gentile
- Hematology Unit AO of Cosenza, Cosenza, Italy
- Biothecnology Research Unit, AO, Cosenza, Italy
| | - Paola Monti
- Mutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Paola Menichini
- Mutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Gilberto Fronza
- Mutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Federica Torricelli
- Laboratory of Translational Research, Azienda USL IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Alessia Ciarrocchi
- Laboratory of Translational Research, Azienda USL IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Antonino Neri
- Scientific Directorate, Azienda USL IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Franco Fais
- Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Claudio Tripodo
- Tumor Immunology Unit, Department of Health Sciences, University of Palermo School of Medicine, Palermo, Italy
| | - Fortunato Morabito
- Biothecnology Research Unit, AO, Cosenza, Italy
- Hematology and Bone Marrow Transplant Unit, Hemato-Oncology Department, Augusta Victoria Hospital, East Jerusalem, Israel
| | - Manlio Ferrarini
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Giovanna Cutrona
- Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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17
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Prieto‐Vila M, Usuba W, Yoshioka Y, Takeshita F, Yoshiike M, Sasaki H, Yamamoto Y, Kikuchi E, Ochiya T. High-grade bladder cancer cells secrete extracellular vesicles containing miRNA-146a-5p and promotes angiogenesis. JOURNAL OF EXTRACELLULAR BIOLOGY 2022; 1:e47. [PMID: 38939052 PMCID: PMC11080795 DOI: 10.1002/jex2.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/23/2022] [Accepted: 06/15/2022] [Indexed: 06/29/2024]
Abstract
Recurrence is one of the major issues in bladder cancer (BCa). Novel technologies, such as the detection of microRNAs carried by extracellular vesicles (EVs) in urine, have been proposed as biomarkers for detecting recurrence in BCa. Although the usefulness of microRNAs in body fluids from cancer patients has been reported, it is also known that they play essential roles in cancer progression. We previously proposed miR-146a-5p as a prognostic marker in BCa, since its urinary expression was associated with grade and tumour depth. However, the specific mechanisms of miR-146a-5p remain unclear. Here, we show the proangiogenic effects of miR-146a-5p secreted by high-grade BCa cells. The urinary miR-146a-5p level was higher in patients with high-grade BCa than in those with low-grade BCa. Similarly, tumours generated by miR-146a-overexpressing BCa cells in mice grew rapidly with high levels of angiogenesis. BCa-derived EV treatment promoted the proliferation of endothelial cells via the inhibition of the demethylase TET2 and the subsequent increase in its downstream target c-Myc. These findings demonstrate that secreted miR-146a-5p contributes to cancer progression by promoting angiogenesis. Therefore, miRNAs in EVs may become not only a diagnostic tool but also a target molecule for therapy.
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Affiliation(s)
- Marta Prieto‐Vila
- Department of Molecular and Cellular Medicine, Institute of Medical ScienceTokyo Medical UniversityTokyoJapan
| | - Wataru Usuba
- Department of UrologySt. Marianna University School of MedicineKawasakiJapan
| | - Yusuke Yoshioka
- Department of Molecular and Cellular Medicine, Institute of Medical ScienceTokyo Medical UniversityTokyoJapan
| | - Fumitaka Takeshita
- Division of Fundamental Innovated OncologyNational Cancer Center Research InstitutesTokyoJapan
| | - Miki Yoshiike
- Department of UrologySt. Marianna University School of MedicineKawasakiJapan
| | - Hideo Sasaki
- Department of UrologySt. Marianna University School of MedicineKawasakiJapan
| | - Yusuke Yamamoto
- Laboratory of Integrative OncologyNational Cancer Center Research InstituteTokyoJapan
| | - Eiji Kikuchi
- Department of UrologySt. Marianna University School of MedicineKawasakiJapan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical ScienceTokyo Medical UniversityTokyoJapan
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18
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Hater N, Iwaniuk KM, Leifeld C, Grüten P, Wiek C, Raba K, Zhang F, Fischer JC, Andreassen PR, Hanenberg H, Trompeter HI. Identification of new RAD51D-regulating microRNAs that also emerge as potent inhibitors of the Fanconi anemia/homologous recombination pathways. Hum Mol Genet 2022; 31:4241-4254. [PMID: 35904444 PMCID: PMC9759333 DOI: 10.1093/hmg/ddac177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/28/2022] [Accepted: 07/27/2022] [Indexed: 01/21/2023] Open
Abstract
The Fanconi anemia (FA) and homologous recombination (HR) pathways, which partially overlap and include RAD51 and its paralogs, are key for the repair of different types of DNA damage, such as DNA interstrand crosslinks. First, to broadly assess the impact of microRNA-mediated regulation, we examined microRNA expression profiles in five isogenic fibroblast cell pairs, either deficient in DNA repair due to germline mutations in FANCA, FANCB, FANCC, FANCI or BRIP1/FANCJ or proficient due to correction with retroviral vectors. In each pair, we observed lower abundance of specific microRNAs in the FA-deficient cells. From the list of microRNAs, we experimentally confirmed the effects of miR-141-3p and miR-369-3p targeting RAD51B and miR-15a-5p, miR-494-3p as well as miR-544a targeting RAD51D. However, by western blotting, only RAD51D protein was reduced by a mixture of its regulating microRNAs. Gene ontology analyses and identification of additional FA/HR factors as targets of miR-15a-5p, miR-494-3p and miR-544a strongly suggested the widespread influence of these microRNAs on HR. Interestingly, only miR-494-3p directly reduced RAD51 foci formation, while a mixture of miR-15a-5p, miR-494-3p and miR-544a strongly reduced HR activity in green fluorescent protein (GFP) repair assays. In summary, by successfully employing this novel loss- and gain-of-function strategy, we have identified new microRNAs strongly inhibiting HR in mammalian cells. Understanding and modulating such miRNA regulation of DNA repair genes/pathways might help to overcome the reduced repair capacity of FA patients with biallelic hypomorphic mutations or help to engineer synthetic lethality strategies for patients with mutations in cancer-associated FA/HR genes.
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Affiliation(s)
- Nina Hater
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital Düsseldorf, Heinrich Heine University, D-40225 Düsseldorf, Germany
| | - Katharina M Iwaniuk
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital Düsseldorf, Heinrich Heine University, D-40225 Düsseldorf, Germany
| | - Carina Leifeld
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital Düsseldorf, Heinrich Heine University, D-40225 Düsseldorf, Germany
| | - Pia Grüten
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital Düsseldorf, Heinrich Heine University, D-40225 Düsseldorf, Germany
| | - Constanze Wiek
- Department of Otorhinolaryngology & Head/Neck Surgery, University Hospital Düsseldorf, Heinrich Heine University, D-40225 Düsseldorf, Germany
| | - Katharina Raba
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital Düsseldorf, Heinrich Heine University, D-40225 Düsseldorf, Germany
| | - Fan Zhang
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Johannes C Fischer
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital Düsseldorf, Heinrich Heine University, D-40225 Düsseldorf, Germany
| | - Paul R Andreassen
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | | | - Hans-Ingo Trompeter
- To whom correspondence should be addressed. Tel: +49 211 8118751; Fax: +49 211 8119109;
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19
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The Breast Cancer Protooncogenes HER2, BRCA1 and BRCA2 and Their Regulation by the iNOS/NOS2 Axis. Antioxidants (Basel) 2022; 11:antiox11061195. [PMID: 35740092 PMCID: PMC9227079 DOI: 10.3390/antiox11061195] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 02/04/2023] Open
Abstract
The expression of inducible nitric oxide synthase (iNOS; NOS2) and derived NO in various cancers was reported to exert pro- and anti-tumorigenic effects depending on the levels of expression and the tumor types. In humans, the breast cancer level of iNOS was reported to be overexpressed, to exhibit pro-tumorigenic activities, and to be of prognostic significance. Likewise, the expression of the oncogenes HER2, BRCA1, and BRCA2 has been associated with malignancy. The interrelationship between the expression of these protooncogenes and oncogenes and the expression of iNOS is not clear. We have hypothesized that there exist cross-talk signaling pathways between the breast cancer protooncogenes, the iNOS axis, and iNOS-mediated NO mutations of these protooncogenes into oncogenes. We review the molecular regulation of the expression of the protooncogenes in breast cancer and their interrelationships with iNOS expression and activities. In addition, we discuss the roles of iNOS, HER2, BRCA1/2, and NO metabolism in the pathophysiology of cancer stem cells. Bioinformatic analyses have been performed and have found suggested molecular alterations responsible for breast cancer aggressiveness. These include the association of BRCA1/2 mutations and HER2 amplifications with the dysregulation of the NOS pathway. We propose that future studies should be undertaken to investigate the regulatory mechanisms underlying the expression of iNOS and various breast cancer oncogenes, with the aim of identifying new therapeutic targets for the treatment of breast cancers that are refractory to current treatments.
