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Rostom MM, Rashwan AA, Sotiropoulou CD, Hozayen SZ, Abdelhamid AM, Abdelhalim MM, Eltahtawy O, Emara HM, Elemam NM, Kontos CK, Youness RA. MIAT: A pivotal oncogenic long noncoding RNA tunning the hallmarks of solid malignancies. Transl Oncol 2025; 54:102329. [PMID: 40014977 PMCID: PMC11910686 DOI: 10.1016/j.tranon.2025.102329] [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: 10/22/2024] [Revised: 01/06/2025] [Accepted: 02/13/2025] [Indexed: 03/01/2025] Open
Abstract
Long non-coding RNAs (LncRNAs) have emerged as intriguing players in cellular regulation, challenging the traditional view of non-coding RNAs as mere "dark genome". Non-coding DNA makes up most of the human genome and plays a pivotal role in cancer development. These RNA molecules, which do not code for proteins, have captivated researchers with their diverse and crucial roles in gene regulation, chromatin dynamics, and other cellular processes. In several physiological and pathological circumstances, lncRNAs serve critical functions. This review will tackle the complex function of the lncRNA myocardial infarction-associated transcript (MIAT) in various solid malignancies. A special emphasis would be directed on the correlation between cancer patients' clinicopathological features and the expression profile of MIAT. MIAT is a oncogenic regulator in many malignant tumors, where it can control the growth, invasion, metastasis, and resistance to death of cells. As a result, MIAT is thought to be a possible biomarker and therapeutic target for cancer patients. The biological functions, mechanisms and potential clinical implications of MIAT during carcinogenesis and finally the current possible therapeutic approaches targeting MIAT are also outlined in this review.
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Affiliation(s)
- Monica M Rostom
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835, Cairo, Egypt
| | - Alaa A Rashwan
- Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo (AUC), 11835, Cairo, Egypt
| | - Christina D Sotiropoulou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701, Athens, Greece
| | - Sama Z Hozayen
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, Cairo, Egypt
| | | | - Miriam Mokhtar Abdelhalim
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, Cairo, Egypt
| | - Omar Eltahtawy
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, Cairo, Egypt
| | - Hadir M Emara
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, Cairo, Egypt; Department of Nanotechnology, School of Sciences and Engineering, The American University in Cairo (AUC), 11835, Cairo, Egypt
| | - Noha M Elemam
- Clinical Sciences Department, College of Medicine, University of Sharjah, 27272, Sharjah, UAE; Research Institute for Medical and Health Sciences, University of Sharjah, 27272, Sharjah, UAE
| | - Christos K Kontos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701, Athens, Greece
| | - Rana A Youness
- Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), 11835, Cairo, Egypt.
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Youness RA, Khater N, El-Khouly A, Nafea H, Manie T, Habashy D, Gad MZ. Direct and indirect modulation of STAT3/CSE/H 2S axis in triple negative breast cancer by non-coding RNAs: MALAT-1 lncRNA, miR-486-5p and miR-30a-5p. Pathol Res Pract 2025; 265:155729. [PMID: 39580879 DOI: 10.1016/j.prp.2024.155729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/06/2024] [Accepted: 11/17/2024] [Indexed: 11/26/2024]
Abstract
Recently, our research group reported an upregulated expression profile of cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), key enzymes involved in hydrogen sulfide (H2S) production, in triple-negative breast cancer (TNBC) patients. However, the regulatory mechanisms underlying such altered expression patterns are not yet fully understood. In this study, we focused on the role of the STAT3/CSE/H2S axis and the potential involvement of non-coding RNAs (ncRNAs), including long and short ncRNAs, in modulating this pivotal pathway. The results revealed that STAT3 was upregulated and positively correlated with CSE expression in BC patients. Additionally, the lncRNA MALAT-1 was found to regulate STAT3 expression, indirectly influencing CSE levels. Furthermore, we explored the interplay between the IGF-1R as a gatekeeper for JAK/STAT pathway and accordingly its impact on the STAT3/CSE/H2S axis in TNBC cell lines. Our results demonstrated that miR-486-5p, a tumor suppressor miRNA, directly targets IGF-1R, leading to the downstream suppression of STAT3 and CSE in MDA-MB-231 cells. To identify a direct upstream repressor of CSE and CBS, we conducted an in silico analysis and identified miR-30a-5p as a promising candidate. When ectopically expressed, miR-30a-5p was downregulated in BC tissues and effectively suppressed CSE and CBS expression. In conclusion, this study revealed novel regulatory mechanisms involved in CSE and CBS expression in TNBC patients and cell lines. Abolishing H2S-synthesizing machinery, particularly via miR-30a-5p, may represent a promising therapeutic strategy for TNBC patients.
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Affiliation(s)
- Rana A Youness
- Molecular Genetics and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), New Administrative Capital, Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
| | - Nour Khater
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Aisha El-Khouly
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Heba Nafea
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Tamer Manie
- Department of Breast Surgery, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Danira Habashy
- Pharmacology and Toxicology and Clinical Pharmacy Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Mohamed Z Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
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Dawoud A, Youness RA, Elsayed K, Nafae H, Allam H, Saad HA, Bourquin C, Szabo C, Abdel-Kader R, Gad MZ. Emerging roles of hydrogen sulfide-metabolizing enzymes in cancer. Redox Rep 2024; 29:2437338. [PMID: 39643979 PMCID: PMC11626870 DOI: 10.1080/13510002.2024.2437338] [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: 12/09/2024] Open
Abstract
Gasotransmitters play crucial roles in regulating many physiological processes, including cell signaling, cellular proliferation, angiogenesis, mitochondrial function, antioxidant production, nervous system functions and immune responses. Hydrogen sulfide (H2S) is the most recently identified gasotransmitter, which is characterized by its biphasic behavior. At low concentrations, H2S promotes cellular bioenergetics, whereas at high concentrations, it can exert cytotoxic effects. Cystathionine β-synthetase (CBS), cystathionine-γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST), and cysteinyl-tRNA synthetase 2 (CARS2) are pivotal players in H2S biosynthesis in mammalian cells and tissues. The focus of this review is the regulation of the various pathways involved in H2S metabolism in various forms of cancer. Key enzymes in this process include the sulfide oxidation unit (SOU), which includes sulfide:quinone oxidoreductase (SQOR), human ethylmalonic encephalopathy protein 1 (hETHE1), rhodanese, sulfite oxidase (SUOX/SO), and cytochrome c oxidase (CcO) enzymes. Furthermore, the potential role of H2S methylation processes mediated by thiol S-methyltransferase (TMT) and thioether S-methyltransferase (TEMT) is outlined in cancer biology, with potential opportunities for targeting them for clinical translation. In order to understand the role of H2S in oncogenesis and tumor progression, one must appreciate the intricate interplay between H2S-synthesizing and H2S-catabolizing enzymes.
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Affiliation(s)
- Alyaa Dawoud
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt
- School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Rana A. Youness
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt
- Molecular Biology and Biochemistry Department, Faculty of Biotechnology, German International University, Cairo, Egypt
| | - Kareem Elsayed
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt
| | - Heba Nafae
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt
| | - Hoda Allam
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt
- Biochemistry Department, Faculty of Biotechnology, October University for Modern Sciences and Arts (MSA), Giza, Egypt
| | - Hager Adel Saad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt
| | - Carole Bourquin
- School of Pharmaceutical Sciences, Institute of Pharmaceutical Sciences of Western Switzerland, Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, University of Geneva, Geneva, Switzerland
| | - Csaba Szabo
- Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Reham Abdel-Kader
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt
| | - Mohamed Z. Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt
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Abdelhamid AM, Zeinelabdeen Y, Manie T, Khallaf E, Assal RA, Youness RA. miR-17-5p/STAT3/H19: A novel regulatory axis tuning ULBP2 expression in young breast cancer patients. Pathol Res Pract 2024; 263:155638. [PMID: 39388743 DOI: 10.1016/j.prp.2024.155638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 09/17/2024] [Accepted: 10/02/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND AND AIM UL-16 binding protein 2 (ULBP2) is a highly altered ligand for the activating receptor, NKG2D in breast cancer (BC). However, the mechanism behind its de-regulation in BC patients remains to be explored. The sophisticated crosstalk between miR-17-5p, the lncRNA H19, and STAT3 as a possible upstream regulatory loop for ULBP2 in young BC patients and cell lines remains as an unexplored area. Therefore, this study aimed at unravelling the ncRNA circuit regulating ULBP2 in young BC patients and cell lines. PATIENTS AND METHODS A total of 30 BC patients were recruited for this study. The expression levels of miR-17-5p, lncRNA H19, and STAT3 were examined in 30 BC tissues compared to their normal counterparts. In addition, the expression signatures of those transcripts were compared in young (<40 years) and old BC (≥40 years) patients. miR-17-5p oligonucleotides, STAT3 and H19 siRNAs were transfected in MDA-MB-231 cells using HiPerfect® Transfection Reagent. miR-17-5p and the transcripts of the target genes quantified using RT-qPCR. Their relative expression was calculated using the 2-ΔΔCT method. RESULTS Through acting as a ceRNA circuit that antagonizes the function of miR-17-5p, H19 prevented the miR-17-5p-induced downregulation of STAT3; this mechanism further contributes to the pathogenesis of BC. Ectopic expression of miR-17-5p in MDA-MB-231 cells displayed its prominent role as an indirect potential activator of NK cells by significantly repressing the expression levels of the oncogenic mediator STAT3 and the oncogenic lncRNA H19 and inducing ULBP2 expression level by 3 folds in TNBC cell lines compared to mock cells. Furthermore, knocking down of STAT3 repressed the lncRNA H19 and increased ULBP2 expression levels, whereas siRNAs against H19 increased the expression levels of ULBP2. CONCLUSION This study highlighted the crosstalk between the novel regulatory network composed of miR-17-5p, H19 and STAT3, and their impact on ULBP2 in BC. Moreover, this study underscored the potential role of miR-17-5p in counteracting the immune evasion tactics, particularly the shedding of ULBP2 in young BC patients, through the modulation of the STAT3/H19/ULBP2 regulatory axis. Thus, targeting this novel regulatory network could potentially enhance our understanding and advance the future application of the innate system-mediated immunotherapy in BC.
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Affiliation(s)
- A M Abdelhamid
- Biotechnology School, Nile University, Giza 12588, Egypt
| | - Y Zeinelabdeen
- Faculty of Medical Sciences/UMCG, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, the Netherlands
| | - T Manie
- Department of Breast Surgery, National Cancer Institute, Cairo University, Cairo, Egypt
| | - E Khallaf
- Department of General Surgery, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - R A Assal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - R A Youness
- Molecular Genetics Research Team (MGRT), Molecular Biology and Biochemistry Department, Faculty of Biotechnology, German International University, New Administrative Capital 11835, Egypt.
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Rostom MM, El-Zohairy MA, Marzouk MA, Berger MR, Schols D, Assal RA, Mandour YM, Adwan H, Zlotos DP. N-[4-(Benzyloxy)-3-methoxybenzyl)]adamantane-1-amine (DZH2), a dual CCR5 and CXCR4 inhibitor as a potential agent against triple negative breast cancer. Arch Pharm (Weinheim) 2024:e2400146. [PMID: 39468982 DOI: 10.1002/ardp.202400146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 10/30/2024]
Abstract
DZH2, a dual inhibitor of the chemokine receptors CCR5 and CXCR4, was discovered from virtual screening for CCR5 antagonists. In specific Ca2+ chemokine signaling assays, DZH2 displayed low micromolar IC50 values at both chemokine receptors. Its binding to intracellular allosteric binding sites of CCR5 and CXCR4 was confirmed by MD simulations and binding free-energy calculations. DZH2 is superior to the CCR5 antagonist maraviroc in terms of its inhibitory activity on the growth of two breast cancer cell lines. In MCF7 and MDA-MB-231 cells, DZH2 was a >100-fold more potent inhibitor of cell viability compared to maraviroc. DZH2 (6.7 µM) reduced migration of MDA-MB-231 cells to 4% compared to 50% inhibition of migration caused by maraviroc (780 µM). Also, DZH2 was a significantly more potent inhibitor of colony formation in MDA-MB-231 cells than maraviroc. In MCF10 cells, DZH2 caused no alteration in the gene expression with respect to cellular pathways mediating cell death, indicating its selectivity to breast cancer cells.
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Affiliation(s)
- Monica M Rostom
- Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Mariam A El-Zohairy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Mohamed A Marzouk
- Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany
| | - Martin R Berger
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dominique Schols
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Reem A Assal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - Yasmine M Mandour
- School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
| | - Hassan Adwan
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Heidelberg, Heidelberg, Germany
| | - Darius P Zlotos
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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Assal RA, Elemam NM, Mekky RY, Attia AA, Soliman AH, Gomaa AI, Efthimiadou EK, Braoudaki M, Fahmy SA, Youness RA. A Novel Epigenetic Strategy to Concurrently Block Immune Checkpoints PD-1/PD-L1 and CD155/TIGIT in Hepatocellular Carcinoma. Transl Oncol 2024; 45:101961. [PMID: 38631259 PMCID: PMC11040172 DOI: 10.1016/j.tranon.2024.101961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 03/29/2024] [Accepted: 04/05/2024] [Indexed: 04/19/2024] Open
Abstract
Tumor microenvironment is an intricate web of stromal and immune cells creating an immune suppressive cordon around the tumor. In hepatocellular carcinoma (HCC), Tumor microenvironment is a formidable barrier towards novel immune therapeutic approaches recently evading the oncology field. In this study, the main aim was to identify the intricate immune evasion tactics mediated by HCC cells and to study the epigenetic modulation of the immune checkpoints; Programmed death-1 (PD-1)/ Programmed death-Ligand 1 (PD-L1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT)/Cluster of Differentiation 155 (CD155) at the tumor-immune synapse. Thus, liver tissues, PBMCs and sera were collected from Hepatitis C Virus (HCV), HCC as well as healthy individuals. Screening was performed to PD-L1/PD-1 and CD155/TIGIT axes in HCC patients. PDL1, CD155, PD-1 and TIGIT were found to be significantly upregulated in liver tissues and peripheral blood mononuclear cells (PBMCs) of HCC patients. An array of long non-coding RNAs (lncRNAs) and microRNAs validated to regulate such immune checkpoints were screened. The lncRNAs; CCAT-1, H19, and MALAT-1 were all significantly upregulated in the sera, PBMCs, and tissues of HCC patients as compared to HCV patients and healthy controls. However, miR-944-5p, miR-105-5p, miR-486-5p, miR-506-5p, and miR-30a-5p were downregulated in the sera and liver tissues of HCC patients. On the tumor cell side, knocking down of lncRNAs-CCAT-1, MALAT-1, or H19-markedly repressed the co-expression of PD-L1 and CD155 and accordingly induced the cytotoxicity of co-cultured primary immune cells. On the immune side, ectopic expression of the under-expressed microRNAs; miR-486-5p, miR-506-5p, and miR-30a-5p significantly decreased the transcript levels of PD-1 in PBMCs with no effect on TIGIT. On the other hand, ectopic expression of miR-944-5p and miR-105-5p in PBMCs dramatically reduced the co-expression of PD-1 and TIGIT. Finally, all studied miRNAs enhanced the cytotoxic effects of PBMCs against Huh7 cells. However, miR-105-5p showed the highest augmentation for PBMCs cytotoxicity against HCC cells. In conclusion, this study highlights a novel co-targeting strategy using miR-105-5p mimics, MALAT-1, CCAT-1 and H19 siRNAs to efficiently hampers the immune checkpoints; PD-L1/PD-1 and CD155/TIGIT immune evasion properties in HCC.
