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Bashar MA, Hossain MA, Kavey MRH, Shazib R, Islam MS, Ansari SA, Rahman MH. Network Pharmacology and In silico Elucidation of Phytochemicals Extracted from Ajwa Dates ( Phoenix dactylifera L.) to Inhibit Akt and PI3K Causing Triple Negative Breast Cancer (TNBC). Curr Pharm Des 2025; 31:774-796. [PMID: 39698883 DOI: 10.2174/0113816128348876241017101729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/22/2024] [Accepted: 09/24/2024] [Indexed: 12/20/2024]
Abstract
BACKGROUND About 10-15% of all breast cancers comprise triple-negative breast cancer (TNBC), defined as cancer cells that lack ER, PR, and HER2 protein receptors. Due to the absence of these receptors, treating TNBC using conventional chemotherapy is challenging and, therefore, requires the discovery of novel chemotherapeutic agents derived from natural sources. OBJECTIVE The current work was intended to study the potential phytochemicals of Ajwa dates (Phoenix dactylifera L.) with the predicted potential targets (namely, Akt and PI3K) to determine possible TNBC inhibitors. METHODS We harnessed network pharmacology, molecular docking, drug-likeness studies, Molecular Dynamics (MD) simulation, and binding free energy (MM-GBSA) calculation to get phytochemicals with potential effects against TNBC. Firstly, molecular docking was performed on 125 phytochemicals against the Akt and PI3K proteins utilizing PyRx. Then, the phytochemicals with the highest binding affinity (≤ -8.1 kcal/mol) were examined for in silico drug-likeness and toxicity profiles. Finally, phytochemicals with optimal druglikeness and toxicity profiles were studied by Molecular Dynamics (MD) simulation and binding free energy (MM-GBSA) to identify compounds that can form stable complexes. RESULTS The results of the network pharmacology revealed that the Akt and PI3K proteins are potential targets of TNBC for the phytochemicals of Phoenix dactylifera L. used in this study. The outcomes of molecular docking displayed that among 125 phytochemicals, 42 of them (with a binding affinity ≤ -8.1 kcal/mol) have potentially inhibiting effects on both proteins PI3K and Akt expressed in TNBC. Then, the results of in silico drug-likeness identified seven phytochemicals with optimal pharmacokinetic profiles. Furthermore, toxicity studies showed that three phytochemicals (namely, Chrysoeriol, Daidzein, and Glycitein) did not cause any toxicities. Finally, the Molecular Dynamics (MD) simulation studies and binding free energy (MM-GBSA) verified that Daidzein stayed within the binding cavities of both proteins (Akt and PI3K) by establishing a stable protein-ligand complex during simulation. CONCLUSION Taken together, the current work emphasizes the potential effects of Daidzein from Phoenix dactylifera L. against TNBC, and it can be further studied to establish it as a standard chemotherapy for TNBC.
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Affiliation(s)
- Md Abul Bashar
- Department of Pharmacy, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh
| | - Md Arju Hossain
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
- Department of Microbiology, Primeasia University, Banani, Dhaka 1213, Bangladesh
| | - Md Reduanul Haque Kavey
- Department of Pharmacy, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh
| | - Rayhanuzzaman Shazib
- Department of Pharmacy, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh
| | - Md Shofiqul Islam
- Institute for Intelligent Systems Research and Innovation (IISRI), Deakin University, 75 Pigdons Rd, Warunponds, Victoria 3216, Australia
| | - Siddique Akber Ansari
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O Box 2457, Riyadh 11451, Saudi Arabia
| | - Md Habibur Rahman
- Department of Computer Science and Engineering, Islamic University, Kushtia 7003, Bangladesh
- Center for Advanced Bioinformatics and Artificial Intelligence Research, Islamic University, Kushtia 7003, Bangladesh
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Liu X, Jia Y, Zheng C. Recent progress in Surface-Enhanced Raman Spectroscopy detection of biomarkers in liquid biopsy for breast cancer. Front Oncol 2024; 14:1400498. [PMID: 39040452 PMCID: PMC11260621 DOI: 10.3389/fonc.2024.1400498] [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: 03/13/2024] [Accepted: 06/24/2024] [Indexed: 07/24/2024] Open
Abstract
Breast cancer is the most commonly diagnosed cancer in women globally and a leading cause of cancer-related mortality. However, current detection methods, such as X-rays, ultrasound, CT scans, MRI, and mammography, have their limitations. Recently, with the advancements in precision medicine and technologies like artificial intelligence, liquid biopsy, specifically utilizing Surface-Enhanced Raman Spectroscopy (SERS), has emerged as a promising approach to detect breast cancer. Liquid biopsy, as a minimally invasive technique, can provide a temporal reflection of breast cancer occurrence and progression, along with a spatial representation of overall tumor information. SERS has been extensively employed for biomarker detection, owing to its numerous advantages such as high sensitivity, minimal sample requirements, strong multi-detection ability, and controllable background interference. This paper presents a comprehensive review of the latest research on the application of SERS in the detection of breast cancer biomarkers, including exosomes, circulating tumor cells (CTCs), miRNA, proteins and others. The aim of this review is to provide valuable insights into the potential of SERS technology for early breast cancer diagnosis.
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Affiliation(s)
- Xiaobei Liu
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yining Jia
- Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, China
- Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, China
| | - Chao Zheng
- Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, China
- Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, China
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Xie N, Wang F, Chen D, Zhou J, Xu J, Qu F. Immune dysfunction mediated by the competitive endogenous RNA network in fetal side placental tissue of polycystic ovary syndrome. PLoS One 2024; 19:e0300461. [PMID: 38512862 PMCID: PMC10956758 DOI: 10.1371/journal.pone.0300461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/27/2024] [Indexed: 03/23/2024] Open
Abstract
Polycystic ovary syndrome (PCOS), a common endocrine and metabolic disorder affecting women in their reproductive years. Emerging evidence suggests that the maternal-fetal immune system is crucial for proper pregnancy. However, whether immune function is altered at the end of pregnancy in PCOS women and the underlying molecular mechanisms is currently unexplored. Herein, the basic maternal immune system was investigated (n = 136 in the control group; n = 103 in the PCOS group), and whole-transcriptome sequencing was carried out to quantify the mRNAs, miRNAs, and lncRNAs expression levels in fetal side placental tissue of women with PCOS. GO, KEGG, and GSEA analysis were employed for functional enrichment analysis. The process of identifying hub genes was conducted utilizing the protein-protein interaction network. CIBERSORT and Connectivity Map were deployed to determine immune cell infiltration and predict potential drugs, respectively. A network of mRNA-miRNA-lncRNA was constructed and then validated by qRT-PCR. First, red blood cell count, neutrophil count, lymphocyte count, hypersensitive C-reactive protein, and procalcitonin were significantly elevated, while placental growth factor was hindered in PCOS women. We identified 308 DEmRNAs, 77 DEmiRNAs, and 332 DElncRNAs in PCOS samples. Functional enrichment analysis revealed that there were significant changes observed in terms of the immune system, especially the chemokine pathway. Eight genes, including FOS, JUN, EGR1, CXCL10, CXCR1, CXCR2, CXCL11, and CXCL8, were considered as hub genes. Furthermore, the degree of infiltration of neutrophils was dramatically decreased in PCOS tissues. In total, 57 ceRNA events were finally obtained, and immune-related ceRNA networks were validated. Some potential drug candidates, such as enalapril and RS-100329, could have a function in PCOS therapy. This study represents the inaugural attempt to evaluate the immune system at the end of pregnancy and placental ceRNA networks in PCOS, indicating alterations in the chemokine pathway, which may impact fetal and placental growth, and provides new therapy targets.
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Affiliation(s)
- Ningning Xie
- Department of Obstetrics and Gynecology, International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Fangfang Wang
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Danqing Chen
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jue Zhou
- College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, China
| | - Jian Xu
- Department of Obstetrics and Gynecology, International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Fan Qu
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Shaw R, Basu M, Karmakar S, Ghosh MK. MGMT in TMZ-based glioma therapy: Multifaceted insights and clinical trial perspectives. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119673. [PMID: 38242327 DOI: 10.1016/j.bbamcr.2024.119673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 01/05/2024] [Accepted: 01/10/2024] [Indexed: 01/21/2024]
Abstract
Temozolomide (TMZ) is the most preferred and approved chemotherapeutic drug for either first- or second-line chemotherapy for glioma patients across the globe. In glioma patients, resistance to treatment with alkylating drugs like TMZ is known to be conferred by exalted levels of MGMT gene expression. On the contrary, epigenetic silencing through MGMT gene promoter methylation leading to subsequent reduction in MGMT transcription and protein expression, is predicted to have a response favoring TMZ treatment. Thus, MGMT protein level in cancer cells is a crucial determining factor in indicating and predicting the choice of alkylating agents in chemotherapy or choosing glioma patients directly for a second line of treatment. Thus, in-depth research is necessary to achieve insights into MGMT gene regulation that has recently enticed a fascinating interest in epigenetic, transcriptional, post-transcriptional, and post-translational levels. Furthermore, MGMT promoter methylation, stability of MGMT protein, and related subsequent adaptive responses are also important contributors to strategic developments in glioma therapy. With applications to its identification as a prognostic biomarker, thus predicting response to advanced glioma therapy, this review aims to concentrate on the mechanistic role and regulation of MGMT gene expression at epigenetic, transcriptional, post-transcriptional, and post-translational levels functioning under the control of multiple signaling dynamics.
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Affiliation(s)
- Rajni Shaw
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Malini Basu
- Department of Microbiology, Dhruba Chand Halder College, Dakshin Barasat, South 24, Paraganas 743372, India
| | - Subhajit Karmakar
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Mrinal K Ghosh
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
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Zhong X, Wang H, Jia X, Chen G, Li H, Li P, Liu W, Yang T, Xie J. Association of noncoding RNAs with Kawasaki disease: A meta-analysis based on the current evidences. Medicine (Baltimore) 2023; 102:e35736. [PMID: 37960719 PMCID: PMC10637536 DOI: 10.1097/md.0000000000035736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 09/29/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND In recent years, many studies have focused on the relationship between noncoding RNAs (ncRNAs) and Kawasaki disease (KD). Studies have indicated that ncRNAs are associated with the occurrence and development of KD. Thus, we performed a systematic review and meta-analysis to investigate the diagnostic value of ncRNAs in KD patients. METHODS We searched the PubMed, Web of Science, Embase and Cochrane Library, China National Knowledge Infrastructure, VIP, China Biology Medicine disc databases, and Wanfang databases until August 25, 2023 and screened all eligible studies focusing on the diagnostic performance of ncRNAs in KD patients. RESULTS In total, 535 articles were found, and 28 articles were included in this systematic review and meta-analysis. The calculated area under the curve value was 0.880 (95% confidence intervals, 0.840-0.900). The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 0.790, 0.830, 4.610, and 0.260, respectively. The pooled diagnostic odds ratio was 17.890 (95% confidence intervals, 13.110-24.420), indicating a relatively good diagnostic performance of the ncRNAs for detecting KD. In addition, the diagnostic value of micro RNAs in KD was better than that of long noncoding RNAs and circular noncoding RNAs. A subgroup analysis by specimen indicated a better diagnostic value of ncRNAs in plasma and platelet than serum. The diagnostic accuracy of ncRNAs was better in febrile controls than in healthy control groups, indicating a relatively good accuracy in distinguishing KD patients from febrile diseases. CONCLUSIONS This systematic review and meta-analysis demonstrated that ncRNAs could be used as novel biomarkers for detecting KD. More studies should be conducted in the future to verify the diagnostic values of ncRNAs in KD.
