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Zahir M, Tavakoli B, Zaki-Dizaji M, Hantoushzadeh S, Majidi Zolbin M. Non-coding RNAs in Recurrent implantation failure. Clin Chim Acta 2024; 553:117731. [PMID: 38128815 DOI: 10.1016/j.cca.2023.117731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 12/23/2023]
Abstract
Recurrent implantation failure (RIF), defined as the inability to achieve conception following multiple consecutive in-vitro fertilization (IVF) attempts, represents a complex and multifaceted challenge in reproductive medicine. The emerging role of non-coding RNAs in RIF etiopathogenesis has only gained prominence over the last decade, illustrating a new dimension to our understanding of the intricate network underlying RIF. Successful embryo implantation demands a harmonious synchronization between an adequately decidualized endometrium, a competent blastocyst, and effective maternal-embryonic interactions. Emerging evidence has clarified the involvement of a sophisticated network of non-coding RNAs, including microRNAs, circular RNAs, and long non-coding RNAs, in orchestrating these pivotal processes. Disconcerted expression of these molecules can disrupt the delicate equilibrium required for implantation, amplifying the risk of RIF. This comprehensive review presents an in-depth investigation of the complex role played by non-coding RNAs in the pathogenesis of RIF. Furthermore, it underscores the vast potential of non-coding RNAs as diagnostic biomarkers and therapeutic targets, with the ultimate goal of enhancing implantation success rates in IVF cycles. As ongoing research continues to unravel the intercalated web of molecular interactions, exploiting the power of non-coding RNAs may offer promising avenues for mitigating the challenges posed by RIF and improving the outcomes of assisted reproduction.
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Affiliation(s)
- Mazyar Zahir
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahareh Tavakoli
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Biology, Maragheh University, Maragheh, Iran
| | - Majid Zaki-Dizaji
- Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
| | - Sedigheh Hantoushzadeh
- Vali-E-Asr Reproductive Health Research Center, Family Health Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Masoumeh Majidi Zolbin
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
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2
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Varrone M, Tavernari D, Santamaria-Martínez A, Walsh LA, Ciriello G. CellCharter reveals spatial cell niches associated with tissue remodeling and cell plasticity. Nat Genet 2024; 56:74-84. [PMID: 38066188 DOI: 10.1038/s41588-023-01588-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 10/23/2023] [Indexed: 12/20/2023]
Abstract
Tissues are organized in cellular niches, the composition and interactions of which can be investigated using spatial omics technologies. However, systematic analyses of tissue composition are challenged by the scale and diversity of the data. Here we present CellCharter, an algorithmic framework to identify, characterize, and compare cellular niches in spatially resolved datasets. CellCharter outperformed existing approaches and effectively identified cellular niches across datasets generated using different technologies, and comprising hundreds of samples and millions of cells. In multiple human lung cancer cohorts, CellCharter uncovered a cellular niche composed of tumor-associated neutrophil and cancer cells expressing markers of hypoxia and cell migration. This cancer cell state was spatially segregated from more proliferative tumor cell clusters and was associated with tumor-associated neutrophil infiltration and poor prognosis in independent patient cohorts. Overall, CellCharter enables systematic analyses across data types and technologies to decode the link between spatial tissue architectures and cell plasticity.
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Affiliation(s)
- Marco Varrone
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
- Swiss Cancer Center Léman, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Daniele Tavernari
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
- Swiss Cancer Center Léman, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Albert Santamaria-Martínez
- Swiss Cancer Center Léman, Lausanne, Switzerland
- Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Logan A Walsh
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
| | - Giovanni Ciriello
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
- Swiss Cancer Center Léman, Lausanne, Switzerland.
- Swiss Institute of Bioinformatics, Lausanne, Switzerland.
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3
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He YX, Shen H, Ji YZ, Hua HR, Zhu Y, Zeng XF, Wang F, Wang KX. N-myc downstream regulated gene 1 inhibition of tumor progression in Caco2 cells. World J Gastrointest Oncol 2022; 14:2313-2328. [PMID: 36568939 PMCID: PMC9782617 DOI: 10.4251/wjgo.v14.i12.2313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/17/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Invasion and migration are the irreversible stages of colorectal cancer (CRC). The key is to find a sensitive, reliable molecular marker that can predict the migration of CRC at an early stage. N-myc downstream regulated gene 1 (NDRG1) is a multifunctional gene that has been tentatively reported to have a strong relationship with tumor invasion and migration, however the current molecular role of NDRG1 in CRC remains unknown.
AIM To explore the role of NDRG1 in the development of CRC.
METHODS NDRG1 stably over-expressed Caco2 cell line was established by lentiviral infection and NDRG1 knock-out Caco2 cell line was established by CRISPR/Cas9. Furthermore, the mRNA and protein levels of NDRG1 in Caco2 cells after NDRG1 over-expression and knockout were detected by real-time polymerase chain reaction and western blot. The cell proliferation rate was measured by the cell counting kit-8 method; cell cycle and apoptosis were detected by flow cytometry; invasion and migration ability were detected by the 24-transwell method.
RESULTS NDRG1 over-expression inhibited Caco2 proliferation and the cell cycle could be arrested at the G1/S phase when NDRG1 was over-expressed, while the number of cells in the G2 phase was significantly increased when NDRG1 was knocked out. This suggests that NDRG1 inhibited the proliferation of Caco2 cells by arresting the cell cycle in the G1/S phase. Our data also demonstrated that NDRG1 promotes early cell apoptosis. Invasion and migration of cells were extensively inhibited when NDRG1 was over-expressed.
CONCLUSION NDRG1 inhibits tumor progression in Caco2 cells which may represent a potential novel therapeutic strategy for the treatment of CRC.