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Affiliation(s)
- Reem A Assal
- Department of Pharmacology and Toxicology, Heliopolis University for Sustainable Development, Cairo-Ismailia Desert Road, 11785, Cairo, Egypt
| | - Noha M Elemam
- Clinical Sciences Department, College of Medicine, University of Sharjah, 27272, Sharjah, United Arab Emirates; Research Institute for Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates
| | - Radwa Y Mekky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA University), Cairo, Egypt
| | - Abdelrahman A Attia
- General Surgery Department, Ain Shams University, Demerdash Hospital, Cairo, Egypt
| | - Aya Hesham Soliman
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835, Cairo, Egypt
| | - Asmaa Ibrahim Gomaa
- Department of Hepatology, National Liver Institute, Menoufiya University, Shebin El-Kom, Egypt
| | - Eleni K Efthimiadou
- Inorganic Chemistry Laboratory, Chemistry Department, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Braoudaki
- Department of Clinical, Pharmaceutical, and Biological Science, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
| | - Sherif Ashraf Fahmy
- Chemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, 11835, Cairo, Egypt
| | - Rana A Youness
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835, Cairo, Egypt; Molecular Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), New Administrative Capital, 11835, Cairo, Egypt.
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Elmasri RA, Rashwan AA, Gaber SH, Rostom MM, Karousi P, Yasser MB, Kontos CK, Youness RA. Puzzling out the role of MIAT LncRNA in hepatocellular carcinoma. Noncoding RNA Res 2024; 9:547-559. [PMID: 38515792 PMCID: PMC10955557 DOI: 10.1016/j.ncrna.2024.01.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 12/31/2023] [Accepted: 01/09/2024] [Indexed: 03/23/2024] Open
Abstract
A non-negligible part of our DNA has been proven to be transcribed into non-protein coding RNA and its intricate involvement in several physiological processes has been highly evidenced. The significant biological role of non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) has been variously reported. In the current review, the authors highlight the multifaceted role of myocardial infarction-associated transcript (MIAT), a well-known lncRNA, in hepatocellular carcinoma (HCC). Since its discovery, MIAT has been described as a regulator of carcinogenesis in several malignant tumors and its overexpression predicts poor prognosis in most of them. At the molecular level, MIAT is closely linked to the initiation of metastasis, invasion, cellular migration, and proliferation, as evidenced by several in-vitro and in-vivo models. Thus, MIAT is considered a possible theranostic agent and therapeutic target in several malignancies. In this review, the authors provide a comprehensive overview of the underlying molecular mechanisms of MIAT in terms of its downstream target genes, interaction with other classes of ncRNAs, and potential clinical implications as a diagnostic and/or prognostic biomarker in HCC.
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Affiliation(s)
- Rawan Amr Elmasri
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), New Administrative Capital, 11835, Cairo, Egypt
| | - Alaa A. Rashwan
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), New Administrative Capital, 11835, Cairo, Egypt
- Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo (AUC), 11835, Cairo, Egypt
| | - Sarah Hany Gaber
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), New Administrative Capital, 11835, Cairo, Egypt
| | - Monica Mosaad Rostom
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), 11835, Cairo, Egypt
| | - Paraskevi Karousi
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15701, Athens, Greece
| | - Montaser Bellah Yasser
- Bioinformatics Group, Center for Informatics Sciences (CIS), School of Information Technology and Computer Science (ITCS), Nile University, Giza, Egypt
| | - Christos K. Kontos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15701, Athens, Greece
| | - Rana A. Youness
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), New Administrative Capital, 11835, Cairo, Egypt
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Zeinelabdeen Y, Abaza T, Yasser MB, Elemam NM, Youness RA. MIAT LncRNA: A multifunctional key player in non-oncological pathological conditions. Noncoding RNA Res 2024; 9:447-462. [PMID: 38511054 PMCID: PMC10950597 DOI: 10.1016/j.ncrna.2024.01.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/27/2023] [Accepted: 01/14/2024] [Indexed: 03/22/2024] Open
Abstract
The discovery of non-coding RNAs (ncRNAs) has unveiled a wide range of transcripts that do not encode proteins but play key roles in several cellular and molecular processes. Long noncoding RNAs (lncRNAs) are specific class of ncRNAs that are longer than 200 nucleotides and have gained significant attention due to their diverse mechanisms of action and potential involvement in various pathological conditions. In the current review, the authors focus on the role of lncRNAs, specifically highlighting the Myocardial Infarction Associated Transcript (MIAT), in non-oncological context. MIAT is a nuclear lncRNA that has been directly linked to myocardial infarction and is reported to control post-transcriptional processes as a competitive endogenous RNA (ceRNA) molecule. It interacts with microRNAs (miRNAs), thereby limiting the translation and expression of their respective target messenger RNA (mRNA) and regulating protein expression. Yet, MIAT has been implicated in other numerous pathological conditions such as other cardiovascular diseases, autoimmune disease, neurodegenerative diseases, metabolic diseases, and many others. In this review, the authors emphasize that MIAT exhibits distinct expression patterns and functions across different pathological conditions and is emerging as potential diagnostic, prognostic, and therapeutic agent. Additionally, the authors highlight the regulatory role of MIAT and shed light on the involvement of lncRNAs and specifically MIAT in various non-oncological pathological conditions.
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Affiliation(s)
- Yousra Zeinelabdeen
- Molecular Genetics Research Team, Molecular Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), Cairo, 11835, Egypt
- Faculty of Medical Sciences/UMCG, University of Groningen, Antonius Deusinglaan 1, Groningen, 9713 AV, the Netherlands
| | - Tasneem Abaza
- Molecular Genetics Research Team, Molecular Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), Cairo, 11835, Egypt
- Biotechnology and Biomolecular Biochemistry Program, Faculty of Science, Cairo University, Cairo, Egypt
| | - Montaser Bellah Yasser
- Bioinformatics Group, Center for Informatics Sciences (CIS), School of Information Technology and Computer Science (ITCS), Nile University, Giza, Egypt
| | - Noha M. Elemam
- Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Rana A. Youness
- Molecular Genetics Research Team, Molecular Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), Cairo, 11835, Egypt
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Xie H, Ding C, Li Q, Sheng W, Xu J, Feng R, Cheng H. Identification of shared gene signatures in major depressive disorder and triple-negative breast cancer. BMC Psychiatry 2024; 24:369. [PMID: 38755543 PMCID: PMC11100035 DOI: 10.1186/s12888-024-05795-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 04/26/2024] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND Patients with major depressive disorder (MDD) have an increased risk of breast cancer (BC), implying that these two diseases share similar pathological mechanisms. This study aimed to identify the key pathogenic genes that lead to the occurrence of both triple-negative breast cancer (TNBC) and MDD. METHODS Public datasets GSE65194 and GSE98793 were analyzed to identify differentially expressed genes (DEGs) shared by both datasets. A protein-protein interaction (PPI) network was constructed using STRING and Cytoscape to identify key PPI genes using cytoHubba. Hub DEGs were obtained from the intersection of hub genes from a PPI network with genes in the disease associated modules of the Weighed Gene Co-expression Network Analysis (WGCNA). Independent datasets (TCGA and GSE76826) and RT-qPCR validated hub gene expression. RESULTS A total of 113 overlapping DEGs were identified between TNBC and MDD. The PPI network was constructed, and 35 hub DEGs were identified. Through WGCNA, the blue, brown, and turquoise modules were recognized as highly correlated with TNBC, while the brown, turquoise, and yellow modules were similarly correlated with MDD. Notably, G3BP1, MAF, NCEH1, and TMEM45A emerged as hub DEGs as they appeared both in modules and PPI hub DEGs. Within the GSE65194 and GSE98793 datasets, G3BP1 and MAF exhibited a significant downregulation in TNBC and MDD groups compared to the control, whereas NCEH1 and TMEM45A demonstrated a significant upregulation. These findings were further substantiated by TCGA and GSE76826, as well as through RT-qPCR validation. CONCLUSIONS This study identified G3BP1, MAF, NCEH1 and TMEM45A as key pathological genes in both TNBC and MDD.
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Affiliation(s)
- Hua Xie
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Shushan District, Hefei, 230601, Anhui, China
- Xuancheng People's Hospital, Affiliated Xuancheng Hospital of Wannan Medical College, Dabatang Road 51, Xuanzhou District, Xuancheng, Anhui, 242000, China
| | - Chenxiang Ding
- Bengbu Medical College, Donghaida Road 2600, Longzihu District, Bengbu, Anhui, 233030, China
| | - Qianwen Li
- Xuancheng People's Hospital, Affiliated Xuancheng Hospital of Wannan Medical College, Dabatang Road 51, Xuanzhou District, Xuancheng, Anhui, 242000, China
| | - Wei Sheng
- Mental Health center of Xuancheng City, Changqiaocun Jinba Road, Economic and Technological Development Zone, Xuancheng, Anhui, 242000, China
| | - Jie Xu
- Xuancheng People's Hospital, Affiliated Xuancheng Hospital of Wannan Medical College, Dabatang Road 51, Xuanzhou District, Xuancheng, Anhui, 242000, China
| | - Renjian Feng
- Xuancheng People's Hospital, Affiliated Xuancheng Hospital of Wannan Medical College, Dabatang Road 51, Xuanzhou District, Xuancheng, Anhui, 242000, China
| | - Huaidong Cheng
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Shushan District, Hefei, 230601, Anhui, China.
- Department of Oncology, Shenzhen Hospital of Southern Medical University, Xinhu Road 1333, Bao'an District, Shenzhen, Guangdong, 518000, China.
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Rashwan HH, Taher AM, Hassan HA, Awaji AA, Kiriacos CJ, Assal RA, Youness RA. Harnessing the supremacy of MEG3 LncRNA to defeat gastrointestinal malignancies. Pathol Res Pract 2024; 256:155223. [PMID: 38452587 DOI: 10.1016/j.prp.2024.155223] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 03/09/2024]
Abstract
Evidence suggests that long non-coding RNAs (lncRNAs) play a pivotal role in the carcinogenesis and progression of various human malignancies including gastrointestinal malignancies. This comprehensive review reports the functions and mechanisms of the lncRNA maternally expressed gene 3 (MEG3) involved in gastrointestinal malignancies. It summarizes its roles in mediating the regulation of cellular proliferation, apoptosis, migration, invasiveness, epithelial-to-mesenchymal transition, and drug resistance in several gastrointestinal cancers such as colorectal cancer, gall bladder cancer, pancreatic cancer, gastric cancer, esophageal cancer, cholangiocarcinoma, gastrointestinal stromal tumors and most importantly, hepatocellular carcinoma. In addition, the authors briefly highlight its implicated mechanistic role and interactions with different non-coding RNAs and oncogenic signaling cascades. This review presents the rationale for developing non coding RNA-based anticancer therapy via harnessing the power of MEG3 in gastrointestinal malignancies.
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Affiliation(s)
- H H Rashwan
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; Bioinformatics Group, Center for Informatics Science (CIS), School of Information Technology and Computer Science (ITCS), Nile University, 12677, Giza, Egypt
| | - A M Taher
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - H A Hassan
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - A A Awaji
- Department of Biology, Faculty of Science, University College of Taymaa, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - C J Kiriacos
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - R A Assal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - R A Youness
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt.
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11
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Mehrotra S, Sharma S, Pandey RK. A journey from omics to clinicomics in solid cancers: Success stories and challenges. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 139:89-139. [PMID: 38448145 DOI: 10.1016/bs.apcsb.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/08/2024]
Abstract
The word 'cancer' encompasses a heterogenous group of distinct disease types characterized by a spectrum of pathological features, genetic alterations and response to therapies. According to the World Health Organization, cancer is the second leading cause of death worldwide, responsible for one in six deaths and hence imposes a significant burden on global healthcare systems. High-throughput omics technologies combined with advanced imaging tools, have revolutionized our ability to interrogate the molecular landscape of tumors and has provided unprecedented understanding of the disease. Yet, there is a gap between basic research discoveries and their translation into clinically meaningful therapies for improving patient care. To bridge this gap, there is a need to analyse the vast amounts of high dimensional datasets from multi-omics platforms. The integration of multi-omics data with clinical information like patient history, histological examination and imaging has led to the novel concept of clinicomics and may expedite the bench-to-bedside transition in cancer. The journey from omics to clinicomics has gained momentum with development of radiomics which involves extracting quantitative features from medical imaging data with the help of deep learning and artificial intelligence (AI) tools. These features capture detailed information about the tumor's shape, texture, intensity, and spatial distribution. Together, the related fields of multiomics, translational bioinformatics, radiomics and clinicomics may provide evidence-based recommendations tailored to the individual cancer patient's molecular profile and clinical characteristics. In this chapter, we summarize multiomics studies in solid cancers with a specific focus on breast cancer. We also review machine learning and AI based algorithms and their use in cancer diagnosis, subtyping, prognosis and predicting treatment resistance and relapse.