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Affiliation(s)
- Xiaoling Zhong
- Department of Pediatrics, The Third People's Hospital of Chengdu/The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, PR China
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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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Ortega MM, Bouamar H. Guidelines on Designing MicroRNA Sponges: From Construction to Stable Cell Line. Methods Mol Biol 2023; 2595:171-183. [PMID: 36441462 DOI: 10.1007/978-1-0716-2823-2_12] [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: 11/29/2022]
Abstract
Single microRNA (miRNA) can be inhibited using antagomiR which efficiently knocks down a specific miRNA. However, the effect is transient and often results in subtle phenotype. Here we report a guideline on designing miRNA sponges inhibiting a miRNA family. As a model system, we targeted miR-30 family, known as tumor suppressor miRNAs in multiple tumors. To achieve an efficient knockdown, we generated perfect and bulged-matched miRNA binding sites (MBS) and introduced multiple copies of MBS. The protocol here demonstrates the miRNA sponge as a useful tool to examine the functional impact of inhibition miRNAs.
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Affiliation(s)
- Manoela Marques Ortega
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista, São Paulo, Brazil.
| | - Hakim Bouamar
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities. Int J Mol Sci 2022; 23:ijms232314672. [PMID: 36499000 PMCID: PMC9735783 DOI: 10.3390/ijms232314672] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain genomic stability and integrity, but different types of cancers are associated with DDR machinery defects. Many improvements have been made in recent years, providing several drugs and therapeutic strategies for cancer patients, including those targeting the DDR pathways. Currently, poly (ADP-ribose) polymerase inhibitors (PARP inhibitors) are the DDR inhibitors (DDRi) approved for several cancers, including breast, ovarian, pancreatic, and prostate cancer. However, PARPi resistance is a growing issue in clinical settings that increases disease relapse and aggravate patients' prognosis. Additionally, resistance to other DDRi is also being found and investigated. The resistance mechanisms to DDRi include reversion mutations, epigenetic modification, stabilization of the replication fork, and increased drug efflux. This review highlights the DDR pathways in cancer therapy, its role in the resistance to conventional treatments, and its exploitation for anticancer treatment. Biomarkers of treatment response, combination strategies with other anticancer agents, resistance mechanisms, and liabilities of treatment with DDR inhibitors are also discussed.
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Soofiyani SR, Hosseini K, Ebrahimi T, Forouhandeh H, Sadeghi M, Beirami SM, Ghasemnejad T, Tarhriz V, Montazersaheb S. Prognostic Value and Biological Role of miR-126 in Breast Cancer. Microrna 2022; 11:95-103. [PMID: 35507794 DOI: 10.2174/1876402914666220428123203] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/23/2022] [Accepted: 03/10/2022] [Indexed: 01/01/2023]
Abstract
In eukaryotic organisms such as humans, some noncoding single-stranded RNAs (ncRNAs) contribute to regulating the expression of some genes before and after the transcription process, which in turn controls a number of vital physiological processes, including cell proliferation, differentiation, invasion, angiogenesis, and embryonic development. miR-126 is one of these miRNAs expressed exclusively in endothelial cells such as capillaries and vessels involved in controlling angiogenesis. In recent years, the link between miRs such as miR-126 and the pathology of breast cancer has attracted the attention of many researchers. Numerous studies have shown that miR-126 may be able to suppress tumor tissue metastasis or to increase tumor metastasis through complex molecular mechanisms. There is ample clinical evidence that miR-126 can be used as a biomarker to predict and diagnose breast cancer due to the increased or decreased expression of certain genes in breast cancer tissue. In this review, we discuss the association between the growth and metastasis (tumorigenesis) of breast cancer and miR-126, as well as the relationship between current research advances in the prognosis, diagnosis, and treatment of breast cancer and miR-126.
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Affiliation(s)
- Saiedeh Razi Soofiyani
- Clinical Research Development Unit, Sina Educational, Research, and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kamran Hosseini
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Molecular Medicine, Faculty of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Ebrahimi
- Department of Nano Biotechnology, Research Center Pasteur Institute of Iran, Tehran, Iran
| | - Haleh Forouhandeh
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammadreza Sadeghi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sohrab Minaei Beirami
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Tohid Ghasemnejad
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
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Petroušková P, Hudáková N, Maloveská M, Humeník F, Cizkova D. Non-Exosomal and Exosome-Derived miRNAs as Promising Biomarkers in Canine Mammary Cancer. Life (Basel) 2022; 12:life12040524. [PMID: 35455015 PMCID: PMC9032658 DOI: 10.3390/life12040524] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 02/06/2023] Open
Abstract
Canine mammary cancer (CMC), similar to human breast cancer (HBC) in many aspects, is the most common neoplasm associated with significant mortality in female dogs. Due to the limited therapy options, biomarkers are highly desirable for early clinical diagnosis or cancer progression monitoring. Since the discovery of microRNAs (miRNAs or miRs) as post-transcriptional gene regulators, they have become attractive biomarkers in oncological research. Except for intracellular miRNAs and cell-free miRNAs, exosome-derived miRNAs (exomiRs) have drawn much attention in recent years as biomarkers for cancer detection. Analysis of exosomes represents a non-invasive, pain-free, time- and money-saving alternative to conventional tissue biopsy. The purpose of this review is to provide a summary of miRNAs that come from non-exosomal sources (canine mammary tumor, mammary tumor cell lines or canine blood serum) and from exosomes as promising biomarkers of CMC based on the current literature. As is discussed, some of the miRNAs postulated as diagnostic or prognostic biomarkers in CMC were also altered in HBC (such as miR-21, miR-29b, miR-141, miR-429, miR-200c, miR-497, miR-210, miR-96, miR-18a, miR19b, miR-20b, miR-93, miR-101, miR-105a, miR-130a, miR-200c, miR-340, miR-486), which may be considered as potential disease-specific biomarkers in both CMC and HBC.
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Affiliation(s)
- Patrícia Petroušková
- Centre of Experimental and Clinical Regenerative Medicine, The University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia; (P.P.); (N.H.); (M.M.); (F.H.)
| | - Nikola Hudáková
- Centre of Experimental and Clinical Regenerative Medicine, The University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia; (P.P.); (N.H.); (M.M.); (F.H.)
| | - Marcela Maloveská
- Centre of Experimental and Clinical Regenerative Medicine, The University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia; (P.P.); (N.H.); (M.M.); (F.H.)
| | - Filip Humeník
- Centre of Experimental and Clinical Regenerative Medicine, The University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia; (P.P.); (N.H.); (M.M.); (F.H.)
| | - Dasa Cizkova
- Centre of Experimental and Clinical Regenerative Medicine, The University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia; (P.P.); (N.H.); (M.M.); (F.H.)
- Institute of Neuroimmunology, Slovak Academy of Sciences, Dúbravská Cesta 9, 845 10 Bratislava, Slovakia
- Correspondence: ; Tel.: +421-918-752-157
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Sun T, Liu D, Wu J, Lu WW, Zhao X, Wong TM, Liu ZL. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma. Open Med (Wars) 2022; 17:441-452. [PMID: 35350838 PMCID: PMC8919822 DOI: 10.1515/med-2022-0441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 12/29/2021] [Accepted: 01/24/2022] [Indexed: 11/15/2022] Open
Abstract
Osteosarcoma (OS) is the most common type of primary malignant bone tumor. The early lung metastasis of osteosarcoma is one of the main factors of poor prognosis. Therefore, searching for new targets and new mechanisms of osteosarcoma metastasis is essential for the prevention and treatment of osteosarcoma. Our previous studies suggested that fatty acid synthase (FASN) was an oncogene and promoted osteosarcoma. In addition, it is reported that the expression of miR-195 was negatively correlated with osteosarcoma. Aberrant DNA methylation can reversely regulate the expression of miRNAs. However, whether miR-195 could target FASN in osteosarcoma and whether ectopic DNA methylation is the upstream regulatory mechanism of miR-195 in metastasis of osteosarcoma are not fully studied. The expressions were detected by qPCR and western blot, and methylation level was determined by methylation-specific PCR. Luciferase reporter assay, MTT, wound healing, and Transwell assay were used. We found that the expression of miR-195 was low in osteosarcoma. The methylation of miR-195 was high. miR-195 targeted and decreased the expression of FASN. In osteosarcoma, miR-195 inhibited cell proliferation, cell migration, and invasion. The methylation of miR-195 was related to decreased miR-195, it might promote osteosarcoma.
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Affiliation(s)
- Tianhao Sun
- Shenzhen Key Laboratory for Innovative Technology in Ortho-paedic Trauma, Guangdong Engineering Technology Research Center for Orthopaedic Trauma Repair, Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital , Shenzhen 518053 , China
- Research Center for Human Tissue and Organs Degeneration, Institute Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 , China
| | - Dongning Liu
- Department of Spinal Surgery, Shenzhen Sixth People’s Hospital(Nanshan Hospital), Huazhong University of Science and Technology Union Shenzhen Hospital , Shenzhen , China
| | - Jun Wu
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, Guangdong Engineering Technology Research Center for Orthopaedic Trauma Repair, Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital , Shenzhen 518053 , China
| | - William W. Lu
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, Guangdong Engineering Technology Research Center for Orthopaedic Trauma Repair, Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital , Shenzhen 518053 , China
- Research Center for Human Tissue and Organs Degeneration, Institute Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 , China
| | - Xiaoli Zhao
- Research Center for Human Tissue and Organs Degeneration, Institute Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 , China
| | - Tak Man Wong
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, Guangdong Engineering Technology Research Center for Orthopaedic Trauma Repair, Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital , Shenzhen 518053 , China
| | - Zhi-Li Liu
- Institute of Spine and Spinal Cord, Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University , Nanchang 330006 , China
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12
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Sahabi K, Selvarajah GT, Mokrish A, Rasedee A, Kqueen CY. Development and molecular characterization of doxorubicin-resistant canine mammary gland tumour cells. JOURNAL OF APPLIED ANIMAL RESEARCH 2022. [DOI: 10.1080/09712119.2022.2032719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Kabiru Sahabi
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | - Gayathri T. Selvarajah
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
- UPM-MAKNA Cancer Research Laboratory (CANRES), Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia
| | - Ajat Mokrish
- Department of Veterinary Preclinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | - Abdullah Rasedee
- Department of Veterinary Diagnostic Laboratory, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Malaysia
| | - Cheah Y. Kqueen
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
- UPM-MAKNA Cancer Research Laboratory (CANRES), Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia
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13
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Ahmed EY, Latif NAA, Nasr T, Awad HM, Abdelhafez OM. Design, Synthesis and Molecular Modeling of Coumarin Derivatives as MDM2 Inhibitors Targeting Breast Cancer. Chem Biol Drug Des 2022; 99:609-619. [PMID: 35156778 DOI: 10.1111/cbdd.14028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 01/21/2022] [Accepted: 01/29/2022] [Indexed: 11/29/2022]
Abstract
The coumarin ring was used as a central scaffold that was substituted with a variety of bioactive functional groups, for designing and synthesizing novel MDM2 inhibitors targeting breast cancer. The synthesized derivatives, 3c, 3d, 3g, 7b, 7c and 8 with IC50s ranging from 9.4 to 9.9 µM were evaluated for their safety on MCF10a normal breast cell line. The compounds showed selectivity indices of 2.15, 3.85, 2.75, 1.38, 3.72 and 5.20 respectively. 7c was selected for further investigation, the compound was capable of down-regulating MDM2 and the anti-apoptosis proteins Bcl-2 and Bcl-xL, up-regulating the level of p53 and the pro-apoptosis protein BAX, causing cell cycle arrest at G2/M phase and activating Caspase-9 to induce apoptosis. Molecular docking study revealed the capability of derivative 7c to interact with the key amino acids in p53 binding pocket of MDM2 protein. Moreover, the physicochemical properties of compound 7c were studied in silico.