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20
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Darbeheshti F, Kadkhoda S, Keshavarz-Fathi M, Razi S, Bahramy A, Mansoori Y, Rezaei N. Investigation of BRCAness associated miRNA-gene axes in breast cancer: cell-free miR-182-5p as a potential expression signature of BRCAness. BMC Cancer 2022; 22:668. [PMID: 35715772 PMCID: PMC9206264 DOI: 10.1186/s12885-022-09761-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 06/08/2022] [Indexed: 12/31/2022] Open
Abstract
The concept of the ‘BRCAness’ phenotype implies the properties that some sporadic breast cancers (BC) share with BRCA1/2-mutation carriers with hereditary BC. Breast tumors with BRCAness have deficiencies in homologous recombination repair (HRR), like BRCA1/2-mutation carriers, and consequently could benefit from poly-(ADP)-ribose polymerase (PARP) inhibitors and DNA-damaging chemotherapy. Triple-negative breast cancers (TNBC) show a higher frequency of BRCAness than the other BC subtypes. Therefore, looking for BRCAness-related biomarkers could improve personalized management of TNBC patients. microRNAs (miRNAs) play a pivotal role in onco-transcriptomic profiles of tumor cells besides their suitable features as molecular biomarkers. The current study aims to evaluate the expression level of some critical miRNAs-mRNA axes in HRR pathway in tumors and plasma samples from BC patients. The expression levels of three multi-target miRNAs, including miR-182-5p, miR-146a-5p, and miR-498, as well as six downstream HRR-related protein-coding genes, have been investigated in the breast tumors and paired adjacent normal tissues by Real-time PCR. In the next step, based on the results derived from the previous step, we examined the level of cell-free miR-182-5p in the blood plasma samples from the patients. Our results highlight the difference between TNBC and non-TNBC tumor subgroups regarding the dysregulation of the key miRNA/mRNA axes involved in the HRR pathway. Also, for the first time, we show that the level of cell-free miR-182-5p in plasma samples from BC patients could be a clue for screening BC patients eligible for receiving PARP inhibitors through a personalized manner. Altogether, some sporadic BC patients, especially sporadic TNBC, have epigenetically dysregulated HRR pathway that could be identified and benefit from BRCAness-specific therapeutic agents.
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Affiliation(s)
- Farzaneh Darbeheshti
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Kadkhoda
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsa Keshavarz-Fathi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Afshin Bahramy
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Yaser Mansoori
- Noncommunicable Disease Research Center, Fasa University of Medical Sciences, Fasa, Iran. .,Department of Medical Genetics, Fasa University of Medical Sciences, Fasa, Iran.
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, Iran. .,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. .,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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21
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Bioinformatic investigation and functional analysis of 214 hereditary genes identified non-coding RNAs as therapeautic tool for breast cancer management. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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22
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Hatmal MM, Al-Hatamleh MAI, Olaimat AN, Alshaer W, Hasan H, Albakri KA, Alkhafaji E, Issa NN, Al-Holy MA, Abderrahman SM, Abdallah AM, Mohamud R. Immunomodulatory Properties of Human Breast Milk: MicroRNA Contents and Potential Epigenetic Effects. Biomedicines 2022; 10:1219. [PMID: 35740242 PMCID: PMC9219990 DOI: 10.3390/biomedicines10061219] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 05/15/2022] [Accepted: 05/17/2022] [Indexed: 02/07/2023] Open
Abstract
Infants who are exclusively breastfed in the first six months of age receive adequate nutrients, achieving optimal immune protection and growth. In addition to the known nutritional components of human breast milk (HBM), i.e., water, carbohydrates, fats and proteins, it is also a rich source of microRNAs, which impact epigenetic mechanisms. This comprehensive work presents an up-to-date overview of the immunomodulatory constituents of HBM, highlighting its content of circulating microRNAs. The epigenetic effects of HBM are discussed, especially those regulated by miRNAs. HBM contains more than 1400 microRNAs. The majority of these microRNAs originate from the lactating gland and are based on the remodeling of cells in the gland during breastfeeding. These miRNAs can affect epigenetic patterns by several mechanisms, including DNA methylation, histone modifications and RNA regulation, which could ultimately result in alterations in gene expressions. Therefore, the unique microRNA profile of HBM, including exosomal microRNAs, is implicated in the regulation of the genes responsible for a variety of immunological and physiological functions, such as FTO, INS, IGF1, NRF2, GLUT1 and FOXP3 genes. Hence, studying the HBM miRNA composition is important for improving the nutritional approaches for pregnancy and infant's early life and preventing diseases that could occur in the future. Interestingly, the composition of miRNAs in HBM is affected by multiple factors, including diet, environmental and genetic factors.
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Affiliation(s)
- Ma’mon M. Hatmal
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Mohammad A. I. Al-Hatamleh
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Malaysia;
| | - Amin N. Olaimat
- Department of Clinical Nutrition and Dietetics, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan; (A.N.O.); (M.A.A.-H.)
| | - Walhan Alshaer
- Cell Therapy Center (CTC), The University of Jordan, Amman 11942, Jordan;
| | - Hanan Hasan
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan;
| | - Khaled A. Albakri
- Faculty of Medicine, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Enas Alkhafaji
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan;
| | - Nada N. Issa
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Murad A. Al-Holy
- Department of Clinical Nutrition and Dietetics, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan; (A.N.O.); (M.A.A.-H.)
| | - Salim M. Abderrahman
- Department of Biology and Biotechnology, Faculty of Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Atiyeh M. Abdallah
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar;
| | - Rohimah Mohamud
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Malaysia;
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23
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Sudhanva MS, Hariharasudhan G, Jun S, Seo G, Kamalakannan R, Kim HH, Lee JH. MicroRNA-145 Impairs Classical Non-Homologous End-Joining in Response to Ionizing Radiation-Induced DNA Double-Strand Breaks via Targeting DNA-PKcs. Cells 2022; 11:1509. [DOI: https:/doi.org/10.3390/cells11091509 academic] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/18/2023] Open
Abstract
DNA double-strand breaks (DSBs) are one of the most lethal types of DNA damage due to the fact that unrepaired or mis-repaired DSBs lead to genomic instability or chromosomal aberrations, thereby causing cell death or tumorigenesis. The classical non-homologous end-joining pathway (c-NHEJ) is the major repair mechanism for rejoining DSBs, and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is a critical factor in this pathway; however, regulation of DNA-PKcs expression remains unknown. In this study, we demonstrate that miR-145 directly suppresses DNA-PKcs by binding to the 3′-UTR and inhibiting translation, thereby causing an accumulation of DNA damage, impairing c-NHEJ, and rendering cells hypersensitive to ionizing radiation (IR). Of note, miR-145-mediated suppression of DNA damage repair and enhanced IR sensitivity were both reversed by either inhibiting miR-145 or overexpressing DNA-PKcs. In addition, we show that the levels of Akt1 phosphorylation in cancer cells are correlated with miR-145 suppression and DNA-PKcs upregulation. Furthermore, the overexpression of miR-145 in Akt1-suppressed cells inhibited c-NHEJ by downregulating DNA-PKcs. These results reveal a novel miRNA-mediated regulation of DNA repair and identify miR-145 as an important regulator of c-NHEJ.
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Affiliation(s)
- Muddenahalli Srinivasa Sudhanva
- Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 61452, Korea
| | - Gurusamy Hariharasudhan
- Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 61452, Korea
- Department of Cellular and Molecular Medicine, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 61452, Korea
| | - Semo Jun
- Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 61452, Korea
| | - Gwanwoo Seo
- Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 61452, Korea
- Department of Cellular and Molecular Medicine, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 61452, Korea
| | - Radhakrishnan Kamalakannan
- Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 61452, Korea
| | - Hyun Hee Kim
- Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 61452, Korea
| | - Jung-Hee Lee
- Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 61452, Korea
- Department of Cellular and Molecular Medicine, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 61452, Korea
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24
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MicroRNA-145 Impairs Classical Non-Homologous End-Joining in Response to Ionizing Radiation-Induced DNA Double-Strand Breaks via Targeting DNA-PKcs. Cells 2022; 11:cells11091509. [PMID: 35563814 PMCID: PMC9102532 DOI: 10.3390/cells11091509] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/21/2022] [Accepted: 04/28/2022] [Indexed: 12/04/2022] Open
Abstract
DNA double-strand breaks (DSBs) are one of the most lethal types of DNA damage due to the fact that unrepaired or mis-repaired DSBs lead to genomic instability or chromosomal aberrations, thereby causing cell death or tumorigenesis. The classical non-homologous end-joining pathway (c-NHEJ) is the major repair mechanism for rejoining DSBs, and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is a critical factor in this pathway; however, regulation of DNA-PKcs expression remains unknown. In this study, we demonstrate that miR-145 directly suppresses DNA-PKcs by binding to the 3′-UTR and inhibiting translation, thereby causing an accumulation of DNA damage, impairing c-NHEJ, and rendering cells hypersensitive to ionizing radiation (IR). Of note, miR-145-mediated suppression of DNA damage repair and enhanced IR sensitivity were both reversed by either inhibiting miR-145 or overexpressing DNA-PKcs. In addition, we show that the levels of Akt1 phosphorylation in cancer cells are correlated with miR-145 suppression and DNA-PKcs upregulation. Furthermore, the overexpression of miR-145 in Akt1-suppressed cells inhibited c-NHEJ by downregulating DNA-PKcs. These results reveal a novel miRNA-mediated regulation of DNA repair and identify miR-145 as an important regulator of c-NHEJ.