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Affiliation(s)
- Yi-Xiao He
- Department of Pathology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, Sichuan Province, China
- Department of Pathology and Pathophysiology, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Hong Shen
- Department of Pathology, Zhaotong First People’s Hospital, Zhaotong 657000, Yunnan Province, China
| | - Yu-Zhu Ji
- Department of Pathology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, Sichuan Province, China
| | - Hai-Rong Hua
- Department of Pathology and Pathophysiology, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Yu Zhu
- School of Nursing, Henan Vocational College of Applied Technology, Kaifeng 450000, Henan Province, China
| | - Xiang-Fei Zeng
- Department of Clinical Pathology, West China Hospital, Sichuan University, Chengdu 610000, Sichuan Province, China
| | - Fang Wang
- Department of Pathology and Pathophysiology, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Kai-Xin Wang
- Department of Pathology, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen 518052, Guangdong Province, China
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4
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Yu SL, Kang Y, Jeong DU, Lee DC, Jeon HJ, Kim TH, Lee SK, Han AR, Kang J, Park SR. The miR-182-5p/NDRG1 Axis Controls Endometrial Receptivity through the NF-κB/ZEB1/E-Cadherin Pathway. Int J Mol Sci 2022; 23:ijms232012303. [PMID: 36293154 PMCID: PMC9602861 DOI: 10.3390/ijms232012303] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/29/2022] [Accepted: 09/29/2022] [Indexed: 11/07/2022] Open
Abstract
Endometrial receptivity is essential for successful pregnancy, and its impairment is a major cause of embryo-implantation failure. MicroRNAs (miRNAs) that regulate epigenetic modifications have been associated with endometrial receptivity. However, the molecular mechanisms whereby miRNAs regulate endometrial receptivity remain unclear. Therefore, we investigated whether miR-182 and its potential targets influence trophoblast cell attachment. miR-182 was expressed at lower levels in the secretory phase than in the proliferative phase of endometrium tissues from fertile donors. However, miR-182 expression was upregulated during the secretory phase in infertile women. Transfecting a synthetic miR-182-5p mimic decreased spheroid attachment of human JAr choriocarcinoma cells and E-cadherin expression (which is important for endometrial receptivity). miR-182-5p also downregulated N-Myc downstream regulated 1 (NDRG1), which was studied further. NDRG1 was upregulated in the secretory phase of the endometrium tissues and induced E-cadherin expression through the nuclear factor-κΒ (NF-κΒ)/zinc finger E-box binding homeobox 1 (ZEB1) signaling pathway. NDRG1-overexpressing or -depleted cells showed altered attachment rates of JAr spheroids. Collectively, our findings indicate that miR-182-5p-mediated NDRG1 downregulation impaired embryo implantation by upregulating the NF-κΒ/ZEB1/E-cadherin pathway. Hence, miR-182-5p is a potential biomarker for negative selection in endometrial receptivity and a therapeutic target for successful embryo implantation.
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Affiliation(s)
- Seong-Lan Yu
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Yujin Kang
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Da-Un Jeong
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Dong Chul Lee
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Hye Jin Jeon
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Tae-Hyun Kim
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea
- Department of Obstetrics and Gynecology, Konyang University Hospital, Daejeon 35365, Korea
| | - Sung Ki Lee
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea
- Department of Obstetrics and Gynecology, Konyang University Hospital, Daejeon 35365, Korea
| | - Ae Ra Han
- I-Dream Clinic, Department of Obstetrics and Gynecology, Mizmedi Hospital, Seoul 07639, Korea
- Daegu cha Fertility Center, CHA University, Daegu 42469, Korea
| | - Jaeku Kang
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea
- Department of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, Korea
- Correspondence: (J.K.); (S.-R.P.); Tel.: +82-42-600-8685 (J.K.); +82-42-600-8695 (S.-R.P.)
| | - Seok-Rae Park
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea
- Department of Microbiology, College of Medicine, Konyang University, Daejeon 35365, Korea
- Correspondence: (J.K.); (S.-R.P.); Tel.: +82-42-600-8685 (J.K.); +82-42-600-8695 (S.-R.P.)
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Mirzaei S, Saghari S, Bassiri F, Raesi R, Zarrabi A, Hushmandi K, Sethi G, Tergaonkar V. NF-κB as a regulator of cancer metastasis and therapy response: A focus on epithelial-mesenchymal transition. J Cell Physiol 2022; 237:2770-2795. [PMID: 35561232 DOI: 10.1002/jcp.30759] [Citation(s) in RCA: 129] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/24/2022] [Accepted: 04/19/2022] [Indexed: 12/13/2022]
Abstract
Metastasis of tumor cells is a complex challenge and significantly diminishes the overall survival and prognosis of cancer patients. The epithelial-to-mesenchymal transition (EMT) is a well-known mechanism responsible for the invasiveness of tumor cells. A number of molecular pathways can regulate the EMT mechanism in cancer cells and nuclear factor-kappaB (NF-κB) is one of them. The nuclear translocation of NF-κB p65 can induce the transcription of several genes involved in EMT induction. The present review describes NF-κB and EMT interaction in cancer cells and their association in cancer progression. Due to the oncogenic role NF-κB signaling, its activation enhances metastasis of tumor cells via EMT induction. This has been confirmed in various cancers including brain, breast, lung and gastric cancers, among others. The ZEB1/2, transforming growth factor-β, and Slug as inducers of EMT undergo upregulation by NF-κB to promote metastasis of tumor cells. After EMT induction driven by NF-κB, a significant decrease occurs in E-cadherin levels, while N-cadherin and vimentin levels undergo an increase. The noncoding RNAs can potentially also function as upstream mediators and modulate NF-κB/EMT axis in cancers. Moreover, NF-κB/EMT axis is involved in mediating drug resistance in tumor cells. Thus, suppressing NF-κB/EMT axis can also promote the sensitivity of cancer cells to chemotherapeutic agents.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Sam Saghari
- Department of Health Services Management, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Farzaneh Bassiri
- Department of Biology, Fars Science and Research Branch, Islamic Azad University, Fars, Iran.,Department of Biology, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Rasoul Raesi
- PhD in Health Services Management, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, Turkey
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology and Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Yong Loo Lin School of Medicine, NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, Singapore
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology (IMCB), 61 Biopolis Drive, Proteos, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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6
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Lin Q, Liu M, Yue GGL, Cheung MK, Lai Z, Kwok FHF, Lee JKM, Wang Z, Lau CBS, Tan N. Anti-inflammatory activities of natural cyclopeptide RA-XII in colitis-associated colon cancer mouse model and its effect on gut microbiome. Phytother Res 2022; 36:2641-2659. [PMID: 35537703 DOI: 10.1002/ptr.7482] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 04/07/2022] [Accepted: 04/09/2022] [Indexed: 12/19/2022]
Abstract
Colorectal cancer (CRC), the third most common cancer globally, is associated with intestinal inflammation that leads to poor prognosis. RA-XII, a natural cyclopeptide, has previously been reported to possess anti-tumor activities. Here, the anti-inflammatory activities of RA-XII were investigated in colitis-associated colon cancer mice and a co-culture in vitro model, in which colon cancer cells HCT116 and macrophages RAW264.7 were grown together to mimic the inflammatory microenvironment of CRC. Changes of inflammatory-related molecules and protein expressions in cells were evaluated after RA-XII incubation. Besides, azoxymethane and dextran sulfate sodium-induced colitis-associated colon cancer mice were treated with RA-XII for 24 days, inflammatory parameters and gut microbiome alterations were studied. Our results showed that RA-XII reversed the inflammatory responses of RAW264.7 cells induced by LPS and modulated the protein expressions of AKT, STAT3/p-STAT3, P70S6K, NF-κB and GSK3β and suppressed the expression of LC3A/B in HCT116 cells in co-culture system. RA-XII treatment restored the colitis damage in colon, reduced colon tumors numbers and decreased inflammatory factors (IL-6, IL-10 and TNF-α). The role of RA-XII on regulating gut microbiome was also demonstrated for the first time. In conclusion, our findings provided new scientific evidence for developing RA-XII as a potent anti-inflammatory agent for CRC.