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Affiliation(s)
- Eman Y Ahmed
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, Egypt
| | - Nehad A Abdel Latif
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, Egypt
| | - Tamer Nasr
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Helwan, Cairo, Egypt
| | - Hanem M Awad
- Tanning Materials and Leather Technology Department, National Research Centre, Dokki, Cairo, Egypt
| | - Omaima M Abdelhafez
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, Egypt
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14
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Arévalo DM, Anokhina VS, Swart OLR, Miller BL. Expanding the known structure space for RNA binding: a test of 2,5-diketopiperazine. Org Biomol Chem 2022; 20:606-612. [PMID: 34927652 PMCID: PMC8900054 DOI: 10.1039/d1ob01976g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
As the importance of RNA as a therapeutic target has become increasingly recognized, the need for new chemotypes able to bind RNA has grown in significance. We hypothesized that diketopiperazines (DKPs), common substructures in natural products and protein-targeting therapeutic agents, could serve as effective scaffolds for targeting RNA. To confirm this hypothesis, we designed and synthesized two analogs, one incorporating a DKP and one not, of compounds previously demonstrated to bind an RNA critical to the life cycle of HIV-1 with high affinity and specificity. Prior to compound synthesis, calculations employing density functional methods and molecular mechanics conformational searches were used to confirm that the DKP could present functionality in a similar (albeit not identical) orientation to the non DKP-containing compound. We found that both the DKP-containing and parent compound had similar affinities to the target RNA as measured by surface plasmon resonance (SPR). Both compounds were found to have modest but equal anti-HIV activity. These results establish the feasibility of using DKPs to target RNA.
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Affiliation(s)
- Diego M. Arévalo
- Department of Chemistry, University of Rochester, Rochester, NY 14642, USA
| | - Viktoriya S. Anokhina
- Department of Biochemistry and Biophysics, University of Rochester, Rochester, NY 14642, USA
| | - Oliver L. R. Swart
- Department of Chemistry, University of Rochester, Rochester, NY 14642, USA
| | - Benjamin L. Miller
- Department of Biochemistry and Biophysics, University of Rochester, Rochester, NY 14642, USA,Department of Dermatology, University of Rochester, Rochester, NY 14642, USA
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15
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Mahmoudian-Sani MR, Asadi-Samani M. Modulation of MicroRNAs by Euphorbia Microsciadia Boiss in MDA-MB-231 Cell Line: New Possibilities in Breast Cancer Therapy. Recent Pat Anticancer Drug Discov 2021; 15:174-184. [PMID: 32603285 DOI: 10.2174/1574892815666200630102944] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 04/16/2020] [Accepted: 06/29/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND A large number of Euphorbia species have been evaluated for anticancer effects; however, their anticancer mechanisms have not been established up to now. OBJECTIVE The present study aimed to evaluate the effects of Euphorbia microsciadia (E. microsciadia) Boiss on the modulation of micro (mi) RNAs in MDA-MB-231 cell line. METHODS As the first step, the inhibitory concentration of hydroalcoholic extract of E. microsciadia on MDA-MB-231 cells was examined using the MTT assay, bypassing 24 and 48h from seeding. The real-time quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) was also utilized to determine Let-7, miR-15, miR-16, miR-29, miR-151, miR-155, miR-21, miR-146b, miR-181b, miR-221, miR-222, miR-21, and miR-146b expressions in MDA-MB-231 cells, by passing 24 and 48h from treating with the extract of E. microsciadia. RESULTS The results reveal the cytotoxic effects of E. microsciadia on MDA-MB-231 cell line in a dose-dependent manner. The half maximal Inhibitory Concentrations (IC50) were also equal to 275 and 240μg/ml for E. microsciadia, by passing 24 and 48h from the treatment, respectively. Furthermore, it was confirmed that, E. microsciadia had augmented the expression levels of Let-7, miR-15, miR-16, miR-29, and miR-34a, which lead to an increase in apoptosis. CONCLUSION E. microsciadia could modulate some miRNAs involved in cell cycle arrest and apoptosis in MDA-MB-231 cell line. Accordingly, targeting miRNAs by E. microsciadia can open some newer avenues for breast cancer therapy.
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Affiliation(s)
- Mohammad-Reza Mahmoudian-Sani
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Majid Asadi-Samani
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Pedroza DA, Ramirez M, Rajamanickam V, Subramani R, Margolis V, Gurbuz T, Estrada A, Lakshmanaswamy R. miRNome and Functional Network Analysis of PGRMC1 Regulated miRNA Target Genes Identify Pathways and Biological Functions Associated With Triple Negative Breast Cancer. Front Oncol 2021; 11:710337. [PMID: 34350123 PMCID: PMC8327780 DOI: 10.3389/fonc.2021.710337] [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: 05/15/2021] [Accepted: 06/24/2021] [Indexed: 12/14/2022] Open
Abstract
Background Increased expression of the progesterone receptor membrane component 1, a heme and progesterone binding protein, is frequently found in triple negative breast cancer tissue. The basis for the expression of PGRMC1 and its regulation on cellular signaling mechanisms remain largely unknown. Therefore, we aim to study microRNAs that target selective genes and mechanisms that are regulated by PGRMC1 in TNBCs. Methods To identify altered miRNAs, whole human miRNome profiling was performed following AG-205 treatment and PGRMC1 silencing. Network analysis identified miRNA target genes while KEGG, REACTOME and Gene ontology were used to explore altered signaling pathways, biological processes, and molecular functions. Results KEGG term pathway analysis revealed that upregulated miRNAs target specific genes that are involved in signaling pathways that play a major role in carcinogenesis. While multiple downregulated miRNAs are known oncogenes and have been previously demonstrated to be overexpressed in a variety of cancers. Overlapping miRNA target genes associated with KEGG term pathways were identified and overexpression/amplification of these genes was observed in invasive breast carcinoma tissue from TCGA. Further, the top two genes (CCND1 and YWHAZ) which are highly genetically altered are also associated with poorer overall survival. Conclusions Thus, our data demonstrates that therapeutic targeting of PGRMC1 in aggressive breast cancers leads to the activation of miRNAs that target overexpressed genes and deactivation of miRNAs that have oncogenic potential.
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Affiliation(s)
- Diego A Pedroza
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Matthew Ramirez
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Venkatesh Rajamanickam
- Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States
| | - Ramadevi Subramani
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States.,Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Victoria Margolis
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Tugba Gurbuz
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Adriana Estrada
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Rajkumar Lakshmanaswamy
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States.,Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
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Mu L, Sun X, Tu M, Zhang D. Non-coding RNAs in polycystic ovary syndrome: a systematic review and meta-analysis. Reprod Biol Endocrinol 2021; 19:10. [PMID: 33446212 PMCID: PMC7807442 DOI: 10.1186/s12958-020-00687-9] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/17/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Genetic, environmental and epigenetical factors may play important roles in the pathogenesis of polycystic ovary syndrome (PCOS), however the etiology of PCOS remains unclear. Studies indicated that non-coding RNAs (ncRNAs) were involved in the occurrence and development of PCOS. Thus, we aim to perform a systematic review and meta-analysis to investigate the presence and dysregulated expression of ncRNAs in human PCOS. METHODS We searched in PubMed, Medline, Web of Science and Embase until July 2019 and summarized all eligible publications focusing on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and small interfering RNAs (siRNAs) in PCOS. RESULTS Sixty-seven articles were included in our systematic review and 9 articles were included in meta-analysis. There is little overlap between studies when comparing miRNA profiles. Sensitivity analysis showed that the expression of miR-93 was upregulated in PCOS patients (WMD 0.75, P < 0.00001), without heterogeneity among remaining studies (I2 = 0%). CONCLUSION A large number of ncRNAs with altered levels were observed in plasma, serum, follicular fluid, granulosa cells or other issues from PCOS patients. Aberrant ncRNAs expression in PCOS may lead to aberrant steroidogenesis, adipocyte dysfunction, altered ovarian cell proliferation and/or apoptosis and have the potential to be used as diagnostic biomarkers.
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Affiliation(s)
- Liangshan Mu
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Xiaoting Sun
- Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People's Republic of China
| | - Mixue Tu
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Dan Zhang
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, People's Republic of China.
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Interplay between p53 and non-coding RNAs in the regulation of EMT in breast cancer. Cell Death Dis 2021; 12:17. [PMID: 33414456 PMCID: PMC7791039 DOI: 10.1038/s41419-020-03327-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 12/02/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023]
Abstract
The epithelial-mesenchymal transition (EMT) plays a pivotal role in the differentiation of vertebrates and is critically important in tumorigenesis. Using this evolutionarily conserved mechanism, cancer cells become drug-resistant and acquire the ability to escape the cytotoxic effect of anti-cancer drugs. In addition, these cells gain invasive features and increased mobility thereby promoting metastases. In this respect, the process of EMT is critical for dissemination of solid tumors including breast cancer. It has been shown that miRNAs are instrumental for the regulation of EMT, where they play both positive and negative roles often as a part of a feed-back loop. Recent studies have highlighted a novel association of p53 and EMT where the mutation status of p53 is critically important for the outcome of this process. Interestingly, p53 has been shown to mediate its effects via the miRNA-dependent mechanism that targets master-regulators of EMT, such as Zeb1/2, Snail, Slug, and Twist1. This regulation often involves interactions of miRNAs with lncRNAs. In this review, we present a detailed overview of miRNA/lncRNA-dependent mechanisms that control interplay between p53 and master-regulators of EMT and their importance for breast cancer.
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19
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Triple negative breast cancer in the era of miRNA. Crit Rev Oncol Hematol 2020; 157:103196. [PMID: 33307198 DOI: 10.1016/j.critrevonc.2020.103196] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 11/12/2020] [Accepted: 12/06/2020] [Indexed: 02/07/2023] Open
Abstract
The objective of this review is to elucidate the role of miRNAs in triple negative breast cancer (TNBC). To achieve our goal, we searched databases such as PubMed, ScienceDirect, Springer, Web of Science and Scopus. We retrieved up to 1233 articles, based a rigorous selection criterion, only 197 articles were extensively reviewed. We selected articles only addressing TNBC, but not other types of breast cancer, with the employed approach being miRNA analysis and/or profiling. Our extensive review resulted in grouping of miRNAs into categories in which specific members of miRNAs have roles in specific mechanism in TNBC i.e., carcinogenesis, invasion, metastasis, apoptosis, diagnosis, prognosis, and treatment. TNBC is an aggressive subtype of breast cancer; therefore, different approaches for accurate diagnosis, prognosis and treatment are needed. In this review we summarize the up-to-date miRNA profiling, prognostic, and therapeutic findings that add to the route of controlling TNBC.
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20
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In-silico modeling and analysis of the therapeutic potential of miRNA-7 on EGFR associated signaling network involved in breast cancer. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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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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Li H, Lian B, Liu Y, Chai D, Li J. MicroRNA-1297 downregulation inhibits breast cancer cell epithelial-mesenchymal transition and proliferation in a FA2H-dependent manner. Oncol Lett 2020; 20:277. [PMID: 33014155 PMCID: PMC7520798 DOI: 10.3892/ol.2020.12140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 07/28/2020] [Indexed: 12/23/2022] Open
Abstract
Breast cancer (BC) is one of the most common malignant tumors among women worldwide. MicroRNAs (miRs) may be involved in several types of human cancer, including gastric, liver, lung and breast cancer. The aim of the present study was to investigate the effect of miR-1297 on MDA-MB-231 cell epithelial-mesenchymal transition (EMT) and proliferation, and the underlying molecular mechanisms. MDA-MB-231 cells were transfected with miR-1297 inhibitor or inhibitor control for 48 h. Subsequently, MTT and flow cytometry assays indicated that miR-1297 inhibitor significantly decreased cell proliferation and induced apoptosis compared with the inhibitor control group. In addition, reverse transcription-quantitative PCR and western blotting suggested that miR-1297 inhibitor suppressed EMT in MDA-MB-231 cells compared with the inhibitor control group. TargetScan bioinformatics analysis and a dual-luciferase reporter gene assay were performed, which predicted that miR-1297 directly targeted fatty acid 2-hydroxylase (FA2H). Furthermore, MDA-MB-231 cells were transfected with control-plasmid or FA2H-plasmid for 48 h. The results demonstrated that FA2H overexpression decreased MDA-MB-231 cell proliferation and increased apoptosis compared with the control-plasmid group. Additionally, FA2H-plasmid increased E-cadherin expression levels, and reduced N-cadherin and matrix metalloproteinase 9 expression levels at both the protein and mRNA level compared with control-plasmid. Finally, MDA-MB-231 cells were transfected with control-small interfering (si)RNA, FA2H-siRNA, inhibitor control, miR-1297 inhibitor, miR-1297 inhibitor + control siRNA or miR-1297 inhibitor + FA2H-siRNA, and the results suggested that the biological effects of miR-1297 inhibitor were reversed by co-transfection with FA2H siRNA. In conclusion, the present study indicated that miR-1297/FA2H might serve as a novel potential biomarker and therapeutic target for BC.