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25
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Interactions between miRNAs and Double-Strand Breaks DNA Repair Genes, Pursuing a Fine-Tuning of Repair. Int J Mol Sci 2022; 23:ijms23063231. [PMID: 35328651 PMCID: PMC8954595 DOI: 10.3390/ijms23063231] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/06/2022] [Accepted: 03/09/2022] [Indexed: 02/04/2023] Open
Abstract
The repair of DNA damage is a crucial process for the correct maintenance of genetic information, thus, allowing the proper functioning of cells. Among the different types of lesions occurring in DNA, double-strand breaks (DSBs) are considered the most harmful type of lesion, which can result in significant loss of genetic information, leading to diseases, such as cancer. DSB repair occurs through two main mechanisms, called non-homologous end joining (NHEJ) and homologous recombination repair (HRR). There is evidence showing that miRNAs play an important role in the regulation of genes acting in NHEJ and HRR mechanisms, either through direct complementary binding to mRNA targets, thus, repressing translation, or by targeting other genes involved in the transcription and activity of DSB repair genes. Therefore, alteration of miRNA expression has an impact on the ability of cells to repair DSBs, which, in turn, affects cancer therapy sensitivity. This latter gives account of the importance of miRNAs as regulators of NHEJ and HRR and places them as a promising target to improve cancer therapy. Here, we review recent reports demonstrating an association between miRNAs and genes involved in NHEJ and HRR. We employed the Web of Science search query TS (“gene official symbol/gene aliases*” AND “miRNA/microRNA/miR-”) and focused on articles published in the last decade, between 2010 and 2021. We also performed a data analysis to represent miRNA–mRNA validated interactions from TarBase v.8, in order to offer an updated overview about the role of miRNAs as regulators of DSB repair.
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26
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Paul U, Banerjee S. The functional significance and cross-talk of non-coding RNAs in triple negative and quadruple negative breast cancer. Mol Biol Rep 2022; 49:6899-6918. [PMID: 35235157 DOI: 10.1007/s11033-022-07288-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/18/2022] [Indexed: 12/13/2022]
Abstract
One of the leading causes of cancer-related deaths worldwide is breast cancer, among which triple-negative breast cancer (TNBC) is the most malignant and lethal subtype. This cancer accounts for 10-20% of all breast cancer deaths. Proliferation, tumorigenesis, and prognosis of TNBC are affected when the androgen receptor (AR) is not expressed, and it is classified as quadruple negative breast cancer (QNBC). Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play a significant role in tumorigenesis by virtue of their oncogenic and tumor-suppressive properties. To regulate tumorigenesis, miRNAs interact with their target mRNAs and modulate their expression, whereas lncRNAs can either act alone or interact with miRNAs or other molecules through various signaling pathways. Conversely, circRNAs regulate tumorigenesis by acting as miRNA sponges predominantly. Recently, non-coding RNAs were studied comprehensively for their roles in tumor proliferation, progression, and metastasis. As a result of existing studies and research progress, non-coding RNAs have been implicated in TNBC, necessitating their use as biomarkers for future diagnostic applications. In this review, the non-coding RNAs are explicitly implicated in the regulation of breast cancer, and their cross-talk between TNBC and QNBC is also discussed.
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Affiliation(s)
- Utpalendu Paul
- School of Bio Science and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Satarupa Banerjee
- School of Bio Science and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
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27
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Li Y, Kong X, Wang Z, Xuan L. Recent advances of transcriptomics and proteomics in triple-negative breast cancer prognosis assessment. J Cell Mol Med 2022; 26:1351-1362. [PMID: 35150062 PMCID: PMC8899180 DOI: 10.1111/jcmm.17124] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 11/18/2021] [Accepted: 12/01/2021] [Indexed: 12/24/2022] Open
Abstract
Triple-negative breast cancer (TNBC), a heterogeneous tumour that lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), is often characterized by aggressiveness and tends to recur or metastasize. TNBC lacks therapeutic targets compared with other subtypes and is not sensitive to endocrine therapy or targeted therapy except chemotherapy. Therefore, identifying the prognostic characteristics and valid therapeutic targets of TNBC could facilitate early personalized treatment. Due to the rapid development of various technologies, researchers are increasingly focusing on integrating 'big data' and biological systems, which is referred to as 'omics', as a means of resolving it. Transcriptomics and proteomics analyses play an essential role in exploring prospective biomarkers and potential therapeutic targets for triple-negative breast cancers, which provides a powerful engine for TNBC's therapeutic discovery when combined with complementary information. Here, we review the recent progress of TNBC research in transcriptomics and proteomics to identify possible therapeutic goals and improve the survival of patients with triple-negative breast cancer. Also, researchers may benefit from this article to catalyse further analysis and investigation to decipher the global picture of TNBC cancer.
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Affiliation(s)
- Yuan Li
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhongzhao Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lixue Xuan
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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28
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miR-146b-5p and miR-520h Expressions Are Upregulated in Serum of Women with Recurrent Spontaneous Abortion. Biochem Genet 2022; 60:1716-1732. [PMID: 35083607 DOI: 10.1007/s10528-021-10173-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 12/06/2021] [Indexed: 12/12/2022]
Abstract
Unexplained recurrent spontaneous abortion (URSA) is characterized by two or more consecutive pregnancy losses before the 20th week of gestation with unknown etiology. Dysregulation of microRNAs (miRNAs) expression has been reported in reproductive diseases. This study aimed to compare differentially expressed miRNAs in the serum samples between URSA patients and healthy individuals. URSA cases were confirmed by a gynecologist. Peripheral blood sample was gathered from 9 URSA patients, 15 normal pregnant, and 10 non-pregnant women without abortion history. After separating serum, the expression levels of the miR-101-3p, miR-517c-3p, miR-146b-5p, miR-221-3p, and miR-520 h were measured by qRT-PCR assay. The circulating level of miR-520 h in URSA patients was significantly up-regulated compared with healthy pregnant (P < 0.01) and healthy non-pregnant (P = 0.002) women. Furthermore, miR-520 h expression was significantly different between healthy non-pregnant and pregnant women (P = 0.002). Statistical analysis indicated miR-146b-5p expression was significantly up-regulated in URSA patients compared to normal pregnant women (P = 0.018). However, the transcription level of miR-146b-5p was insignificantly different between normal non-pregnant women and the other two groups. Also, circulating levels of miR-101-3p, miR-221-3p, and miR-517c-3p were not significantly different in the studied groups. Statistical analysis showed significant correlations between both miR-221-3p and miR-517c-3p and other miRNAs (P < 0.05). The circulating levels of miR-520 h and miR-146b-5p could be considered biomarkers for URSA diagnosis. Also, miR-517c-3p and miR-221-3p might play a regulatory role in other miRNAs expressions during pregnancy. Previous work, in contrary to our findings, claims that the expression levels of miR-221-3p, miR-101-3p, and miR-517c-3p increased in plasma and tissue samples of patients with URSA. However, our research for the first time indicates that the expression level of miR-520 h and miR-146b-5p in the serum of these patients has increased. Future investigations are necessary to confirm these findings.
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29
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Keikha M, Ali-Hassanzadeh M, Bagheri R, Karbalaei M. Dysregulation of immune gene expression profiles during HTLV-1 infection. Meta Gene 2021; 30:100944. [DOI: 10.1016/j.mgene.2021.100944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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30
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Paik ES, Chang CS, Chae YL, Oh SY, Byeon SJ, Kim CJ, Lee YY, Kim TJ, Lee JW, Kim BG, Choi CH. Prognostic Relevance of BRCA1 Expression in Survival of Patients With Cervical Cancer. Front Oncol 2021; 11:770103. [PMID: 34820332 PMCID: PMC8606581 DOI: 10.3389/fonc.2021.770103] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/21/2021] [Indexed: 11/13/2022] Open
Abstract
Objective BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in several cancers, the objective of this study was to investigate BRCA1 expression using immunohistochemistry (IHC) in cervical cancer and its possible prognostic relevance. Methods Seventy patients with cervical cancer were enrolled in this study. Samples from each tumor were stained for BRCA1 and reviewed independently by gynecologic pathologists blinded to the BRCA status. Kaplan-Meier methods were used to estimate overall survival according to BRCA1 expression. Differentially expressed genes (DEGs) by BRCA1 expression were selected using GSE44001 dataset, which included 300 samples treated with radical hysterectomy. In addition, cox regression analysis with backward elimination was performed to select independent prognostic markers. Gene set enrichment analysis (GSEA) was done using these DEGs. Results BRCA1 IHC was positive in 62.9% (44/70) of cases. Patients with BRCA1 expression showed better overall survival (100% vs. 76.2%, HR 0.20, 95% CI 0.04 - 0.99, p = 0.028) than those without BRCA1 expression. Analysis of gene expression profiles according to BRCA1 expression identified 321 differentially expressed mRNAs. Gene set enrichment analysis results showed two dysregulated pathways (VEGF_A_UP.V1_DN and E2F1_UP.V1_UP). Of these DEGs, alterations of 20 gene signatures were found to be independently associated with survival outcomes of patients. Conclusions BRCA1 expression in cervical cancer tissue is associated with survival. In addition, the identification of specific gene alterations associated with BRCA1 expression could help to provide individualized prediction in these patients.