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12
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Elemam NM, Mekky RY, Rashid G, Braoudaki M, Youness RA. Pharmacogenomic and epigenomic approaches to untangle the enigma of IL-10 blockade in oncology. Expert Rev Mol Med 2024; 26:e1. [PMID: 38186186 PMCID: PMC10941350 DOI: 10.1017/erm.2023.26] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/29/2023] [Accepted: 11/10/2023] [Indexed: 01/09/2024]
Abstract
The host immune system status remains an unresolved mystery among several malignancies. An immune-compromised state or smart immune-surveillance tactics orchestrated by cancer cells are the primary cause of cancer invasion and metastasis. Taking a closer look at the tumour-immune microenvironment, a complex network and crosstalk between infiltrating immune cells and cancer cells mediated by cytokines, chemokines, exosomal mediators and shed ligands are present. Cytokines such as interleukins can influence all components of the tumour microenvironment (TME), consequently promoting or suppressing tumour invasion based on their secreting source. Interleukin-10 (IL-10) is an interlocked cytokine that has been associated with several types of malignancies and proved to have paradoxical effects. IL-10 has multiple functions on cellular and non-cellular components within the TME. In this review, the authors shed the light on the regulatory role of IL-10 in the TME of several malignant contexts. Moreover, detailed epigenomic and pharmacogenomic approaches for the regulation of IL-10 were presented and discussed.
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Affiliation(s)
- Noha M. Elemam
- Research Instiute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Radwa Y. Mekky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA University), Cairo 12622, Egypt
| | - Gowhar Rashid
- Amity Medical School, Amity University, Gurugram (Manesar) 122413, Haryana, India
| | - Maria Braoudaki
- Department of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
| | - Rana A. Youness
- Biology and Biochemistry Department, Faculty of Biotechnology, German International University, Cairo 11835, Egypt
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13
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Yang Q, Fu Y, Wang J, Yang H, Zhang X. Roles of lncRNA in the diagnosis and prognosis of triple-negative breast cancer. J Zhejiang Univ Sci B 2023; 24:1123-1140. [PMID: 38057269 PMCID: PMC10710915 DOI: 10.1631/jzus.b2300067] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 06/24/2023] [Indexed: 12/08/2023]
Abstract
Breast cancer is a malignant tumor that seriously endangers women's lives. The prognosis of breast cancer patients differs among molecular types. Compared with other subtypes, triple-negative breast cancer (TNBC) has been a research hotspot in recent years because of its high degree of malignancy, strong invasiveness, rapid progression, easy of recurrence, distant metastasis, poor prognosis, and high mortality. Many studies have found that long non-coding RNA (lncRNA) plays an important role in the occurrence, proliferation, migration, recurrence, chemotherapy resistance, and other characteristics of TNBC. Some lncRNAs are expected to become biomarkers in the diagnosis and prognosis of TNBC, and even new targets for its treatment. Based on a PubMed literature search, this review summarizes the progress in research on lncRNAs in TNBC and discusses their roles in TNBC diagnosis, prognosis, and chemotherapy with the hope of providing help for future research.
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Affiliation(s)
- Qiuhui Yang
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou 310022, China
| | - Yeqin Fu
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou 310022, China
| | - Jiaxuan Wang
- Shanxi Medical University, Jinzhong 030600, China
| | - Hongjian Yang
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Xiping Zhang
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China.
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14
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Soliman AH, Youness RA, Sebak AA, Handoussa H. Phytochemical-derived tumor-associated macrophage remodeling strategy using Phoenix dactylifera L. boosted photodynamic therapy in melanoma via H19/iNOS/PD-L1 axis. Photodiagnosis Photodyn Ther 2023; 44:103792. [PMID: 37689125 DOI: 10.1016/j.pdpdt.2023.103792] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 09/11/2023]
Abstract
BACKGROUND The tumor microenvironment (TME) represents a barrier to PDT efficacy among melanoma patients. The aim of this study is to employ a novel muti-tactic TME-remodeling strategy via repolarization of tumor-associated macrophages (TAMs), the main TME immune cells in melanoma, from the pro-tumor M2 into the antitumor M1 phenotype using Phoenix dactylifera L. (date palm) in combination with PDT. METHODS Screening of different date cultivars was employed to choose extracts of selective toxicity to melanoma and TAMs, not normal macrophages. Potential extracts were then fractionated and characterized by gas chromatography-mass spectrometry (GC-MS). Finally, the efficacy and the potential molecular mechanism of the co-treatment were portrayed via quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RESULTS Initial screening resulted in the selection of the two Phoenix dactylifera L. cultivars Safawi and Sukkari methanolic extracts. Sukkari showed superior capacity to revert TAM phenotype into M1 as well as more prominent upregulation of M1 markers and repression of melanoma immunosuppressive markers relative to positive control (resiquimod). Molecularly, it was shown that PDT of melanoma cells in the presence of the secretome of repolarized TAMs surpassed the monotherapy via the modulation of the H19/iNOS/PD-L1immune-regulatory axis. CONCLUSION This study highlights the potential utilization of nutraceuticals in combination with PDT in the treatment of melanoma to provide a dual activity through alleviating the immune suppressive TME and potentiating the anti-tumor responses.
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Affiliation(s)
- Aya H Soliman
- Department of Pharmaceutical Biology, Faculty of Pharmacy & Biotechnology, The German University in Cairo, Main Entrance El Tagamoa El Khames, New Cairo 11511, Egypt.
| | - Rana A Youness
- Department of Pharmaceutical Biology, Faculty of Pharmacy & Biotechnology, The German University in Cairo, Main Entrance El Tagamoa El Khames, New Cairo 11511, Egypt; Department of Biology and Biochemistry, Faculty of Biotechnology, German International University, New Administrative Capital, New Cairo 11835, Egypt
| | - Aya A Sebak
- Department of Pharmaceutical Technology, Faculty of Pharmacy & Biotechnology, The German University in Cairo, New Cairo 11511, Egypt.
| | - Heba Handoussa
- Department of Pharmaceutical Biology, Faculty of Pharmacy & Biotechnology, The German University in Cairo, Main Entrance El Tagamoa El Khames, New Cairo 11511, Egypt
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15
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Abaza T, El-Aziz MKA, Daniel KA, Karousi P, Papatsirou M, Fahmy SA, Hamdy NM, Kontos CK, Youness RA. Emerging Role of Circular RNAs in Hepatocellular Carcinoma Immunotherapy. Int J Mol Sci 2023; 24:16484. [PMID: 38003674 PMCID: PMC10671287 DOI: 10.3390/ijms242216484] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly fatal malignancy with limited therapeutic options and high recurrence rates. Recently, immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) have emerged as a new paradigm shift in oncology. ICIs, such as programmed cell death protein 1 (PD-1) inhibitors, have provided a new source of hope for patients with advanced HCC. Yet, the eligibility criteria of HCC patients for ICIs are still a missing piece in the puzzle. Circular RNAs (circRNAs) have recently emerged as a new class of non-coding RNAs that play a fundamental role in cancer pathogenesis. Structurally, circRNAs are resistant to exonucleolytic degradation and have a longer half-life than their linear counterparts. Functionally, circRNAs possess the capability to influence various facets of the tumor microenvironment, especially at the HCC tumor-immune synapse. Notably, circRNAs have been observed to control the expression of immune checkpoint molecules within tumor cells, potentially impeding the therapeutic effectiveness of ICIs. Therefore, this renders them potential cancer-immune biomarkers for diagnosis, prognosis, and therapeutic regimen determinants. In this review, the authors shed light on the structure and functional roles of circRNAs and, most importantly, highlight the promising roles of circRNAs in HCC immunomodulation and their potential as promising biomarkers and immunotherapeutic regimen determinants.
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Affiliation(s)
- Tasneem Abaza
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
- Biotechnology and Biomolecular Chemistry Program, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Mostafa K. Abd El-Aziz
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
- Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71631, Egypt
| | - Kerolos Ashraf Daniel
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo 11835, Egypt
| | - Paraskevi Karousi
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (P.K.); (M.P.)
| | - Maria Papatsirou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (P.K.); (M.P.)
| | - Sherif Ashraf Fahmy
- Department of Chemistry, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, R5 New Garden City, New Capital, Cairo 11835, Egypt;
| | - Nadia M. Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt;
| | - Christos K. Kontos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece; (P.K.); (M.P.)
| | - Rana A. Youness
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; (T.A.); (M.K.A.E.-A.); (K.A.D.)
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Nafea H, Youness RA, Dawoud A, Khater N, Manie T, Abdel-Kader R, Bourquin C, Szabo C, Gad MZ. Dual targeting of H 2S synthesizing enzymes; cystathionine β-synthase and cystathionine γ-lyase by miR-939-5p effectively curbs triple negative breast cancer. Heliyon 2023; 9:e21063. [PMID: 37916110 PMCID: PMC10616356 DOI: 10.1016/j.heliyon.2023.e21063] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 10/08/2023] [Accepted: 10/13/2023] [Indexed: 11/03/2023] Open
Abstract
Introduction Hydrogen sulfide (H2S) has been recently scrutinized for its critical role in aggravating breast cancer (BC) tumorigenicity. Several cancers aberrantly express H2S synthesizing enzymes; Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). However, their levels and interdependence in BC require further studies. Objectives Firstly, this study aimed to demonstrate a comparative expression profile of H2S synthesizing enzymes in BC vs normal tissue. Moreover, to investigate the reciprocal relationship between CBS and CSE and highlight the importance of dual targeting. Finally, to search for a valid dual repressor of the H2S synthesizing enzymes that could cease H2S production and reduce TNBC pathogenicity. Methods Pairwise analysis of tumor vs. normal tissues of 40 BC patients was carried out. The TNBC cell line MDA-MB-231 was transfected with oligonucleotides to study the H2S mediated molecular mechanisms. In silico screening was performed to identify dual regulator(s) for CBS and CSE. Gene expression analysis was performed using qRT-PCR and was confirmed on protein level using Western blot. TNBC hallmarks were evaluated using MTT, migration, and clonogenicity assays. H2S levels were detected using a AzMc fluorescent probe. Results BC tissues exhibited elevated levels of both CBS and CSE. Interestingly, upon CBS knockdown, CSE levels increased compensating for H2S production in TNBC cells, underlining the importance of dually targeting both enzymes in TNBC. In silico screening suggested miR-939-5p as a regulator of both CBS and CSE with high binding scores. Low expression levels of miR-939-5p were found in BC tissues, especially the aggressive subtypes. Ectopic expression of miR-939-5p significantly repressed CBS and CSE transcript and protein levels, diminished H2S production and attenuated TNBC hallmarks. Moreover, it improved the immune surveillance potency of TNBC cells through up regulating the NKG2D ligands, MICB and ULBP2 and reducing the immune suppressive cytokine IL-10. Conclusion This study sheds light on the reciprocal relationship between CBS and CSE and on the importance of their dual targeting, particularly in TNBC. It also postulates miR-939-5p as a potent dual repressor for CBS and CSE overcoming their redundancy in H2S production, a mechanism that can potentially attenuate TNBC oncogenicity and improves the immunogenic response.
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Affiliation(s)
- Heba Nafea
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Rana A. Youness
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
- Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo, Egypt
| | - Alyaa Dawoud
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Nour Khater
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Tamer Manie
- Breast Surgery Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Reham Abdel-Kader
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Carole Bourquin
- School of Pharmaceutical Sciences and Institute of Pharmaceutical Sciences of Western Switzerland and Department of Anesthesiology, Pharmacology, Intensive Care and Emergency Medicine, University of Geneva, Geneva 1211, Switzerland
| | - Csaba Szabo
- Chair of Pharmacology, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Mohamed Z. Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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Hussen BM, Hidayat HJ, Abdullah SR, Mohamadtahr S, Rasul MF, Samsami M, Taheri M. Role of long non-coding RNAs and TGF-β signaling in the regulation of breast cancer pathogenesis and therapeutic targets. Cytokine 2023; 170:156351. [PMID: 37657235 DOI: 10.1016/j.cyto.2023.156351] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 08/22/2023] [Accepted: 08/25/2023] [Indexed: 09/03/2023]
Abstract
The cytokine known as transforming growth factor (TGF) is essential for cell development, differentiation, and apoptosis in BC. TGF-β dysregulation can either promote or inhibit tumor development, and it is a key signaling pathway in BC spread. A recently identified family of ncRNAs known as lncRNAs has received a great deal of effort and is an important regulator of many cellular processes, including transcription of genes, chromatin remodeling, progression of the cell cycle, and posttranscriptional processing. Furthermore, both TGF-β signaling and lncRNAs serve as important early-stage biomarkers for BC diagnosis and prognosis and also play a significant role in BC drug resistance. According to recent studies, lncRNAs can regulate TGF-β by modulating its cofactors in BC. However, the particular functions of lncRNAs and the TGF-β pathway in controlling BC progression are not well understood yet. This review explores the lncRNAs' functional properties in BC as tumor suppressors or oncogenes in the regulation of genes, with a focus on dysregulated TGF-β signaling. Further, we emphasize the functional roles of lncRNAs and TGF-β pathway in the progression of BC to discover new treatment strategies and better comprehend the fundamental cellular pathways.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq; Department of Biomedical Sciences, Cihan University-Erbil, Erbil, Kurdistan Region 44001, Iraq
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University-Erbil, Kurdistan Region, Iraq
| | - Snur Rasool Abdullah
- Department of Medical Laboratory Science, College of Health Sciences, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Sayran Mohamadtahr
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Mohammad Fatih Rasul
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Majid Samsami
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany; Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Kiaei SZF, Nouralishahi A, Ghasemirad M, Barkhordar M, Ghaffari S, Kheradjoo H, Saleh M, Mohammadzadehsaliani S, Molaeipour Z. Advances in natural killer cell therapies for breast cancer. Immunol Cell Biol 2023; 101:705-726. [PMID: 37282729 DOI: 10.1111/imcb.12658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/28/2023] [Accepted: 05/06/2023] [Indexed: 06/08/2023]
Abstract
Breast cancer (BC) is the most common cause of cancer death in women. According to the American Cancer Society's yearly cancer statistics, BC constituted almost 15% of all the newly diagnosed cancer cases in 2022 for both sexes. Metastatic disease occurs in 30% of patients with BC. The currently available treatments fail to cure metastatic BC, and the average survival time for patients with metastatic BC is approximately 2 years. Developing a treatment method that terminates cancer stem cells without harming healthy cells is the primary objective of novel therapeutics. Adoptive cell therapy is a branch of cancer immunotherapy that utilizes the immune cells to attack cancer cells. Natural killer (NK) cells are an essential component of innate immunity and are critical in destroying tumor cells without prior stimulation with antigens. With the advent of chimeric antigen receptors (CARs), the autologous or allogeneic use of NK/CAR-NK cell therapy has raised new hopes for treating patients with cancer. Here, we describe recent developments in NK and CAR-NK cell immunotherapy, including the biology and function of NK cells, clinical trials, different sources of NK cells and their future perspectives on BC.