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Affiliation(s)
- Hong Li
- Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Bin Lian
- Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Yaobang Liu
- Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Dahai Chai
- Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Jinping Li
- Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
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23
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Therapeutically Significant MicroRNAs in Primary and Metastatic Brain Malignancies. Cancers (Basel) 2020; 12:cancers12092534. [PMID: 32906592 PMCID: PMC7564168 DOI: 10.3390/cancers12092534] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 12/11/2022] Open
Abstract
Simple Summary The overall survival of brain cancer patients remains grim, with conventional therapies such as chemotherapy and radiotherapy only providing marginal benefits to patient survival. Cancers are complex, with multiple pathways being dysregulated simultaneously. Non-coding RNAs such as microRNA (miRNAs) are gaining importance due to their potential in regulating a variety of targets implicated in the pathology of cancers. This could be leveraged for the development of targeted and personalized therapies for cancers. Since miRNAs can upregulate and/or downregulate proteins, this review aims to understand the role of these miRNAs in primary and metastatic brain cancers. Here, we discuss the regulatory mechanisms of ten miRNAs that are highly dysregulated in glioblastoma and metastatic brain tumors. This will enable researchers to develop miRNA-based targeted cancer therapies and identify potential prognostic biomarkers. Abstract Brain cancer is one among the rare cancers with high mortality rate that affects both children and adults. The most aggressive form of primary brain tumor is glioblastoma. Secondary brain tumors most commonly metastasize from primary cancers of lung, breast, or melanoma. The five-year survival of primary and secondary brain tumors is 34% and 2.4%, respectively. Owing to poor prognosis, tumor heterogeneity, increased tumor relapse, and resistance to therapies, brain cancers have high mortality and poor survival rates compared to other cancers. Early diagnosis, effective targeted treatments, and improved prognosis have the potential to increase the survival rate of patients with primary and secondary brain malignancies. MicroRNAs (miRNAs) are short noncoding RNAs of approximately 18–22 nucleotides that play a significant role in the regulation of multiple genes. With growing interest in the development of miRNA-based therapeutics, it is crucial to understand the differential role of these miRNAs in the given cancer scenario. This review focuses on the differential expression of ten miRNAs (miR-145, miR-31, miR-451, miR-19a, miR-143, miR-125b, miR-328, miR-210, miR-146a, and miR-126) in glioblastoma and brain metastasis. These miRNAs are highly dysregulated in both primary and metastatic brain tumors, which necessitates a better understanding of their role in these cancers. In the context of the tumor microenvironment and the expression of different genes, these miRNAs possess both oncogenic and/or tumor-suppressive roles within the same cancer.
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Dong W, Wu P, Qin M, Guo S, Liu H, Yang X, He W, Bouakaz A, Wan M, Zong Y. Multipotent miRNA Sponge-Loaded Magnetic Nanodroplets with Ultrasound/Magnet-Assisted Delivery for Hepatocellular Carcinoma Therapy. Mol Pharm 2020; 17:2891-2910. [PMID: 32678617 DOI: 10.1021/acs.molpharmaceut.0c00336] [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: 02/06/2023]
Abstract
Gene therapy is likely to be the most promising way to tackle cancer, while defects in molecular strategies and delivery systems have led to an impasse in clinical application. Here, it is found that onco-miRNAs of the miR-515 and -449 families were upregulated in hepatocellular carcinoma (HCC), and the sponge targeting miR-515 family had a significant probability to suppress cancer cell proliferation. Then, we constructed non-toxic sponge-loaded magnetic nanodroplets containing 20% C6F14 (SLMNDs-20%) that are incorporated with fluorinated superparamagnetic iron oxide nanoparticles enhancing external magnetism-assisted targeting and enabling a direct visualization of SLMNDs-20% distribution in vivo via magnetic resonance imaging monitoring. SLMNDs-20% could be vaporized by programmable focused ultrasound (FUS) activation, achieving ∼45% in vitro sponge delivery efficiency and significantly enhancing in vivo sponge delivery without a clear apoptosis. Moreover, the sponge-1-carrying SLMNDs-20% could effectively suppress proliferation of xenograft HCC after FUS exposure because sponge-1-suppressing onco-miR-515 enhanced the expression of anti-oncogenes (P21, CD22, TIMP1, NFKB, and E-cadherin) in cancer cells. The current results indicated that ultrasonic cavitation-inducing sonoporation enhanced the intracellular delivery of sponge-1 using SLMNDs-20% after magnetic-assisted accumulation, which was a therapeutic approach to inhibit HCC progression.
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Affiliation(s)
- Wei Dong
- Department of Biomedical Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Pengying Wu
- Department of Biomedical Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Mengfan Qin
- Department of Biomedical Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Shifang Guo
- Department of Biomedical Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Huasheng Liu
- Department of Hematology, The First Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, China
| | - Xinxing Yang
- Department of Biomedical Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.,Department of Ultrasound, The First Affiliated Hospital of AFMU (Xijing Hospital), Air Force Medical University, Xi'an, Shaanxi 710032, China
| | - Wen He
- Department of Biomedical Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.,Department of Pharmacy, The First Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, China
| | - Ayache Bouakaz
- Department of Biomedical Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.,Inserm Imaging and Ultrasound, INSERM U930, Imagerie et Cerveau, Université François-Rabelais de Tours, Tours 37000, France
| | - Mingxi Wan
- Department of Biomedical Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Yujin Zong
- Department of Biomedical Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
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Dawood DH, Nossier ES, Ali MM, Mahmoud AE. Synthesis and molecular docking study of new pyrazole derivatives as potent anti-breast cancer agents targeting VEGFR-2 kinase. Bioorg Chem 2020; 101:103916. [PMID: 32559576 DOI: 10.1016/j.bioorg.2020.103916] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 05/01/2020] [Accepted: 05/04/2020] [Indexed: 12/18/2022]
Abstract
Based on the previous studies that revealed the valuable role of pyrazole scaffold in cancer management and VEGFR-2 inhibition, a new set of pyrazole conjugated with pyrazoline, triazolopyrimidine and pyrazolone moieties were synthesized and investigated for their anticancer efficiency against human breast cancer MCF-7. The anticancer screening revealed the significant sensitivity of breast carcinoma towards compounds 4b, 5c, 6c, 7b, 7c and 12c with IC50 values ranging from 16.50 - 26.73 µM in comparison with tamoxifen (IC50 = 23.31 µM). Moreover, the new analogues were further examined for their VEGFR-2 inhibitory activity, among the tested derivatives 5c, 6c, 7b, 7c and 12c displayed prominent inhibitory efficiency versus VEGFR-2 kinase with % inhibition ranging from 70 to 79%. Compounds 6c, 7c and 12c revealed inhibitory efficiency in nanomolar level with IC50 (913.51, 225.17 and 828.23 nM, respectively) comparing to sorafenib (IC50 = 186.54 nM). Flow cytometric analysis revealed that the promising compound 12c prompted pre-G1 apoptosis and cell growth cessation at G2/M phase and stimulated apoptosis via activation of caspase-3. Moreover, molecular docking study of the promising derivatives was performed to highlight their binding modes and interactions with the amino acid residues of VEGFR-2 enzyme.
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Affiliation(s)
- Dina H Dawood
- Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El Bohouth St., Dokki, Giza, P.O. Box 12622, Egypt.
| | - Eman S Nossier
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy(Girls), Al-Azhar University, Cairo, P.O. Box 11754, Egypt
| | - Mamdouh M Ali
- Biochemistry Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, 33 El Bohouth St., Dokki, Giza, P.O. Box 12622, Egypt
| | - Abeer E Mahmoud
- Biochemistry Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, 33 El Bohouth St., Dokki, Giza, P.O. Box 12622, Egypt
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26
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Wang Y, Xu S, Wang Y, Qi G, Hou Y, Sun C, Wu X. Identification and potential value of candidate microRNAs in granulosa cells of polycystic ovary syndrome. Technol Health Care 2020; 27:579-587. [PMID: 30932905 DOI: 10.3233/thc-181510] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Polycystic Ovary Syndrome (PCOS) is a major cause of anovulatory infertility. Some studies showed that miRNAs were used as diagnostic/prognostic biomarkers for various diseases. OBJECTIVE To identify candidate miRNAs in Granulosa Cells (GCs) of PCOS and evaluate their potential values for PCOS diagnosis. METHODS We screened differentially expressed miRNAs in GCs between PCOS and controls by the microarray data from the GEO database. GCs were collected from 21 controls and 24 PCOS. The candidate miRNAs were verified by qRT-PCR. The correlation was investigated between candidate miRNAs and clinical characteristics in participants. Diagnostic value of candidate miRNAs was analyzed by receiver operating characteristic (ROC) curve. RESULTS Seven miRNAs were differentially expressed in PCOS compared with controls. Furthermore, the validation results demonstrated that hsa-miR-3188 and hsa-miR-3135b showed higher levels in GCs with PCOS patients (p< 0.05). In addition, the expressions of hsa-miR-3188 and hsa-miR-3135b were negative correlated with FSH and hsa-miR-3188 was positive correlated with BMI (p< 0.05). ROC analysis indicated that hsa-miR-3188 and hsa-miR-3135b could differentiate PCOS from controls, and the hsa-miR-3188/3135b improved the predictive accuracy for PCOS. CONCLUSIONS The expressions of hsa-miR-3188 and hsa-miR-3135b in human GCs were significantly associated with PCOS. Moreover, the hsa-miR-3188/3135b has certain diagnostic value for distinguishing PCOS.
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Affiliation(s)
- Yaoqin Wang
- Center of Reproductive Medicine, Children's Hospital of Shanxi and Women Health Center of Shanxi, Taiyuan, Shanxi 030013, China
| | - Suming Xu
- Center of Reproductive Medicine, Children's Hospital of Shanxi and Women Health Center of Shanxi, Taiyuan, Shanxi 030013, China
| | - Yonglian Wang
- Center of Reproductive Medicine, Children's Hospital of Shanxi and Women Health Center of Shanxi, Taiyuan, Shanxi 030013, China
| | - Gaimei Qi
- Center of Reproductive Medicine, Children's Hospital of Shanxi and Women Health Center of Shanxi, Taiyuan, Shanxi 030013, China
| | - Yan Hou
- Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Chunqing Sun
- Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Xueqing Wu
- Center of Reproductive Medicine, Children's Hospital of Shanxi and Women Health Center of Shanxi, Taiyuan, Shanxi 030013, China
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27
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microRNAs in the Antitumor Immune Response and in Bone Metastasis of Breast Cancer: From Biological Mechanisms to Therapeutics. Int J Mol Sci 2020; 21:ijms21082805. [PMID: 32316552 PMCID: PMC7216039 DOI: 10.3390/ijms21082805] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/03/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022] Open
Abstract
Breast cancer is the most common type of cancer in women, and the occurrence of metastasis drastically worsens the prognosis and reduces overall survival. Understanding the biological mechanisms that regulate the transformation of malignant cells, the consequent metastatic transformation, and the immune surveillance in the tumor progression would contribute to the development of more effective and targeted treatments. In this context, microRNAs (miRNAs) have proven to be key regulators of the tumor-immune cells crosstalk for the hijack of the immunosurveillance to promote tumor cells immune escape and cancer progression, as well as modulators of the metastasis formation process, ranging from the preparation of the metastatic site to the transformation into the migrating phenotype of tumor cells. In particular, their deregulated expression has been linked to the aberrant expression of oncogenes and tumor suppressor genes to promote tumorigenesis. This review aims at summarizing the role and functions of miRNAs involved in antitumor immune response and in the metastasis formation process in breast cancer. Additionally, miRNAs are promising targets for gene therapy as their modulation has the potential to support or inhibit specific mechanisms to negatively affect tumorigenesis. With this perspective, the most recent strategies developed for miRNA-based therapeutics are illustrated.