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Affiliation(s)
- E Sun Paik
- Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Chi-Son Chang
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Ye Lin Chae
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - So Young Oh
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sun-Ju Byeon
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, South Korea
| | - Chul Jung Kim
- Department of Obstetrics and Gynecology, College of Medicine, Konyang University, Daejeon, South Korea
| | - Yoo-Young Lee
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Tae-Joong Kim
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jeong-Won Lee
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Byoung-Gie Kim
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Chel Hun Choi
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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31
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Thai SF, Jones CP, Robinette BL, Ren H, Vallanat B, Fisher AA, Kitchin KT. Effects of Silver Nanoparticles and Silver Nitrate on mRNA and microRNA Expression in Human Hepatocellular Carcinoma Cells (HepG2). JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY 2021; 21:5414-5428. [PMID: 33980351 PMCID: PMC10563035 DOI: 10.1166/jnn.2021.19481] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
In order to understand toxicity of nano silver, human hepatocellular carcinoma (HepG2) cells were treated either with silver nitrate (AgNO₃) or with nano silver capped with glutathione (Ag-S) at various concentration. Differentially expressed genelists for mRNA and microRNA were obtained through Illumina RNA sequencing and DEseq data analyses. Both treatments showed non-linear dose response relationships for mRNA and microRNA. Gene expression analysis showed signaling pathways common to both nano Ag-S and AgNO₃, such as cell cycle regulation, DNA damage response and cancer related pathways. But, nano Ag-S caused signaling pathway changes that were not altered by AgNO₃ such as NRF2-mediated oxidative stress response inflammation, cell membrane signaling, and cell proliferation. Nano Ag-S also affected p53 signaling, survival, apoptosis, tissue repair, lipid synthesis, angiogenesis, liver fibrosis and tumor development. Several of the pathways affected by nano Ag-S are hypothesized as major contributors to nanotoxicity. MicroRNA target filter analysis revealed additional affected pathways that were not reflected in the mRNA expression response alone, including DNA damage signaling, genomic stability, ROS, cell cycle, ubiquitination, DNA methylation, cell proliferation and fibrosis for AgNO₃; and cell cycle regulation, P53 signaling, cell proliferation, survival, apoptosis, tissue repair and so on for nano Ag-S. These pathways may be mediated by microRNA repression of protein translation.Our study clearly showed that the addition of microRNA profiling increased the numbers of signaling pathways discovered that affected by the treatments on HepG2 cells and gave US a better picture of the effects of these reagents in the cells.
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Affiliation(s)
- Sheau-Fung Thai
- Center for Computational Toxicology and Exposure, US Environmental Protection Agency, 109 TWAlexander Dr, Durham NC 27709, USA
| | - Carlton P Jones
- Center for Computational Toxicology and Exposure, US Environmental Protection Agency, 109 TWAlexander Dr, Durham NC 27709, USA
| | - Brian L Robinette
- Center for Computational Toxicology and Exposure, US Environmental Protection Agency, 109 TWAlexander Dr, Durham NC 27709, USA
| | - Hongzu Ren
- Center for Public Health and Environmental Assessment, US Environmental Production Agency, 109 TW Alexander Dr., Durham NC 27709, USA
| | | | - Anna A Fisher
- Center for Public Health and Environmental Assessment, US Environmental Production Agency, 109 TW Alexander Dr., Durham NC 27709, USA
| | - Kirk T Kitchin
- US Environmental Protection Agency, Retired from EPA, Durham NC 27709, USA
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32
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Tommasi C, Pellegrino B, Boggiani D, Sikokis A, Michiara M, Uliana V, Bortesi B, Bonatti F, Mozzoni P, Pinelli S, Squadrilli A, Viani MV, Cassi D, Maglietta G, Meleti M, Musolino A. Biological Role and Clinical Implications of microRNAs in BRCA Mutation Carriers. Front Oncol 2021; 11:700853. [PMID: 34552867 PMCID: PMC8450578 DOI: 10.3389/fonc.2021.700853] [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: 04/27/2021] [Accepted: 08/20/2021] [Indexed: 12/20/2022] Open
Abstract
Women with pathogenic germline mutations in BRCA1 and BRCA2 genes have an increased risk to develop breast and ovarian cancer. There is, however, a high interpersonal variability in the modality and timing of tumor onset in those subjects, thus suggesting a potential role of other individual’s genetic, epigenetic, and environmental risk factors in modulating the penetrance of BRCA mutations. MicroRNAs (miRNAs) are small noncoding RNAs that can modulate the expression of several genes involved in cancer initiation and progression. MiRNAs are dysregulated at all stages of breast cancer and although they are accessible and evaluable, a standardized method for miRNA assessment is needed to ensure comparable data analysis and accuracy of results. The aim of this review was to highlight the role of miRNAs as potential biological markers for BRCA mutation carriers. In particular, biological and clinical implications of a link between lifestyle and nutritional modifiable factors, miRNA expression and germline BRCA1 and BRCA2 mutations are discussed with the knowledge of the best available scientific evidence.
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Affiliation(s)
- Chiara Tommasi
- Medical Oncology and Breast Unit, University Hospital of Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy.,GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
| | - Benedetta Pellegrino
- Medical Oncology and Breast Unit, University Hospital of Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy.,GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
| | - Daniela Boggiani
- Medical Oncology and Breast Unit, University Hospital of Parma, Parma, Italy.,GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
| | - Angelica Sikokis
- Medical Oncology and Breast Unit, University Hospital of Parma, Parma, Italy.,GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
| | - Maria Michiara
- Medical Oncology and Breast Unit, University Hospital of Parma, Parma, Italy
| | - Vera Uliana
- Medical Genetics Unit, University Hospital of Parma, Parma, Italy
| | - Beatrice Bortesi
- Medical Oncology and Breast Unit, University Hospital of Parma, Parma, Italy.,GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
| | - Francesco Bonatti
- Medical Oncology and Breast Unit, University Hospital of Parma, Parma, Italy
| | - Paola Mozzoni
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Silvana Pinelli
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Anna Squadrilli
- Medical Oncology and Breast Unit, University Hospital of Parma, Parma, Italy
| | - Maria Vittoria Viani
- Dental School, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Diana Cassi
- Unit of Dentistry and Oral-Maxillo-Facial Surgery, Surgical, Medical and Dental Department of Morphological Sciences related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Giuseppe Maglietta
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy.,Research and Innovation Unit, University Hospital of Parma, Parma, Italy
| | - Marco Meleti
- Dental School, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Antonino Musolino
- Medical Oncology and Breast Unit, University Hospital of Parma, Parma, Italy.,Department of Medicine and Surgery, University of Parma, Parma, Italy.,GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
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33
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Priya S, Kaur E, Kulshrestha S, Pandit A, Gross I, Kumar N, Agarwal H, Khan A, Shyam R, Bhagat P, Prabhu JS, Nagarajan P, Deo SVS, Bajaj A, Freund JN, Mukhopadhyay A, Sengupta S. CDX2 inducible microRNAs sustain colon cancer by targeting multiple DNA damage response pathway factors. J Cell Sci 2021; 134:jcs258601. [PMID: 34369561 DOI: 10.1242/jcs.258601] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 07/05/2021] [Indexed: 12/15/2022] Open
Abstract
Meta-analysis of transcripts in colon adenocarcinoma patient tissues led to the identification of a DNA damage responsive miR signature called DNA damage sensitive miRs (DDSMs). DDSMs were experimentally validated in the cancerous colon tissues obtained from an independent cohort of colon cancer patients and in multiple cellular systems with high levels of endogenous DNA damage. All the tested DDSMs were transcriptionally upregulated by a common intestine-specific transcription factor, CDX2. Reciprocally, DDSMs were repressed via the recruitment of HDAC1/2-containing complexes onto the CDX2 promoter. These miRs downregulated multiple key targets in the DNA damage response (DDR) pathway, namely BRCA1, ATM, Chk1 (also known as CHEK1) and RNF8. CDX2 directly regulated the DDSMs, which led to increased tumor volume and metastasis in multiple preclinical models. In colon cancer patient tissues, the DDSMs negatively correlated with BRCA1 levels, were associated with decreased probability of survival and thereby could be used as a prognostic biomarker. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Swati Priya
- Signal Transduction Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Ekjot Kaur
- Signal Transduction Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Swati Kulshrestha
- Signal Transduction Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Awadhesh Pandit
- Signal Transduction Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Isabelle Gross
- Université de Strasbourg, Inserm, IRFAC UMR_S1113, FMTS, 67200 Strasbourg, France
| | - Nitin Kumar
- Signal Transduction Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Himanshi Agarwal
- Signal Transduction Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Aamir Khan
- Signal Transduction Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Radhey Shyam
- Signal Transduction Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Prakash Bhagat
- Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Jyothi S Prabhu
- Division of Molecular Medicine, St. John's Research Institute, Bengaluru, Karnataka 560034, India
| | - Perumal Nagarajan
- Signal Transduction Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - S V S Deo
- Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Avinash Bajaj
- Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana 121001, India
| | - Jean-Noël Freund
- Université de Strasbourg, Inserm, IRFAC UMR_S1113, FMTS, 67200 Strasbourg, France
| | - Arnab Mukhopadhyay
- Signal Transduction Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Sagar Sengupta
- Signal Transduction Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
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34
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The Anticancer Effects of Flavonoids through miRNAs Modulations in Triple-Negative Breast Cancer. Nutrients 2021; 13:nu13041212. [PMID: 33916931 PMCID: PMC8067583 DOI: 10.3390/nu13041212] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/31/2022] Open
Abstract
Triple- negative breast cancer (TNBC) incidence rate has regularly risen over the last decades and is expected to increase in the future. Finding novel treatment options with minimum or no toxicity is of great importance in treating or preventing TNBC. Flavonoids are new attractive molecules that might fulfill this promising therapeutic option. Flavonoids have shown many biological activities, including antioxidant, anti-inflammatory, and anticancer effects. In addition to their anticancer effects by arresting the cell cycle, inducing apoptosis, and suppressing cancer cell proliferation, flavonoids can modulate non-coding microRNAs (miRNAs) function. Several preclinical and epidemiological studies indicate the possible therapeutic potential of these compounds. Flavonoids display a unique ability to change miRNAs' levels via different mechanisms, either by suppressing oncogenic miRNAs or activating oncosuppressor miRNAs or affecting transcriptional, epigenetic miRNA processing in TNBC. Flavonoids are not only involved in the regulation of miRNA-mediated cancer initiation, growth, proliferation, differentiation, invasion, metastasis, and epithelial-to-mesenchymal transition (EMT), but also control miRNAs-mediated biological processes that significantly impact TNBC, such as cell cycle, immune system, mitochondrial dysregulation, modulating signaling pathways, inflammation, and angiogenesis. In this review, we highlighted the role of miRNAs in TNBC cancer progression and the effect of flavonoids on miRNA regulation, emphasizing their anticipated role in the prevention and treatment of TNBC.