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Affiliation(s)
- Seyedeh Zahra Fotook Kiaei
- Department of Pulmonary and Critical Care, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohammad Ghasemirad
- Department of Periodontics, Faculty of Dentistry, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Maryam Barkhordar
- Hematology, Oncology and Stem Cell Transplantation Research Center (HORCSCT), Tehran University of Medical Sciences, Tehran, Iran
| | - Sasan Ghaffari
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | | | - Mahshid Saleh
- Wisconsin National Primate Research Center, University of Wisconsin Graduate School, Madison, WI, USA
| | | | - Zahra Molaeipour
- Hematology Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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El-Aziz MKA, Dawoud A, Kiriacos CJ, Fahmy SA, Hamdy NM, Youness RA. Decoding hepatocarcinogenesis from a noncoding RNAs perspective. J Cell Physiol 2023; 238:1982-2009. [PMID: 37450612 DOI: 10.1002/jcp.31076] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/11/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023]
Abstract
Being a leading lethal malignancy worldwide, the pathophysiology of hepatocellular carcinoma (HCC) has gained a lot of interest. Yet, underlying mechanistic basis of the liver tumorigenesis is poorly understood. The role of some coding genes and their respective translated proteins, then later on, some noncoding RNAs (ncRNAs) such as microRNAs have been extensively studied in context of HCC pathophysiology; however, the implication of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in HCC is indeed less investigated. As a subclass of the ncRNAs which has been elusive for long time ago, lncRNAs was found to be involved in plentiful cellular functions such as DNA, RNA, and proteins regulation. Hence, it is undisputed that lncRNAs dysregulation profoundly contributes to HCC via diverse etiologies. Accordingly, lncRNAs represent a hot research topic that requires prime focus in HCC. In this review, the authors discuss breakthrough discoveries involving lncRNAs and circRNAs dysregulation that have contributed to the contemporary concepts of HCC pathophysiology and how these concepts could be leveraged as potential novel diagnostic and prognostic HCC biomarkers. Further, this review article sheds light on future trends, thereby discussing the pathological roles of lncRNAs and circRNAs in HCC proliferation, migration, and epithelial-to-mesenchymal transition. Along this line of reasoning, future recommendations of how these targets could be exploited to achieve effective HCC-related drug development is highlighted.
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Affiliation(s)
- Mostafa K Abd El-Aziz
- Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
| | - Alyaa Dawoud
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Caroline J Kiriacos
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Sherif Ashraf Fahmy
- Chemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
| | - Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Rana A Youness
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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Palcau AC, Brandi R, Mehterov NH, Botti C, Blandino G, Pulito C. Exploiting Long Non-Coding RNAs and Circular RNAs as Pharmacological Targets in Triple-Negative Breast Cancer Treatment. Cancers (Basel) 2023; 15:4181. [PMID: 37627209 PMCID: PMC10453179 DOI: 10.3390/cancers15164181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/13/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Breast cancer is one of the most frequent causes of cancer death among women worldwide. In particular, triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype because it is characterized by the absence of molecular targets, thus making it an orphan type of malignancy. The discovery of new molecular druggable targets is mandatory to improve treatment success. In that context, non-coding RNAs represent an opportunity for modulation of cancer. They are RNA molecules with apparently no protein coding potential, which have been already demonstrated to play pivotal roles within cells, being involved in different processes, such as proliferation, cell cycle regulation, apoptosis, migration, and diseases, including cancer. Accordingly, they could be used as targets for future TNBC personalized therapy. Moreover, the peculiar characteristics of non-coding RNAs make them reliable biomarkers to monitor cancer treatment, thus, to monitor recurrence or chemoresistance, which are the most challenging aspects in TNBC. In the present review, we focused on the oncogenic or oncosuppressor role of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) mostly involved in TNBC, highlighting their mode of action and depicting their potential role as a biomarker and/or as targets of new non-coding RNA-based therapeutics.
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Affiliation(s)
- Alina Catalina Palcau
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (A.C.P.); (R.B.); (G.B.)
| | - Renata Brandi
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (A.C.P.); (R.B.); (G.B.)
| | - Nikolay Hristov Mehterov
- Department of Medical Biology, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria;
- Research Institute, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria
| | - Claudio Botti
- Breast Surgery Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Giovanni Blandino
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (A.C.P.); (R.B.); (G.B.)
| | - Claudio Pulito
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (A.C.P.); (R.B.); (G.B.)
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21
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Selem NA, Nafae H, Manie T, Youness RA, Gad MZ. Let-7a/cMyc/CCAT1/miR-17-5p Circuit Re-sensitizes Atezolizumab Resistance in Triple Negative Breast Cancer through Modulating PD-L1. Pathol Res Pract 2023; 248:154579. [PMID: 37301086 DOI: 10.1016/j.prp.2023.154579] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 05/23/2023] [Accepted: 05/27/2023] [Indexed: 06/12/2023]
Abstract
BACKGROUND Triple negative breast cancer (TNBC) is an immunogenically hot tumor. The immune checkpoint blockades (ICBs) have been recently emerged as promising therapeutic candidates for several malignancies including TNBC. Yet, the development of innate and/or adaptive resistance by TNBC patients towards ICBs such as programmed death-ligand 1 (PD-L1) inhibitors (e.g. Atezolizumab) shed the light on importance of identifying the underlying mechanisms regulating PD-L1 in TNBC. Recently, it was reported that non-coding RNAs (ncRNAs) perform a fundamental role in regulating PD-L1 expression in TNBC. Hence, this study aims to explore a novel ncRNA axis tuning PD-L1 in TNBC patients and investigate its possible involvement in fighting Atezolizumab resistance. METHODS In-silico screening was executed to identify ncRNAs that could potentially target PD-L1. Screening of PD-L1 and the nominated ncRNAs (miR-17-5p, let-7a and CCAT1 lncRNA) was performed in BC patients and cell lines. Ectopic expression and/or knockdown of respective ncRNAs were performed in MDA-MB-231. Cellular viability, migration and clonogenic capacities were evaluated using MTT, scratch assay and colony-forming assay, respectively. RESULTS PD-L1 was upregulated in BC patients, especially in TNBC patients. PD-L1 is positively associated with lymph node metastasis and high Ki-67 in recruited BC patients. Let-7a and miR-17-5p were nominated as potential regulators of PD-L1. Ectopic expression of let-7a and miR-17-5p caused a noticeable reduction in PD-L1 levels in TNBC cells. In order to investigate the whole ceRNA circuit regulating PD-L1 in TNBC, intensive bioinformatic studies were performed. The lncRNA, Colon Cancer-associated transcript 1 (CCAT1), was reported to target PD-L1 regulating miRNAs. Results showed that CCAT1 is an upregulated oncogenic lncRNA in TNBC patients and cell lines. CCAT1 siRNAs induced a noticeable reduction in PD-L1 levels and a marked increase in miR-17-5p level, building up a novel regulatory axis CCAT1/miR-17-5p/PD-L1 in TNBC cells that was tuned by the let-7a/c-Myc engine. On the functional level, co-treatment of CCAT-1 siRNAs and let-7a mimics efficiently relieved Atezolizumab resistance in MDA-MB-231 cells. CONCLUSION The present study revealed a novel PD-L1 regulatory axis via targeting let-7a/c-Myc/CCAT/miR-17-5p. Additionally, it sheds the light on the potential combinational role of CCAT-1 siRNAs and Let-7a mimics in relieving Atezolizumab resistance in TNBC patients.
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Affiliation(s)
- Noha A Selem
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Heba Nafae
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Tamer Manie
- Department of Breast Surgery, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Rana A Youness
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt; Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt.
| | - Mohamed Z Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
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22
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Mekky RY, Ragab MF, Manie T, Attia AA, Youness RA. MALAT-1: Immunomodulatory lncRNA hampering the innate and the adaptive immune arms in triple negative breast cancer. Transl Oncol 2023; 31:101653. [PMID: 36907052 PMCID: PMC10025146 DOI: 10.1016/j.tranon.2023.101653] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/05/2023] [Accepted: 03/05/2023] [Indexed: 03/13/2023] Open
Abstract
BACKGROUND Triple negative breast cancer (TNBC) is known as hot immunogenic tumor. Yet, it is one of the most aggressive BC subtypes. TNBC evolve several tactics to evade the immune surveillance phenomena, one of which is shedding of natural killer (NK) cells activating immune ligands such as MICA/B and/or by inducing the expression of the immune checkpoints such as PD-L1 and B7-H4. MALAT-1 is an oncogenic lncRNA. MALAT-1 immunogenic profile is not well investigated. AIM The study aims at exploring the immunogenic role of MALAT-1 in TNBC patients and cell lines and to identify its molecular mechanism in altering both innate and adaptive immune cells present at the tumor microenvironment of TNBC METHODS: BC patients (n = 35) were recruited. Primary NK cells and cytotoxic T lymphocytes were isolated from normal individuals using the negative selection method. MDA-MB-231 cells were cultured and transfected by several oligonucleotides by lipofection technique. Screening of ncRNAs was performed using q-RT-PCR. Immunological functional analysis experiments were performed upon co-culturing primary natural killer cells and cytotoxic T lymphocytes using LDH assay. Bioinformatics analysis was performed to identify potential microRNAs targeted by MALAT-1. RESULTS MALAT-1 expression was significantly upregulated in BC patinets with a profound expression in TNBC patients compared to their normal counterparts. Correlation analysis revealed a positive correlation between MALAT-1, tumor size and lymph node metastasis. Knocking down of MALAT-1 in MDA-MB-231 cells resulted in a significant induction of MICA/B, repression of PD-L1 and B7-H4 expression levels. Enhancement of cytotoxic activity of co-cultured NK and CD8+ cells with MALAT-1 siRNAs transfected MDA-MB-231 cells. In silico analysis revealed that miR-34a and miR-17-5p are potential targets to MALAT-1; accordingly, they were found to be downregulated in BC patients. Forcing the expression of miR-34a in MDA-MB-231 cells resulted in a significant induction in MICA/B levels. Ectopic expression of miR-17-5p in MDA-MB-231 cells significantly repressed the expression of PD-L1 and B7-H4 checkpoints. Validations of MALAT-1/miR-34a" and "MALAT-1/miR-17-5p axes were performed by a series of co-transfections and functional assessment of cytotoxic profile of primary immune cells. CONCLUSION This study proposes a novel epigenetic alteration exerted by TNBC cells mainly by inducing the expression of MALAT-1 lncRNA. MALAT-1 mediates innate and adaptive immune suppression events partially via targeting miR-34a/MICA/B and miR-175p/PD-L1/B7-H4 axes in TNBC patients and cell lines.
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Affiliation(s)
- Radwa Y Mekky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA University), Cairo 12622, Egypt
| | - Mai F Ragab
- Pharmacology Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo 11835, Egypt
| | - Tamer Manie
- Department of Breast Surgery, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Abdelrahman A Attia
- General Surgery Department, Ain Shams University, Demerdash Hospital, Cairo, Egypt
| | - Rana A Youness
- Biology and Biochemistry Department, Molecular Genetics Research Team (MGRT), School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo 11835, Egypt.
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Singh DD, Lee HJ, Yadav DK. Recent Clinical Advances on Long Non-Coding RNAs in Triple-Negative Breast Cancer. Cells 2023; 12:cells12040674. [PMID: 36831341 PMCID: PMC9955037 DOI: 10.3390/cells12040674] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/13/2023] [Accepted: 02/17/2023] [Indexed: 02/23/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a more aggressive type of breast cancer due to its heterogeneity and complex molecular mechanisms. TNBC has a high risk for metastasis, and it is difficult to manage clinical conditions of the patients. Various investigations are being conducted to overcome these challenges using RNA, DNA, and proteins for early diagnosis and treatment. Recently, long non-coding RNAs (lncRNAs) have emerged as a novel target to treat the multistep process of TNBC. LncRNAs regulate epigenetic expression levels, cell proliferation and apoptosis, and tumour invasiveness and metastasis. Thus, lncRNA-based early diagnosis and treatment options could be helpful, especially for patients with severe TNBC. lncRNAs are expressed in a highly specific manner in cells and tissues and are involved in TNBC progression and development. lncRNAs could be used as sensitive and specific targets for diagnosis, treatment, and monitoring of patients with TNBC. Therefore, the exploration of novel diagnostic and prognostic biomarkers is of extreme importance. Here, we discuss the molecular advances on lncRNA regulation of TNBC and lncRNA-based early diagnosis, treatment, and drug resistance.
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Affiliation(s)
- Desh Deepak Singh
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur 303002, India
| | - Hae-Jeung Lee
- Department of Food and Nutrition, College of Bionano Technology, Gachon University, Seongnam-si 13120, Republic of Korea
- Correspondence: (H.-J.L.); (D.K.Y.)
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Kashyap D, Sharma R, Goel N, Buttar HS, Garg VK, Pal D, Rajab K, Shaikh A. Coding roles of long non-coding RNAs in breast cancer: Emerging molecular diagnostic biomarkers and potential therapeutic targets with special reference to chemotherapy resistance. Front Genet 2023; 13:993687. [PMID: 36685962 PMCID: PMC9852779 DOI: 10.3389/fgene.2022.993687] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 11/07/2022] [Indexed: 01/08/2023] Open
Abstract
Dysregulation of epigenetic mechanisms have been depicted in several pathological consequence such as cancer. Different modes of epigenetic regulation (DNA methylation (hypomethylation or hypermethylation of promotor), histone modifications, abnormal expression of microRNAs (miRNAs), long non-coding RNAs, and small nucleolar RNAs), are discovered. Particularly, lncRNAs are known to exert pivot roles in different types of cancer including breast cancer. LncRNAs with oncogenic and tumour suppressive potential are reported. Differentially expressed lncRNAs contribute a remarkable role in the development of primary and acquired resistance for radiotherapy, endocrine therapy, immunotherapy, and targeted therapy. A wide range of molecular subtype specific lncRNAs have been assessed in breast cancer research. A number of studies have also shown that lncRNAs may be clinically used as non-invasive diagnostic biomarkers for early detection of breast cancer. Such molecular biomarkers have also been found in cancer stem cells of breast tumours. The objectives of the present review are to summarize the important roles of oncogenic and tumour suppressive lncRNAs for the early diagnosis of breast cancer, metastatic potential, and chemotherapy resistance across the molecular subtypes.