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Affiliation(s)
- Qianwen Lin
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Mingyu Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Grace Gar-Lee Yue
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Man Kit Cheung
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Zhixing Lai
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Frankie Hin-Fai Kwok
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Julia Kin-Ming Lee
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Zhe Wang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Clara Bik-San Lau
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ninghua Tan
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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You GR, Chang JT, Li HF, Cheng AJ. Multifaceted and Intricate Oncogenic Mechanisms of NDRG1 in Head and Neck Cancer Depend on Its C-Terminal 3R-Motif. Cells 2022; 11:cells11091581. [PMID: 35563887 PMCID: PMC9104279 DOI: 10.3390/cells11091581] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/04/2022] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
N-Myc downstream-regulated 1 (NDRG1) has inconsistent oncogenic functions in various cancers. We surveyed and characterized the role of NDRG1 in head and neck cancer (HNC). Cellular methods included spheroid cell formation, clonogenic survival, cell viability, and Matrigel invasion assays. Molecular techniques included transcriptomic profiling, RT-qPCR, immunoblotting, in vitro phosphorylation, immunofluorescent staining, and confocal microscopy. Prognostic significance was assessed by Kaplan–Meier analysis. NDRG1 participated in diverse oncogenic functions in HNC cells, mainly stress response and cell motility. Notably, NDRG1 contributed to spheroid cell growth, radio-chemoresistance, and upregulation of stemness-related markers (CD44 and Twist1). NDRG1 facilitated cell migration and invasion, and was associated with modulation of the extracellular matrix molecules (fibronectin, vimentin). Characterizing the 3R-motif in NDRG1 revealed its mechanism in the differential regulation of the phenotypes. The 3R-motif displayed minimal effect on cancer stemness but was crucial for cell motility. Phosphorylating the motif by GSK3b at serine residues led to its nuclear translocation to promote motility. Clinical analyses supported the oncogenic function of NDRG1, which was overexpressed in HNC and associated with poor prognosis. The data elucidate the multifaceted and intricate mechanisms of NDRG1 in HNC. NDRG1 may be a prognostic indicator or therapeutic target for refractory HNC.
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Affiliation(s)
- Guo-Rung You
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
| | - Joseph T. Chang
- Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 33302, Taiwan;
- School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Hsiao-Fan Li
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
| | - Ann-Joy Cheng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 33302, Taiwan;
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Correspondence: ; Tel.: +886-3-211-8800
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Ge H, Xu C, Chen H, Liu L, Zhang L, Wu C, Lu Y, Yao Q. Traditional Chinese Medicines as Effective Reversals of Epithelial-Mesenchymal Transition Induced-Metastasis of Colorectal Cancer: Molecular Targets and Mechanisms. Front Pharmacol 2022; 13:842295. [PMID: 35308223 PMCID: PMC8931761 DOI: 10.3389/fphar.2022.842295] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/28/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common type of cancer worldwide. Distant metastasis is the major cause of cancer-related mortality in patients with CRC. Epithelial-mesenchymal transition (EMT) is a critical process triggered during tumor metastasis, which is also the main impetus and the essential access within this duration. Therefore, targeting EMT-related molecular pathways has been considered a novel strategy to explore effective therapeutic agents against metastatic CRC. Traditional Chinese medicines (TCMs) with unique properties multi-target and multi-link that exert their therapeutic efficacies holistically, which could inhibit the invasion and metastasis ability of CRC cells via inhibiting the EMT process by down-regulating transforming growth factor-β (TGF-β)/Smads, PI3K/Akt, NF-κB, Wnt/β-catenin, and Notch signaling pathways. The objective of this review is to summarize and assess the anti-metastatic effect of TCM-originated bioactive compounds and Chinese medicine formulas by mediating EMT-associated signaling pathways in CRC therapy, providing a foundation for further research on the exact mechanisms of action through which TCMs affect EMT transform in CRC.
