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Huang X, Chen W, Wang Y, Shytikov D, Wang Y, Zhu W, Chen R, He Y, Yang Y, Guo W. Canonical and noncanonical NOTCH signaling in the nongenetic resistance of cancer: distinct and concerted control. Front Med 2025; 19:23-52. [PMID: 39745621 DOI: 10.1007/s11684-024-1107-1] [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: 04/19/2024] [Accepted: 09/18/2024] [Indexed: 02/27/2025]
Abstract
Therapeutic resistance in cancer is responsible for numerous cancer deaths in clinical practice. While target mutations are well recognized as the basis of genetic resistance to targeted therapy, nontarget mutation resistance (or nongenetic resistance) remains poorly characterized. Despite its complex and unintegrated mechanisms in the literature, nongenetic resistance is considered from our perspective to be a collective response of innate or acquired resistant subpopulations in heterogeneous tumors to therapy. These subpopulations, e.g., cancer stem-like cells, cancer cells with epithelial-to-mesenchymal transition, and drug-tolerant persisters, are protected by their resistance traits at cellular and molecular levels. This review summarizes recent advances in the research on resistant populations and their resistance traits. NOTCH signaling, as a central regulator of nongenetic resistance, is discussed with a special focus on its canonical maintenance of resistant cancer cells and noncanonical regulation of their resistance traits. This novel view of canonical and noncanonical NOTCH signaling pathways is translated into our proposal of reshaping therapeutic strategies targeting NOTCH signaling in resistant cancer cells. We hope that this review will lead researchers to study the canonical and noncanonical arms of NOTCH signaling as an integrated resistant mechanism, thus promoting the development of innovative therapeutic strategies.
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Affiliation(s)
- Xianzhe Huang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wenwei Chen
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanyan Wang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Dmytro Shytikov
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanwen Wang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wangyi Zhu
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Ruyi Chen
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yuwei He
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanjia Yang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wei Guo
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China.
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
- Biomedical and Health Translational Research Center of Zhejiang Province, Jiaxing, 314400, China.
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2
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Li S, Cheng Y, Gao C, Yuan Q, Lu X. SEMA3C promotes thyroid cancer via the Wnt/β-catenin pathway. Exp Cell Res 2025; 444:114378. [PMID: 39667698 DOI: 10.1016/j.yexcr.2024.114378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/28/2024] [Accepted: 12/09/2024] [Indexed: 12/14/2024]
Abstract
Semaphorin 3C (SEMA3C) regulates the progression of several tumors. However, the role of SEMA3C in thyroid cancer remains unknow. In the present study, SEMA3C was overexpressed or knocked down in thyroid cancer cell lines BCPAP and IHH-4. It was found that SEMA3C promoted the cell migration, invasion, and mesenchymal-epithelial transition (EMT) process. SEMA3C overexpression enhanced tumor cell stemness, while SEMA3C knockdown showed the opposite effects. In vivo experiments suggested that SEMA3C accelerated the tumor growth and metastasis. Moreover, SEMA3C enhanced β-catenin nuclear translocation. When cells were treated with Dickkopf-1 (DKK1), an inhibitor of Wnt/β-catenin pathway, the promoting effects of SEMA3C on cell migration and stemness were offset. Wnt/β-catenin pathway mediated the roles of SEMA3C in thyroid cancer. Additionally, an upstream regulator of SEMA3C was identified. E1A binding protein P300 (P300) was found to increase the histone three lysine 27 acetylation (H3K27ac) level of SEMA3C, promoting its transcriptional activation. Therefore, we clarify that SEMA3C exerts a tumor-promoting effect on thyroid cancer, and Wnt/β-catenin pathway is the critical downstream pathway.
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Affiliation(s)
- Shiwei Li
- Department of Otorhinolaryngology and Head-Neck Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Zhengzhou, Henan, China
| | - Yanmei Cheng
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Zhengzhou, Henan, China
| | - Changhui Gao
- Department of Otorhinolaryngology and Head-Neck Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Zhengzhou, Henan, China
| | - Qingling Yuan
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Zhengzhou, Henan, China
| | - Xiubo Lu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Zhengzhou, Henan, China.
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Uchida Y, Kurimoto R, Chiba T, Matsushima T, Oda G, Onishi I, Takeuchi Y, Gotoh N, Asahara H. RNA binding protein ZCCHC24 promotes tumorigenicity in triple-negative breast cancer. EMBO Rep 2024; 25:5352-5382. [PMID: 39420119 PMCID: PMC11624195 DOI: 10.1038/s44319-024-00282-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 08/28/2024] [Accepted: 09/26/2024] [Indexed: 10/19/2024] Open
Abstract
Triple-negative breast cancer (TNBC) lacks the expression of hormone and HER2 receptors and is highly malignant with no effective therapeutic targets. In TNBC, the cancer stem-like cell (CSC) population is considered to be the main cause of resistance to treatment. Thus, the therapeutic targeting of this population could substantially improve patient survival. Here, we identify the RNA-binding protein ZCCHC24 as enriched in the mesenchymal-like TNBC population. ZCCHC24 promotes the expression of a set of genes related to tumorigenicity and treatment resistance by directly binding to the cis-element "UGUWHWWA" in their mRNAs, thereby stabilizing them. One of the ZCCHC24 targets, ZEB1, is a transcription factor that promotes the expression of cancer stemness genes and reciprocally induces ZCCHC24 expression. ZCCHC24 knockdown by siRNAs shows a therapeutic effect and reduces the mesenchymal-like cell population in TNBC patient-derived xenografts. ZCCHC24 knockdown also has additive effects with the BET inhibitor JQ1 in suppressing tumor growth in TNBC patient-derived xenografts.
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Affiliation(s)
- Yutaro Uchida
- Department of Systems Biomedicine, Institute of Science Tokyo, Tokyo, 113-8510, Japan
| | - Ryota Kurimoto
- Department of Systems Biomedicine, Institute of Science Tokyo, Tokyo, 113-8510, Japan
| | - Tomoki Chiba
- Department of Systems Biomedicine, Institute of Science Tokyo, Tokyo, 113-8510, Japan
| | - Takahide Matsushima
- Department of Systems Biomedicine, Institute of Science Tokyo, Tokyo, 113-8510, Japan
| | - Goshi Oda
- Department of Surgery, Breast Surgery, Institute of Science Tokyo, Tokyo, 113-8510, Japan
| | - Iichiroh Onishi
- Department of Comprehensive Pathology, Institute of Science Tokyo, Tokyo, 113-8510, Japan
| | - Yasuto Takeuchi
- Division of Cancer Cell Biology, Kanazawa University, Kanazawa, 920-1192, Japan
- Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, 920-1192, Japan
| | - Noriko Gotoh
- Division of Cancer Cell Biology, Kanazawa University, Kanazawa, 920-1192, Japan
- Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, 920-1192, Japan
| | - Hiroshi Asahara
- Department of Systems Biomedicine, Institute of Science Tokyo, Tokyo, 113-8510, Japan.
- Department of Molecular and Cellular Biology, Scripps Research, La Jolla, CA, 92037, USA.