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35
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Tordonato C, Marzi MJ, Giangreco G, Freddi S, Bonetti P, Tosoni D, Di Fiore PP, Nicassio F. miR-146 connects stem cell identity with metabolism and pharmacological resistance in breast cancer. J Cell Biol 2021; 220:211945. [PMID: 33819341 PMCID: PMC8025236 DOI: 10.1083/jcb.202009053] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 01/26/2021] [Accepted: 03/01/2021] [Indexed: 02/07/2023] Open
Abstract
Although ectopic overexpression of miRNAs can influence mammary normal and cancer stem cells (SCs/CSCs), their physiological relevance remains uncertain. Here, we show that miR-146 is relevant for SC/CSC activity. MiR-146a/b expression is high in SCs/CSCs from human/mouse primary mammary tissues, correlates with the basal-like breast cancer subtype, which typically has a high CSC content, and specifically distinguishes cells with SC/CSC identity. Loss of miR-146 reduces SC/CSC self-renewal in vitro and compromises patient-derived xenograft tumor growth in vivo, decreasing the number of tumor-initiating cells, thus supporting its pro-oncogenic function. Transcriptional analysis in mammary SC-like cells revealed that miR-146 has pleiotropic effects, reducing adaptive response mechanisms and activating the exit from quiescent state, through a complex network of finely regulated miRNA targets related to quiescence, transcription, and one-carbon pool metabolism. Consistent with these findings, SCs/CSCs display innate resistance to anti-folate chemotherapies either in vitro or in vivo that can be reversed by miR-146 depletion, unmasking a “hidden vulnerability” exploitable for the development of anti-CSC therapies.
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Affiliation(s)
- Chiara Tordonato
- European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, Università Degli Studi di Milano, Milano, Italy
| | - Matteo Jacopo Marzi
- Center for Genomic Science of Istituto Italiano di Tecnologia at European School of Molecular Medicine, Istituto Italiano di Tecnologia, Milan, Italy
| | - Giovanni Giangreco
- European Institute of Oncology IRCCS, Milan, Italy.,Tumour Cell Biology Laboratory, The Francis Crick Institute, London, UK
| | | | - Paola Bonetti
- Center for Genomic Science of Istituto Italiano di Tecnologia at European School of Molecular Medicine, Istituto Italiano di Tecnologia, Milan, Italy
| | | | - Pier Paolo Di Fiore
- European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, Università Degli Studi di Milano, Milano, Italy
| | - Francesco Nicassio
- Center for Genomic Science of Istituto Italiano di Tecnologia at European School of Molecular Medicine, Istituto Italiano di Tecnologia, Milan, Italy
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36
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Cai X, Yu L, Chen Z, Ye F, Ren Z, Jin P. Arsenic trioxide-induced upregulation of miR-1294 suppresses tumor growth in hepatocellular carcinoma by targeting TEAD1 and PIM1. Cancer Biomark 2021; 28:221-230. [PMID: 32280078 DOI: 10.3233/cbm-190490] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Recently, Arsenic trioxide (ATO) has been reported as an efficient drug for suppression of cancer cell growth. Existing studies revealed the extensive involvement of microRNAs (miRNAs) in initiation and development of hepatocellular carcinoma (HCC). However, the potential correlation between ATO and miRNAs in HCC progression remains to be explored. To conduct our research, we applied a qRT-PCR analysis to find miRNAs that were upregulated in HCC cells treated with ATO. In our present study, miR-1294 was found to be significantly upregulated in ATO-treated HCC cells. To confirm the function of ATO and miR-1294 in HCC progression, gain-of function assays were designed and conducted. As expected, proliferative ability of ATO-treated HCC cells was markedly weakened compared to DMSO-treated HCC cells. More importantly, proliferation was further suppressed in ATO-induced HCC cells after overexpression of miR-1294. Through bioinformatics analysis, some potential targets of miR-1294 were predicted. Further investigation revealed that Pim-1 proto-oncogene (PIM1) and TEA domain transcription factor 1 (TEAD1) were two downstream targets of miR-1294 and could be negatively regulated by ATO. Functionally, we determined that cell proliferation and apoptosis resistance suppressed by miR-1294 and ATO were recovered by introduction of TEAD1 and PIM1. Collectively, this study revealed that a novel ATO-miR-1294-TEAD1/PIM1 axis regulated HCC cell growth, offering a potential insight into the HCC therapy.
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Affiliation(s)
- Xiaoniao Cai
- Department of Gastroenterology, Pingyang People's Hospital, Pingyang, Wenzhou, Zhejiang, China
| | - Leilei Yu
- Department of Gastroenterology, Ruian People's Hospital, Ruian, Wenzhou, Zhejiang, China
| | - Zhen Chen
- Department of General Surgery, Ruian People's Hospital, Ruian, Wenzhou, Zhejiang, China
| | - Fangpeng Ye
- Department of Gastroenterology, Ruian People's Hospital, Ruian, Wenzhou, Zhejiang, China
| | - Zonghai Ren
- Department of Gastroenterology, Ruian People's Hospital, Ruian, Wenzhou, Zhejiang, China
| | - Peisheng Jin
- Department of Gastroenterology, Ruian People's Hospital, Ruian, Wenzhou, Zhejiang, China
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37
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Singh S, Raza W, Parveen S, Meena A, Luqman S. Flavonoid display ability to target microRNAs in cancer pathogenesis. Biochem Pharmacol 2021; 189:114409. [PMID: 33428895 DOI: 10.1016/j.bcp.2021.114409] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/01/2021] [Accepted: 01/05/2021] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are non-coding, conserved, single-stranded nucleotide sequences involved in physiological and developmental processes. Recent evidence suggests an association between miRNAs' deregulation with initiation, promotion, progression, and drug resistance in cancer cells. Besides, miRNAs are known to regulate the epithelial-mesenchymal transition, angiogenesis, autophagy, and senescence in different cancer types. Previous reports proposed that apart from the antioxidant potential, flavonoids play an essential role in miRNAs modulation associated with changes in cancer-related proteins, tumor suppressor genes, and oncogenes. Thus, flavonoids can suppress proliferation, help in the development of drug sensitivity, suppress metastasis and angiogenesis by modulating miRNAs expression. In the present review, we summarize the role of miRNAs in cancer, drug resistance, and the chemopreventive potential of flavonoids mediated by miRNAs. The potential of flavonoids to modulate miRNAs expression in different cancer types demonstrate their selectivity and importance as regulators of carcinogenesis. Flavonoids as chemopreventive agents targeting miRNAs are extensively studied in vitro, in vivo, and pre-clinical studies, but their efficiency in targeting miRNAs in clinical studies is less investigated. The evidence presented in this review highlights the potential of flavonoids in cancer prevention/treatment by regulating miRNAs, although further investigations are required to validate and establish their clinical usefulness.
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Affiliation(s)
- Shilpi Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Waseem Raza
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Jawahar Lal Nehru University, New Delhi 110067, India
| | - Shahnaz Parveen
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India.
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38
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Li K, Zhou Z, Li J, Xiang R. miR-146b Functions as an Oncogene in Oral Squamous Cell Carcinoma by Targeting HBP1. Technol Cancer Res Treat 2020; 19:1533033820959404. [PMID: 33327874 PMCID: PMC7750896 DOI: 10.1177/1533033820959404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) represents more than 90% of all oral cancer and is the most common oral threat around the world. In this study, we examined the roles of miR-146b in OSCC cells. The miR-146b expression in OSCC tissues and cell lines was evaluated by quantitative real-time PCR (qRT-PCR). MTT assay was used to investigate the impact of miR-146b on the growth of OSCC cells in vitro. Transwell assay was utilized to analyze the effect of miR-146b on the migration and invasion of OSCC cells. Target prediction and luciferase assay were employed to demonstrate the interaction between miR-146b and HMG-Box Transcription Factor 1 (HBP1). Western blot was carried out to investigate the protein expressions of HBP1 related genes. miR-146b expression was significantly higher in OSCC tissues and cells compared with paired normal tissues and normal oral keratinocyte cells. Inhibition of miR-146b decreased cell proliferation, migration, and invasion of OSCC cells. Further studies found that HBP1 was a direct target of miR-146b. Co-inhibition of HBP1 reversed the suppressive impact of miR-146b inhibition on OSCC cell proliferation, migration, and invasion. In conclusion-ourresults reveal that miR-146b potentially regulates the proliferation, migration, and invasion of OSCC cells through binding and downregulating HBP1 expression in OSCC cells.