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Affiliation(s)
- Hongzhang Ge
- Department of Integrated Traditional Chinese and Western Medicine, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Integration of Chinese and Western Medicine Oncology, Zhejiang Cancer Hospital, Hangzhou, China
- Key Laboratory of Head and Neck Cancer Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
| | - Chao Xu
- Department of Integrated Traditional Chinese and Western Medicine, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Integration of Chinese and Western Medicine Oncology, Zhejiang Cancer Hospital, Hangzhou, China
- Key Laboratory of Head and Neck Cancer Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
| | - Haitao Chen
- Department of Integrated Traditional Chinese and Western Medicine, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Integration of Chinese and Western Medicine Oncology, Zhejiang Cancer Hospital, Hangzhou, China
- Key Laboratory of Head and Neck Cancer Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
| | - Ling Liu
- Department of Integrated Traditional Chinese and Western Medicine, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Integration of Chinese and Western Medicine Oncology, Zhejiang Cancer Hospital, Hangzhou, China
- Key Laboratory of Head and Neck Cancer Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
| | - Lei Zhang
- Department of Integrated Traditional Chinese and Western Medicine, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Integration of Chinese and Western Medicine Oncology, Zhejiang Cancer Hospital, Hangzhou, China
- Key Laboratory of Head and Neck Cancer Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
| | - Changhong Wu
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yi Lu
- Department of Clinical Nutrition, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Qinghua Yao
- Department of Integrated Traditional Chinese and Western Medicine, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Integration of Chinese and Western Medicine Oncology, Zhejiang Cancer Hospital, Hangzhou, China
- Key Laboratory of Head and Neck Cancer Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Clinical Nutrition, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- *Correspondence: Qinghua Yao,
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Zhang J, Yang Y, Dong Y, Liu C. Microrchidia family CW‑type zinc finger 2 promotes the proliferation, invasion, migration and epithelial‑mesenchymal transition of glioma by regulating PTEN/PI3K/AKT signaling via binding to N‑myc downstream regulated gene 1 promoter. Int J Mol Med 2021; 49:16. [PMID: 34913078 PMCID: PMC8711590 DOI: 10.3892/ijmm.2021.5071] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 07/02/2021] [Indexed: 11/05/2022] Open
Abstract
Glioma is a common malignant tumor of the central nervous system with high incidence and mortality. The present study aimed to investigate the role of Microrchidia family CW‑type zinc finger 2 (MORC2) in the development of glioma. Firstly, MORC2 expression was detected in several glioma cell lines (U251, SHG44, LN229 and T98G). Following MORC2 silencing, cell proliferation was evaluated using the Cell Counting Kit‑8 assay and the expression of proliferation‑related proteins was assessed via immunofluorescence staining or western blotting. Cell invasion and migration were assessed using transwell and wound healing assays, respectively. Western blotting and immunofluorescence staining were employed to determine the expression of epithelial‑mesenchymal transition (EMT)‑associated proteins. The protein expression of N‑myc downstream regulated gene 1 (NDRG1) and PTEN/PI3K/AKT signaling was determined with western blot analysis. Then, the luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were employed to evaluate the binding between MORC2 and NDRG1 promoter. Subsequently, cellular functional experiments were performed to assess the effects of NDRG1 on the progression of glioma after NDRG1 and MORC2 overexpression. In addition, tumor‑bearing experiments were conducted using a U251 tumor‑bearing nude mice model to detect tumor growth. The expression of proliferation (proliferating cell nuclear antigen, cyclin‑dependent kinase 2 and cyclin E1), migration [matrix metalloproteinase (MMP)2 and MMP9], EMT (E‑cadherin, N‑cadherin and Vimentin) and PTEN/PI3K/AKT signaling proteins in tumor tissues was examined with immunohistochemistry assay or western blotting. Results revealed that MORC2 was notably unregulated in glioma cells compared with the normal human astrocyte. Loss‑function of MORC2 inhibited the proliferation, invasion, migration and EMT of glioma cells. Importantly, MORC2 silencing upregulated NDRG1 expression and inactivated PTEN/PI3K/AKT signaling. Additionally, the luciferase reporter‑ and ChIP assays confirmed that MORC2 could bind to the NDRG1 promoter. NDRG1 upregulation suppressed the progression of glioma and these effects were partially reversed by MORC2 overexpression. Results of tumor‑bearing experiments suggested that gain‑function of NDRG1 inhibited tumor growth and downregulated the expression of proliferation, migration and EMT‑related proteins in tumorous tissue in U251 tumor‑bearing mice, which was partially counteracted after MORC2 overexpression. In addition, MORC2 overexpression abrogated the inhibitory effect of NDRG1 on PTEN/PI3K/AKT signaling. In summary, MORC2 promoted the progression of glioma by inactivation of PTEN/PI3K/AKT signaling via binding to NDRG1 promoter, providing a novel and potent target for the treatment of glioma.
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Affiliation(s)
- Jing Zhang
- Department of Neurosurgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Yunna Yang
- Department of Neurosurgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Yipeng Dong
- Department of Neurosurgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Cang Liu
- Department of Neurosurgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
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10
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Luo Z, Fan Y, Liu X, Liu S, Kong X, Ding Z, Li Y, Wei L. MiR-188-3p and miR-133b Suppress Cell Proliferation in Human Hepatocellular Carcinoma via Post-Transcriptional Suppression of NDRG1. Technol Cancer Res Treat 2021; 20:15330338211033074. [PMID: 34355586 PMCID: PMC8358491 DOI: 10.1177/15330338211033074] [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] [Indexed: 12/24/2022] Open
Abstract
Background: Previous studies reported that N-myc downstream-regulated gene 1 (NDRG1) was upregulated in various cancer tissues and decreased expression of miR-188-3p and miR-133b could suppress cell proliferation, metastasis, and invasion and induce apoptosis of cancer cells. However, the molecular mechanism of NRDG1 involved in hepatocellular carcinoma (HCC) tumorigenesis is still unknown. Methods: The expressions of miR-188-3p, miR-133b, and NRDG1 in HCC tissues and cells were quantified by qRT-PCR and Western blot. MTT assay and transwell invasion assay were performed to evaluate cell growth and cell migration, respectively. Luciferase reporter assay were performed to determine whether miR-188-3p and miR-133b could directly bind to NRDG1 in HCC cells. Results: The results showed that NRDG1 was upregulated and these 2 microRNAs were downregulated in HCC tissues. NRDG1 was negatively correlated with miR-188-3p and miR-133b in HCC tissues. MiR-188-3p and miR-133b were demonstrated to directly bind to 3′UTR of NRDG1 and inhibit its expression. Upregulation of miR-188-3p and miR-133b reduced NRDG1 expression in hepatocellular carcinoma cell lines, which consequently inhibited cell growth and cell migration. Conclusions: Our finding suggested that miR-188-3p and miR-133b exert a suppressive effect on hepatocellular carcinoma proliferation, invasion, and migration through downregulation of NDRG1.