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4
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Patra A, Arora A, Ghosh SS, Kaur Saini G. Beauvericin Reverses Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer Cells through Regulation of Notch Signaling and Autophagy. ACS Pharmacol Transl Sci 2024; 7:2878-2893. [PMID: 39296261 PMCID: PMC11406685 DOI: 10.1021/acsptsci.4c00370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/19/2024] [Accepted: 08/22/2024] [Indexed: 09/21/2024]
Abstract
Metastasis stands as a prime contributor to triple-negative breast cancer (TNBC) associated mortality worldwide, presenting heightened severity and significant challenges due to limited treatment options. Addressing TNBC metastasis necessitates innovative approaches and novel therapeutics to specifically target its propensity for dissemination to distant organs. Targeted therapies capable of reversing epithelial-to-mesenchymal transition (EMT) play a crucial role in suppressing metastasis and enhancing the treatment response. Beauvericin, a promising fungal secondary metabolite, exhibits significant potential in diminishing the viability of EMT-induced TNBC cells by triggering intracellular oxidative stress, as evidenced by an enhanced reactive oxygen species level and reduced mitochondrial transmembrane potential. In monolayer cultures, it has exhibited an IC50 of 2.3 μM in both MDA-MB-468 and MDA-MB-231 cells, while in 3D spheroids, the IC50 values are 9.7 and 7.1 μM, respectively. Beauvericin has also reduced the migratory capability of MDA-MB-468 and MDA-MB-231 cells by 1.5- and 1.7-fold, respectively. Both qRT-PCR and Western blot analysis have shown significant upregulation in the expression of epithelial marker (E-cadherin) and downregulation in the expression of mesenchymal markers (N-cadherin, vimentin, Snail, Slug, and β-catenin), following treatment, indicating reversal of EMT. Furthermore, beauvericin has suppressed the Notch signaling pathway by substantially downregulating Notch-1, Notch-3, Hes-1, and cyclinD3 expression and induced autophagy as observed by elevated expression of autophagy markers LC3 and Beclin-1. In conclusion, beauvericin has successfully downregulated TNBC cell survival by inducing oxidative stress and suppressed their migratory potential by reversing EMT through the inhibition of Notch signaling and activation of autophagy.
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Affiliation(s)
- Arupam Patra
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, North Guwahati, Assam 781039, India
| | - Arisha Arora
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, North Guwahati, Assam 781039, India
| | - Siddhartha Sankar Ghosh
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, North Guwahati, Assam 781039, India
| | - Gurvinder Kaur Saini
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, North Guwahati, Assam 781039, India
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Lailler C, Didelot A, Garinet S, Berthou H, Sroussi M, de Reyniès A, Dedhar S, Martin-Lannerée S, Fabre E, Le Pimpec-Barthes F, Perrier A, Poindessous V, Mansuet-Lupo A, Djouadi F, Launay JM, Laurent-Puig P, Blons H, Mouillet-Richard S. PrP C controls epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient follow-up. Oncogene 2024; 43:2781-2794. [PMID: 39147880 PMCID: PMC11379626 DOI: 10.1038/s41388-024-03130-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 08/17/2024]
Abstract
Patients with EGFR-mutated non-small cell lung cancer (NSCLC) benefit from treatment with tyrosine kinase inhibitors (TKI) targeting EGFR. Despite improvements in patient care, especially with the 3rd generation TKI osimertinib, disease relapse is observed in all patients. Among the various processes involved in TKI resistance, epithelial-to-mesenchymal transition (EMT) is far from being fully characterized. We hypothesized that the cellular prion protein PrPC could be involved in EMT and EGFR-TKI resistance in NSCLC. Using 5 independent lung adenocarcinoma datasets, including our own cohort, we document that the expression of the PRNP gene encoding PrPC is associated with EMT. By manipulating the levels of PrPC in different EGFR-mutated NSCLC cell lines, we firmly establish that the expression of PrPC is mandatory for cells to maintain or acquire a mesenchymal phenotype. Mechanistically, we show that PrPC operates through an ILK-RBPJ cascade, which also controls the expression of EGFR. Our data further demonstrate that PrPC levels are elevated in EGFR-mutated versus wild-type tumours or upon EGFR activation in vitro. In addition, we provide evidence that PRNP levels increase with TKI resistance and that reducing PRNP expression sensitizes cells to osimertinib. Finally, we found that plasma PrPC levels are increased in EGFR-mutated NSCLC patients from 2 independent cohorts and that their longitudinal evolution mirrors that of disease. Altogether, these findings define PrPC as a candidate driver of EMT-dependent resistance to EGFR-TKI in NSCLC. They further suggest that monitoring plasma PrPC levels may represent a valuable non-invasive strategy for patient follow-up and warrant considering PrPC-targeted therapies for EGFR-mutated NSCLC patients with TKI failure.
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Affiliation(s)
- Claire Lailler
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Audrey Didelot
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Simon Garinet
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Hugo Berthou
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Marine Sroussi
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
- Institut du Cancer Paris CARPEM, AP-HP, Department of Genetics and Molecular Medicine, Hôpital Européen Georges Pompidou, Paris, France
| | - Aurélien de Reyniès
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Shoukat Dedhar
- Genetics Unit, Integrative Oncology, BC Cancer, Vancouver, BC, Canada
| | - Séverine Martin-Lannerée
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Elizabeth Fabre
- AP-HP Department of Thoracic Oncology, Hôpital Européen Georges Pompidou, Paris, France
| | | | - Alexandre Perrier
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Virginie Poindessous
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Audrey Mansuet-Lupo
- AP-HP Department of Pathology, Hôpital Cochin, Université Paris Cité, Paris, France
| | - Fatima Djouadi
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Jean-Marie Launay
- INSERM U942 Lariboisière Hospital, Paris, France
- Pharma Research Department, F. Hoffmann-La-Roche Ltd., Basel, Switzerland
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France
- Institut du Cancer Paris CARPEM, AP-HP, Department of Genetics and Molecular Medicine, Hôpital Européen Georges Pompidou, Paris, France
| | - Hélène Blons
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France.
- Institut du Cancer Paris CARPEM, AP-HP, Department of Biochemistry, Pharmacogenetics and Molecular Oncology, Hôpital Européen Georges Pompidou, Paris, France.
| | - Sophie Mouillet-Richard
- Centre de Recherche des Cordeliers, INSERM UMRS-1138, Sorbonne Université, Université Paris Cité, Paris, France.
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6
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Bracken CP, Goodall GJ, Gregory PA. RNA regulatory mechanisms controlling TGF-β signaling and EMT in cancer. Semin Cancer Biol 2024; 102-103:4-16. [PMID: 38917876 DOI: 10.1016/j.semcancer.2024.06.001] [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: 12/15/2023] [Revised: 06/05/2024] [Accepted: 06/13/2024] [Indexed: 06/27/2024]
Abstract
Epithelial-mesenchymal transition (EMT) is a major contributor to metastatic progression and is prominently regulated by TGF-β signalling. Both EMT and TGF-β pathway components are tightly controlled by non-coding RNAs - including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) - that collectively have major impacts on gene expression and resulting cellular states. While miRNAs are the best characterised regulators of EMT and TGF-β signaling and the miR-200-ZEB1/2 feedback loop plays a central role, important functions for lncRNAs and circRNAs are also now emerging. This review will summarise our current understanding of the roles of non-coding RNAs in EMT and TGF-β signaling with a focus on their functions in cancer progression.