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Pakizehkar S, Ranji N, Naderi Sohi A, Sadeghizadeh M. Curcumin loaded PEG
400
‐OA nanoparticles: A suitable system to increase apoptosis, decrease migration, and deregulate miR‐125b/miR182 in MDA‐MB‐231 human breast cancer cells. POLYM ADVAN TECHNOL 2020. [DOI: 10.1002/pat.4906] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Safura Pakizehkar
- Department of Biology, Faculty of Sciences, Rasht BranchIslamic Azad University Rasht Iran
| | - Najmeh Ranji
- Department of Biology, Faculty of Sciences, Rasht BranchIslamic Azad University Rasht Iran
| | - Alireza Naderi Sohi
- Department of Nanotechnology and Tissue Engineering, Stem Cell Technology Research Center Tehran Iran
| | - Majid Sadeghizadeh
- Department of GeneticsSchool of Biological Sciences, Tarbiat Modares University Tehran Iran
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29
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Mercurio S, Cauteruccio S, Manenti R, Candiani S, Scarì G, Licandro E, Pennati R. Exploring miR-9 Involvement in Ciona intestinalis Neural Development Using Peptide Nucleic Acids. Int J Mol Sci 2020; 21:ijms21062001. [PMID: 32183450 PMCID: PMC7139483 DOI: 10.3390/ijms21062001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/12/2020] [Accepted: 03/13/2020] [Indexed: 12/16/2022] Open
Abstract
The microRNAs are small RNAs that regulate gene expression at the post-transcriptional level and can be involved in the onset of neurodegenerative diseases and cancer. They are emerging as possible targets for antisense-based therapy, even though the in vivo stability of miRNA analogues is still questioned. We tested the ability of peptide nucleic acids, a novel class of nucleic acid mimics, to downregulate miR-9 in vivo in an invertebrate model organism, the ascidian Ciona intestinalis, by microinjection of antisense molecules in the eggs. It is known that miR-9 is a well-conserved microRNA in bilaterians and we found that it is expressed in epidermal sensory neurons of the tail in the larva of C. intestinalis. Larvae developed from injected eggs showed a reduced differentiation of tail neurons, confirming the possibility to use peptide nucleic acid PNA to downregulate miRNA in a whole organism. By identifying putative targets of miR-9, we discuss the role of this miRNA in the development of the peripheral nervous system of ascidians.
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Affiliation(s)
- Silvia Mercurio
- Department of Environmental Science and Policy, Università degli Studi di Milano, 20133 Milano, Italy; (S.M.); (R.M.); (R.P.)
| | - Silvia Cauteruccio
- Department of Chemistry, Università degli Studi di Milano, 20133 Milano, Italy;
- Correspondence: (S.C.); (S.C.); Tel.: +39-0250314147 (S.C.); +39-0103538051 (S.C.)
| | - Raoul Manenti
- Department of Environmental Science and Policy, Università degli Studi di Milano, 20133 Milano, Italy; (S.M.); (R.M.); (R.P.)
| | - Simona Candiani
- Department of Earth Science, Environment and Life, Università degli Studi di Genova, 16132 Genova, Italy
- Correspondence: (S.C.); (S.C.); Tel.: +39-0250314147 (S.C.); +39-0103538051 (S.C.)
| | - Giorgio Scarì
- Department of Biosciences, Università degli Studi di Milano, 20133 Milano, Italy;
| | - Emanuela Licandro
- Department of Chemistry, Università degli Studi di Milano, 20133 Milano, Italy;
| | - Roberta Pennati
- Department of Environmental Science and Policy, Università degli Studi di Milano, 20133 Milano, Italy; (S.M.); (R.M.); (R.P.)
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30
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Model-Based Integration Analysis Revealed Presence of Novel Prognostic miRNA Targets and Important Cancer Driver Genes in Triple-Negative Breast Cancers. Cancers (Basel) 2020; 12:cancers12030632. [PMID: 32182819 PMCID: PMC7139587 DOI: 10.3390/cancers12030632] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/21/2020] [Accepted: 03/05/2020] [Indexed: 12/24/2022] Open
Abstract
Background: miRNAs (microRNAs) play a key role in triple-negative breast cancer (TNBC) progression, and its heterogeneity at the expression, pathological and clinical levels. Stratification of breast cancer subtypes on the basis of genomics and transcriptomics profiling, along with the known biomarkers’ receptor status, has revealed the existence of subgroups known to have diverse clinical outcomes. Recently, several studies have analysed expression profiles of matched mRNA and miRNA to investigate the underlying heterogeneity of TNBC and the potential role of miRNA as a biomarker within cancers. However, the miRNA-mRNA regulatory network within TNBC has yet to be understood. Results and Findings: We performed model-based integrated analysis of miRNA and mRNA expression profiles on breast cancer, primarily focusing on triple-negative, to identify subtype-specific signatures involved in oncogenic pathways and their potential role in patient survival outcome. Using univariate and multivariate Cox analysis, we identified 25 unique miRNAs associated with the prognosis of overall survival (OS) and distant metastases-free survival (DMFS) with “risky” and “protective” outcomes. The association of these prognostic miRNAs with subtype-specific mRNA genes was established to investigate their potential regulatory role in the canonical pathways using anti-correlation analysis. The analysis showed that miRNAs contribute to the positive regulation of known breast cancer driver genes as well as the activation of respective oncogenic pathway during disease formation. Further analysis on the “risk associated” miRNAs group revealed significant regulation of critical pathways such as cell growth, voltage-gated ion channel function, ion transport and cell-to-cell signalling. Conclusion: The study findings provide new insights into the potential role of miRNAs in TNBC disease progression through the activation of key oncogenic pathways. The results showed previously unreported subtype-specific prognostic miRNAs associated with clinical outcome that may be used for further clinical evaluation.
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Yu K, Rohr J, Liu Y, Li M, Xu J, Wang K, Chai J, Zhao D, Liu Y, Ma J, Fan L, Wang Z, Guo S. Progress in triple negative breast carcinoma pathophysiology: Potential therapeutic targets. Pathol Res Pract 2020; 216:152874. [PMID: 32088086 DOI: 10.1016/j.prp.2020.152874] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 01/17/2020] [Accepted: 02/11/2020] [Indexed: 12/17/2022]
Abstract
Triple-negative breast carcinoma (TNBC) is a subtype of breast carcinoma defined by negativity for estrogen receptor (ER) or progesterone receptor (PR) by immunohistochemical analysis and negativity for human epidermal growth factor receptor (Her2) by immunohistochemistry or in situ hybridization. TNBC is clinically marked by its high aggressiveness, particularly poor outcomes including a low survival rate, and the lack of specific and effective treatments. Therefore, new potential targets for the treatment of TNBC must be identified. This review summarizes recent evidence supporting novel targets and possible therapeutic regimens in the treatment of TNBC.
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Affiliation(s)
- Kangjie Yu
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Joseph Rohr
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Yang Liu
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Mingyang Li
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Junpeng Xu
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Kaijing Wang
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Jia Chai
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Danhui Zhao
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Yixiong Liu
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Jing Ma
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Linni Fan
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China
| | - Zhe Wang
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China.
| | - Shuangping Guo
- State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China.
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32
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Mercurio S, Cauteruccio S, Manenti R, Candiani S, Scarì G, Licandro E, Pennati R. miR-7 Knockdown by Peptide Nucleic Acids in the Ascidian Ciona intestinalis. Int J Mol Sci 2019; 20:ijms20205127. [PMID: 31623150 PMCID: PMC6829576 DOI: 10.3390/ijms20205127] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 10/10/2019] [Accepted: 10/14/2019] [Indexed: 12/12/2022] Open
Abstract
Peptide Nucleic Acids (PNAs) are synthetic mimics of natural oligonucleotides, which bind complementary DNA/RNA strands with high sequence specificity. They display numerous advantages, but in vivo applications are still rare. One of the main drawbacks of PNAs application is the poor cellular uptake that could be overcome by using experimental models, in which microinjection techniques allow direct delivery of molecules into eggs. Thus, in this communication, we investigated PNAs efficiency in miR-7 downregulation and compared its effects with those obtained with the commercially available antisense molecule, Antagomir (Dharmacon) in the ascidian Ciona intestinalis. Ascidians are marine invertebrates closely related to vertebrates, in which PNA techniques have not been applied yet. Our results suggested that anti-miR-7 PNAs were able to reach their specific targets in the developing ascidian embryos with high efficiency, as the same effects were obtained with both PNA and Antagomir. To the best of our knowledge, this is the first evidence that unmodified PNAs can be applied in in vivo knockdown strategies when directly injected into eggs.
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Affiliation(s)
- Silvia Mercurio
- Department of Environmental Science and Policy, Università degli Studi di Milano, 20133 Milano, Italy.
| | - Silvia Cauteruccio
- Department of Chemistry, Università degli Studi di Milano, 20133 Milano, Italy.
| | - Raoul Manenti
- Department of Environmental Science and Policy, Università degli Studi di Milano, 20133 Milano, Italy.
| | - Simona Candiani
- Department of Earth Science, Environment and Life, Università degli Studi di Genova, 16126 Genova, Italy.
| | - Giorgio Scarì
- Department of Biosciences, Università degli Studi di Milano, 20133 Milano, Italy.
| | - Emanuela Licandro
- Department of Chemistry, Università degli Studi di Milano, 20133 Milano, Italy.
| | - Roberta Pennati
- Department of Environmental Science and Policy, Università degli Studi di Milano, 20133 Milano, Italy.
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Gasparello J, Papi C, Zurlo M, Corradini R, Gambari R, Finotti A. Demonstrating specificity of bioactive peptide nucleic acids (PNAs) targeting microRNAs for practical laboratory classes of applied biochemistry and pharmacology. PLoS One 2019; 14:e0221923. [PMID: 31509554 PMCID: PMC6738603 DOI: 10.1371/journal.pone.0221923] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 08/19/2019] [Indexed: 12/26/2022] Open
Abstract
Practical laboratory classes teaching molecular pharmacology approaches employed in the development of therapeutic strategies are of great interest for students of courses in Biotechnology, Applied Biology, Pharmaceutic and Technology Chemistry, Translational Oncology. Unfortunately, in most cases the technology to be transferred to learning students is complex and requires multi-step approaches. In this respect, simple and straightforward experimental protocols might be of great interest. This study was aimed at presenting a laboratory exercise focusing (a) on a very challenging therapeutic strategy, i.e. microRNA therapeutics, and (b) on the employment of biomolecules of great interest in applied biology and pharmacology, i.e. peptide nucleic acids (PNAs). The aims of the practical laboratory were to determine: (a) the possible PNA-mediated arrest in RT-qPCR, to be eventually used to demonstrate PNA targeting of selected miRNAs; (b) the possible lack of activity on mutated PNA sequences; (c) the effects (if any) on the amplification of other unrelated miRNA sequences. The results which can be obtained support the following conclusions: PNA-mediated arrest in RT-qPCR can be analyzed in a easy way; mutated PNA sequences are completely inactive; the effects of the employed PNAs are specific and no inhibitory effect occurs on other unrelated miRNA sequences. This activity is simple (cell culture, RNA extraction, RT-qPCR are all well-established technologies), fast (starting from isolated and characterized RNA, few hours are just necessary), highly reproducible (therefore easily employed by even untrained students). On the other hand, these laboratory lessons require some facilities, the most critical being the availability of instruments for PCR. While this might be a problem in the case these instruments are not available, we would like to underline that determination of the presence or of a lack of amplified product can be also obtained using standard analytical approaches based on agarose gel electrophoresis.