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Affiliation(s)
- Zhenzhao Luo
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Yue Fan
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Xianchang Liu
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Shuiyi Liu
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyu Kong
- Department of General Surgery, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Zhonghuan Ding
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Ying Li
- Physical Examination Center, 117921Renmin Hospital of Wuhan University, Wuhan, China
| | - Liqing Wei
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
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11
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Wang J, Yu S, Chen G, Kang M, Jin X, Huang Y, Lin L, Wu D, Wang L, Chen J. A novel prognostic signature of immune-related genes for patients with colorectal cancer. J Cell Mol Med 2020; 24:8491-8504. [PMID: 32564470 PMCID: PMC7412433 DOI: 10.1111/jcmm.15443] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/03/2020] [Accepted: 05/07/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers with an estimated 1.8 million new cases worldwide and associated with high mortality rates of 881 000 CRC-related deaths in 2018. Screening programs and new therapies have only marginally improved the survival of CRC patients. Immune-related genes (IRGs) have attracted attention in recent years as therapeutic targets. The aim of this study was to identify an immune-related prognostic signature for CRC. To this end, we combined gene expression and clinical data from the CRC data sets of The Cancer Genome Atlas (TCGA) into an integrated immune landscape profile. We identified a total of 476 IRGs that were differentially expressed in CRC vs normal tissues, of which 18 were survival related according to univariate Cox analysis. Stepwise multivariate Cox proportional hazards analysis established an immune-related prognostic signature consisting of SLC10A2, FGF2, CCL28, NDRG1, ESM1, UCN, UTS2 and TRDC. The predictive ability of this signature for 3- and 5-year overall survival was determined using receiver operating characteristics (ROC), and the respective areas under the curve (AUC) were 79.2% and 76.6%. The signature showed moderate predictive accuracy in the validation and GSE38832 data sets as well. Furthermore, the 8-IRG signature correlated significantly with tumour stage, invasion, lymph node metastasis and distant metastasis by univariate Cox analysis, and was established an independent prognostic factor by multivariate Cox regression analysis for CRC. Gene set enrichment analysis (GSEA) revealed a relationship between the IRG prognostic signature and various biological pathways. Focal adhesions and ECM-receptor interactions were positively correlated with the risk scores, while cytosolic DNA sensing and metabolism-related pathways were negatively correlated. Finally, the bioinformatics results were validated by real-time RT-qPCR. In conclusion, we identified and validated a novel, immune-related prognostic signature for patients with CRC, and this signature reflects the dysregulated tumour immune microenvironment and has a potential for better CRC patient management.
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Affiliation(s)
- Jun Wang
- Department of Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Shaojun Yu
- Department of Surgical Oncologythe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Guofeng Chen
- Department of Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Muxing Kang
- Department of Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaoli Jin
- Department of Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yi Huang
- Department of Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Lele Lin
- Department of Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Dan Wu
- Department of Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Lie Wang
- Bone Marrow Transplantation Center of the First Affiliated HospitalInstitute of ImmunologyZhejiang University School of MedicineHangzhouChina
| | - Jian Chen
- Department of Surgerythe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
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12
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Maltseva D, Raygorodskaya M, Knyazev E, Zgoda V, Tikhonova O, Zaidi S, Nikulin S, Baranova A, Turchinovich A, Rodin S, Tonevitsky A. Knockdown of the α5 laminin chain affects differentiation of colorectal cancer cells and their sensitivity to chemotherapy. Biochimie 2020; 174:107-116. [PMID: 32334043 DOI: 10.1016/j.biochi.2020.04.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023]
Abstract
The interaction of tumor cells with the extracellular matrix (ECM) may affect the rate of cancer progression and metastasis. One of the major components of ECM are laminins, the heterotrimeric glycoproteins consisting of α-, β-, and γ-chains (αβγ). Laminins interact with their cell surface receptors and, thus, regulate multiple cellular processes. In this work, we demonstrate that shRNA-mediated knockdown of the α5 laminin chain results in Wnt- and mTORC1-dependent partial dedifferentiation of colorectal cancer cells. Furthermore, we showed that this dedifferentiation involved activation of ER-stress signaling, pathway promoting the sensitivity of cells to 5-fluorouracil.
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Affiliation(s)
- Diana Maltseva
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Myasnitskaya str. 13/4, 117997, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya str. 16/10, 117997, Moscow, Russia; Scientific Research Center Bioclinicum, Ugreshskaya str. 2/85, 115088, Moscow, Russia.
| | - Maria Raygorodskaya
- Scientific Research Center Bioclinicum, Ugreshskaya str. 2/85, 115088, Moscow, Russia
| | - Evgeny Knyazev
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Myasnitskaya str. 13/4, 117997, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya str. 16/10, 117997, Moscow, Russia
| | - Victor Zgoda
- Institute of Biomedical Chemistry, Pogodinskaya str. 10, 119121, Moscow, Russia
| | - Olga Tikhonova
- Institute of Biomedical Chemistry, Pogodinskaya str. 10, 119121, Moscow, Russia
| | - Shan Zaidi
- School of Systems Biology, George Mason University, Fairfax, VA, 22030, USA
| | - Sergey Nikulin
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Myasnitskaya str. 13/4, 117997, Moscow, Russia; Moscow Institute of Physics and Technology, Institutskiy per. 9, 141700, Dolgoprudny, Russia
| | - Ancha Baranova
- School of Systems Biology, George Mason University, Fairfax, VA, 22030, USA; Moscow Institute of Physics and Technology, Institutskiy per. 9, 141700, Dolgoprudny, Russia; Research Center of Medical Genetics, Moskvorechye str. 1, 115522, Moscow, Russia
| | | | - Sergey Rodin
- Department of Surgical Sciences, Ångström Laboratory, Uppsala University, 752 37, Uppsala, Sweden
| | - Alexander Tonevitsky
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Myasnitskaya str. 13/4, 117997, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya str. 16/10, 117997, Moscow, Russia; Scientific Research Center Bioclinicum, Ugreshskaya str. 2/85, 115088, Moscow, Russia.