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Affiliation(s)
- Kui Li
- Department of Stomatology, Guangyuan Central Hospital, Guangyuan, Sichuan Province, China
| | - Zheng Zhou
- Department of stomatology, Xiangyang Stomatological Hospital, Xiangyang City, Hubei Province, China
| | - Ju Li
- Department of stomatology, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan Province, China
| | - Rui Xiang
- Department of prosthodontics, WuXi Stomatology Hospital, Jiangsu Province, China
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39
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Volovat SR, Volovat C, Hordila I, Hordila DA, Mirestean CC, Miron OT, Lungulescu C, Scripcariu DV, Stolniceanu CR, Konsoulova-Kirova AA, Grigorescu C, Stefanescu C, Volovat CC, Augustin I. MiRNA and LncRNA as Potential Biomarkers in Triple-Negative Breast Cancer: A Review. Front Oncol 2020; 10:526850. [PMID: 33330019 PMCID: PMC7716774 DOI: 10.3389/fonc.2020.526850] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 10/13/2020] [Indexed: 12/21/2022] Open
Abstract
Noncoding RNAs (ncRNAs) include a diverse range of RNA species, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). MiRNAs, ncRNAs of approximately 19-25 nucleotides in length, are involved in gene expression regulation either via degradation or silencing of the messenger RNAs (mRNAs) and have roles in multiple biological processes, including cell proliferation, differentiation, migration, angiogenesis, and apoptosis. LncRNAs, which are longer than 200 nucleotides, comprise one of the largest and most heterogeneous RNA families. LncRNAs can activate or repress gene expression through various mechanisms, acting alone or in combination with miRNAs and other molecules as part of various pathways. Until recently, most research has focused on individual lncRNA and miRNA functions as regulators, and there is limited available data on ncRNA interactions relating to the tumor growth, metastasis, and therapy of cancer, acting either on mRNA alone or as competing endogenous RNA (ceRNA) networks. Triple-negative breast cancer (TNBC) represents approximately 10%-20% of all breast cancers (BCs) and is highly heterogenous and more aggressive than other types of BC, for which current targeted treatment options include hormonotherapy, PARP inhibitors, and immunotherapy; however, no targeted therapies for TNBC are available, partly because of a lack of predictive biomarkers. With advances in proteomics, new evidence has emerged demonstrating the implications of dysregulation of ncRNAs in TNBC etiology. Here, we review the roles of lncRNAs and miRNAs implicated in TNBC, including their interactions and regulatory networks. Our synthesis provides insight into the mechanisms involved in TNBC progression and has potential to aid the discovery of new diagnostic and therapeutic strategies.
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Affiliation(s)
- Simona Ruxandra Volovat
- Department of Medical Oncology-Radiotherapy, Grigore T Popa University of Medicine and Pharmacy, Iași, Romania
| | - Constantin Volovat
- Department of Medical Oncology-Radiotherapy, Grigore T Popa University of Medicine and Pharmacy, Iași, Romania.,Center of Oncology Euroclinic, Iași, Romania
| | | | | | | | | | - Cristian Lungulescu
- Department of Medical Oncology, University of Medicine and Pharmacy, Craiova, Romania
| | | | - Cati Raluca Stolniceanu
- Department of Biophysics and Medical Physics-Nuclear Medicine, University of Medicine and Pharmacy Gr. T. Popa Iasi, Iași, Romania
| | | | - Cristina Grigorescu
- Department of Surgery, Grigore T Popa University of Medicine and Pharmacy, Iași, Romania
| | - Cipriana Stefanescu
- Department of Biophysics and Medical Physics-Nuclear Medicine, University of Medicine and Pharmacy Gr. T. Popa Iasi, Iași, Romania
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40
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Abstract
Breast cancer (BC) is increasing as a significant cause of mortality among women. In this context, early diagnosis and treatment strategies for BC are being developed by researchers at the cellular level using advanced nanomaterials. However, immaculate etiquette is the prerequisite for their implementation in clinical practice. Considering the stolid nature of cancer, combining diagnosis and therapy (theranostics) using graphene quantum dots (GQDs) is a prime focus and challenge for researchers. In a nutshell, GQDs is a new shining star among various fluorescent materials, which has acclaimed fame in a short duration in materials science and the biomedical field as well. From this perspective, we review various strategies in BC treatment using GQDs alone or in combination. In addition, the photophysical properties of GQDs explored in photothermal therapy, hyperthermia therapy, and photodynamic therapy are also discussed. Moreover, we also focus on the strategic use of GQDs both as drug carriers and as combinatorial-guided drug delivery motifs. This Review provides an update for the scientific community to plan and expand advanced theranostic horizons in BC using GQDs.
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Affiliation(s)
- Rahul S Tade
- Department of Pharmaceutical Chemistry, H. R. Patel Institute of Pharmaceutical Education and Research, Shirpur-425405, Maharashtra, India
| | - Pravin O Patil
- Department of Pharmaceutical Chemistry, H. R. Patel Institute of Pharmaceutical Education and Research, Shirpur-425405, Maharashtra, India
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41
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Angius A, Cossu-Rocca P, Arru C, Muroni MR, Rallo V, Carru C, Uva P, Pira G, Orrù S, De Miglio MR. Modulatory Role of microRNAs in Triple Negative Breast Cancer with Basal-Like Phenotype. Cancers (Basel) 2020; 12:E3298. [PMID: 33171872 PMCID: PMC7695196 DOI: 10.3390/cancers12113298] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/05/2020] [Accepted: 11/05/2020] [Indexed: 12/16/2022] Open
Abstract
Development of new research, classification, and therapeutic options are urgently required due to the fact that TNBC is a heterogeneous malignancy. The expression of high molecular weight cytokeratins identifies a biologically and clinically distinct subgroup of TNBCs with a basal-like phenotype, representing about 75% of TNBCs, while the remaining 25% includes all other intrinsic subtypes. The triple negative phenotype in basal-like breast cancer (BLBC) makes it unresponsive to endocrine therapy, i.e., tamoxifen, aromatase inhibitors, and/or anti-HER2-targeted therapies; for this reason, only chemotherapy can be considered an approach available for systemic treatment even if it shows poor prognosis. Therefore, treatment for these subgroups of patients is a strong challenge for oncologists due to disease heterogeneity and the absence of unambiguous molecular targets. Dysregulation of the cellular miRNAome has been related to huge cellular process deregulations underlying human malignancy. Consequently, epigenetics is a field of great promise in cancer research. Increasing evidence suggests that specific miRNA clusters/signatures might be of clinical utility in TNBCs with basal-like phenotype. The epigenetic mechanisms behind tumorigenesis enable progress in the treatment, diagnosis, and prevention of cancer. This review intends to summarize the epigenetic findings related to miRNAome in TNBCs with basal-like phenotype.
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Affiliation(s)
- Andrea Angius
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
| | - Paolo Cossu-Rocca
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (P.C.-R.); (M.R.M.)
- Department of Diagnostic Services, “Giovanni Paolo II” Hospital, ASSL Olbia-ATS Sardegna, 07026 Olbia, Italy
| | - Caterina Arru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Maria Rosaria Muroni
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (P.C.-R.); (M.R.M.)
| | - Vincenzo Rallo
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Paolo Uva
- CRS4, Science and Technology Park Polaris, Piscina Manna, 09010 Pula, CA, Italy;
| | - Giovanna Pira
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Sandra Orrù
- Department of Pathology, “A. Businco” Oncologic Hospital, ASL Cagliari, 09121 Cagliari, Italy;
| | - Maria Rosaria De Miglio
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
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Duică F, Condrat CE, Dănila CA, Boboc AE, Radu MR, Xiao J, Li X, Creţoiu SM, Suciu N, Creţoiu D, Predescu DV. MiRNAs: A Powerful Tool in Deciphering Gynecological Malignancies. Front Oncol 2020; 10:591181. [PMID: 33194751 PMCID: PMC7646292 DOI: 10.3389/fonc.2020.591181] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/01/2020] [Indexed: 12/14/2022] Open
Abstract
Accumulated evidence on the clinical roles of microRNAs (miRNAs) in cancer prevention and control has revealed the emergence of new genetic techniques that have improved the understanding of the mechanisms essential for pathology induction and progression. Comprehension of the modifications and individual differences of miRNAs and their interactions in the pathogenesis of gynecological malignancies, together with an understanding of the phenotypic variations have considerably improved the management of the diagnosis and personalized treatment for different forms of cancer. In recent years, miRNAs have emerged as signaling molecules in biological pathways involved in different categories of cancer and it has been demonstrated that these molecules could regulate cancer-relevant processes, our focus being on malignancies of the gynecologic tract. The aim of this paper is to summarize novel research findings in the literature regarding the parts that miRNAs play in cancer-relevant processes, specifically regarding gynecological malignancy, while emphasizing their pivotal role in the disruption of cancer-related signaling pathways.