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Affiliation(s)
- Jessica Gasparello
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Chiara Papi
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Matteo Zurlo
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Roberto Corradini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
| | - Roberto Gambari
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
- Interuniversity Consortium for Biotechnology (CIB), Trieste, Italy
- * E-mail:
| | - Alessia Finotti
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
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Kim DH, Khan H, Ullah H, Hassan STS, Šmejkal K, Efferth T, Mahomoodally MF, Xu S, Habtemariam S, Filosa R, Lagoa R, Rengasamy KR. MicroRNA targeting by quercetin in cancer treatment and chemoprotection. Pharmacol Res 2019; 147:104346. [PMID: 31295570 DOI: 10.1016/j.phrs.2019.104346] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/05/2019] [Accepted: 07/05/2019] [Indexed: 02/08/2023]
Abstract
A growing number of evidences from clinical and preclinical studies have shown that dysregulation of microRNA (miRNA) function contributes to the progression of cancer and thus miRNA can be an effective target in therapy. Dietary phytochemicals, such as quercetin, are natural products that have potential anti-cancer properties due to their proven antioxidant, anti-inflammatory, and anti-proliferative effects. Available experimental studies indicate that quercetin could modulate multiple cancer-relevant miRNAs including let-7, miR-21, miR-146a and miR-155, thereby inhibiting cancer initiation and development. This paper reviews the data supporting the use of quercetin for miRNA-mediated chemopreventive and therapeutic strategies in various cancers, with the aim to comprehensively understand its health-promoting benefits and pharmacological potential. Integration of technology platforms for miRNAs biomarker and drug discovery is also presented.
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Affiliation(s)
- Doo Hwan Kim
- Department of Bioresources and Food Science, Konkuk University, Seoul, 05029, South Korea
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan.
| | - Hammad Ullah
- Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan
| | - Sherif T S Hassan
- Department of Natural Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého tř. 1946/1, 612 42, Brno, Czech Republic
| | - Karel Šmejkal
- Department of Natural Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého tř. 1946/1, 612 42, Brno, Czech Republic
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany
| | | | - Suowen Xu
- University of Rochester, Aab Cardiovascular Research Institute, Rochester, NY, 14623, USA
| | - Solomon Habtemariam
- Pharmacognosy Research Laboratories and Herbal Analysis Services UK, University of Greenwich, UK
| | - Rosanna Filosa
- Institute of Food Sciences, National Research Council, Roma str. 64, Avellino, 83100, Italy; Consorzio Sannio Tech, AMP Biotec, Appia Str, Apollosa, Benevento, 82030, Italy
| | - Ricardo Lagoa
- School of Technology and Management, Polytechnic Institute of Leiria, Portugal; UCIBIO-Faculty of Science and Technology, University NOVA of Lisbon, Portugal.
| | - Kannan Rr Rengasamy
- Department of Bioresources and Food Science, Konkuk University, Seoul, 05029, South Korea.
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Why the Gold Standard Approach by Mammography Demands Extension by Multiomics? Application of Liquid Biopsy miRNA Profiles to Breast Cancer Disease Management. Int J Mol Sci 2019; 20:ijms20122878. [PMID: 31200461 PMCID: PMC6627787 DOI: 10.3390/ijms20122878] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 06/07/2019] [Accepted: 06/11/2019] [Indexed: 02/06/2023] Open
Abstract
In the global context, the epidemic of breast cancer (BC) is evident for the early 21st century. Evidence shows that national mammography screening programs have sufficiently reduced BC related mortality. Therefore, the great utility of the mammography-based screening is not an issue. However, both false positive and false negative BC diagnosis, excessive biopsies, and irradiation linked to mammography application, as well as sub-optimal mammography-based screening, such as in the case of high-dense breast tissue in young females, altogether increase awareness among the experts regarding the limitations of mammography-based screening. Severe concerns regarding the mammography as the “golden standard” approach demanding complementary tools to cover the evident deficits led the authors to present innovative strategies, which would sufficiently improve the quality of the BC management and services to the patient. Contextually, this article provides insights into mammography deficits and current clinical data demonstrating the great potential of non-invasive diagnostic tools utilizing circulating miRNA profiles as an adjunct to conventional mammography for the population screening and personalization of BC management.
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Milani R, Brognara E, Fabbri E, Manicardi A, Corradini R, Finotti A, Gasparello J, Borgatti M, Cosenza LC, Lampronti I, Dechecchi MC, Cabrini G, Gambari R. Targeting miR‑155‑5p and miR‑221‑3p by peptide nucleic acids induces caspase‑3 activation and apoptosis in temozolomide‑resistant T98G glioma cells. Int J Oncol 2019; 55:59-68. [PMID: 31180529 PMCID: PMC6561624 DOI: 10.3892/ijo.2019.4810] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 03/26/2019] [Indexed: 12/11/2022] Open
Abstract
The present study investigated the effects of the combined treatment of two peptide nucleic acids (PNAs), directed against microRNAs involved in caspase‑3 mRNA regulation (miR‑155‑5p and miR‑221‑3p) in the temozolomide (TMZ)‑resistant T98G glioma cell line. These PNAs were conjugated with an octaarginine tail in order to obtain an efficient delivery to treated cells. The effects of singularly administered PNAs or a combined treatment with both PNAs were examined on apoptosis, with the aim to determine whether reversion of the drug‑resistance phenotype was obtained. Specificity of the PNA‑mediated effects was analyzed by reverse transcription‑quantitative polymerase‑chain reaction, which demonstrated that the effects of R8‑PNA‑a155 and R8-PNA-a221 anti‑miR PNAs were specific. Furthermore, the results obtained confirmed that both PNAs induced apoptosis when used on the temozolomide‑resistant T98G glioma cell line. Notably, co‑administration of both anti‑miR‑155 and anti‑miR‑221 PNAs was associated with an increased proapoptotic activity. In addition, TMZ further increased the induction of apoptosis in T98G cells co‑treated with anti‑miR‑155 and anti‑miR‑221 PNAs.
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Affiliation(s)
- Roberta Milani
- Department of Life Sciences and Biotechnology, University of Ferrara, I‑144121 Ferrara, Italy
| | - Eleonora Brognara
- Department of Life Sciences and Biotechnology, University of Ferrara, I‑144121 Ferrara, Italy
| | - Enrica Fabbri
- Department of Life Sciences and Biotechnology, University of Ferrara, I‑144121 Ferrara, Italy
| | - Alex Manicardi
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, I‑143214 Parma, Italy
| | - Roberto Corradini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, I‑143214 Parma, Italy
| | - Alessia Finotti
- Department of Life Sciences and Biotechnology, University of Ferrara, I‑144121 Ferrara, Italy
| | - Jessica Gasparello
- Department of Life Sciences and Biotechnology, University of Ferrara, I‑144121 Ferrara, Italy
| | - Monica Borgatti
- Department of Life Sciences and Biotechnology, University of Ferrara, I‑144121 Ferrara, Italy
| | - Lucia Carmela Cosenza
- Department of Life Sciences and Biotechnology, University of Ferrara, I‑144121 Ferrara, Italy
| | - Ilaria Lampronti
- Department of Life Sciences and Biotechnology, University of Ferrara, I‑144121 Ferrara, Italy
| | | | - Giulio Cabrini
- Laboratory of Molecular Pathology, University‑Hospital of Verona, I‑37126 Verona, Italy
| | - Roberto Gambari
- Department of Life Sciences and Biotechnology, University of Ferrara, I‑144121 Ferrara, Italy
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Gamba CDO, Damasceno KA, Ferreira IC, Rodrigues MA, Gomes DA, Alves MR, Rocha RM, Lima AE, Ferreira E, Cassali GD. The investigation of transcriptional repression mediated by ZEB2 in canine invasive micropapillary carcinoma in mammary gland. PLoS One 2019; 14:e0209497. [PMID: 30645591 PMCID: PMC6333364 DOI: 10.1371/journal.pone.0209497] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 12/06/2018] [Indexed: 02/07/2023] Open
Abstract
The E-cadherin loss has frequently been associated with transcriptional repression mediated by transcription factors, such as the Zinc Finger E-Box Binding Homeobox-2 (ZEB2). Invasive micropapillary carcinomas (IMPCs) of the breast are aggressive neoplasms frequently related to lymph node metastasis and poor overall survival. In the canine mammary gland, IMPCs has just been reported and, based on its behavioral similarity with the human IMPCs, appears to be a good spontaneous model to this human entity. This study aimed to evaluate the relationship between E-cadherin and ZEB2 in a spontaneous canine model of invasive micropapillary carcinoma of the mammary gland. The correlation among gene expression (ZEB2 and CDH1) and clinicopathological findings was also explored. Nineteen cases of IMPC of the canine mammary gland were obtained, protein and mRNA expression were investigated through immunohistochemistry and RNA In Situ Hybridization, respectively. To better understand the relationship between E-cadherin and ZEB2, immunofluorescence was performed in canine IMPCs. Immunohistochemically, most of IMPCs showed 1+ (14/19, 73.7%) for E-cadherin; and positivity for ZEB2 was diagnosed in 47.4% of the IMPCs. Regarding the RNA In Situ Hybridization (ISH), most of IMPCs showed 4+ and 0+ for E-cadherin (CDH1) and ZEB2 respectively. Through immunofluorescence, the first and second more frequent combinatorial group were E-cadherin+ZEB2- and E-cadherin+ZEB2+; neoplastic cells showing concomitantly weak expression for E-cadherin and positivity for ZEB2 were frequently observed. A negative correlation was observed between E-cadherin and progesterone receptor expression in IMPCs. Based on these results, canine mammary IMPCs show E-cadherin lost and, at times reveals nuclear positivity for the transcription factor ZEB2 that seems to exert transcriptional repression of the CDH1.
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Affiliation(s)
- Conrado de Oliveira Gamba
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.,Curso de Medicina Veterinária, Universidade do Oeste de Santa Catarina, Campus aproximado de Campos Novos, Campos Novos, Santa Catarina, Brazil
| | - Karine Araújo Damasceno
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.,Laboratório de Patologia Experimental, Instituto Gonçalo Moniz, Fiocruz, Salvador, Bahia, Brazil
| | - Izabel Cristina Ferreira
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Michele Angela Rodrigues
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Dawidson Assis Gomes
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Mariana Resende Alves
- International Center of Research in Cancer (CIPE), A.C. Camargo Cancer Center, São Paulo, São Paulo, Brazil
| | - Rafael Malagoli Rocha
- International Center of Research in Cancer (CIPE), A.C. Camargo Cancer Center, São Paulo, São Paulo, Brazil
| | - Alessandra Estrela Lima
- Departamento de Patologia e Clínicas, Escola de Medicina Veterinária, Universidade Federal da Bahia, Salvador, Bahia, Brazil
| | - Enio Ferreira
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Geovanni Dantas Cassali
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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38
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Li D, Tian B, Jin X. [ARTICLE WITHDRAWN] miR-630 Inhibits Epithelial-to-Mesenchymal Transition (EMT) by Regulating the Wnt/β-Catenin Pathway in Gastric Cancer Cells. Oncol Res 2018; 27:9-17. [PMID: 29422112 PMCID: PMC7848419 DOI: 10.3727/096504018x15178732625479] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
THIS ARTICLE WAS WITHDRAWN BY THE PUBLISHERS IN NOVEMBER 2020.
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Affiliation(s)
- Dong Li
- *Medical Care Branch of Panjin Vocational and Technical College, Panjin, P.R. China
| | - Bo Tian
- †Department of Surgical Oncology, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, P.R. China
| | - Xiaosheng Jin
- ‡Department of Gastroenterology, Ruian People’s Hospital, Ruian, P.R. China
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Vahidian F, Mohammadi H, Ali-Hasanzadeh M, Derakhshani A, Mostaan M, Hemmatzadeh M, Baradaran B. MicroRNAs and breast cancer stem cells: Potential role in breast cancer therapy. J Cell Physiol 2018; 234:3294-3306. [PMID: 30362508 DOI: 10.1002/jcp.27246] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Accepted: 07/24/2018] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs) can control cancer and cancer stem cells (CSCs), and this topic has drawn immense attention recently. Stem cells are a tiny population of a bulk of tumor cells that have enormous potential in expansion and metastasis of the tumor. miRNA have a crucial role in the management of the function of stem cells. This role is to either promote or suppress the tumor. In this review, we investigated the function and different characteristics of CSCs and function of the miRNAs that are related to them. We also demonstrated the role and efficacy of these miRNAs in breast cancer and breast cancer stem cells (BCSC). Eventually, we revealed the metastasis, tumor formation, and their role in the apoptosis process. Also, the therapeutic potential of miRNA as an effective method for the treatment of BCSC was described. Extensive research is required to investigate the employment or suppression of these miRNAs for therapeutics approached in different cancers in the future.