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13
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Fouani L, Kovacevic Z, Richardson DR. Targeting Oncogenic Nuclear Factor Kappa B Signaling with Redox-Active Agents for Cancer Treatment. Antioxid Redox Signal 2019; 30:1096-1123. [PMID: 29161883 DOI: 10.1089/ars.2017.7387] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
SIGNIFICANCE Nuclear factor kappa B (NF-κB) signaling is essential under physiologically relevant conditions. However, aberrant activation of this pathway plays a pertinent role in tumorigenesis and contributes to resistance. Recent Advances: The importance of the NF-κB pathway means that its targeting must be specific to avoid side effects. For many currently used therapeutics and those under development, the ability to generate reactive oxygen species (ROS) is a promising strategy. CRITICAL ISSUES As cancer cells exhibit greater ROS levels than their normal counterparts, they are more sensitive to additional ROS, which may be a potential therapeutic niche. It is known that ROS are involved in (i) the activation of NF-κB signaling, when in sublethal amounts; and (ii) high levels induce cytotoxicity resulting in apoptosis. Indeed, ROS-induced cytotoxicity is valuable for its capabilities in killing cancer cells, but establishing the potency of ROS for effective inhibition of NF-κB signaling is necessary. Indeed, some cancer treatments, currently used, activate NF-κB and may stimulate oncogenesis and confer resistance. FUTURE DIRECTIONS Thus, combinatorial approaches using ROS-generating agents alongside conventional therapeutics may prove an effective tactic to reduce NF-κB activity to kill cancer cells. One strategy is the use of thiosemicarbazones, which form redox-active metal complexes that generate high ROS levels to deliver potent antitumor activity. These agents also upregulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), which functions as an NF-κB signaling inhibitor. It is proposed that targeting NF-κB signaling may proffer a new therapeutic niche to improve the efficacy of anticancer regimens.
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Affiliation(s)
- Leyla Fouani
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
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14
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Li W, Li Q, Wei L, Pan X, Huang D, Gan J, Tang S. Rosmarinic Acid Analogue-11 Induces Apoptosis of Human Gastric Cancer SGC-7901 Cells via the Epidermal Growth Factor Receptor (EGFR)/Akt/Nuclear Factor kappa B (NF-κB) Pathway. Med Sci Monit Basic Res 2019; 25:63-75. [PMID: 30799435 PMCID: PMC6404632 DOI: 10.12659/msmbr.913331] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 01/07/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND According to the latest statistics from the American Cancer Society, there will be 1.73 million cancer cases and more than 600 000 cancer deaths in the United States in 2018, among which there will be 26 240 new cases of gastric cancer and around 10 800 deaths arising from gastric cancer. The objective of this study was to use RAA-11 to intervene in SGC-7901 cells to understand its effects on cell proliferation and apoptosis, and to explore the apoptosis mechanism. MATERIAL AND METHODS MTT assay was used to detect the survival of human gastric mucosal epithelial GES-1 cells and human gastric cancer SGC-7901 cells. Colony formation assay was used to observe the colony forming ability in SGC-7901 cells. The apoptotic rate of SGC-7901 cells was evaluated by Hoechst33258 staining and flow cytometry. qRT-PCR was used to analyze the epidermal growth factor receptor (EGFR) mRNA expression level in SGC-7901 cells. Western blot was used to examine the expression levels of caspase-3, Bcl-2, BAX, EGFR, Akt, p-Akt, and NF-κB in SGC-7901 cells. RESULTS RAA-11 is capable of inhibiting the proliferation and inducing the apoptosis of SGC-7901 cells in a time- and dose-dependent manner. Western blot showed that the expression levels of caspase-3 and BAX were upregulated, while the expression levels of Bcl-2, EGFR, Akt, p-Akt, and NF-κB in the SGC-7901 cells were downregulated. CONCLUSIONS Apoptosis can be induced in SGC-7901 cells by RAA-11, potentially via the EGFR/Akt/NF-κB pathway, indicating that RAA-11 might be a potent agent for cancer treatment.
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Affiliation(s)
- Wanting Li
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Qing Li
- College of Pharmacy, Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Liqun Wei
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Xiaohang Pan
- Department of Colorectal Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Daohang Huang
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Jialiang Gan
- Department of Colorectal Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Shuangyi Tang
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
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15
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Vaes N, Schonkeren SL, Brosens E, Koch A, McCann CJ, Thapar N, Hofstra RM, van Engeland M, Melotte V. A combined literature and in silico analysis enlightens the role of the NDRG family in the gut. Biochim Biophys Acta Gen Subj 2018; 1862:2140-2151. [DOI: 10.1016/j.bbagen.2018.07.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/29/2018] [Accepted: 07/05/2018] [Indexed: 12/12/2022]
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16
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Chen K, Liu XH, Wang FR, Liu HP, Huang ZP, Chen X. The prognostic value of decreased NDRG1 expression in patients with digestive system cancers: A meta-analysis. Medicine (Baltimore) 2018; 97:e12455. [PMID: 30313035 PMCID: PMC6203522 DOI: 10.1097/md.0000000000012455] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Digestive system cancers are recognized as associated with high morbidity and mortality. It is generally accepted that N-myc downstream-regulated gene 1 (NDRG1) is aberrantly overexpressed or downregulated in digestive system cancers, and its prognostic value remains controversial. Accordingly, we herein conducted a meta-analysis to explore whether NDRG1 expression is correlated with overall survival (OS) and clinicopathological characteristics of patients with digestive system cancers. METHODS We systematically searched PubMed, EMBASE, and Web of Science for eligible studies up to June 6, 2017. In all, 19 publications with 21 studies, were included. RESULTS The pooled results showed that low NDRG1 expression was significantly associated with worse OS in colorectal cancer (pooled HR = 1.67, 95% CI: 1.22-2.28, P < .001) and pancreatic cancer (pooled HR = 1.87, 95% CI: 1-3.5, P < .0001). Moreover, the relationships between low NDRG1 expression and higher OS ratio of patients with liver cancer (pooled HR = 0.44, 95% CI: 0.32-0.62, P = .009) and gallbladder cancer (pooled HR = 0.56, 95% CI: 0.23-1.38, P = .01) were observed. Nevertheless, no significant association was observed between low NDRG1 expression and OS in gastric cancer (pooled HR = 0.81, 95% CI: 0.45-1.43, P = .46) or esophageal cancer (pooled HR = 0.76, 95% CI: 0.26-2.24, P = .62). CONCLUSION The prognostic significance of NDRG1 expression varies according to cancer type in patients with DSCs. Considering that several limitations existed in this meta-analysis, more studies are required to further assess the prognostic value of NDRG1 expression in patients with DSCs and relevant mechanisms.