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Affiliation(s)
- Dharambir Kashyap
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Riya Sharma
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Neelam Goel
- Department of Information Technology, University Institute of Engineering & Technology, Panjab University, Chandigarh, India
| | - Harpal S. Buttar
- Department of Pathology and Laboratory Medicine, University of Ottawa, Faculty of Medicine, Ottawa, ON, Canada
| | - Vivek Kumar Garg
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Gharuan, Mohali, India
| | - Deeksha Pal
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Khairan Rajab
- College of Computer Science and Information Systems, Najran University, Najran, Saudi Arabia
| | - Asadullah Shaikh
- College of Computer Science and Information Systems, Najran University, Najran, Saudi Arabia
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Shuaib M, Prajapati KS, Gupta S, Kumar S. Natural Steroidal Lactone Induces G1/S Phase Cell Cycle Arrest and Intrinsic Apoptotic Pathway by Up-Regulating Tumor Suppressive miRNA in Triple-Negative Breast Cancer Cells. Metabolites 2022; 13:29. [PMID: 36676955 PMCID: PMC9863888 DOI: 10.3390/metabo13010029] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/07/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with minimal treatment options. In the present work, Withaferin A (WA), a natural steroidal lactone found in Withania somnifera (Solanaceae), was studied to deduce the miRNA expression modulation mediated anticancer mode of action in TNBC cells. Small RNA next generation sequencing (NGS) of WA (2 µM) and vehicle (0.1% DMSO)-treated MDA-MB-231 cells revealed a total of 413 differentially expressed miRNAs (DEMs) and demonstrated that WA potentially up-regulates the miR-181c-5p, miR-15a-5p, miR-500b-5p, miR-191-3p, and miR-34a-5p and down-regulates miR-1275, miR-326, miR-1908-5p, and miR-3940-3p among total DEMs. The NGS and qRT-PCR expression analysis revealed a significantly higher expression of miR-181c-5p among the top 10 DEMs. Predicted target genes of the DEMs showed enrichment in cancer-associated gene ontology terms and KEGG signaling pathways. Transient up-expression of mir-181c-5p showed a time-dependent decrease in MDA-MB-231 and MDA-MB-453 cell viability. Co-treatment of miR-181c-5p mimic and WA (at varying concentration) down-regulated cell cycle progression markers (CDK4 and Cyclin D1) at mRNA and protein levels. The treatment induced apoptosis in MDA-MB-231 cells by modulating the expression/activity of Bax, Bcl2, Caspase 3, Caspase 8, Caspase 3/7, and PARP at mRNA and protein levels. Confocal microscopy and Annexin PI assays revealed apoptotic induction in miRNA- and steroidal-lactone-treated MDA-MB-231 cells. Results indicate that the Withaferin A and miRNA mimic co-treatment strategy may be utilized as a newer therapeutic strategy to treat triple-negative breast cancer.
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Affiliation(s)
- Mohd Shuaib
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Guddha, Bathinda 151401, Punjab, India
| | - Kumari Sunita Prajapati
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Guddha, Bathinda 151401, Punjab, India
| | - Sanjay Gupta
- Department of Urology, Nutrition, Pharmacology and Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Shashank Kumar
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Guddha, Bathinda 151401, Punjab, India
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26
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Zhang Y, Lai X, Yue Q, Cao F, Zhang Y, Sun Y, Tian J, Lu Y, He L, Bai J, Wei Y. Bone marrow mesenchymal stem cells-derived exosomal microRNA-16-5p restrains epithelial-mesenchymal transition in breast cancer cells via EPHA1/NF-κB signaling axis. Genomics 2022; 114:110341. [PMID: 35283197 DOI: 10.1016/j.ygeno.2022.110341] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 02/09/2022] [Accepted: 03/07/2022] [Indexed: 01/14/2023]
Abstract
OBJECTIVE This study intends to conquer the mystery of microRNA-16-5p/erythropoietin-producing hepatocellular A1/nuclear factor-κB signaling (miR-16-5p/EPHA1/NF-κB signaling) in breast cancer. METHODS Expression of miR-16-5p, EPHA1 and NF-κB signaling-related proteins were detected. Gene overexpression or silencing was used to examine the biological roles of bone marrow mesenchymal stem cells (BMSCs)-derived exo-miR-16-5p in breast cancer. The effect of exo-miR-16-5p on tumorigenesis of breast cancer was confirmed by the xenograft nude mouse model. RESULTS Low miR-16-5p and high EPHA1 expression were examined in breast cancer. BMSCs-derived exosomes, up-regulated miR-16-5p or down-regulated EPHA1 restrained epithelial-mesenchymal transition (EMT) of breast cancer cells and tumor growth in nude mice. Down-regulated miR-16-5p or up-regulated EPHA1 activated NF-κB signaling. Knockdown of EPHA1 or inhibition of NF-κB signaling reversed the effects of down-regulated miR-16-5p on breast cancer cells. CONCLUSION BMSCs-derived exosomal miR-16-5p hinders breast cancer cells progression via EPHA1/NF-κB signaling axis.
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Affiliation(s)
- Yuan Zhang
- Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, China
| | - Xiaofeng Lai
- Fujian Key Laboratory of Aptamer Technology, Affiliated Dongfang Hospital of School of Medicine, Xiamen University, China; Department of Clinical Laboratory Medicine, Fuzhou General Clinical Medical School, Fuzhou 350108, Fujian, China; the 900th Hospital, Fujian Medical University, Fuzhou 350108, Fujian, China
| | - Qingfang Yue
- Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, China
| | - Fei Cao
- Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, China
| | - Yue Zhang
- Department of Pathology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, China
| | - Yang Sun
- Xi'an Medical University, Xi'an 710021, Shaanxi, China
| | - Jun Tian
- Department of Dermatology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, China
| | - Yizhao Lu
- Department of Emergency, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, China
| | - Li He
- Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, China
| | - Jun Bai
- Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, China
| | - Yifang Wei
- Center for Reproductive Medicine, Naval Medical Center, Second, Military Medical University, Shanghai 200052, China.
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27
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Paul U, Banerjee S. The functional significance and cross-talk of non-coding RNAs in triple negative and quadruple negative breast cancer. Mol Biol Rep 2022; 49:6899-6918. [PMID: 35235157 DOI: 10.1007/s11033-022-07288-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/18/2022] [Indexed: 12/13/2022]
Abstract
One of the leading causes of cancer-related deaths worldwide is breast cancer, among which triple-negative breast cancer (TNBC) is the most malignant and lethal subtype. This cancer accounts for 10-20% of all breast cancer deaths. Proliferation, tumorigenesis, and prognosis of TNBC are affected when the androgen receptor (AR) is not expressed, and it is classified as quadruple negative breast cancer (QNBC). Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play a significant role in tumorigenesis by virtue of their oncogenic and tumor-suppressive properties. To regulate tumorigenesis, miRNAs interact with their target mRNAs and modulate their expression, whereas lncRNAs can either act alone or interact with miRNAs or other molecules through various signaling pathways. Conversely, circRNAs regulate tumorigenesis by acting as miRNA sponges predominantly. Recently, non-coding RNAs were studied comprehensively for their roles in tumor proliferation, progression, and metastasis. As a result of existing studies and research progress, non-coding RNAs have been implicated in TNBC, necessitating their use as biomarkers for future diagnostic applications. In this review, the non-coding RNAs are explicitly implicated in the regulation of breast cancer, and their cross-talk between TNBC and QNBC is also discussed.
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Affiliation(s)
- Utpalendu Paul
- School of Bio Science and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Satarupa Banerjee
- School of Bio Science and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
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28
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ZeinElAbdeen YA, AbdAlSeed A, Youness RA. Decoding Insulin-Like Growth Factor Signaling Pathway From a Non-coding RNAs Perspective: A Step Towards Precision Oncology in Breast Cancer. J Mammary Gland Biol Neoplasia 2022; 27:79-99. [PMID: 35146629 DOI: 10.1007/s10911-022-09511-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 01/24/2022] [Indexed: 12/21/2022] Open
Abstract
Breast cancer (BC) is a highly complex and heterogenous disease. Several oncogenic signaling pathways drive BC oncogenic activity, thus hindering scientists to unravel the exact molecular pathogenesis of such multifaceted disease. This highlights the urgent need to find a key regulator that tunes up such intertwined oncogenic drivers to trim the malignant transformation process within the breast tissue. The Insulin-like growth factor (IGF) signaling pathway is a tenacious axis that is heavily intertwined with BC where it modulates the amplitude and activity of vital downstream oncogenic signaling pathways. Yet, the complexity of the pathway and the interactions driven by its different members seem to aggravate its oncogenicity and hinder its target-ability. In this review, the authors shed the light on the stubbornness of the IGF signaling pathway and its potential regulation by non-coding RNAs in different BC subtypes. Nonetheless, this review also spots light on the possible transport systems available for efficient delivery of non-coding RNAs to their respective targets to reach a personalized treatment code for BC patients.
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Affiliation(s)
- Yousra Ahmed ZeinElAbdeen
- The Molecular Genetics Research Team, Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University, Main Entrance Al Tagamoa Al Khames, New Cairo CityCairo, 11835, Egypt
| | - Amna AbdAlSeed
- The Molecular Genetics Research Team, Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University, Main Entrance Al Tagamoa Al Khames, New Cairo CityCairo, 11835, Egypt
- University of Khartoum, Al-Gama a Avenue, 11115, Khartoum, Sudan
| | - Rana A Youness
- The Molecular Genetics Research Team, Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University, Main Entrance Al Tagamoa Al Khames, New Cairo CityCairo, 11835, Egypt.
- School of Life and Medical Sciences, University of Hertfordshire Hosted By Global Academic Foundation, New Administrative Capital, Cairo, 11586, Egypt.
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Abdel-Latif M, Riad A, Soliman RA, Elkhouly AM, Nafae H, Gad MZ, Motaal AA, Youness RA. MALAT-1/p53/miR-155/miR-146a ceRNA circuit tuned by methoxylated quercitin glycoside alters immunogenic and oncogenic profiles of breast cancer. Mol Cell Biochem 2022; 477:1281-1293. [PMID: 35129780 DOI: 10.1007/s11010-022-04378-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/27/2022] [Indexed: 12/15/2022]
Abstract
Triple-Negative Breast Cancer (TNBC) is one of the most aggressive and hot BC subtypes. Our research group has recently shed the light on the utility of natural compounds as effective immunotherapeutic agents. The aim of this study is to investigate the role of a methoxylated quercetin glycoside (MQG) isolated from Cleome droserifolia in harnessing TNBC progression and tuning the tumor microenvironment and natural killer cells cytotoxicity. Results showed that MQG showed the highest potency (IC50 = 12 µM) in repressing cellular proliferation, colony-forming ability, migration, and invasion capacities. Mechanistically, MQG was found to modulate a circuit of competing endogenous RNAs where it was found to reduce the oncogenic MALAT-1 lncRNA and induce TP53 and its downstream miRNAs; miR-155 and miR-146a. Accordingly, this leads to alteration in several downstream signaling pathways such as nitric oxide synthesizing machinery, natural killer cells' cytotoxicity through inducing the expression of its activating ligands such as MICA/B, ULBP2, CD155, and ICAM-1 and trimming of the immune-suppressive cytokines such as TNF-α and IL-10. In conclusion, this study shows that MQG act as a compelling anti-cancer agent repressing TNBC hallmarks, activating immune cell recognition, and alleviating the immune-suppressive tumor microenvironment experienced by TNBC patients.
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Affiliation(s)
- Mustafa Abdel-Latif
- Molecular Genetics Research Team (MGRT), Biotechnology Program, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.,Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Ahmed Riad
- Molecular Genetics Research Team (MGRT), Biotechnology Program, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.,Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Raghda A Soliman
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Aisha M Elkhouly
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.,Department of Biochemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Heba Nafae
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.,Department of Biochemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Mohamed Z Gad
- Department of Biochemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Amira Abdel Motaal
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia.,Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Rana A Youness
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt. .,Department of Biology and Biochemistry, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo, 11578, Egypt.
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30
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Li M, Jiao Y, Duan C. A dual-emission fluorescence-enhanced probe for hydrogen sulfide and its application in biological imaging. NEW J CHEM 2022. [DOI: 10.1039/d2nj01195f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A fluorescence-enhanced probe with unique dual-channel emissions was designed for the detection and bioimaging of hydrogen sulfide.
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Affiliation(s)
- Minghao Li
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Yang Jiao
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Chunying Duan
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
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31
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Selem NA, Youness RA, Gad MZ. What is beyond LncRNAs in breast cancer: A special focus on colon cancer-associated Transcript-1 (CCAT-1). Noncoding RNA Res 2021; 6:174-186. [PMID: 34938928 PMCID: PMC8666458 DOI: 10.1016/j.ncrna.2021.11.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 02/07/2023] Open
Abstract
Long non-coding RNAs (LncRNAs) play a vital role in the process of malignant transformation. In breast cancer (BC), lncRNAs field is currently under intensive investigations. Yet, the role of lncRNAs as promising diagnostic and/or prognostic biomarkers and as therapeutic target/tool among BC patients still needs a special focus from the biomedical scientists. In BC, triple negative breast cancer patients (TNBC) are the unlucky group as they are always represented with the worst prognosis and the highest mortality rates. For that reason, a special focus on TNBC and associated lncRNAs was addressed in this review. Colon cancer-associated transcript 1 (CCAT-1) is a newly discovered oncogenic lncRNA that has been emerged as a vital biomarker for diagnosis, prognosis and therapeutic interventions in multiple malignancies and showed differential expression among TNBC patients. In this review, the authors shed the light onto the general role of lncRNAs in BC and the specific functional activities, molecular mechanisms, competing endogenous ncRNA role of CCAT-1 in TNBC.