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Affiliation(s)
- Cameron P Bracken
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; School of Biological Sciences, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, SA 5000, Australia.
| | - Gregory J Goodall
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia; School of Biological Sciences, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, SA 5000, Australia.
| | - Philip A Gregory
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5000, Australia.
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7
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Tolue Ghasaban F, Ghanei M, Mahmoudian RA, Taghehchian N, Abbaszadegan MR, Moghbeli M. MicroRNAs as the critical regulators of epithelial mesenchymal transition in pancreatic tumor cells. Heliyon 2024; 10:e30599. [PMID: 38726188 PMCID: PMC11079401 DOI: 10.1016/j.heliyon.2024.e30599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 04/26/2024] [Accepted: 04/30/2024] [Indexed: 05/12/2024] Open
Abstract
Pancreatic cancer (PC), as one of the main endocrine and digestive systems malignancies has the highest cancer related mortality in the world. Lack of the evident clinical symptoms and appropriate diagnostic markers in the early stages of tumor progression are the main reasons of the high mortality rate among PC patients. Therefore, it is necessary to investigate the molecular pathways involved in the PC progression, in order to introduce novel early diagnostic methods. Epithelial mesenchymal transition (EMT) is a critical cellular process associated with pancreatic tumor cells invasion and distant metastasis. MicroRNAs (miRNAs) are also important regulators of EMT process. In the present review, we discussed the role of miRNAs in regulation of EMT process during PC progression. It has been reported that the miRNAs mainly regulate the EMT process in pancreatic tumor cells through the regulation of EMT-specific transcription factors and several signaling pathways such as WNT, NOTCH, TGF-β, JAK/STAT, and PI3K/AKT. Considering the high stability of miRNAs in body fluids and their role in regulation of EMT process, they can be introduced as the non-invasive diagnostic markers in the early stages of malignant pancreatic tumors. This review paves the way to introduce a non-invasive EMT based panel marker for the early tumor detection among PC patients.
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Affiliation(s)
- Faezeh Tolue Ghasaban
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Ghanei
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reihaneh Alsadat Mahmoudian
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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8
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Rashid M, Devi BM, Banerjee M. Combinatorial Cooperativity in miR200-Zeb Feedback Network can Control Epithelial-Mesenchymal Transition. Bull Math Biol 2024; 86:48. [PMID: 38555331 DOI: 10.1007/s11538-024-01277-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 02/27/2024] [Indexed: 04/02/2024]
Abstract
Carcinomas often utilize epithelial-mesenchymal transition (EMT) programs for cancer progression and metastasis. Numerous studies report SNAIL-induced miR200/Zeb feedback circuit as crucial in regulating EMT by placing cancer cells in at least three phenotypic states, viz. epithelial (E), hybrid (h-E/M), mesenchymal (M), along the E-M phenotypic spectrum. However, a coherent molecular-level understanding of how such a tiny circuit controls carcinoma cell entrance into and residence in various states is lacking. Here, we use molecular binding data and mathematical modeling to report that the miR200/Zeb circuit can essentially utilize combinatorial cooperativity to control E-M phenotypic plasticity. We identify minimal combinatorial cooperativities that give rise to E, h-E/M, and M phenotypes. We show that disrupting a specific number of miR200 binding sites on Zeb as well as Zeb binding sites on miR200 can have phenotypic consequences-the circuit can dynamically switch between two (E, M) and three (E, h-E/M, M) phenotypes. Further, we report that in both SNAIL-induced and SNAIL knock-out miR200/Zeb circuits, cooperative transcriptional feedback on Zeb as well as Zeb translation inhibition due to miR200 are essential for the occurrence of intermediate h-E/M phenotype. Finally, we demonstrate that SNAIL can be dispensable for EMT, and in the absence of SNAIL, the transcriptional feedback can control cell state transition from E to h-E/M, to M state. Our results thus highlight molecular-level regulation of EMT in miR200/Zeb circuit and we expect these findings to be crucial to future efforts aiming to prevent EMT-facilitated dissemination of carcinomas.
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Affiliation(s)
- Mubasher Rashid
- Department of Mathematics and Statistics, Indian Institute of Technology Kanpur, Kanpur, 208016, India.
| | - Brasanna M Devi
- Department of Mathematics and Statistics, Indian Institute of Technology Kanpur, Kanpur, 208016, India
| | - Malay Banerjee
- Department of Mathematics and Statistics, Indian Institute of Technology Kanpur, Kanpur, 208016, India
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9
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Ebrahimi N, Manavi MS, Faghihkhorasani F, Fakhr SS, Baei FJ, Khorasani FF, Zare MM, Far NP, Rezaei-Tazangi F, Ren J, Reiter RJ, Nabavi N, Aref AR, Chen C, Ertas YN, Lu Q. Harnessing function of EMT in cancer drug resistance: a metastasis regulator determines chemotherapy response. Cancer Metastasis Rev 2024; 43:457-479. [PMID: 38227149 DOI: 10.1007/s10555-023-10162-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 12/08/2023] [Indexed: 01/17/2024]
Abstract
Epithelial-mesenchymal transition (EMT) is a complicated molecular process that governs cellular shape and function changes throughout tissue development and embryogenesis. In addition, EMT contributes to the development and spread of tumors. Expanding and degrading the surrounding microenvironment, cells undergoing EMT move away from the main location. On the basis of the expression of fibroblast-specific protein-1 (FSP1), fibroblast growth factor (FGF), collagen, and smooth muscle actin (-SMA), the mesenchymal phenotype exhibited in fibroblasts is crucial for promoting EMT. While EMT is not entirely reliant on its regulators like ZEB1/2, Twist, and Snail proteins, investigation of upstream signaling (like EGF, TGF-β, Wnt) is required to get a more thorough understanding of tumor EMT. Throughout numerous cancers, connections between tumor epithelial and fibroblast cells that influence tumor growth have been found. The significance of cellular crosstalk stems from the fact that these events affect therapeutic response and disease prognosis. This study examines how classical EMT signals emanating from various cancer cells interfere to tumor metastasis, treatment resistance, and tumor recurrence.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | | | | | - Siavash Seifollahy Fakhr
- Department of Biotechnology, Faculty of Applied Ecology, Agricultural Science and Biotechnology, Campus Hamar, Inland Norway University of Applied Sciences, Hamar, Norway
| | | | | | - Mohammad Mehdi Zare
- Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Nazanin Pazhouhesh Far
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Jun Ren
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, 77030, USA
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Amir Reza Aref
- Translational Medicine Group, Xsphera Biosciences, 6 Tide Street, Boston, MA, 02210, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
| | - Chu Chen
- Department of Cardiology, Affiliated Hospital of Nantong University, Jiangsu, 226001, China
| | - Yavuz Nuri Ertas
- ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, 38039, Türkiye.