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Affiliation(s)
- Kang Chen
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
| | - Xiao-Hong Liu
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
| | - Fu-Rong Wang
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
- Department of pathology, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Hai-Peng Liu
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
| | - Ze-Ping Huang
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
| | - Xiao Chen
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
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17
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Huang M, Geng Y, Deng Q, Li R, Shao X, Zhang Z, Xu W, Wu Y, Ma Q. Translationally controlled tumor protein affects colorectal cancer metastasis through the high mobility group box 1-dependent pathway. Int J Oncol 2018; 53:1481-1492. [PMID: 30066846 PMCID: PMC6086624 DOI: 10.3892/ijo.2018.4502] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 06/06/2018] [Indexed: 12/14/2022] Open
Abstract
Recently, accumulating evidence from clinical and experimental researches have suggested that translationally controlled tumor protein (TCTP) and high mobility group box 1 (HMGB1) are implicated in colorectal cancer (CRC) metastasis. However, whether there is an interconnection between these two tumor-promoting proteins and how they affect CRC metastasis remain to be fully elucidated. In the present study, the expression level of TCTP in CRC tissues was assessed by immunohistochemical staining and immunoblotting, and the serum concentration of HMGB1 in patients with CRC was detected by enzyme-linked immunosorbent assay. In vitro, following the modulation of TCTP expression in colon cancer LoVo cells, the translocation behavior of HMGB1 was observed by immunofluorescence assay. Furthermore, the activity of nuclear factor-κB (NF-κB) in LoVo cells was evaluated by immunoblotting and luciferase assay, and the invasion ability of LoVo cells after different treatments was determined using cell invasion assay. In vivo, xenograft tumor model was established and the correlation of TCTP and HMGB1 expression in xenografted tumors was studied by immunohistochemical examination. The results revealed that the expression level of TCTP in CRC tissue and the serum concentration of HMGB1 in patients with CRC were significantly increased, and there was a strong positive correlation between them. In vitro experiments showed that the overexpression of TCTP on LoVo cells resulted in the release of HMGB1 from the nucleus to the cytoplasm and into the extracellular space. In addition, the overexpression of TCTP led to the activation of NF-κB in LoVo cells, and this effect was reversed by treatment with antibodies targeting HMGB1 or to its receptors Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products advanced glycation end products (RAGE). Furthermore, inhibition of the HMGB1-TLR4/RAGE-NF-κB pathway significantly inhibited the TCTP-stimulated invasion of LoVo cells. In vivo experiments demonstrated that the over-expression of TCTP in nude mice promoted the development and spread of xenografted tumors, and concurrently enhanced the expression of HMGB1 in tumor tissues. Collectively, these findings suggested that TCTP promotes CRC metastasis through regulating the behaviors of HMGB1 and the downstream activation of the NF-κB signaling pathway.
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Affiliation(s)
- Maoliang Huang
- Fuzhou Dingxiang Clinic, Fuzhou, Fujian 350028, P.R. China
| | - Yan Geng
- Department of Intensive Care Unit, 303 Hospital of Chinese People's Liberation Army, Nanning, Guanxi 530021, P.R. China
| | - Qiaoting Deng
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Ru Li
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xiangyang Shao
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Zhigao Zhang
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Weiwen Xu
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yingsong Wu
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qiang Ma
- Institute of Antibody Engineering, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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18
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El Bairi K, Tariq K, Himri I, Jaafari A, Smaili W, Kandhro AH, Gouri A, Ghazi B. Decoding colorectal cancer epigenomics. Cancer Genet 2018; 220:49-76. [PMID: 29310839 DOI: 10.1016/j.cancergen.2017.11.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 11/01/2017] [Accepted: 11/06/2017] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is very heterogeneous and presents different types of epigenetic alterations including DNA methylation, histone modifications and microRNAs. These changes are considered as characteristics of various observed clinical phenotypes. Undoubtedly, the discovery of epigenetic pathways with novel epigenetic-related mechanisms constitutes a promising advance in cancer biomarker discovery. In this review, we provide an evidence-based discussing of the current understanding of CRC epigenomics and its role in initiation, epithelial-to-mesenchymal transition and metastasis. We also discuss the recent findings regarding the potential clinical perspectives of these alterations as potent biomarkers for CRC diagnosis, prognosis, and therapy in the era of liquid biopsy.
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Affiliation(s)
- Khalid El Bairi
- Independent Research Team in Cancer Biology and Bioactive Compounds, Mohamed 1(st) University, Oujda, Morocco.