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Affiliation(s)
- Fatemeh Vahidian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Ali-Hasanzadeh
- Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Afshin Derakhshani
- Department of Immunology, Birjand University of Medical Sciences, Birjand, Iran.,Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Masoud Mostaan
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Islamic Azad university, Tabriz, Iran
| | - Maryam Hemmatzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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40
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Finotti A, Allegretti M, Gasparello J, Giacomini P, Spandidos DA, Spoto G, Gambari R. Liquid biopsy and PCR-free ultrasensitive detection systems in oncology (Review). Int J Oncol 2018; 53:1395-1434. [PMID: 30085333 PMCID: PMC6086621 DOI: 10.3892/ijo.2018.4516] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 07/31/2018] [Indexed: 02/07/2023] Open
Abstract
In oncology, liquid biopsy is used in the detection of next-generation analytes, such as tumor cells, cell-free nucleic acids and exosomes in peripheral blood and other body fluids from cancer patients. It is considered one of the most advanced non-invasive diagnostic systems to enable clinically relevant actions and implement precision medicine. Medical actions include, but are not limited to, early diagnosis, staging, prognosis, anticipation (lead time) and the prediction of therapy responses, as well as follow-up. Historically, the applications of liquid biopsy in cancer have focused on circulating tumor cells (CTCs). More recently, this analysis has been extended to circulating free DNA (cfDNA) and microRNAs (miRNAs or miRs) associated with cancer, with potential applications for development into multi-marker diagnostic, prognostic and therapeutic signatures. Liquid biopsies avoid some key limitations of conventional tumor tissue biopsies, including invasive tumor sampling, under-representation of tumor heterogeneity and poor description of clonal evolution during metastatic dissemination, strongly reducing the need for multiple sampling. On the other hand, this approach suffers from important drawbacks, i.e., the fragmentation of cfDNA, the instability of RNA, the low concentrations of certain analytes in body fluids and the confounding presence of normal, as well as aberrant DNAs and RNAs. For these reasons, the analysis of cfDNA has been mostly focused on mutations arising in, and pathognomonicity of, tumor DNA, while the analysis of cfRNA has been mostly focused on miRNA patterns strongly associated with neoplastic transformation/progression. This review lists some major applicative areas, briefly addresses how technology is bypassing liquid biopsy limitations, and places a particular emphasis on novel, PCR-free platforms. The ongoing collaborative efforts of major international consortia are reviewed. In addition to basic and applied research, we will consider technological transfer, including patents, patent applications and available information on clinical trials aimed at verifying the potential of liquid biopsy in cancer.
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Affiliation(s)
- Alessia Finotti
- Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy
| | - Matteo Allegretti
- Oncogenomics and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Jessica Gasparello
- Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy
| | - Patrizio Giacomini
- Oncogenomics and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Crete, Greece
| | - Giuseppe Spoto
- Department of Chemistry, Catania University, 95125 Catania, Italy
| | - Roberto Gambari
- Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy
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41
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Guo D, Guo J, Li X, Guan F. Enhanced motility and proliferation by miR-10b/FUT8/p-AKT axis in breast cancer cells. Oncol Lett 2018; 16:2097-2104. [PMID: 30008906 PMCID: PMC6036446 DOI: 10.3892/ol.2018.8891] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 11/07/2017] [Indexed: 12/30/2022] Open
Abstract
Upregulation of microRNA (miR)-10b has been confirmed in multiple types of cancer, however, the role of miR-10b in glycosylation remains unclear. Protein core-fucosylation is an important N-linked glycosylation modification and serves important roles in cancer progression. In a previous study, a glycogene array was applied to profile the alterations of glycogene expression in miR-10b-overexpressed MCF10A cells. Notably, fucosyltranferase 8 (FUT8), which is responsible for the addition of core-fucose to N-glycan, was significantly upregulated by miR-10b. In the present study, increased motility and proliferation were observed in miR-10b-overexpressed MCF10A cells. To assess the mechanism involved, the role of FUT8 in MCF10A cells was studied and it was confirmed that miR-10b promotes motility and proliferation by regulating FUT8 and activating the protein kinase B (AKT) signaling pathway. Consistent with the aforementioned result, decreased motility and proliferation were detected when miR-10b expression was inhibited in MDA-MB-231 cells, transforming growth factor-β-induced and Twist-overexpressed MCF10A cells. To conclude, the findings from the present study indicate that miR-10b promotes motility and proliferation by increasing FUT8 and activating AKT in breast cancer cells.
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Affiliation(s)
- Dong Guo
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Jia Guo
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Xiang Li
- Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Feng Guan
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
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42
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Swellam M, El Magdoub HM, Hassan NM, Hefny MM, Sobeih ME. Potential diagnostic role of circulating MiRNAs in breast cancer: Implications on clinicopathological characters. Clin Biochem 2018; 56:47-54. [PMID: 29679553 DOI: 10.1016/j.clinbiochem.2018.04.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 04/09/2018] [Accepted: 04/16/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Circulating miRNAs are stable in body fluids and resembles their levels in cancer tissue/cells. They have been expressed in many cancers among them is breast cancer. Authors aimed to investigate the expression levels of three circulating oncomiRNAs (miRNA-21, miRNA-222 and miRNA-373) in serum samples as a minimally non-invasive method for early detection of breast cancer, and study their relation with clinicopathological characters. METHODS MiRNAs expression levels were determined using quantitative real-time polymerase chain reaction (qPCR) in serum samples from three groups: primary breast cancer patients (n = 137), benign breast lesion patients (n = 60), and healthy individuals as control group (n = 38). Statistical analyses were carried out using SPSS. RESULTS Significant differences were observed between the expression levels of the studied miRNAs in the investigated groups, as their median levels were increased in breast cancer patients followed by benign group patients then the healthy individuals. MiRNA-373 reported the highest diagnostic efficacy as compared to miRNA-21 and miRNA-222 with high area under the curve (AUC equals 0.987). The relation between tested miRNAs and clinicopathological factors revealed significant difference with clinical stages and histological grades. Level of miRNA-21 and miRNA-373 were statistically significantly higher in invasive duct carcinoma (IDC) as compared to non-IDC. Similarly, their levels were increased in lymph node metastasis (P < 0.01). MiRNA-222 and miRNA-373 were significantly increased in positive PgR and positive Her-2/neu status, respectively. CONCLUSION Assessment of miRNAs in serum samples can be applied as minimally non-invasive markers for early detection of breast cancer, and as discriminator between different clinicopathological characters.
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MESH Headings
- Adult
- Aged
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/metabolism
- Breast/metabolism
- Breast/pathology
- Breast Neoplasms/blood
- Breast Neoplasms/diagnosis
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/diagnosis
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/secondary
- Diagnosis, Differential
- Early Diagnosis
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Lymphatic Metastasis/diagnosis
- Lymphatic Metastasis/pathology
- MicroRNAs/blood
- MicroRNAs/metabolism
- Middle Aged
- Neoplasm Grading
- Neoplasm Staging
- RNA, Neoplasm/blood
- RNA, Neoplasm/metabolism
- Up-Regulation
- Young Adult
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Affiliation(s)
- Menha Swellam
- Biochemistry Department, Genetic Engineering and Biotechnology Research Division, High Throughput Molecular and Genetic Laboratory, Center for Excellences for Advanced Sciences, National Research Centre, Dokki, Giza, Egypt.
| | - Hekmat M El Magdoub
- Biochemistry Department, Faculty of Pharmacy, Misr International University, Cairo, Egypt
| | - Naglaa M Hassan
- Clinical Pathology Department, National Cancer Institute, Cairo, Egypt
| | - Mona M Hefny
- Medical Biochemistry Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Sahabi K, Selvarajah GT, Abdullah R, Cheah YK, Tan GC. Comparative aspects of microRNA expression in canine and human cancers. J Vet Sci 2018; 19:162-171. [PMID: 28927253 PMCID: PMC5879064 DOI: 10.4142/jvs.2018.19.2.162] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 05/19/2017] [Accepted: 07/14/2017] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) have important roles in all biological pathways in multicellular organisms. Over 1,400 human miRNAs have been identified, and many are conserved among vertebrates and invertebrates. Regulation of miRNA is the most common mode of post-transcriptional gene regulation. The miRNAs that are involved in the initiation and progression of cancers are termed oncomiRs and several of them have been identified in canine and human cancers. Similarly, several miRNAs have been reported to be down-regulated in cancers of the two species. In this review, current information on the expression and roles of miRNAs in oncogenesis and progression of human and canine cancers, as well the roles miRNAs have in cancer stem cell biology, are highlighted. The potential for the use of miRNAs as therapeutic targets in personalized cancer therapy in domestic dogs and their possible application in human cancer counterparts are also discussed.
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Affiliation(s)
- Kabiru Sahabi
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Malaysia
| | - Gayathri T Selvarajah
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Malaysia
| | - Rasedee Abdullah
- Department of Veterinary Laboratory Diagnostics, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Malaysia
| | - Yoke Kqueen Cheah
- Department of Biomedical Sciences, Faculty of Medicine and Biomedical Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia
| | - Geok Chin Tan
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
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Abstract
Single microRNA (miRNA) can be inhibited using antagomiR which efficiently knockdown a specific miRNA. However, the effect is transient and often results in subtle phenotype. Here we report a guideline on designing miRNA sponge inhibiting a miRNA family. As a model system, we targeted miR-30 family, known as tumor suppressor miRNAs in multiple tumors. To achieve an efficient knockdown, we generated perfect and bulged-matched miRNA binding sites (MBS) and introduced multiple copies of MBS. The protocol here demonstrates the miRNA sponge as a useful tool to examine the functional impact of inhibition miRNAs.
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45
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Wang G, Fang X, Han M, Wang X, Huang Q. MicroRNA-493-5p promotes apoptosis and suppresses proliferation and invasion in liver cancer cells by targeting VAMP2. Int J Mol Med 2018; 41:1740-1748. [PMID: 29328362 DOI: 10.3892/ijmm.2018.3358] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 12/15/2017] [Indexed: 11/05/2022] Open
Abstract
The aim of the present study was to explore the role of miR‑493-5p in liver cancer tissues and cell lines, and its effect on cell behavioral characteristics. The expression of miR-493-5p was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in liver cancer tissues and cell lines (hepatic cell line HL-7702 and the liver cancer cell lines HCCC-9810, HuH-7 and HepG2). In addition, the mechanism by which miR-493-5p mediates its effects was analyzed via the transfection of miR-493-5p mimic and negative control miRNA into HepG2 cells. The viability, proliferation, apoptosis and invasion of the cells were analyzed using MTT assay, flow cytometry and Transwell chamber experiments. Furthermore, the effect of miR-493-5p on the expression of vesicle associated membrane protein 2 (VAMP2) was assayed using a dual-luciferase reporter system, and VAMP2 protein levels were determined by western blot analysis. In addition, following the cotransfection of HepG2 cells with pcDNA3.1‑VAMP2 plasmid and miR‑493-5p mimic, the role of miR-493-5p as a regulator of VAMP2 was evaluated using MTT assay, flow cytometry and Transwell chamber experiments. RT-qPCR analysis indicated that the expression of miR-493-5p in liver cancer tissues and cell lines was decreased significantly compared with that in adjacent normal liver tissues and normal liver cell lines, respectively. Compared with the control group, the cells transfected with miR-493-5p mimic (the miR-493-5p overexpression group) exhibited reduced cell viability, a reduced percentage of cells in the S phase and an increased percentage of apoptotic cells. In addition, fewer cells passed through the Transwell membrane in the miR-493-5p overexpression group compared with the control group. In the dual-luciferase reporter assay, luciferase activity in the miR‑493-5p overexpression group was attenuated compared with that in the control group. In addition, western blot analysis indicated that the VAMP2 protein levels in the miR‑493-5p overexpression group were lower than those in the control group. Furthermore, in cells overexpressing miR-493-5p and VAMP2 simultaneously, the biological behavior of the cells, including cell viability, cell cycle and cell invasiveness, was significantly rescued compared with that of the control group transfected with miR‑493-5p alone. In conclusion, miR-493-5p is indicated to be a tumor suppressor gene, and is downregulated in human liver cancer. miR-493-5p overexpression promotes cell apoptosis and inhibits the proliferation and migration of liver cancer cells by negatively regulating the expression of VAMP. These observations suggest the potential of treating liver cancer by the overexpression of microRNA-493-5p.