- Department of Biomedical Engineering, Erciyes University, Kayseri, 38039, Türkiye.
| | - Qi Lu
- Department of Cardiology, Affiliated Hospital of Nantong University, Jiangsu, 226001, China.
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10
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Ding Q, Remy M, Upara C, Hu J, Mora Mata A, Haes A, Lanzel E, Sun H, Buchakjian M, Hong L. CaCO 3 Nanoparticles Delivering MicroRNA-200c Suppress Oral Squamous Cell Carcinoma. J Dent Res 2024; 103:147-155. [PMID: 38149503 PMCID: PMC10915176 DOI: 10.1177/00220345231216110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023] Open
Abstract
MicroRNA (miR)-200c suppresses the initiation and progression of oral squamous cell carcinoma (OSCC), the most prevalent head and neck cancer with high recurrence, metastasis, and mortality rates. However, miR-200c-based gene therapy to inhibit OSCC growth has yet to be reported. To develop an miR-based gene therapy to improve the outcomes of OSCC treatment, this study investigates the feasibility of plasmid DNA (pDNA) encoding miR-200c delivered via nonviral CaCO3-based nanoparticles to inhibit OSCC tumor growth. CaCO3-based nanoparticles with various ratios of CaCO3 and protamine sulfate (PS) were used to transfect pDNA encoding miR-200c into OSCC cells, and the efficiency of these nanoparticles was evaluated. The proliferation, migration, and associated oncogene production, as well as in vivo tumor growth for OSCC cells overexpressing miR-200c, were also quantified. It was observed that, while CaCO3-based nanoparticles improve transfection efficiencies of pDNA miR-200c, the ratio of CaCO3 to PS significantly influences the transfection efficiency. Overexpression of miR-200c significantly reduced proliferation, migration, and oncogene expression of OSCC cells, as well as the tumor size of cell line-derived xenografts (CDX) in mice. In addition, a local administration of pDNA miR-200c using CaCO3 delivery significantly enhanced miR-200c transfection and suppressed tumor growth of CDX in mice. These results strongly indicate that the nanocomplexes of CaCO3/pDNA miR-200c may potentially be used to reduce oral cancer recurrence and improve clinical outcomes in OSCC treatment, while more comprehensive examinations to confirm the safety and efficacy of the CaCO3/pDNA miR-200c system using various preclinical models are needed.
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Affiliation(s)
- Q.J. Ding
- Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA, USA
| | - M.T. Remy
- Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA, USA
| | - C. Upara
- Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA, USA
| | - J. Hu
- Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA, USA
| | - A.V. Mora Mata
- Department of Chemistry, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA, USA
| | - A.J. Haes
- Department of Chemistry, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA, USA
| | - E. Lanzel
- Department of Oral Pathology, Radiology, & Medicine, College of Dentistry, University of Iowa, Iowa City, Iowa, IA, USA
| | - H. Sun
- Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA, USA
| | - M.R. Buchakjian
- Department of Otolaryngology–Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - L. Hong
- Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA, USA
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11
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Rithvik A, Samarpita S, Rasool M. Unleashing the pathological imprinting of cancer in autoimmunity: Is ZEB1 the answer? Life Sci 2023; 332:122115. [PMID: 37739160 DOI: 10.1016/j.lfs.2023.122115] [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: 06/30/2023] [Revised: 09/05/2023] [Accepted: 09/19/2023] [Indexed: 09/24/2023]
Abstract
The intriguing scientific relationship between autoimmunity and cancer immunology have been traditionally indulged to throw spotlight on novel pathological targets. Understandably, these "slowly killing" diseases are on the opposite ends of the immune spectrum. However, the immune regulatory mechanisms between autoimmunity and cancer are not always contradictory and sometimes mirror each other based on disease stage, location, and timepoint. Moreover, the blockade of immune checkpoint molecules or signalling pathways that unleashes the immune response against cancer is being leveraged to preserve self-tolerance and treat many autoimmune disorders. Therefore, understanding the common crucial factors involved in cancer is of paramount importance to paint the autoimmune disease spectrum and validate novel drug candidates. In the current review, we will broadly describe how ZEB1, or Zinc-finger E-box Binding Homeobox 1, reinforces immune exhaustion in cancer or contributes to loss of self-tolerance in auto-immune conditions. We made an effort to exchange information about the molecular pathways and pathological responses (immune regulation, cell proliferation, senescence, autophagy, hypoxia, and circadian rhythm) that can be regulated by ZEB1 in the context of autoimmunity. This will help untwine the intricate and closely postured pathogenesis of ZEB1, that is less explored from the perspective of autoimmunity than its counterpart, cancer. This review will further consider several approaches for targeting ZEB1 in autoimmunity.
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Affiliation(s)
- Arulkumaran Rithvik
- Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nādu, India
| | - Snigdha Samarpita
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Mahaboobkhan Rasool
- Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nādu, India.
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12
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Sánchez-Tilló E, Pedrosa L, Vila I, Chen Y, Győrffy B, Sánchez-Moral L, Siles L, Lozano JJ, Esteve-Codina A, Darling DS, Cuatrecasas M, Castells A, Maurel J, Postigo A. The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas. JCI Insight 2023; 8:e164629. [PMID: 37870961 PMCID: PMC10619495 DOI: 10.1172/jci.insight.164629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 09/05/2023] [Indexed: 10/25/2023] Open
Abstract
Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. Using samples from patients with CRC, mouse models of KrasG12D and BrafV600E CRC, and a Zeb1-deficient mouse, we show that ZEB1 had opposite functions in KRAS- and BRAF-mutant CRCs. In KrasG12D CRCs, ZEB1 was correlated with a worse prognosis and a higher number of larger and undifferentiated (mesenchymal or EMT-like) tumors. Surprisingly, in BrafV600E CRC, ZEB1 was associated with better prognosis; fewer, smaller, and more differentiated (reduced EMT) primary tumors; and fewer metastases. ZEB1 was positively correlated in KRAS-mutant CRC cells and negatively in BRAF-mutant CRC cells with gene signatures for EMT, cell proliferation and survival, and ERK signaling. On a mechanistic level, ZEB1 knockdown in KRAS-mutant CRC cells increased apoptosis and reduced clonogenicity and anchorage-independent growth; the reverse occurred in BRAFV600E CRC cells. ZEB1 is associated with better prognosis and reduced EMT signature in patients harboring BRAF CRCs. These data suggest that ZEB1 can function as a tumor suppressor in BRAF-mutant CRCs, highlighting the importance of considering the KRAS/BRAF mutational background of CRCs in therapeutic strategies targeting ZEB1/EMT.