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Affiliation(s)
- Noha A. Selem
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
| | - Rana A. Youness
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
- School of Life and Medical Sciences, University of Hertfordshire Hosted By Global Academic Foundation, New Administrative Capital, 11586, Cairo, Egypt
| | - Mohamed Z. Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
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32
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Mahmoud MM, Sanad EF, Elshimy RAA, Hamdy NM. Competitive Endogenous Role of the LINC00511/miR-185-3p Axis and miR-301a-3p From Liquid Biopsy as Molecular Markers for Breast Cancer Diagnosis. Front Oncol 2021; 11:749753. [PMID: 34745973 PMCID: PMC8567754 DOI: 10.3389/fonc.2021.749753] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/15/2021] [Indexed: 12/24/2022] Open
Abstract
Breast cancer (BC) is the leading cause of female cancer-related mortalities. Evidence has illustrated the role of long non-coding RNAs (lncRNA) and microRNAs (miRNA) as promising pool of protein non-coding regulators, for tuning the aggressiveness of several malignancies. This research aims to unravel the expression pattern and the emphases of the diagnostic value of the long intergenic ncRNA00511 (LINC00511) and its downstream microRNA (miR-185-3p) and the pathogenic significance of the onco-miR-301a-3p in naïve BC patients. LINC00511 was chosen and validated, and its molecular binding was confirmed using bioinformatics. LINC00511 was measured in 25 controls and 70 patients using qPCR. The association between the investigated ncRNA’s expression and the BC patients’ clinicopathological features was assessed. Receiver operating characteristic (ROC) curve was blotted to weigh out their diagnostic efficacy over the classical tumor markers (TMs). Bioinformatics and Spearman correlation were used to predict the interaction between LINC00511, miR-185-3p, and miR-301a-3p altogether to patients’ features. LINC00511 and miR-301a-3p, in BC patients’ blood, were overexpressed, and their median levels increased significantly, while miR-185-3p was, in contrast, downregulated, being decreased fourfold. LINC00511 was elevated in BC early stages, when compared to late stages (p < 0.0003). LINC00511, miR-185-3p, and miR-301a-3p showed AUC superior to classical TMs, allowing us to conclude that the investigated ncRNAs, in BC patients’ liquid biopsy, are novel diagnostic molecular biomarker signatures. Lymph node metastasis (LNM) and advanced tumor grade were directly correlated with LINC00511 significantly. Additionally, both LINC00511 and miR-301a-3p were positively correlated with the aggressiveness of BC, as manifested in patients with larger tumors (>2 cm) at (p < 0.001). Therefore, these findings aid our understanding of BC pathogenesis, in the clinical setting, being related in part to the LINC00511/miR axis, which could be a future potential therapeutic target.
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Affiliation(s)
- Marwa M Mahmoud
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Eman F Sanad
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Reham A A Elshimy
- Clinical and Chemical Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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Jin H, Du W, Huang W, Yan J, Tang Q, Chen Y, Zou Z. lncRNA and breast cancer: Progress from identifying mechanisms to challenges and opportunities of clinical treatment. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 25:613-637. [PMID: 34589282 PMCID: PMC8463317 DOI: 10.1016/j.omtn.2021.08.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Breast cancer is a malignant tumor that has a high mortality rate and mostly occurs in women. Although significant progress has been made in the implementation of personalized treatment strategies for molecular subtypes in breast cancer, the therapeutic response is often not satisfactory. Studies have reported that long non-coding RNAs (lncRNAs) are abnormally expressed in breast cancer and closely related to the occurrence and development of breast cancer. In addition, the high tissue and cell-type specificity makes lncRNAs particularly attractive as diagnostic biomarkers, prognostic factors, and specific therapeutic targets. Therefore, an in-depth understanding of the regulatory mechanisms of lncRNAs in breast cancer is essential for developing new treatment strategies. In this review, we systematically elucidate the general characteristics, potential mechanisms, and targeted therapy of lncRNAs and discuss the emerging functions of lncRNAs in breast cancer. Additionally, we also highlight the advantages and challenges of using lncRNAs as biomarkers for diagnosis or therapeutic targets for drug resistance in breast cancer and present future perspectives in clinical practice.
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Affiliation(s)
- Huan Jin
- Genetic and Prenatal Diagnosis Center, Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China.,MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Wei Du
- Department of Neurosurgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
| | - Wentao Huang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.,Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Jiajing Yan
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.,Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Qing Tang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.,Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China
| | - Yibing Chen
- Genetic and Prenatal Diagnosis Center, Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
| | - Zhengzhi Zou
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.,Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.,Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou 510631, China
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34
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Ezzeldeen Y, Swidan S, ElMeshad A, Sebak A. Green Synthesized Honokiol Transfersomes Relieve the Immunosuppressive and Stem-Like Cell Characteristics of the Aggressive B16F10 Melanoma. Int J Nanomedicine 2021; 16:5693-5712. [PMID: 34465990 PMCID: PMC8402984 DOI: 10.2147/ijn.s314472] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/17/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Honokiol (HK) is a natural bioactive compound with proven antineoplastic properties against melanoma. However, it shows very low bioavailability when administered orally. Alternatively, topical administration may offer a promising route. The objective of the current study was to fabricate HK transfersomes (HKTs) for topical treatment of melanoma. As an ultradeformable carrier system, transfersomes can overcome the physiological barriers to topical treatment of melanoma: the stratum corneum and the anomalous tumor microenvironment. Moreover, the immunomodulatory and stemness-regulation roles of HKTs were the main interest of this study. METHODS TFs were prepared using the modified scalable heating method. A three-factor, three-level Box-Behnken design was utilized for the optimization of the process and formulation variables. Intracellular uptake and cytotoxicity of HKTs were evaluated in nonactivated and stromal cell-activated B16F10 melanoma cells to investigate the influence of the complex tumor microenvironment on the efficacy of HK. Finally, ELISA and Western blot were performed to evaluate the expression levels of TGF-β and clusters of differentiation (CD47 and CD133, respectively). RESULTS The optimized formula exhibited a mean size of 190 nm, highly negative surface charge, high entrapment efficiency, and sustained release profile. HKTs showed potential to alleviate the immunosuppressive characteristics of B16F10 melanoma in vitro via downregulation of TGF-β signaling. In addition, HKTs reduced expression of the "do not eat me" signal - CD47. Moreover, HKTs possessed additional interesting potential to reduce the expression of the stem-like cell marker CD133. These outcomes were boosted upon combination with metformin, an antihyperglycemic drug recently reported to possess different functions in cancer, while combination with collagenase, an extracellular matrix-depleting enzyme, produced detrimental effects. CONCLUSION HKTs represent a promising scalable formulation for treatment of the aggressive B16F10 melanoma, which is jam-packed with immunosuppressive and stem-like cell markers.
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Affiliation(s)
- Yasmeen Ezzeldeen
- Department of Pharmaceutics, Faculty of Pharmacy, The British University in Egypt (BUE), El-Sherouk City, Cairo, 11837, Egypt
| | - Shady Swidan
- Department of Pharmaceutics, Faculty of Pharmacy, The British University in Egypt (BUE), El-Sherouk City, Cairo, 11837, Egypt
- The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt
| | - Aliaa ElMeshad
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
- Department of Bio Nano, Faculty of Nanotechnology for Postgraduate Studies, Cairo University, El-Sheikh Zayed, Giza, 12588, Egypt
| | - Aya Sebak
- Department of Pharmaceutical Technology, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo, Egypt
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35
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Multifaceted roles of long non-coding RNAs in triple-negative breast cancer: biology and clinical applications. Biochem Soc Trans 2021; 48:2791-2810. [PMID: 33258920 DOI: 10.1042/bst20200666] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 02/06/2023]
Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype that lacks targeted therapy due to the absence of estrogen, progesterone, and HER2 receptors. Moreover, TNBC was shown to have a poor prognosis, since it involves aggressive phenotypes that confer significant hindrance to therapeutic treatments. Recent state-of-the-art sequencing technologies have shed light on several long non-coding RNAs (lncRNAs), previously thought to have no biological function and were considered as genomic junk. LncRNAs are involved in various physiological as well as pathological conditions, and play a key role in drug resistance, gene expression, and epigenetic regulation. This review mainly focuses on exploring the multifunctional roles of candidate lncRNAs, and their strong association with TNBC development. We also summarise various emerging research findings that establish novel paradigms of lncRNAs function as oncogenes and/or tumor suppressors in TNBC development, suggesting their role as prospective therapeutic targets.
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36
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Xu J, Wu KJ, Jia QJ, Ding XF. Roles of miRNA and lncRNA in triple-negative breast cancer. J Zhejiang Univ Sci B 2021; 21:673-689. [PMID: 32893525 PMCID: PMC7519626 DOI: 10.1631/jzus.b1900709] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 05/28/2020] [Indexed: 12/11/2022]
Abstract
Triple-negative breast cancer (TNBC) is currently the most malignant subtype of breast cancer without effective targeted therapies, which makes its pathogenesis an important target for research. A growing number of studies have shown that non-coding RNA (ncRNA), including microRNA (miRNA) and long non-coding RNA (lncRNA), plays a significant role in tumorigenesis. This review summarizes the roles of miRNA and lncRNA in the progression, diagnosis, and neoadjuvant chemotherapy of TNBC. Aberrantly expressed miRNA and lncRNA are listed according to their roles. Further, it describes the multiple mechanisms that lncRNA shows for regulating gene expression in the nucleus and cytoplasm, and more importantly, describes lncRNA-regulated TNBC progression through complete combining with miRNA at the post-transcriptional level. Focusing on miRNA and lncRNA associated with TNBC can provide new insights for early diagnosis and treatment-they can be targeted in the future as a novel anticancer target of TNBC.
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Thakur KK, Kumar A, Banik K, Verma E, Khatoon E, Harsha C, Sethi G, Gupta SC, Kunnumakkara AB. Long noncoding RNAs in triple-negative breast cancer: A new frontier in the regulation of tumorigenesis. J Cell Physiol 2021; 236:7938-7965. [PMID: 34105151 DOI: 10.1002/jcp.30463] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/11/2021] [Accepted: 05/20/2021] [Indexed: 12/16/2022]
Abstract
In recent years, triple-negative breast cancer (TNBC) has emerged as the most aggressive subtype of breast cancer and is usually associated with increased mortality worldwide. The severity of TNBC is primarily observed in younger women, with cases ranging from approximately 12%-24% of all breast cancer cases. The existing hormonal therapies offer limited clinical solutions in completely circumventing the TNBC, with chemoresistance and tumor recurrences being the common hurdles in the path of TNBC treatment. Accumulating evidence has correlated the dysregulation of long noncoding RNAs (lncRNAs) with increased cell proliferation, invasion, migration, tumor growth, chemoresistance, and decreased apoptosis in TNBC. Various clinical studies have revealed that aberrant expression of lncRNAs in TNBC tissues is associated with poor prognosis, lower overall survival, and disease-free survival. Due to these specific characteristics, lncRNAs have emerged as novel diagnostic and prognostic biomarkers for TNBC treatment. However, the underlying mechanism through which lncRNAs perform their actions remains unclear, and extensive research is being carried out to reveal it. Therefore, understanding of mechanisms regulating the modulation of lncRNAs will be a substantial breakthrough in effective treatment therapies for TNBC. This review highlights the association of several lncRNAs in TNBC progression and treatment, along with their possible functions and mechanisms.
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Affiliation(s)
- Krishan K Thakur
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Aviral Kumar
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Kishore Banik
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Elika Verma
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Elina Khatoon
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Choudhary Harsha
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Subash C Gupta
- Department of Biochemistry, Laboratory for Translational Cancer Research, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh, India
| | - Ajaikumar B Kunnumakkara
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India
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38
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Tong SJ, Zhang XY, Guo HF, Yang J, Qi YP, Lu S. Study on effects of miR-141-3p in proliferation, migration, invasion and apoptosis of colon cancer cells by inhibiting Bcl2. Clin Transl Oncol 2021; 23:2526-2535. [PMID: 34086253 DOI: 10.1007/s12094-021-02653-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 05/24/2021] [Indexed: 11/27/2022]
Abstract
PURPOSE This study aimed to investigate the relationship between miR-141-3p and B lymphocyte-2 gene (Bcl2) gene and its biological behavior on colon cancer cell line SW480. METHODS qRT-PCR was used to detect the expression level of miR-141-3p in colon cancer tissues and adjacent tissues, as well as in colon cancer cell line and normal human colonic epithelial cell line FHC. MTT assay, wound assay, and Transwell demonstrated the effects of miR-141-3p on colon cancer proliferation, migration and invasion. Targetscan7.1 predictive software and dual luciferase reporter assays were used to detect the targeted regulation of miR-141-3p on the apoptosis-related gene Bcl2. MTT assay, wound assay, Transwell and flow cytometry were used to detect the effect of Bcl2 on miR-141-3p on colon cancer proliferation, migration, invasion and apoptosis. RESULTS Compared with adjacent tissues, the expression of miR-141-3p in colon cancer tissues was significantly down-regulated. Colon cancer patients with low expression of miR-141-3p had poorer prognosis. Compared with normal colonic epithelial cells, miR-141-3p expression was significantly down-regulated in colon cancer cell lines, and overexpression of miR-141-3p significantly attenuated the proliferation, migration and invasion of colon cancer cells. Knockdown of miR-141-3p significantly promoted the proliferation, migration and invasion of colon cancer cells. miR-141-3p targets the negative regulation of Bcl2. Knockdown of Bcl2 significantly attenuated the promotion of miR-141-3p inhibitor on proliferation, migration and invasion of colon cancer cells and inhibition of apoptosis. Knockdown of Bcl2 significantly enhanced the inhibition effect of miR-141-3p inhibitor on proliferation, migration and invasion of colon cancer cells. CONCLUSIONS In conclusion, miR-141-3p can inhibit the cancer by regulating Bcl2, and miR-141-3p has the potential to become a potential therapeutic target for colon cancer.