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Affiliation(s)
- Guannan Wang
- Department of Pancreato-Biliary Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230001, P.R. China
| | - Xiaosan Fang
- Department of Hepatobiliary Surgery, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Meng Han
- Department of Hepatobiliary Surgery, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Qiang Huang
- Department of Pancreato-Biliary Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230001, P.R. China
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Uva P, Cossu-Rocca P, Loi F, Pira G, Murgia L, Orrù S, Floris M, Muroni MR, Sanges F, Carru C, Angius A, De Miglio MR. miRNA-135b Contributes to Triple Negative Breast Cancer Molecular Heterogeneity: Different Expression Profile in Basal-like Versus non-Basal-like Phenotypes. Int J Med Sci 2018; 15:536-548. [PMID: 29725243 PMCID: PMC5930454 DOI: 10.7150/ijms.23402] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 01/05/2018] [Indexed: 01/03/2023] Open
Abstract
The clinical and genetic heterogeneity of Triple Negative Breast Cancer (TNBC) and the lack of unambiguous molecular targets contribute to the inadequacy of current therapeutic options for these variants. MicroRNAs (miRNA) are a class of small highly conserved regulatory endogenous non-coding RNA, which can alter the expression of genes encoding proteins and may play a role in the dysregulation of cellular pathways. Our goal was to improve the knowledge of the molecular pathogenesis of TNBC subgroups analyzing the miRNA expression profile, and to identify new prognostic and predictive biomarkers. We conducted a human miRNome analysis by TaqMan Low Density Array comparing different TNBC subtypes, defined by immunohistochemical basal markers EGFR and CK5/6. RT-qPCR confirmed differential expression of microRNAs. To inspect the function of the selected targets we perform Gene Ontology and KEGG enrichment analysis. We identified a single miRNA signature given by miR-135b expression level, which was strictly related to TNBC with basal-like phenotype. miR-135b target analysis revealed a role in the TGF-beta, WNT and ERBB pathways. A significant positive correlation was identified between neoplastic proliferative index and miR-135b expression. These findings confirm the oncogenic roles of miR-135b in the pathogenesis of TNBC expressing basal markers. A potential negative prognostic role of miR-135b overexpression might be related to the positive correlation with high proliferative index. Our study implies potential clinical applications: miR-135b could be a potential therapeutic target in basal-like TNBCs.
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Affiliation(s)
- Paolo Uva
- CRS4, Science and Technology Park Polaris, Piscina Manna, 09010, Pula, Cagliari, Italy
| | - Paolo Cossu-Rocca
- Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 8, 07100, Sassari, Italy.,Department of Diagnostic Services, Pathology Unit, "Giovanni Paolo II" Hospital, ASSL Olbia - ATS Sardegna, Via Bazzoni-Sircana, 07026, Olbia, Italy
| | - Federica Loi
- Osservatorio Epidemiologico Veterinario Regionale, Via XX Settembre 9, OEVR, 09125, Cagliari, Italy
| | - Giovanna Pira
- Department of Biomedical Sciences, University of Sassari, 07100,Viale San Pietro 43b, Sassari, Italy
| | - Luciano Murgia
- Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 8, 07100, Sassari, Italy
| | - Sandra Orrù
- Department of Pathology, "A. Businco" Oncologic Hospital, ASL Cagliari, Via Jenner 1, 09121, Cagliari, Italy
| | - Matteo Floris
- CRS4, Science and Technology Park Polaris, Piscina Manna, 09010, Pula, Cagliari, Italy
| | - Maria Rosaria Muroni
- Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 8, 07100, Sassari, Italy
| | - Francesca Sanges
- Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 8, 07100, Sassari, Italy
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, 07100,Viale San Pietro 43b, Sassari, Italy
| | - Andrea Angius
- Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042, Monserrato (CA), Italy
| | - Maria Rosaria De Miglio
- Department of Clinical and Experimental Medicine, University of Sassari, Viale San Pietro 8, 07100, Sassari, Italy
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Search of MicroRNAs Regulating the Receptor Status of Breast Cancer In Silico and Experimental Confirmation of Their Expression in Tumors. Bull Exp Biol Med 2017; 163:655-659. [PMID: 28944429 DOI: 10.1007/s10517-017-3872-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Indexed: 12/18/2022]
Abstract
MicroRNA whose expression depends on the receptor status of breast cancer were selected using bioinformatic analysis. The expression of 9 microRNAs (16, 17, 21, 27, 125, 146, 155, 200a, and 221) was analyzed in 76 samples of breast cancer with various receptor phenotypes. The expression of microRNAs 155, 27, and 200a did not differ in various types of breast cancer. The data on positive correlation between the expression of microRNA-21 and microRNA-221 and negative receptor status of the tumor were confirmed. The expression of the tumor suppressing microRNA-125b decreased in samples of breast cancer expressing HER2 and ER and in triple negative breast cancer, which characterizes it as a universal marker of breast cancer. An increase in the expression of microRNA-16 was shown in samples of breast cancer expressing HER2 and ER. The expression of microRNA-17 decreased in triple negative breast cancer and increased in ER+, PR+, and HER+ types of breast cancer. MicroRNAs 16, 17, 21, 125b, 146b, and 221 can be promising markers for differential diagnostics of various phenotypes of breast cancer.
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Sorace AG, Harvey S, Syed A, Yankeelov TE. Imaging Considerations and Interprofessional Opportunities in the Care of Breast Cancer Patients in the Neoadjuvant Setting. Semin Oncol Nurs 2017; 33:425-439. [PMID: 28927763 DOI: 10.1016/j.soncn.2017.08.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To discuss standard-of-care and emerging imaging techniques employed for screening and detection, diagnosis and staging, monitoring response to therapy, and guiding cancer treatments. DATA SOURCES Published journal articles indexed in the National Library of Medicine database and relevant websites. CONCLUSION Imaging plays a fundamental role in the care of cancer patients and specifically, breast cancer patients in the neoadjuvant setting, providing an excellent opportunity for interprofessional collaboration between oncologists, researchers, radiologists, and oncology nurses. Quantitative imaging strategies to assess cellular, molecular, and vascular characteristics within the tumor is needed to better evaluate initial diagnosis and treatment response. IMPLICATIONS FOR NURSING PRACTICE Nurses caring for patients in all settings must continue to seek education on emerging imaging techniques. Oncology nurses provide education about the test, ensure the patient has appropriate pre-testing instructions, and manage patient expectations about timing of results availability.
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Zhou C, Zou QY, Li H, Wang RF, Liu AX, Magness RR, Zheng J. Preeclampsia Downregulates MicroRNAs in Fetal Endothelial Cells: Roles of miR-29a/c-3p in Endothelial Function. J Clin Endocrinol Metab 2017; 102:3470-3479. [PMID: 28911139 PMCID: PMC5587062 DOI: 10.1210/jc.2017-00849] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 06/27/2017] [Indexed: 12/23/2022]
Abstract
CONTEXT Preeclampsia is a leading cause of fetal and maternal morbidity and mortality during pregnancy. Although the etiology of preeclampsia is unknown, preeclampsia offspring have increased risks of developing cardiovascular disorders in adulthood, implicating that preeclampsia programs fetal vasculature in utero. OBJECTIVE We hypothesize that preeclampsia alters expression profiles of endothelial microRNAs (miRNAs) in fetal endothelial cells and disturbs the vascular endothelial growth factor A (VEGFA)- and fibroblast growth factor 2 (FGF2)-induced endothelial function. DESIGN AND SETTING Unpassaged (P0) human umbilical vein endothelial cells (HUVECs) were isolated immediately after cesarean-section delivery from normotensive (NT) and preeclamptic (PE) pregnancies. Differentially expressed miRNAs between P0-HUVECs from NT and PE pregnancies were identified using a miRNA polymerase chain reaction (PCR) array and confirmed using reverse transcription quantitative PCR. To determine the function of these differentially expressed miRNAs, miRNAs of interest were knocked down in NT-HUVECs following by cell functional assays. RESULTS Sixteen miRNAs, including miR-29a/c-3p, were downregulated in P0-HUVECs from the PE group compared with the NT group. Bioinformatics analysis predicted the PI3K-v-akt murine thymoma viral oncogene homolog 1 (AKT) signaling pathway was dysregulated in P0-HUVECs from the PE group, which was associated with the miR-29a/c-3p downregulation. We further demonstrated that miR-29a/c-3p knockdown inhibited the VEGFA- and FGF2-induced endothelial migration as well as FGF2-induced AKT1 phosphorylation in HUVECs. However, miR-29a/c-3p knockdown did not alter the extracellular signal-regulated kinase 1/2 phosphorylation, cell proliferation, and endothelial monolayer integrity in response to VEGFA and FGF2 in HUVECs. CONCLUSIONS Preeclampsia-downregulated miR-29a/c-3p may impair fetal endothelial function by disturbing the FGF2-activated PI3K-AKT signaling pathway, hence inhibiting endothelial cell migration.
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Affiliation(s)
- Chi Zhou
- Department of Obstetrics and Gynecology, University of Wisconsin–Madison, Madison, Wisconsin 53715
| | - Qing-yun Zou
- Department of Obstetrics and Gynecology, University of Wisconsin–Madison, Madison, Wisconsin 53715
| | - Hua Li
- Department of Obstetrics and Gynecology, University of Wisconsin–Madison, Madison, Wisconsin 53715
- Department of Rheumatology and Immunology, the Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong, China
| | - Rui-fang Wang
- Department of Obstetrics and Gynecology, University of Wisconsin–Madison, Madison, Wisconsin 53715
- 302 Military Hospital of China, Beijing 100039, China
| | - Ai-xia Liu
- Department of Obstetrics and Gynecology, University of Wisconsin–Madison, Madison, Wisconsin 53715
- Department of Reproductive Endocrinology, Zhejiang University, Hangzhou 310006, Zhejiang, China
| | - Ronald R. Magness
- Department of Obstetrics and Gynecology, University of Wisconsin–Madison, Madison, Wisconsin 53715
| | - Jing Zheng
- Department of Obstetrics and Gynecology, University of Wisconsin–Madison, Madison, Wisconsin 53715
- Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China
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Safarzadeh E, Orangi M, Mohammadi H, Babaie F, Baradaran B. Myeloid-derived suppressor cells: Important contributors to tumor progression and metastasis. J Cell Physiol 2017; 233:3024-3036. [DOI: 10.1002/jcp.26075] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 06/28/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Elham Safarzadeh
- Immunology Research Center; Tabriz University of Medical Sciences; Tabriz Iran
- Faculty of Medicine, Department of Immunology; Tabriz University of Medical Sciences; Tabriz Iran
| | - Mona Orangi
- Immunology Research Center; Tabriz University of Medical Sciences; Tabriz Iran
- Faculty of Medicine, Department of Immunology; Tabriz University of Medical Sciences; Tabriz Iran
| | - Hamed Mohammadi
- Immunology Research Center; Tabriz University of Medical Sciences; Tabriz Iran
- Faculty of Medicine, Department of Immunology; Tabriz University of Medical Sciences; Tabriz Iran
| | - Farhad Babaie
- Immunology Research Center; Tabriz University of Medical Sciences; Tabriz Iran
- Faculty of Medicine, Department of Immunology; Tabriz University of Medical Sciences; Tabriz Iran
| | - Behzad Baradaran
- Immunology Research Center; Tabriz University of Medical Sciences; Tabriz Iran
- Faculty of Medicine, Department of Immunology; Tabriz University of Medical Sciences; Tabriz Iran
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