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Affiliation(s)
- Ester Sánchez-Tilló
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Group of Gastrointestinal and Pancreatic Oncology, Department of Liver, Digestive System and Metabolism, IDIBAPS, Barcelona, Spain
- Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III National Health Institute (ISCIII), Barcelona, Spain
| | - Leire Pedrosa
- Group of Translational Genomics and Targeted Therapeutics in Solid Tumors, IDIBAPS, and Department of Medical Oncology, Hospital Clinic, Barcelona, Spain
| | - Ingrid Vila
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Yongxu Chen
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Balázs Győrffy
- Cancer Biomarker Research Group, Research Centre for Natural Sciences (TKK), and Department of Bioinformatics and 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Lidia Sánchez-Moral
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Laura Siles
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Juan J. Lozano
- Bioinformatics Platform, CIBEREHD, ISCIII, Barcelona, Spain
| | - Anna Esteve-Codina
- National Centre for Genomic Analysis (CNAG) Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Department of Medicine and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Douglas S. Darling
- Department of Oral Immunology, and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Miriam Cuatrecasas
- Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III National Health Institute (ISCIII), Barcelona, Spain
- Group of Molecular Pathology of Inflammatory Conditions and Solid Tumours, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain
- Department of Pathology, Hospital Clínic and University of Barcelona School of Medicine, Barcelona, Spain
| | - Antoni Castells
- Group of Gastrointestinal and Pancreatic Oncology, Department of Liver, Digestive System and Metabolism, IDIBAPS, Barcelona, Spain
- Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III National Health Institute (ISCIII), Barcelona, Spain
- Department of Gastroenterology, Hospital Clinic and University of Barcelona School of Medicine, Barcelona, Spain
| | - Joan Maurel
- Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III National Health Institute (ISCIII), Barcelona, Spain
- Group of Translational Genomics and Targeted Therapeutics in Solid Tumors, IDIBAPS, and Department of Medical Oncology, Hospital Clinic, Barcelona, Spain
| | - Antonio Postigo
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III National Health Institute (ISCIII), Barcelona, Spain
- Molecular Targets Program, Department of Medicine, J.G. Brown Cancer Center, Louisville, Kentucky, USA
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
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13
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Zeng Z, Fu M, Hu Y, Wei Y, Wei X, Luo M. Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer. Mol Cancer 2023; 22:172. [PMID: 37853437 PMCID: PMC10583419 DOI: 10.1186/s12943-023-01877-w] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/05/2023] [Indexed: 10/20/2023] Open
Abstract
Cancer stem cells (CSCs), initially identified in leukemia in 1994, constitute a distinct subset of tumor cells characterized by surface markers such as CD133, CD44, and ALDH. Their behavior is regulated through a complex interplay of networks, including transcriptional, post-transcriptional, epigenetic, tumor microenvironment (TME), and epithelial-mesenchymal transition (EMT) factors. Numerous signaling pathways were found to be involved in the regulatory network of CSCs. The maintenance of CSC characteristics plays a pivotal role in driving CSC-associated tumor metastasis and conferring resistance to therapy. Consequently, CSCs have emerged as promising targets in cancer treatment. To date, researchers have developed several anticancer agents tailored to specifically target CSCs, with some of these treatment strategies currently undergoing preclinical or clinical trials. In this review, we outline the origin and biological characteristics of CSCs, explore the regulatory networks governing CSCs, discuss the signaling pathways implicated in these networks, and investigate the influential factors contributing to therapy resistance in CSCs. Finally, we offer insights into preclinical and clinical agents designed to eliminate CSCs.
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Affiliation(s)
- Zhen Zeng
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Minyang Fu
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuan Hu
- Department of Pediatric Nephrology Nursing, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Min Luo
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China.
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14
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Ding QJ, Remy MT, Upara C, Hu J, Mata AVM, Haes AJ, Lanzel E, Sun H, Buchakjian MR, Hong L. CaCO 3 Nanoparticles Delivering MicroRNA-200c Suppress Oral Squamous Cell Carcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.05.561110. [PMID: 37873146 PMCID: PMC10592969 DOI: 10.1101/2023.10.05.561110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
MicroRNA (miR)-200c suppresses the initiation and progression of oral squamous cell carcinoma (OSCC), the most prevalent head and neck cancer with high recurrence, metastasis, and mortality rates. However, miR-200c -based gene therapy to inhibit OSCC growth and metastasis has yet to be reported. To develop an miR-based gene therapy to improve the outcomes of OSCC treatment, this study investigates the feasibility of plasmid DNA encoding miR-200c delivered via non-viral CaCO 3 -based nanoparticles to inhibit OSCC tumor growth. CaCO 3 -based nanoparticles with various ratios of CaCO 3 and protamine sulfate (PS) were utilized to transfect pDNA encoding miR-200c into OSCC cells and the efficiency of these nanoparticles was evaluated. The proliferation, migration, and associated oncogene production, as well as in vivo tumor growth for OSCC cells overexpressing miR-200c were also quantified. It was observed that, while CaCO 3 -based nanoparticles improve transfection efficiencies of pDNA miR-200c , the ratio of CaCO 3 to PS significantly influences the transfection efficiency. Overexpression of miR-200c significantly reduced proliferation, migration, and oncogene expression of OSCC cells, as well as the tumor size of cell line-derived xenografts (CDX) in mice. In addition, a local administration of pDNA miR-200c using CaCO 3 delivery significantly enhanced miR-200c transfection and suppressed tumor growth of CDX in mice. These results strongly indicate that the nanocomplexes of CaCO 3 /pDNA miR-200c may potentially be used to reduce oral cancer recurrence and metastasis and improve clinical outcomes in OSCC treatment. (227 words).
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15
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Hou Y, Diao L, Hu Y, Zhang Q, Lv G, Tao S, Xu W, Xie S, Zhang Q, Xiao Z. The Conserved LncRNA DIO3OS Restricts Hepatocellular Carcinoma Stemness by Interfering with NONO-Mediated Nuclear Export of ZEB1 mRNA. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301983. [PMID: 37271897 PMCID: PMC10427364 DOI: 10.1002/advs.202301983] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/28/2023] [Indexed: 06/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive and fatal disease caused by a subset of cancer stem cells (CSCs). It is estimated that there are approximately 100 000 long noncoding RNAs (lncRNAs) in humans. However, the mechanisms by which lncRNAs affect tumor stemness remain poorly understood. In the present study, it is found that DIO3OS is a conserved lncRNA that is generally downregulated in multiple cancers, including HCC, and its low expression correlates with poor clinical outcomes in HCC. In in vitro cancer cell lines and an in vivo spontaneous HCC mouse model, DIO3OS markedly represses tumor development via its suppressive role in CSCs through downregulation of zinc finger E-box binding homeobox 1 (ZEB1). Interestingly, DIO3OS represses ZEB1 post-transcriptionally without affecting its mRNA levels. Subsequent experiments show that DIO3OS interacts with the NONO protein and restricts NONO-mediated nuclear export of ZEB1 mRNA. Overall, these findings demonstrate that the DIO3OS-NONO-ZEB1 axis restricts HCC development and offers a valuable candidate for CSC-targeted therapeutics for HCC.