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Affiliation(s)
- S J Tong
- Ward 1, Department of General Surgery, The Third Affiliated Hospital of Qiqihaer Medical University, No. 27 Taishun Street, Tiefeng District, Qiqihaer City, 161000, Heilongjiang Province, China
| | - X Y Zhang
- Department of Stomatology, The Third Affiliated Hospital of Qiqihaer Medical University, Qiqihaer City, 161000, China
| | - H F Guo
- Ward 1, Department of General Surgery, The Third Affiliated Hospital of Qiqihaer Medical University, No. 27 Taishun Street, Tiefeng District, Qiqihaer City, 161000, Heilongjiang Province, China
| | - J Yang
- Ward 1, Department of General Surgery, The Third Affiliated Hospital of Qiqihaer Medical University, No. 27 Taishun Street, Tiefeng District, Qiqihaer City, 161000, Heilongjiang Province, China
| | - Y P Qi
- Ward 1, Department of General Surgery, The Third Affiliated Hospital of Qiqihaer Medical University, No. 27 Taishun Street, Tiefeng District, Qiqihaer City, 161000, Heilongjiang Province, China
| | - S Lu
- Ward 1, Department of General Surgery, The Third Affiliated Hospital of Qiqihaer Medical University, No. 27 Taishun Street, Tiefeng District, Qiqihaer City, 161000, Heilongjiang Province, China.
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Shen Y, Xu Y, Huang L, Chi Y, Meng L. MiR-205 suppressed the malignant behaviors of breast cancer cells by targeting CLDN11 via modulation of the epithelial-to-mesenchymal transition. Aging (Albany NY) 2021; 13:13073-13086. [PMID: 33971623 PMCID: PMC8148491 DOI: 10.18632/aging.202988] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 03/27/2021] [Indexed: 02/06/2023]
Abstract
Some Aberrant expression of miRNAs plays an important role in the occurrence and distant metastasis of breast cancer. This study aimed to identify crucial miRNA signatures for breast cancer using microarray data from the Gene Expression Omnibus database, including ductal carcinoma in situ and invasive duct carcinoma. In this study, we founded that miR-205 was significantly down-regulated in breast cancer, and the low expression of miR-205 was significantly associated with the TNM stage of breast cancer. In vitro, functional studies revealed that over-expression of miR-205 inhibited the proliferation and promoted apoptosis of breast cancer cells MDA-MB-231. Mechanistically, claudin 11 (CLDN11) was found to be the direct target of miR-205; the function of miR-205 could be exerted via downregulation of the target gene CLDN11 in breast cancer cells. Furthermore, the over-expression of miR-205 promoted the expression of the epithelial marker E-cadherin but reduced the mesenchymal markers in breast cancer cells. These results collectively indicated the tumor-suppressive role of miR-205 in breast cancer by targeting CLDN11; implying miR-205 may serve as a novel therapeutic target for breast cancer.
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Affiliation(s)
- Yupeng Shen
- Medical School of Shaoxing University, Yuecheng, Shaoxing 312000, Zhejiang Province, People's Republic of China
| | - Yingchun Xu
- Department of Breast and Thyroid Surgery, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, People's Republic of China
| | - Liming Huang
- Department of Breast and Thyroid Surgery, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, People's Republic of China
| | - Yongxin Chi
- Department of Breast and Thyroid Surgery, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, People's Republic of China
| | - Liwei Meng
- Department of Breast and Thyroid Surgery, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, People's Republic of China
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Abdallah RM, Elkhouly AM, Soliman RA, El Meckawy N, El Sebaei A, Motaal AA, El-Askary H, Youness RA, Assal RA. Hindering The Synchronization Between Mir-486-5p And H19 Lncrna By Hesperetin Halts Breast Cancer Aggressiveness Through Tuning ICAM-1. Anticancer Agents Med Chem 2021; 22:586-595. [PMID: 33882812 DOI: 10.2174/1871520621666210419093652] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 02/16/2021] [Accepted: 03/01/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Recently, a novel crosstalk between non-coding RNAs (ncRNAs) has been casted. However, this has been seldomly investigated in metastatic BC (mBC). H19 and miR-486-5p role in mBC is controversial. ICAM-1 is a recently recognized metastatic engine in mBC. Natural compounds were recently found to alter ncRNAs/target circuits. Yet, Hesperitin modulatory role in altering such circuits has never been investigated in mBC. OBJECTIVE The aim of this study is to investigate the impact of hesperitin on miR-486-5p/H19/ICAM-1 axis Methodology: BC patients (n=20) were recruited in the study. Bioinformatic analysis was performed using different prediction softwares. MDA-MB-231 and MCF-7 cells were cultured and transfected using several oligonucleotides or treated with serial dilutions of hesperitin. RNA was extracted and gene expression analysis was performed using q-RT-PCR. ICAM-1 protein levels were assessed using human ICAM-1 Elisa Kit. Cytotoxic potential of hesperitin against normal cells was assessed by LDH assay. Several functional analysis experiments were performed such as MTT, colony forming and migration assays. RESULTS The study showed that miR-486-5p and H19 has a paradoxical expression profiles in mBC patients. miR-486-5p mimics and H19 siRNAs repressed ICAM-1 and halted mBC hallmarks. A novel crosstalk between miR-486-5p and H19 was observed highlighting a bi-directional relationship between them. Hesperetin restored the expression of miR-486-5p, inhibited H19 lncRNA and ICAM-1 expression and selectively regressed mBC cell aggressiveness. CONCLUSION miR-486-5p and H19 are inter-connected upstream regulators for ICAM-1 building up miR-486-5p/H19/ICAM-1 axis that has been successfully tuned in mBC cells by hesperitin.
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Affiliation(s)
- Ramah M Abdallah
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
| | - Aisha M Elkhouly
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
| | - Raghda A Soliman
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
| | | | - Ahmed El Sebaei
- Pathology Department International Medical center, Cairo, Egypt
| | - Amira A Motaal
- Department of Pharmacognosy, Cairo University, Cairo, Egypt
| | | | - Rana A Youness
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
| | - Reem A Assal
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
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El Kilany FH, Youness RA, Assal RA, Gad MZ. miR-744/eNOS/NO axis: A novel target to halt triple negative breast cancer progression. Breast Dis 2021; 40:161-169. [PMID: 33749631 DOI: 10.3233/bd-200454] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Nitric oxide (NO) may have a dual role in cancer. At low concentrations, endogenous NO promotes tumor growth and proliferation. However, at very high concentrations, it mediates cancer cell apoptosis and inhibits cancer growth. High levels of NO have been observed in blood of breast cancer (BC) patients, which increases tumor blood flow and promotes angiogenesis. To date, the regulation of NO-synthesizing enzyme, eNOS, by miRNAs has not been adequately investigated in BC. Therefore, the main aim of this study is to unravel the possible regulation of eNOS by miRNAs in BC and to examine their influence on NO production and BC progression. METHODS Expression profile of eNOS in Egyptian BC patients and MDA-MB-231 cell lines was investigated using qRT-PCR. In-silico analysis was performed to predict a putative upstream regulator of eNOS. miR-744-5p was selected and its expression was quantified in BC tissues using qRT-PCR. MDA-MB-231 cells were cultured and transfected with miR-744-5p using lipofection method. NO levels were determined using Griess Reagent. Cellular viability and colony-forming ability were assessed using MTT and colony-forming assays; respectively. RESULTS eNOS and miR-744-5p were significantly up-regulated in BC tissues compared to paired normal tissues. In-silico analysis revealed that miR-744-5p putatively binds to eNOS transcript with high binding scores. Transfection of MDA-MB-231 cells with miR-744-5p mimics resulted in a significant up-regulation of eNOS and consequently NO levels. In addition, miR-744-5p transfection led to an increase in cellular viability and colony-forming ability of the MDA-MB-231. CONCLUSION miR-744-5p acts as an upstream positive regulator of the NO synthesizing enzyme, eNOS which in turn elevates NO levels. Furthermore, miR-744-5p is a novel oncogenic miRNA in BC. Thus, targeting miR-744/eNOS/NO axis may act as a therapeutic tool in TNBC.
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Affiliation(s)
- Farah Hady El Kilany
- Department of Biochemistry, German University in Cairo, New Cairo City, Cairo, Egypt
| | - Rana Ahmed Youness
- Pharmaceutical Biology Department, German University in Cairo, New Cairo City, Cairo, Egypt
| | - Reem Amr Assal
- Department of Pharmacology and Toxicology, German University in Cairo, New Cairo City, Cairo, Egypt
| | - Mohamed Zakaria Gad
- Department of Biochemistry, German University in Cairo, New Cairo City, Cairo, Egypt
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A. Youness R, Kamel R, A. Elkasabgy N, Shao P, A. Farag M. Recent Advances in Tannic Acid (Gallotannin) Anticancer Activities and Drug Delivery Systems for Efficacy Improvement; A Comprehensive Review. Molecules 2021; 26:1486. [PMID: 33803294 PMCID: PMC7967207 DOI: 10.3390/molecules26051486] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/23/2021] [Accepted: 02/26/2021] [Indexed: 12/24/2022] Open
Abstract
Tannic acid is a chief gallo-tannin belonging to the hydrolysable tannins extracted from gall nuts and other plant sources. A myriad of pharmaceutical and biological applications in the medical field has been well recognized to tannic acid. Among these effects, potential anticancer activities against several solid malignancies such as liver, breast, lung, pancreatic, colorectal and ovarian cancers have been reported. Tannic acid was found to play a maestro-role in tuning several oncological signaling pathways including JAK/STAT, RAS/RAF/mTOR, TGF-β1/TGF-β1R axis, VEGF/VEGFR and CXCL12/CXCR4 axes. The combinational beneficial effects of tannic acid with other conventional chemotherapeutic drugs have been clearly demonstrated in literature such as a synergistic anticancer effect and enhancement of the chemo-sensitivity in several resistant cases. Yet, clinical applications of tannic acid have been limited owing to its poor lipid solubility, low bioavailability, off-taste, and short half-life. To overcome such obstacles, novel drug delivery systems have been employed to deliver tannic acid with the aim of improving its applications and/or efficacy against cancer cells. Among these drug delivery systems are several types of organic and metallic nanoparticles. In this review, the authors focus on the molecular mechanisms of tannic acid in tuning several neoplastic diseases as well as novel drug delivery systems that can be used for its clinical applications with an attempt to provide a systemic reference to promote the development of tannic acid as a cheap drug and/or drug delivery system in cancer management.
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Affiliation(s)
- Rana A. Youness
- The Molecular Genetics Research Team, Department of Pharmaceutical Biology, Faculty of Pharmacy andBiotechnology, German University in Cairo, Cairo 12622, Egypt;
| | - Rabab Kamel
- Pharmaceutical Technology Department, National Research Centre, Cairo 12622, Egypt;
| | - Nermeen A. Elkasabgy
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt;
| | - Ping Shao
- Department of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China;
| | - Mohamed A. Farag
- Pharmacognosy Department, College of Pharmacy, Cairo University, Kasr El Aini St., Cairo 11562, Egypt
- Chemistry Department, School of Sciences & Engineering, The American University in Cairo, New Cairo 11835, Egypt
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Ghafouri-Fard S, Tamizkar KH, Hussen BM, Taheri M. An update on the role of long non-coding RNAs in the pathogenesis of breast cancer. Pathol Res Pract 2021; 219:153373. [DOI: 10.1016/j.prp.2021.153373] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 12/18/2022]
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Zhang W, Guan X, Tang J. The long non-coding RNA landscape in triple-negative breast cancer. Cell Prolif 2021; 54:e12966. [PMID: 33314471 PMCID: PMC7848969 DOI: 10.1111/cpr.12966] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 11/03/2020] [Accepted: 11/25/2020] [Indexed: 02/06/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a type of breast cancer that has a higher risk of distant recurrence and metastasis, leading to a relatively aggressive biological behaviour and poor outcome. So far, the clinical management of TNBC is challenging because of its heterogeneity and paucity of specific targeted therapy. Recently, various studies have identified a lot of differently expressed long non-coding RNAs (lncRNAs) in TNBC. Those lncRNAs have been reported to play important roles in the multistep process of TNBC tumorigenesis. Here, we review the biological characteristics of lncRNAs, and present the current state of knowledge concerning the expression, function and regulation of lncRNAs in TNBC. Accumulating studies explored the potential lncRNAs-based therapeutics in TNBC, including the techniques of genetic modification using antisense oligonucleotides, locked nucleic acid and RNA nanotechnology. In current review, we also discuss the future prospects of studies about lncRNAs in TNBC and development of lncRNA-based strategies for clinical TNBC patients.
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Affiliation(s)
- Wenwen Zhang
- Department of OncologyNanjing First Hospital, Nanjing Medical UniversityNanjingChina
| | - Xiaoxiang Guan
- Department of OncologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Jinhai Tang
- Department of General SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
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Zhang Y, Dong X, Wang Y, Wang L, Han G, Jin L, Fan Y, Xu G, Yuan D, Zheng J, Guo X, Gao P. Overexpression of LncRNA BM466146 Predicts Better Prognosis of Breast Cancer. Front Oncol 2021; 10:628757. [PMID: 33585256 PMCID: PMC7878538 DOI: 10.3389/fonc.2020.628757] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 12/10/2020] [Indexed: 12/19/2022] Open
Abstract
This study analyzes the expression and clinical significance of long non-coding RNA (lncRNA) BM466146 in breast cancer, and explores the role of BM466146 in immune regulation. The expression of BM466146 in 89 cases of breast cancer and their corresponding non-cancerous breast tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier survival analysis was applied to evaluate patient survival. EDU and CCK-8 experiments on breast cancer cells were performed to verify the function of BM466146 in vitro. The target genes of BM466146 were screened by informatics analysis to predict associated miRNAs and their corresponding mRNAs, immune genes associated with lncRNAs and chemokines associated with CD8. Immunohistochemistry was used to detect the expression of CD8, Ki-67, and CXCL-13 in the 89 breast cancer tissues. It was found that the expression of lncRNA BM466146 in breast cancer tissues was significantly lower than that in normal breast tissues (P < 0.001). In breast cancer, tissues that overexpressed BM466146 exhibited a lower Ki-67 index compared with that of low BM466146 expression (P = 0.048). Kaplan-Meier survival analysis showed that breast cancer patients with overexpression of BM466146 had longer overall survival. EDU and CCK8 experiments showed that overexpression of BM466146 inhibited the proliferation of breast cancer cells. The hsa-miR-224-3p is associated with BM466146, and its target gene might be CXCL-13. The positive CD8 cells in the BM466146 overexpression group was higher than that in the low BM466146 expression group (P=0.027), and the positive CD8 cells in the CXCL-13 positive group was higher (P=0.023) than that of the negative group. Our results indicate that the lncRNA BM466146 has the function of tumor suppressor gene. Overexpression of BM466146 is associated with better prognosis. BM466146 could regulate CXCL-13 by adsorbing hsa-miR-224-3p and inducing CD8+ T cells to accumulate in the tumor area which regulate immune response. Therefore, BM466146 could be a prognostic biomarker and a molecular immune target of breast cancer.