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Affiliation(s)
- Florentina Duică
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania
| | - Carmen Elena Condrat
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania
| | - Cezara Alina Dănila
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania
| | - Andreea Elena Boboc
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania
| | - Mihaela Raluca Radu
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania
| | - Junjie Xiao
- Institute of Cardiovascular Sciences, Shanghai University, Shanghai, China
| | - Xinli Li
- Department of Cardiology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China
| | - Sanda Maria Creţoiu
- Cellular and Molecular Biology and Histology Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Nicolae Suciu
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania.,Department of Obstetrics and Gynecology, Polizu Clinical Hospital, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania.,Obstetrics, Gynecology and Neonatology Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Dragoş Creţoiu
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania.,Cellular and Molecular Biology and Histology Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Dragoş-Valentin Predescu
- Department of General Surgery, Sf. Maria Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Targeting MALAT1 induces DNA damage and sensitize non-small cell lung cancer cells to cisplatin by repressing BRCA1. Cancer Chemother Pharmacol 2020; 86:663-672. [PMID: 33030583 DOI: 10.1007/s00280-020-04152-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 09/17/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA which has been identified to be involved in alternative non-homologous end joining (A-NHEJ) pathways by binding with PARP1 and LIG3 in myeloma cells. This study aims to explore the roles of MALAT1 in DNA repair processes in non-small cell lung cancer (NSCLC). METHODS The interactions between MALAT1 and proteins were identified by co-immunoprecipitation and RNA pulldown. The interactions between MALAT1 and microRNAs (miRNA) were predicted by bioinformatics tools and confirmed by luciferase assay and RNA pulldown. The DNA damages were quantified by comet assay. The cell viability was examined by MTT assay and the cell apoptosis was determined by flow cytometry. RESULTS MALAT1 is identified to be involved in A-NHEJ pathway in NSCLC cells. However, in LIG3-null cells where A-NHEJ pathway is inactivated, targeting MALAT1 still increases DNA damages, suggesting that MALAT1 participates in other DNA repair pathways. Subsequently, MALAT1 is identified to bind with miR-146a and miR-216b, which directly target the 3'UTR of BRCA1. MALAT1 is confirmed to functions as a competing endogenous RNA (ceRNA) absorbing miR-146a and miR-216b, upregulating BRCA1 expression and protecting Homologous Recombination (HR) pathway in NSCLC cells. Finally, overexpression MALAT1 protects NSCLC cells from the cytotoxic effect of cisplatin. While, targeting MALAT1 in NSCLC cells induces DNA damages by repressing HR pathway and sensitizes NSCLC cells to cisplatin which had the potential for NSCLC treatment. CONCLUSION MALAT1 is involved in HR pathway by protecting BRCA1 and targeting MALAT1 induces DNA damages in NSCLC.
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Hincapie V, Gallego-Gómez JC. TRANSICIÓN EPITELIO-MESÉNQUIMA INDUCIDA POR VIRUS. ACTA BIOLÓGICA COLOMBIANA 2020. [DOI: 10.15446/abc.v26n1.79358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
La Transición Epitelio-Mesénquima (EMT) es un proceso de dediferenciación altamente conservado en vertebrados. Este ocurre en células epiteliales con la activación progresiva de la pérdida de la polaridad, la adquisición de motilidad individual y la capacidad invasiva a otros tejidos. La EMT es un proceso normal durante el desarrollo; no obstante, en condiciones patológicas está relacionada con la inducción de metástasis, lo cual representa una vía alterna al desarrollo de procesos oncogénicos tempranos. Aunque la EMT es activada principalmente por factores de crecimiento, también se puede desencadenar por infecciones de patógenos intracelulares mediante la activación de rutas moleculares inductoras de este proceso. Por lo tanto, una infección bacteriana o viral pueda generar predisposición al desarrollo de tumores. Nuestro interés está enfocado principalmente encaracterizar la relación virus-hospedero, y en el caso de los virus, varios ya se han descrito como inductores de la EMT. En este artículo de revisión se describenelfenómeno de la plasticidad celular y la ocurrencia detallada del proceso de EMT, los patógenos virales reportados como inductores, los mecanismos moleculares usados para ello y las vías de regulación mediante miRNAs. Por último, se discute cómo esta relación virus-hospedero puede explicar la patogénesis de la enfermedad causada por Dengue virus, favoreciendo la identificación de blancos moleculares para terapia, estrategia conocida como Antivirales dirigidos a blancos celulares o HTA (Host-targeting antivirals).
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Hong HC, Chuang CH, Huang WC, Weng SL, Chen CH, Chang KH, Liao KW, Huang HD. A panel of eight microRNAs is a good predictive parameter for triple-negative breast cancer relapse. Theranostics 2020; 10:8771-8789. [PMID: 32754277 PMCID: PMC7392022 DOI: 10.7150/thno.46142] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 06/16/2020] [Indexed: 12/14/2022] Open
Abstract
Rationale: Triple-negative breast cancer (TNBC), which has the highest recurrence rate and shortest survival time of all breast cancers, is in urgent need of a risk assessment method to determine an accurate treatment course. Recently, miRNA expression patterns have been identified as potential biomarkers for diagnosis, prognosis, and personalized therapy. Here, we investigate a combination of candidate miRNAs as a clinically applicable signature that can precisely predict relapse in TNBC patients after surgery. Methods: Four total cohorts of training (TCGA_TNBC and GEOD-40525) and validation (GSE40049 and GSE19783) datasets were analyzed with logistic regression and Gaussian mixture analyses. We established a miRNA signature risk model and identified an 8-miRNA signature for the prediction of TNBC relapse. Results: The miRNA signature risk model identified ten candidate miRNAs in the training set. By combining 8 of the 10 miRNAs (miR-139-5p, miR-10b-5p, miR-486-5p, miR-455-3p, miR-107, miR-146b-5p, miR-324-5p and miR-20a-5p), an accurate predictive model of relapse in TNBC patients was established and was highly correlated with prognosis (AUC of 0.80). Subsequently, this 8-miRNA signature prognosticated relapse in the two validation sets with AUCs of 0.89 and 0.90. Conclusion: The 8-miRNA signature predictive model may help clinicians provide a prognosis for TNBC patients with a high risk of recurrence after surgery and provide further personalized treatment to decrease the chance of relapse.
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Affiliation(s)
- Hsiao-Chin Hong
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong Province 518172, China
- School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong Province 518172, China
| | - Cheng-Hsun Chuang
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu City 30068, Taiwan, ROC
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu City 30068, Taiwan, ROC
| | - Wei-Chih Huang
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu City 30068, Taiwan, ROC
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu City 30068, Taiwan, ROC
- Come True Biomedical Inc., Taichung 408, Taiwan, ROC
| | - Shun-Long Weng
- Department of Obstetrics and Gynecology, Hsinchu MacKay Memorial Hospital, Hsinchu City 300, Taiwan, ROC
- Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan, ROC
- MacKay Junior College of Medicine, Nursing and Management College, Taipei City 112, Taiwan, ROC
| | - Chia-Hung Chen
- Department of Medical Research, Hsinchu Mackay Memorial Hospital, Hsinchu City 30071, Taiwan, ROC
| | - Kuang-Hsin Chang
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu City 30068, Taiwan, ROC
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu City 30068, Taiwan, ROC
| | - Kuang-Wen Liao
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu City 30068, Taiwan, ROC
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu City 30068, Taiwan, ROC
- Center for Intelligent Drug Systems and Smart Bio-Devices, National Chiao Tung University, Hsinchu City 30068, Taiwan, ROC
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, ROC
| | - Hsien-Da Huang
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong Province 518172, China
- School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong Province 518172, China
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu City 30068, Taiwan, ROC
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Yang SI, Choi YS. Expressions of miRNAs in Papillary Thyroid Carcinoma and Their Associations with the BRAFV600E Mutation and Clinicopathological Features. KOSIN MEDICAL JOURNAL 2020. [DOI: 10.7180/kmj.2020.35.1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Objectives The microRNAs (miRNAs) are known to be commonly expressed in papillary thyroid carcinoma. The BRAFV600E mutation is the most common genetic mutation in thyroid cancer. The main aim of this study was to determine the possible association between expression of the three miRNAs and that of BRAFV600E mutation and the clinicopathological features in papillary thyroid carcinoma. Methods This study was conducted on 51 paraffin-embedded tissues (42 thyroid cancer, 9 benign tumor) obtained from patients undergoing thyroidectomy at the Endocrine Center of OOO University Hospital. Results miRNAs expression was significantly high in patients with cervical lymph node metastasis and advanced TNM stage. In addition, miR-146b expression levels were significantly higher in papillary thyroid carcinoma patients with BRAFV600E mutation. The relative quantification (2-ΔΔCt) of miR-146b was also high among the miRNAs. Individually, the AUCs for miRNA-146b was 0.923 (cutoff value −1.97, sensitivity 88.9%, specificity 85.7%). Conclusions Especially, expression of miR-146b increased higher in PTC patients with BRAFV600E mutation. These findings showed a role of miR-146b as potential biomarkers in differentiating PTC from benign tumor and as a prognostic indicator of PTCs. Further investigation will need for the roles of miRNAs in the pathogenesis of papillary thyroid carcinomas.