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Affiliation(s)
- Ya‐Rui Hou
- Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630P. R. China
| | - Li‐Ting Diao
- Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630P. R. China
| | - Yan‐Xia Hu
- Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630P. R. China
| | - Qian‐Qian Zhang
- School of Life Sciences and BiopharmaceuticsGuangdong Pharmaceutical UniversityGuangzhou510006P. R. China
| | - Guo Lv
- Guangdong Key Laboratory of Liver Disease ResearchThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630P. R. China
| | - Shuang Tao
- Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630P. R. China
| | - Wan‐Yi Xu
- Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630P. R. China
| | - Shu‐Juan Xie
- Institute of VaccineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630P. R. China
| | - Qi Zhang
- Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630P. R. China
- Institute of VaccineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630P. R. China
| | - Zhen‐Dong Xiao
- Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630P. R. China
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16
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Saini M, Schmidleitner L, Moreno HD, Donato E, Falcone M, Bartsch JM, Klein C, Vogel V, Würth R, Pfarr N, Espinet E, Lehmann M, Königshoff M, Reitberger M, Haas S, Graf E, Schwarzmayr T, Strom TM, Spaich S, Sütterlin M, Schneeweiss A, Weichert W, Schotta G, Reichert M, Aceto N, Sprick MR, Trumpp A, Scheel CH. Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer. Cell Rep 2023; 42:112533. [PMID: 37257449 DOI: 10.1016/j.celrep.2023.112533] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 10/04/2022] [Accepted: 05/03/2023] [Indexed: 06/02/2023] Open
Abstract
The acquisition of mesenchymal traits is considered a hallmark of breast cancer progression. However, the functional relevance of epithelial-to-mesenchymal transition (EMT) remains controversial and context dependent. Here, we isolate epithelial and mesenchymal populations from human breast cancer metastatic biopsies and assess their functional potential in vivo. Strikingly, progressively decreasing epithelial cell adhesion molecule (EPCAM) levels correlate with declining disease propagation. Mechanistically, we find that persistent EPCAM expression marks epithelial clones that resist EMT induction and propagate competitively. In contrast, loss of EPCAM defines clones arrested in a mesenchymal state, with concomitant suppression of tumorigenicity and metastatic potential. This dichotomy results from distinct clonal trajectories impacting global epigenetic programs that are determined by the interplay between human ZEB1 and its target GRHL2. Collectively, our results indicate that susceptibility to irreversible EMT restrains clonal propagation, whereas resistance to mesenchymal reprogramming sustains disease spread in multiple models of human metastatic breast cancer, including patient-derived cells in vivo.
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Affiliation(s)
- Massimo Saini
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany; Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
| | - Laura Schmidleitner
- Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany; Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Center for Functional Protein Assemblies (CPA), Technical University of Munich (TUM), Garching, Germany; Center for Organoid Systems (COS), Technical University of Munich (TUM), Garching, Germany; Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), Garching, Germany
| | - Helena Domínguez Moreno
- Division of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilian University of Munich (LMU), Munich, Germany
| | - Elisa Donato
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Mattia Falcone
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Johanna M Bartsch
- Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany
| | - Corinna Klein
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Vanessa Vogel
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Roberto Würth
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Nicole Pfarr
- Institute of Pathology, Technical University of Munich (TUM), Munich, Germany
| | - Elisa Espinet
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Mareike Lehmann
- Institute for Lung Health and Immunity (LHI) and Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Germany; Institute for Lung Research, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany
| | - Melanie Königshoff
- Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Member of the German Center of Lung Research (DZL), Munich, Germany
| | - Manuel Reitberger
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Simon Haas
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Elisabeth Graf
- Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany
| | - Thomas Schwarzmayr
- Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany
| | - Tim-Matthias Strom
- Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany
| | - Saskia Spaich
- Department of Gynaecology and Obstetrics, University Women's Clinic, University Medical Centre Mannheim, Mannheim, Germany
| | - Marc Sütterlin
- Department of Gynaecology and Obstetrics, University Women's Clinic, University Medical Centre Mannheim, Mannheim, Germany
| | - Andreas Schneeweiss
- National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Wilko Weichert
- Institute of Pathology, Technical University of Munich (TUM), Munich, Germany; German Cancer Consortium (DKTK), Germany
| | - Gunnar Schotta
- Division of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilian University of Munich (LMU), Munich, Germany
| | - Maximilian Reichert
- Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Center for Functional Protein Assemblies (CPA), Technical University of Munich (TUM), Garching, Germany; Center for Organoid Systems (COS), Technical University of Munich (TUM), Garching, Germany; Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), Garching, Germany; German Cancer Consortium (DKTK), Germany
| | - Nicola Aceto
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Martin R Sprick
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; German Cancer Consortium (DKTK), Germany.
| | - Andreas Trumpp
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; German Cancer Consortium (DKTK), Germany.
| | - Christina H Scheel
- Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany.
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17
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Singh S, Saini H, Sharma A, Gupta S, Huddar VG, Tripathi R. Breast cancer: miRNAs monitoring chemoresistance and systemic therapy. Front Oncol 2023; 13:1155254. [PMID: 37397377 PMCID: PMC10312137 DOI: 10.3389/fonc.2023.1155254] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/05/2023] [Indexed: 07/04/2023] Open
Abstract
With a high mortality rate that accounts for millions of cancer-related deaths each year, breast cancer is the second most common malignancy in women. Chemotherapy has significant potential in the prevention and spreading of breast cancer; however, drug resistance often hinders therapy in breast cancer patients. The identification and the use of novel molecular biomarkers, which can predict response to chemotherapy, might lead to tailoring breast cancer treatment. In this context, accumulating research has reported microRNAs (miRNAs) as potential biomarkers for early cancer detection, and are conducive to designing a more specific treatment plan by helping analyze drug resistance and sensitivity in breast cancer treatment. In this review, miRNAs are discussed in two alternative ways-as tumor suppressors to be used in miRNA replacement therapy to reduce oncogenesis and as oncomirs to lessen the translation of the target miRNA. Different miRNAs like miR-638, miR-17, miR-20b, miR-342, miR-484, miR-21, miR-24, miR-27, miR-23 and miR-200 are involved in the regulation of chemoresistance through diverse genetic targets. For instance, tumor-suppressing miRNAs like miR-342, miR-16, miR-214, and miR-128 and tumor-promoting miRNAs like miR101 and miR-106-25 cluster regulate the cell cycle, apoptosis, epithelial to mesenchymal transition and other pathways to impart breast cancer drug resistance. Hence, in this review, we have discussed the significance of miRNA biomarkers that could assist in providing novel therapeutic targets to overcome potential chemotherapy resistance to systemic therapy and further facilitate the design of tailored therapy for enhanced efficacy against breast cancer.