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Affiliation(s)
- Yunxiang Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education, Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, China.,Pathology Department, First Affiliated Hospital of Weifang Medical University, (Weifang People's Hospital), Weifang, China
| | - Xiaotong Dong
- Pathology Department, First Affiliated Hospital of Weifang Medical University, (Weifang People's Hospital), Weifang, China
| | - Yang Wang
- Breast Surgery Department, First Affiliated Hospital of Weifang Medical University, (Weifang People's Hospital), Weifang, China
| | - Liquan Wang
- Breast Surgery Department, First Affiliated Hospital of Weifang Medical University, (Weifang People's Hospital), Weifang, China
| | - Guiyan Han
- Pathology Department, First Affiliated Hospital of Weifang Medical University, (Weifang People's Hospital), Weifang, China
| | - Lvcheng Jin
- Pathology Department, First Affiliated Hospital of Weifang Medical University, (Weifang People's Hospital), Weifang, China
| | - Yanping Fan
- Pathology Department, First Affiliated Hospital of Weifang Medical University, (Weifang People's Hospital), Weifang, China
| | - Guodong Xu
- Pathology Department, First Affiliated Hospital of Weifang Medical University, (Weifang People's Hospital), Weifang, China
| | - Dawei Yuan
- Precision Medicine Department, Geneis Beijing Co., Ltd., Beijing, China
| | - Jie Zheng
- Department of Diagnostic Pathology, Weifang Medical University, Weifang, China
| | - Xiangyu Guo
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, China
| | - Peng Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education, Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, China
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Youness RA, Gad AZ, Sanber K, Ahn YJ, Lee GJ, Khallaf E, Hafez HM, Motaal AA, Ahmed N, Gad MZ. Targeting hydrogen sulphide signaling in breast cancer. J Adv Res 2021; 27:177-190. [PMID: 33318876 PMCID: PMC7728592 DOI: 10.1016/j.jare.2020.07.006] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/06/2020] [Accepted: 07/12/2020] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Hydrogen sulphide (H2S) has been established as a key member of the gasotransmitters family that recently showed a pivotal role in various pathological conditions including cancer. OBJECTIVES This study investigated the role of H2S in breast cancer (BC) pathogenesis, on BC immune recognition capacity and the consequence of targeting H2S using non-coding RNAs. METHODS Eighty BC patients have been recruited for the study. BC cell lines were cultured and transfected using validated oligonucleotide delivery system. Gene and protein expression analysis was performed using qRT-PCR, western blot and flow-cytometry. In-vitro analysis for BC hallmarks was performed using MTT, BrdU, Modified Boyden chamber, migration and colony forming assays. H2S and nitric oxide (NO) levels were measured spectrophotometrically. Primary natural killer cells (NK cells) and T cell isolation and chimeric antigen receptor transduction (CAR T cells) were performed using appropriate kits. NK and T cells cytotoxicity was measured. Finally, computational target prediction analysis and binding confirmation analyses were performed using different software and dual luciferase assay kit, respectively. RESULTS The H2S synthesizing enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), exhibited elevated levels in the clinical samples that correlated with tumor proliferation index. Knock-down of CBS and CSE in the HER2+ BC and triple negative BC (TNBC) cells resulted in significant attenuation of BC malignancy. In addition to increased susceptibility of HER2+ BC and TNBC to the cytotoxic activity of HER2 targeting CAR T cells and NK cells, respectively. Transcriptomic and phosphoprotein analysis revealed that H2S signaling is mediated through Akt in MCF7, STAT3 in MDA-MB-231 and miR-155/ NOS2/NO signaling in both cell lines. Lastly, miR-4317 was found to function as an upstream regulator of CBS and CSE synergistically abrogates the malignancy of BC cells. CONCLUSION These findings demonstrate the potential role of H2S signaling in BC pathogenesis and the potential of its targeting for disease mitigation.
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Key Words
- 41BBL, 41BB Ligand
- 51Cr-release, Chromium release assay
- BC, Breast Cancer
- Breast cancer
- CAR T cells
- CAR, Chimeric antigen receptor
- CBS, Cystathionine β-synthase
- CD80, Cluster of differentiation 80
- CD86, Cluster of differentiation 86
- CSE, Cystathionine γ-lyase
- CTL, Cytotoxic T lymphocyte
- H2S, Hydrogen sulphide
- HCC, Hepatocellular carcinoma
- HLA-DR, Human Leukocytic antigen DR
- Hydrogen sulphide
- IFN-γ, Interferon gamma
- KD, Knock down
- LDH, Lactate dehydrogenase Assay
- MICA/B, MHC class I polypeptide-related sequence A/B
- NK, Natural killer
- NKG2D, Natural Killer Group 2D
- NO, Nitric oxide
- NOS2, Inducible nitric oxide synthase-2
- NOS3, Endothelial nitric oxide synthase-3
- Natural killer cells
- Nitric oxide
- PD-L1, Programmed death-ligand 1
- PI3K/AKT signaling pathway
- Scr-miRNAs, Scrambled microRNAs
- Scr-siRNAs, Scrambled siRNAs
- TNBC, Triple negative breast cancer
- TNF-α, Tumor necrosis factor-α
- ULBP2/5/6, UL16 binding protein 2/5/6
- miR-155/NOS2/NO signaling pathway
- miR-4317
- miRNA, MicroRNA
- ncRNAs, Non-coding RNAs
- siRNAs, Small interfering RNAs
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Affiliation(s)
- Rana Ahmed Youness
- Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
| | - Ahmed Zakaria Gad
- Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Cell and Gene Therapy, Texas Children’s Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children’s Cancer and Hematology Centers, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Khaled Sanber
- Center for Cell and Gene Therapy, Texas Children’s Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children’s Cancer and Hematology Centers, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yong Jin Ahn
- Department of Medical Engineering, Graduate School, Kyung Hee University, Seoul 130-701, Republic of Korea
- Department of Biomedical Engineering, College of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea
| | - Gi-Ja Lee
- Department of Medical Engineering, Graduate School, Kyung Hee University, Seoul 130-701, Republic of Korea
- Department of Biomedical Engineering, College of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea
| | - Emad Khallaf
- Department of General Surgery, Faculty of Medicine, Cairo University, 12613 Cairo, Egypt
| | - Hafez Mohamed Hafez
- Department of General Surgery, Faculty of Medicine, Cairo University, 12613 Cairo, Egypt
| | - Amira Abdel Motaal
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Egypt
| | - Nabil Ahmed
- Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Cell and Gene Therapy, Texas Children’s Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children’s Cancer and Hematology Centers, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mohamed Zakaria Gad
- Department of Biochemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
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Nafea H, Youness RA, Abou-Aisha K, Gad MZ. LncRNA HEIH/miR-939-5p interplay modulates triple-negative breast cancer progression through NOS2-induced nitric oxide production. J Cell Physiol 2020; 236:5362-5372. [PMID: 33368266 DOI: 10.1002/jcp.30234] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/17/2020] [Accepted: 12/11/2020] [Indexed: 12/17/2022]
Abstract
This study aimed to unravel the regulatory role of noncoding RNAs (ncRNA) on the nitric oxide (NO) machinery system in triple-negative breast cancer (TNBC) patients and to further assess the influence of NO-modulating ncRNAs on TNBC progression, immunogenic profile, and the tumor microenvironment (TME). The results revealed miR-939-5p and lncRNA HEIH as novel ncRNAs modulating NO machinery in TNBC. MiR-939-5p, an underexpressed microRNA (miRNA) in BC patients, showed an inhibitory effect on NOS2 and NOS3 transcript levels on TNBC cells. In contrast, HEIH was found to be markedly upregulated in TNBC patients and showed a modulatory role on miR-939-5p/NOS2/NO axis. Functionally, miR-939-5p was characterized as a tumor suppressor miRNA while HEIH was categorized as a novel oncogenic lncRNA in TNBC. Finally, knocking down of HEIH resulted in improvement of immunogenic profile of TNBC cells through inducing MICA/B and suppressing the immune checkpoint inhibitor PDL1. In the same context, knockdown of HEIH resulted in the alleviation of the immune-suppressive TME by repressing interleukin-10 and tumor necrosis factor-α levels. In conclusion, this study identifies miR-939-5p as a tumor suppressor miRNA while HEIH as an oncogenic lncRNA exhibiting its effect through miR-939-5p/NOS2/NO axis. Therefore, repressing BC hallmarks, improving TNBC immunogenic profile, and trimming TME.
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Affiliation(s)
- Heba Nafea
- Department of Biochemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, New Cairo City, Egypt
| | - Rana A Youness
- Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, New Cairo City, Egypt
| | - Khaled Abou-Aisha
- Department of Microbiology and Immunology, Faculty of Pharmacy and Biotechnology, German University in Cairo, New Cairo City, Egypt
| | - Mohamed Z Gad
- Department of Biochemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, New Cairo City, Egypt
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Xu HK, Chen LJ, Zhou SN, Li YF, Xiang C. Multifunctional role of microRNAs in mesenchymal stem cell-derived exosomes in treatment of diseases. World J Stem Cells 2020; 12:1276-1294. [PMID: 33312398 PMCID: PMC7705472 DOI: 10.4252/wjsc.v12.i11.1276] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/23/2020] [Accepted: 09/18/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells can be replaced by exosomes for the treatment of inflammatory diseases, injury repair, degenerative diseases, and tumors. Exosomes are small vesicles rich in a variety of nucleic acids [including messenger RNA, Long non-coding RNA, microRNA (miRNA), and circular RNA], proteins, and lipids. Exosomes can be secreted by most cells in the human body and are known to play a key role in the communication of information and material transport between cells. Like exosomes, miRNAs were neglected before their role in various activities of organisms was discovered. Several studies have confirmed that miRNAs play a vital role within exosomes. This review focuses on the specific role of miRNAs in MSC-derived exosomes (MSC-exosomes) and the methods commonly used by researchers to study miRNAs in exosomes. Taken together, miRNAs from MSC-exosomes display immense potential and practical value, both in basic medicine and future clinical applications, in treating several diseases.
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Affiliation(s)
- Hui-Kang Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Li-Jun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Si-Ning Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Yi-Fei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.
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Abdel-Latif M, Youness RA. Why natural killer cells in triple negative breast cancer? World J Clin Oncol 2020; 11:464-476. [PMID: 32821652 PMCID: PMC7407924 DOI: 10.5306/wjco.v11.i7.464] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/28/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
The triple-negative subtype of breast cancer (TNBC) has the bleakest prognosis, owing to its lack of either hormone receptor as well as human epidermal growth factor receptor 2. Henceforth, immunotherapy has emerged as the front-runner for TNBC treatment, which avoids potentially damaging chemotherapeutics. However, despite its documented association with aggressive side effects and developed resistance, immune checkpoint blockade continues to dominate the TNBC immunotherapy scene. These immune checkpoint blockade drawbacks necessitate the exploration of other immunotherapeutic methods that would expand options for TNBC patients. One such method is the exploitation and recruitment of natural killer cells, which by harnessing the innate rather than adaptive immune system could potentially circumvent the downsides of immune checkpoint blockade. In this review, the authors will elucidate the advantageousness of natural killer cell-based immuno-oncology in TNBC as well as demonstrate the need to more extensively research such therapies in the future.
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Affiliation(s)
- Mustafa Abdel-Latif
- Biotechnology Program, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Rana Ahmed Youness
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
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Wu H, Wei M, Jiang X, Tan J, Xu W, Fan X, Zhang R, Ding C, Zhao F, Shao X, Zhang Z, Shi R, Zhang W, Wu G. lncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 20:438-450. [PMID: 32276209 PMCID: PMC7139143 DOI: 10.1016/j.omtn.2020.03.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 03/12/2020] [Indexed: 01/07/2023]
Abstract
Recently, the long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was reported to be involved in the pathogenesis of several cancers, including human colorectal cancer (CRC). However, the molecular basis for cancer initiation, development, and progression remains unclear. In this study, we observe that upregulated PVT1 is associated with poor prognosis and bad clinicopathological features of CRC patients. In vitro means of PVT1 loss in a CRC cell line inhibit cell proliferation, migration, and invasion. Furthermore, dual-luciferase reporter and RNA pull-down assays indicated that PVT1 binds to miR-16-5p, which has been shown to play strong tumor suppressive roles in CRC. Targeted loss of miR-16-5p partially rescues the suppressive effect induced by PVT1 knockdown. Vascular endothelial growth factor A (VEGFA), a direct downstream target of miR-16-5p, was suppressed by PVT1 knockdown in CRC cells. Overexpression of VEGFA is known to modulate the AKT signaling cascade by activating vascular endothelial growth factor receptor 1 (VEGFR1). We, therefore, show that PVT1 loss combined with miR-16-5p overexpression reduces tumor volume maximally when propagated within a mouse xenograft model. We conclude that the PVT1-miR-16-5p/VEGFA/VEGFR1/AKT axis directly coordinates the response in CRC pathogenesis and suggest PVT1 as a novel target for potential CRC therapy.
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Affiliation(s)
- Hailu Wu
- Medical School of Southeast University, Nanjing 210009, People's Republic of China; Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Ming Wei
- Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Xinglu Jiang
- Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Jiacheng Tan
- Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Wei Xu
- Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Xiaobo Fan
- Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Rui Zhang
- Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Chenbo Ding
- Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Fengfeng Zhao
- Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Xiangyu Shao
- Department of Gastrointestinal Surgery, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Zhigang Zhang
- Medical School of Southeast University, Nanjing 210009, People's Republic of China; Department of Gastrointestinal Surgery, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Ruihua Shi
- Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China
| | - Weijia Zhang
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Guoqiu Wu
- Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China.
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