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Santos JSD, Zunta GL, Negrini AB, Ribeiro MSG, Martinez CAR, Ribeiro ML, Lourenço GJ, Ortega MM. The association of a single-nucleotide variant in the microRNA-146a with advanced colorectal cancer prognosis. Tumour Biol 2020; 42:1010428320923856. [PMID: 32438863 DOI: 10.1177/1010428320923856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The aim of this study was to evaluate the association of single-nucleotide variant n.60G>C (rs2910164) of microRNA (miR)-146a, related to suppressing of BRCA1/2 DNA repair protein, with the risk and survival of colorectal cancer patients, as well as miR-146a and BRCA1/2 levels and miR binding efficiency. The genotypes were identified in 125 colorectal cancer patients and 276 controls using TaqMan polymerase chain reaction assay. The miR-146a and BRCA1/2 levels were assessed by quantitative-polymerase chain reaction protocols. Primary precursor of miR-146a containing G (wild-type) and C (variant) allele were cloned into pcDNA.3.3 vector and co-transfected in HT-29 colorectal cancer cell line. Luciferase reporter assay was performed to assess miR-146a binding to BRCA2 3'-untranslated region in HT-29. The differences between groups were calculated using chi-square or Fisher's exact test, logistic regression, and Mann-Whitney test. The prognostic impact of single-nucleotide variant genotypes on overall survival was evaluated by Kaplan-Meier estimate and Cox regression. The GC or CC genotypes prevalence was similar in patients and controls (50.4% vs 50.7%, p = 0.74). However, patients with tumors in advanced stage with miR-146a GG genotype had 2.41 more chance of dying than GC or CC genotypes. In addition, tumor tissues of patients with GG genotype presented higher miR-146a (p = 0.02) and lower BRCA1 (p = 0.01) and BRCA2 (p < 0.0001) levels when compared to those with GC or CC genotypes. In fact, pcDNA.3.3-miR-146a-G presented increased binding capacity to the 3'-untranslated region of BRCA2 (p = 0.001) compared to pcDNA.3.3-miR-146a-C. In addition, the G allele altered the binding affinity between miR-146a and its BRCA2 3'-untranslated region target (p < 0.001), thus enhancing suppression of BRCA2 expression. Our results suggest that single-nucleotide variant rs2910164 does not influence the colorectal cancer risk in Brazilian patients; however, the GG genotype could act as a factor of worse prognosis in patients with advanced disease due to suppression of BRCA1/2 modulated by miR-146a.
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Affiliation(s)
- Jéssica Silva Dos Santos
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University (USF), Bragança Paulista, Brazil
| | - Gabriella Lucatto Zunta
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University (USF), Bragança Paulista, Brazil
| | - Amanda Binatto Negrini
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University (USF), Bragança Paulista, Brazil
| | - Marina Silva Guinda Ribeiro
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University (USF), Bragança Paulista, Brazil
| | | | - Marcelo Lima Ribeiro
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University (USF), Bragança Paulista, Brazil
| | - Gustavo Jacob Lourenço
- Laboratory of Cancer Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Manoela Marques Ortega
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University (USF), Bragança Paulista, Brazil
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Gao J, Zhang H, Wang Z. A DNA tetrahedron nanoprobe-based fluorescence resonance energy transfer sensing platform for intracellular tumor-related miRNA detection. Analyst 2020; 145:3535-3542. [PMID: 32314984 DOI: 10.1039/c9an02610j] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Accurate and sensitive detection of disease-related microRNAs (miRNAs) is of great significance for early disease diagnosis. In this work, a DNA tetrahedron nanoprobe (DTNP)-based fluorescence resonance energy transfer (FRET) sensing platform (termed DTNP sensor) was constructed for sensitive detection of tumor-related miRNA (e.g., hsa-miR-146b-5p) with DNA assisted cyclic amplification. DTNP was synthesized by DNA self-assembly. In the absence of hsa-miR-146b-5p, the fluorescence DNA (HP) modified with FAM at the 5' terminal and TAMRA at the 3' terminal cannot form the hairpin structure because of the hybridization with the extended DNA strand of the DNA tetrahedron, resulting in a low FRET effect. In the presence of hsa-miR-146b-5p, it would complementarily hybridize with the extended DNA strand of the DNA tetrahedron, leading to the release of HP and occurrence of strong FRET. Thus, the concentration of hsa-miR-146b-5p can be revealed by the change in the fluorescence intensity. Moreover, an assistant DNA was employed to replace hsa-miR-146b-5p for cyclic signal amplification, which can further enhance the detection sensitivity. Under the optimal experimental conditions, the limit of detection for hsa-miR-146b-5p was as low as 6 pM (S/N = 3). Furthermore, the DTNP sensor was successfully applied to evaluate the hsa-miR-146b-5p expression levels in different cell lines. The inhibition of hsa-miR-146b-5p expression in different cells was also investigated and a satisfactory result was obtained.
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Affiliation(s)
- Jiaxue Gao
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China.
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Stevenson M, Nath Banerjee H, Banerjee N, Rawat K, Chen L, Worthington M, Hodge S, Walker R, Verma M, Sarkar F, Mandal S. A health disparities study of MicroRNA-146a expression in prostate cancer samples derived from African American and European American patients. ACTA ACUST UNITED AC 2020; 10. [PMID: 32968471 DOI: 10.5430/jst.v10n2p1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Considering the prevalence of prostate cancer all over the world, it is desired to have tools, technologies, and biomarkers which help in early detection of the disease and discriminate different races and ethnic groups. Genetic information from the single gene analysis and genome-wide association studies have identified few biomarkers, however, the drivers of prostate cancer remain unknown in the majority of prostate cancer patients. In those cases where genetic association has been identified, the genes confer only a modest risk of this cancer, hence, making them less relevant for risk counseling and disease management. There is a need for additional biomarkers for diagnosis and prognosis of prostate cancer. MicroRNAs are a class of non-protein coding RNA molecules that are frequently dysregulated in different cancers including prostate cancer and show promise as diagnostic biomarkers and targets for therapy. Here we describe the role of micro RNA 146a (miR-146a) which may serve as a diagnostic and prognostic marker for prostate cancer, as indicated from the data presented in this report. Also, a pilot study indicated differential expression of miR-146a in prostate cancer cell lines and tissues from different racial groups. Reduced expression of miR-146a was observed in African American tumor tissues compared to those from European Whites This report provides a novel insight into understanding the prostate carcinogenesis.
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Affiliation(s)
- Monet Stevenson
- Department of Natural,Pharmacy and Health, Elizabeth City State University/University of North Carolina, Elizabeth, United States
| | - Hirendra Nath Banerjee
- Department of Natural,Pharmacy and Health, Elizabeth City State University/University of North Carolina, Elizabeth, United States
| | - Narendra Banerjee
- Department of Natural,Pharmacy and Health, Elizabeth City State University/University of North Carolina, Elizabeth, United States
| | - Kuldeep Rawat
- Department of Natural,Pharmacy and Health, Elizabeth City State University/University of North Carolina, Elizabeth, United States
| | - Lin Chen
- Department of Natural,Pharmacy and Health, Elizabeth City State University/University of North Carolina, Elizabeth, United States
| | - Myla Worthington
- Department of Natural,Pharmacy and Health, Elizabeth City State University/University of North Carolina, Elizabeth, United States
| | - Sasha Hodge
- Department of Natural,Pharmacy and Health, Elizabeth City State University/University of North Carolina, Elizabeth, United States
| | - Rayshawn Walker
- Department of Natural,Pharmacy and Health, Elizabeth City State University/University of North Carolina, Elizabeth, United States
| | - Mukesh Verma
- Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Suite 4E102, 9609 Medical Center Drive, Bethesda, United States
| | - Fazlul Sarkar
- Department of Pathology, Wayne State University and Barbara Karmanos Cancer Center, Detroit, United States
| | - Santosh Mandal
- Department of Chemistry, Morgan State University, Baltimore, United States
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Yuan F, Zhang S, Xie W, Yang S, Lin T, Chen X. Effect and mechanism of miR-146a on malignant biological behaviors of lung adenocarcinoma cell line. Oncol Lett 2020; 19:3643-3652. [PMID: 32382320 PMCID: PMC7202298 DOI: 10.3892/ol.2020.11474] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 06/28/2019] [Indexed: 12/28/2022] Open
Abstract
The aim of the present study was to assess the expression of microRNA-146a (miR-146a) in human lung adenocarcinoma cells, its effect on cellular behaviors, and the underlying molecular mechanisms. Reverse transcription-quantitative PCR (RT-qPCR) was used to measure miR-146a expression in the human normal lung epithelial cell line, BEAS-2B, and human lung adenocarcinoma cell lines, A549, PC-9 and H1299, to determine whether miR-146a acts as an oncogene or anti-oncogene. miR-146a mimics were transfected into target cells to observe the proliferation, apoptosis, invasion and migration of human lung adenocarcinoma cells. The target genes of miR-146a were predicted using bioinformatics analysis, and binding sites were validated by dual-luciferase reporter assay. Target gene expression at the mRNA and protein levels was measured by RT-qPCR and western blot analysis, respectively. The expression levels of miR-146a in human lung adenocarcinoma cell lines were lower than its expression in BEAS-2B (P<0.01). A549 cell line is a EGFR wild-type lung adenocarcinoma cell line, which is also the most widely studied in NSCLC, and therefore this was chosen as the target cell line for further investigation. Overexpression of miR-146a in A549 cells can inhibit cell proliferation (P<0.05), promote apoptosis (P<0.05), and reduce the cells' migratory ability (P<0.01). Bioinformatics prediction indicated that interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor associated factor 6 (TRAF6) are the target genes of miR-146a. Dual-luciferase reporter assay showed that miR-146a could specifically bind to 3′-untranslated regions of IRAK1 and TRAF6. The protein and mRNA levels of IRAK1 and TRAF6 were significantly downregulated after miR-146a overexpression in A549 cells (P<0.01). The results of this study demonstrated that the expression of miR-146a in human lung adenocarcinoma cells was significantly lower than in normal lung epithelial cells, indicating that miR-146a acts as an anti-oncogene. miR-146a suppresses the proliferation and migration of human lung adenocarcinoma cells by downregulating the expression of IRAK1 and TRAF6.
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Affiliation(s)
- Fang Yuan
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China.,Department of Respiratory, The First Hospital of Jiujiang City, Jiujiang, Jiangxi 332000, P.R. China
| | - Suyun Zhang
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Wenying Xie
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Sheng Yang
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Tingyan Lin
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Xiangqi Chen
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
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