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Affiliation(s)
- Shivam Singh
- Department of Radiation Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Heena Saini
- Integrated translational Molecular Biology laboratory, Department of Rog Nidan and Vikriti vigyan (Pathology), All India Institute of Ayurveda (AIIA), New Delhi, India
| | - Ashok Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Subhash Gupta
- Department of Radiation Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - V. G. Huddar
- Department of Kaya Chikitsa (Internal Medicine), All India Institute of Ayurveda (AIIA), New Delhi, India
| | - Richa Tripathi
- Integrated translational Molecular Biology laboratory, Department of Rog Nidan and Vikriti vigyan (Pathology), All India Institute of Ayurveda (AIIA), New Delhi, India
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18
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Waryah C, Alves E, Mazzieri R, Dolcetti R, Thompson EW, Redfern A, Blancafort P. Unpacking the Complexity of Epithelial Plasticity: From Master Regulator Transcription Factors to Non-Coding RNAs. Cancers (Basel) 2023; 15:3152. [PMID: 37370762 DOI: 10.3390/cancers15123152] [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: 03/22/2023] [Revised: 06/09/2023] [Accepted: 06/10/2023] [Indexed: 06/29/2023] Open
Abstract
Cellular plasticity in cancer enables adaptation to selective pressures and stress imposed by the tumor microenvironment. This plasticity facilitates the remodeling of cancer cell phenotype and function (such as tumor stemness, metastasis, chemo/radio resistance), and the reprogramming of the surrounding tumor microenvironment to enable immune evasion. Epithelial plasticity is one form of cellular plasticity, which is intrinsically linked with epithelial-mesenchymal transition (EMT). Traditionally, EMT has been regarded as a binary state. Yet, increasing evidence suggests that EMT involves a spectrum of quasi-epithelial and quasi-mesenchymal phenotypes governed by complex interactions between cellular metabolism, transcriptome regulation, and epigenetic mechanisms. Herein, we review the complex cross-talk between the different layers of epithelial plasticity in cancer, encompassing the core layer of transcription factors, their interacting epigenetic modifiers and non-coding RNAs, and the manipulation of cancer immunogenicity in transitioning between epithelial and mesenchymal states. In examining these factors, we provide insights into promising therapeutic avenues and potential anti-cancer targets.
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Affiliation(s)
- Charlene Waryah
- Cancer Epigenetics Group, Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
- School of Human Sciences, University of Western Australia, Perth, WA 6009, Australia
| | - Eric Alves
- Cancer Epigenetics Group, Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
- School of Human Sciences, University of Western Australia, Perth, WA 6009, Australia
| | - Roberta Mazzieri
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Riccardo Dolcetti
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
- Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Erik W Thompson
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia
- Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Andrew Redfern
- School of Medicine, University of Western Australia, Perth, WA 6009, Australia
| | - Pilar Blancafort
- Cancer Epigenetics Group, Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
- School of Human Sciences, University of Western Australia, Perth, WA 6009, Australia
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19
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Akhmetkaliyev A, Alibrahim N, Shafiee D, Tulchinsky E. EMT/MET plasticity in cancer and Go-or-Grow decisions in quiescence: the two sides of the same coin? Mol Cancer 2023; 22:90. [PMID: 37259089 DOI: 10.1186/s12943-023-01793-z] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 05/20/2023] [Indexed: 06/02/2023] Open
Abstract
Epithelial mesenchymal transition (EMT) and mesenchymal epithelial transition (MET) are genetic determinants of cellular plasticity. These programs operate in physiological (embryonic development, wound healing) and pathological (organ fibrosis, cancer) conditions. In cancer, EMT and MET interfere with various signalling pathways at different levels. This results in gross alterations in the gene expression programs, which affect most, if not all hallmarks of cancer, such as response to proliferative and death-inducing signals, tumorigenicity, and cell stemness. EMT in cancer cells involves large scale reorganisation of the cytoskeleton, loss of epithelial integrity, and gain of mesenchymal traits, such as mesenchymal type of cell migration. In this regard, EMT/MET plasticity is highly relevant to the Go-or-Grow concept, which postulates the dichotomous relationship between cell motility and proliferation. The Go-or-Grow decisions are critically important in the processes in which EMT/MET plasticity takes the central stage, mobilisation of stem cells during wound healing, cancer relapse, and metastasis. Here we outline the maintenance of quiescence in stem cell and metastatic niches, focusing on the implication of EMT/MET regulatory networks in Go-or-Grow switches. In particular, we discuss the analogy between cells residing in hybrid quasi-mesenchymal states and GAlert, an intermediate phase allowing quiescent stem cells to enter the cell cycle rapidly.
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Affiliation(s)
- Azamat Akhmetkaliyev
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, 020000, Kazakhstan
| | | | - Darya Shafiee
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, 020000, Kazakhstan
| | - Eugene Tulchinsky
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, 020000, Kazakhstan.
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
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20
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Olczak M, Orzechowska MJ, Bednarek AK, Lipiński M. The Transcriptomic Profiles of ESR1 and MMP3 Stratify the Risk of Biochemical Recurrence in Primary Prostate Cancer beyond Clinical Features. Int J Mol Sci 2023; 24:ijms24098399. [PMID: 37176106 PMCID: PMC10179071 DOI: 10.3390/ijms24098399] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 04/29/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
The molecular determinants of the heterogenic course of prostate cancer (PC) remain elusive. We aimed to determine the drivers predisposing to unfavorable PC outcomes anticipated by BCR events among patients of similar preoperative characteristics. The TCGA transcriptomic and clinical data of 497 PC individuals were used, stratified according to the risk of BCR by EAU-EANM-ESTRO-ESUR-SIOG. The relevance of the functional markers regarding BCR-free survival was examined by the cutp algorithm. Through UpSetR, subgroups of PC patients bearing an unfavorable signature were identified, followed by the hierarchical clustering of the major markers of the epithelial-to-mesenchymal transition (EMT). BCR-free survival was estimated with the Cox proportional hazards regression model. ESR1 significantly differentiated BCR-free survival, whereas AR did not. An elevation in KLK3 correlated with better prognosis, although PGR, KLK3, CDH1, and MMP3 predicted BCR better than the preoperative PSA level. Patients sharing an unfavorable profile of ESR1 and MMP3 together with lymph node status, Gleason score, T, and EAU risk groups were at a higher risk of BCR originating from mesenchymal features of PC cells. To conclude, we revealed an ESR1-driven unfavorable profile of EMT underpinning a worse PC trajectory. ESR1 may have a major role in PC progression; therefore, it could become a major focus for further investigations.
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Affiliation(s)
- Michał Olczak
- II Clinic of Urology, Medical University of Lodz, Pabianicka 62, 93-513 Lodz, Poland
| | | | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland
| | - Marek Lipiński
- II Clinic of Urology, Medical University of Lodz, Pabianicka 62, 93-513 Lodz, Poland
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21
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Verstappe J, Berx G. A role for partial epithelial-to-mesenchymal transition in enabling stemness in homeostasis and cancer. Semin Cancer Biol 2023; 90:15-28. [PMID: 36773819 DOI: 10.1016/j.semcancer.2023.02.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/19/2023] [Accepted: 02/02/2023] [Indexed: 02/12/2023]
Abstract
Stem cells have self-renewal capacities and the ability to give rise to differentiated cells thereby sustaining tissues during homeostasis and injury. This structural hierarchy extends to tumours which harbor stem-like cells deemed cancer stem cells that propagate the tumour and drive metastasis and relapse. The process of epithelial-to-mesenchymal transition (EMT), which plays an important role in development and cancer cell migration, was shown to be correlated with stemness in both homeostasis and cancer indicating that stemness can be acquired and is not necessarily an intrinsic trait. Nowadays it is experimentally proven that the activation of an EMT program does not necessarily drive cells towards a fully mesenchymal phenotype but rather to hybrid E/M states. This review offers the latest advances in connecting the EMT status and stem-cell state of both non-transformed and cancer cells. Recent literature clearly shows that hybrid EMT states have a higher probability of acquiring stem cell traits. The position of a cell along the EMT-axis which coincides with a stem cell-like state is known as the stemness window. We show how the original EMT-state of a cell dictates the EMT/MET inducing programmes required to reach stemness. Lastly we present the mechanism of stemness regulation and the regulatory feedback loops which position cells at a certain EMT state along the EMT axis.