| | - Kanwal Tariq
- B-10 Jumani Center, Garden East, Karachi 74400, Pakistan
| | - Imane Himri
- Laboratory of Biochemistry, Faculty of Sciences, Mohamed I(st) Universiy, Oujda, Morocco; Delegation of the Ministry of Health, Oujda, Morocco
| | - Abdeslam Jaafari
- Laboratoire de Génie Biologique, Equipe d'Immunopharmacologie, Faculté des Sciences et Techniques, Université Sultan Moulay Slimane, Beni Mellal, Maroc
| | - Wiam Smaili
- Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohamed V, Rabat, Maroc; Département de Génétique Médicale, Institut National d'Hygiène, Rabat, Maroc
| | - Abdul Hafeez Kandhro
- Department of Biochemistry, Healthcare Molecular and Diagnostic Laboratory, Hyderabad, Pakistan
| | - Adel Gouri
- Laboratory of Medical Biochemistry, Ibn Rochd University Hospital, Annaba, Algeria
| | - Bouchra Ghazi
- National Laboratory of Reference, Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
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MicroRNA-105 is involved in TNF-α-related tumor microenvironment enhanced colorectal cancer progression. Cell Death Dis 2017; 8:3213. [PMID: 29238068 PMCID: PMC5870598 DOI: 10.1038/s41419-017-0048-x] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 10/10/2017] [Indexed: 12/15/2022]
Abstract
TNF-α is a central proinflammatory cytokine contributing to malignant tumor progression in tumor microenvironment. In this study, we found the upregulation of miR-105 in colorectal cancer was associated with aggressive phenotype, and the enhanced expression of miR-105 was required for TNF-α-induced epithelial–mesenchymal transition (EMT). The expression of miR-105 was remarkably stimulated by TNF-α in a time-dependent manner using real-time qPCR analysis. Inhibition of miR-105 remarkably weakened the aggressive effects of TNF-α through preventing the activation of NF-κB signaling and the initiation of EMT. Furthermore, miR-105 was demonstrated directly targeted on the 3′-UTRs of RAP2C, a Rap2 subfamily of small GTP-binding protein. Consistently, suppression of RAP2C stimulated the role of miR-105, which dramatically promoted the invasion and metastasis of CRC cells. Thalidomide, a TNF-α and NF-κB inhibitor, significantly weakened the metastasis and homing capacity of miR-105-overexpressed CRC cells in nude mice. Our investigation initiatively illustrated the modulatory role of miR-105 in TNF-α-induced EMT and further CRC metastasis. We also offer a better understanding of TNFα-induced metastasis and suggest an effective therapeutic strategy against CRC metastasis.
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Ambrosio S, Saccà CD, Majello B. Epigenetic regulation of epithelial to mesenchymal transition by the Lysine-specific demethylase LSD1/KDM1A. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2017; 1860:905-910. [PMID: 28720390 DOI: 10.1016/j.bbagrm.2017.07.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 06/20/2017] [Accepted: 07/12/2017] [Indexed: 01/03/2023]
Abstract
The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia. LSD1 regulates the epithelial mesenchymal transition (EMT) in epithelial cells, i.e., the ability to transition into mesenchymal cells, to lose homotypic adhesion and to acquire migratory capacity. From its initial discovery as a component of the Snail complex, multiple studies highlighted the causative role of LSD1 in cell invasiveness and EMT, describing its direct involvement in different molecular processes through the interaction with specific partners. Here we present an overview of the role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in cancer.
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Affiliation(s)
- Susanna Ambrosio
- Department of Biology, University of Naples 'Federico II', Naples, Italy
| | - Carmen D Saccà
- Department of Biology, University of Naples 'Federico II', Naples, Italy
| | - Barbara Majello
- Department of Biology, University of Naples 'Federico II', Naples, Italy.
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Konstantakou EG, Velentzas AD, Anagnostopoulos AK, Litou ZI, Konstandi OA, Giannopoulou AF, Anastasiadou E, Voutsinas GE, Tsangaris GT, Stravopodis DJ. Deep-proteome mapping of WM-266-4 human metastatic melanoma cells: From oncogenic addiction to druggable targets. PLoS One 2017; 12:e0171512. [PMID: 28158294 PMCID: PMC5291375 DOI: 10.1371/journal.pone.0171512] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 01/20/2017] [Indexed: 12/22/2022] Open
Abstract
Cutaneous melanoma is a malignant tumor of skin melanocytes that are pigment-producing cells located in the basal layer (stratum basale) of epidermis. Accumulation of genetic mutations within their oncogenes or tumor-suppressor genes compels melanocytes to aberrant proliferation and spread to distant organs of the body, thereby resulting in severe and/or lethal malignancy. Metastatic melanoma's heavy mutational load, molecular heterogeneity and resistance to therapy necessitate the development of novel biomarkers and drug-based protocols that target key proteins involved in perpetuation of the disease. To this direction, we have herein employed a nano liquid chromatography-tandem mass spectrometry (nLC-MS/MS) proteomics technology to profile the deep-proteome landscape of WM-266-4 human metastatic melanoma cells. Our advanced melanoma-specific catalogue proved to contain 6,681 unique proteins, which likely constitute the hitherto largest single cell-line-derived proteomic collection of the disease. Through engagement of UNIPROT, DAVID, KEGG, PANTHER, INTACT, CYTOSCAPE, dbEMT and GAD bioinformatics resources, WM-266-4 melanoma proteins were categorized according to their sub-cellular compartmentalization, function and tumorigenicity, and successfully reassembled in molecular networks and interactomes. The obtained data dictate the presence of plastically inter-converted sub-populations of non-cancer and cancer stem cells, and also indicate the oncoproteomic resemblance of melanoma to glioma and lung cancer. Intriguingly, WM-266-4 cells seem to be subjected to both epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) programs, with 1433G and ADT3 proteins being identified in the EMT/MET molecular interface. Oncogenic addiction of WM-266-4 cells to autocrine/paracrine signaling of IL17-, DLL3-, FGF(2/13)- and OSTP-dependent sub-routines suggests their critical contribution to the metastatic melanoma chemotherapeutic refractoriness. Interestingly, the 1433G family member that is shared between the BRAF- and EMT/MET-specific interactomes likely emerges as a novel and promising druggable target for the malignancy. Derailed proliferation and metastatic capacity of WM-266-4 cells could also derive from their metabolic addiction to pathways associated with glutamate/ammonia, propanoate and sulfur homeostasis, whose successful targeting may prove beneficial for advanced melanoma-affected patients.
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Affiliation(s)
- Eumorphia G. Konstantakou
- Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanassios D. Velentzas
- Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios K. Anagnostopoulos
- Proteomics Core Facility, Systems Biology Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Zoi I. Litou
- Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece
| | - Ourania A. Konstandi
- Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece
| | - Aikaterini F. Giannopoulou
- Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece
| | - Ema Anastasiadou
- Basic Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Gerassimos E. Voutsinas
- Laboratory of Environmental Mutagenesis and Carcinogenesis, Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, Athens, Greece
| | - George Th. Tsangaris
- Proteomics Core Facility, Systems Biology Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Dimitrios J. Stravopodis
- Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece
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