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Affiliation(s)
- Jeroen Verstappe
- Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Geert Berx
- Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
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22
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Zhou J, Li Y, He J, Liu L, Hu S, Guo M, Liu T, Liu J, Wang J, Guo B, Wang W. ROS Scavenging Graphene-Based Hydrogel Enhances Type H Vessel Formation and Vascularized Bone Regeneration via ZEB1/Notch1 Mediation. Macromol Biosci 2023; 23:e2200502. [PMID: 36637816 DOI: 10.1002/mabi.202200502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/06/2023] [Indexed: 01/14/2023]
Abstract
The regeneration strategy for bone defects is greatly limited by the bone microenvironment, and excessive reactive oxygen species (ROS) seriously hinder the formation of new bone. Reduced graphene oxide (rGO) is expected to meet the requirements because of its ability to scavenge free radicals through electron transfer. Antioxidant hydrogels based on gelatine methacrylate (GM), acrylyl-β-cyclodextrin (Ac-CD), and rGO functionalized with β-cyclodextrin (β-CD) are developed for skull defect regeneration, but the mechanism of how rGO-based hydrogels enhance bone repair remains unclear. In this work, it is confirmed that the GM/Ac-CD/rGO hydrogel has good antioxidant capacity, and promotes osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and angiogenesis of human umbilical vein endothelial cells (HUVECs). The rGO-based hydrogel affects ZEB1/Notch1 to promote tube formation. Furthermore, two-photon laser scanning microscopy is used to observe the ROS in a skull defect. The rGO-based hydrogel promotes type H vessel formation in a skull defect. In conclusion, the hydrogel neutralizes ROS in the vicinity of a skull defect and stimulates ZEB1/Notch1 to promote the coupling of osteogenesis and angiogenesis, which may be a possible approach for bone regeneration.
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Affiliation(s)
- Junpeng Zhou
- Department of Bone and Joint Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, NO. 157, Xiwu Road, Xi'an, Shaanxi, 710004, P. R. China
| | - Yongwei Li
- Department of Bone and Joint Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, NO. 157, Xiwu Road, Xi'an, Shaanxi, 710004, P. R. China
| | - Jiahui He
- State Key Laboratory for Mechanical Behavior of Materials, and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Liying Liu
- Biomedical Experimental Center of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710116, China
| | - Shugang Hu
- Department of Bone and Joint Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, NO. 157, Xiwu Road, Xi'an, Shaanxi, 710004, P. R. China
| | - Meng Guo
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Tun Liu
- Department of Bone and Joint Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, NO. 157, Xiwu Road, Xi'an, Shaanxi, 710004, P. R. China
| | - Junzheng Liu
- Department of Bone and Joint Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, NO. 157, Xiwu Road, Xi'an, Shaanxi, 710004, P. R. China
| | - Jiaxin Wang
- State Key Laboratory for Mechanical Behavior of Materials, and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Baolin Guo
- State Key Laboratory for Mechanical Behavior of Materials, and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.,Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Wei Wang
- Department of Bone and Joint Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, NO. 157, Xiwu Road, Xi'an, Shaanxi, 710004, P. R. China
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23
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Poonaki E, Kahlert UD, Meuth SG, Gorji A. The role of the ZEB1–neuroinflammation axis in CNS disorders. J Neuroinflammation 2022; 19:275. [PMCID: PMC9675144 DOI: 10.1186/s12974-022-02636-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/31/2022] [Indexed: 11/21/2022] Open
Abstract
Zinc finger E-box binding homeobox 1 (ZEB1) is a master modulator of the epithelial–mesenchymal transition (EMT), a process whereby epithelial cells undergo a series of molecular changes and express certain characteristics of mesenchymal cells. ZEB1, in association with other EMT transcription factors, promotes neuroinflammation through changes in the production of inflammatory mediators, the morphology and function of immune cells, and multiple signaling pathways that mediate the inflammatory response. The ZEB1–neuroinflammation axis plays a pivotal role in the pathogenesis of different CNS disorders, such as brain tumors, multiple sclerosis, cerebrovascular diseases, and neuropathic pain, by promoting tumor cell proliferation and invasiveness, formation of the hostile inflammatory micromilieu surrounding neuronal tissues, dysfunction of microglia and astrocytes, impairment of angiogenesis, and dysfunction of the blood–brain barrier. Future studies are needed to elucidate whether the ZEB1–neuroinflammation axis could serve as a diagnostic, prognostic, and/or therapeutic target for CNS disorders.
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Affiliation(s)
- Elham Poonaki
- grid.411327.20000 0001 2176 9917Department of Neurology, Faculty of Medicine, Heinrich-Heine-University, Düsseldorf, Germany ,grid.5949.10000 0001 2172 9288Epilepsy Research Center, Department of Neurosurgery, Westfälische Wilhelms-Universität Münster, Domagkstr. 11, 48149 Münster, Germany
| | - Ulf Dietrich Kahlert
- grid.5807.a0000 0001 1018 4307Molecular and Experimental Surgery, Faculty of Medicine, University Clinic for General-, Visceral-, Vascular- and Transplantation Surgery, Otto-Von-Guericke-University, Magdeburg, Germany
| | - Sven G. Meuth
- grid.411327.20000 0001 2176 9917Department of Neurology, Faculty of Medicine, Heinrich-Heine-University, Düsseldorf, Germany
| | - Ali Gorji
- grid.5949.10000 0001 2172 9288Epilepsy Research Center, Department of Neurosurgery, Westfälische Wilhelms-Universität Münster, Domagkstr. 11, 48149 Münster, Germany ,grid.512981.60000 0004 0612 1380Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran ,grid.411583.a0000 0001 2198 6209Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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24
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Insight into LncRNA- and CircRNA-Mediated CeRNAs: Regulatory Network and Implications in Nasopharyngeal Carcinoma—A Narrative Literature Review. Cancers (Basel) 2022; 14:cancers14194564. [PMID: 36230487 PMCID: PMC9559536 DOI: 10.3390/cancers14194564] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/16/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a kind of head-and-neck malignant tumor, and distant metastasis treatment resistance is the leading cause of patient death. In-depth understanding of NPC progression and treatment failure remains to be explored. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are noncoding RNAs that play key regulatory role in shaping tumor cell activities. Recent studies have revealed that lncRNA and circRNA function as competitive endogenous RNAs (ceRNAs) by regulating the posttranscriptional expression of genes as miRNA baits. The imbalanced ceRNA networks derived from lncRNA/circRNA-miRNA-mRNA interaction are widely found to contribute to NPC development. Herein, we summarize typical examples of lncRNA/circRNA-associated ceRNAs in recent years, which involved the potential molecular mechanisms in the regulation of proliferation, apoptosis, treatment resistance and metastasis of NPC, and discuss their potential clinical significance in the prognosis and treatment of NPC. Interpreting the involvement of ceRNAs networks will provide new insight into the pathogenesis and treatment strategies of NPC. However, ceRNA regulatory mechanism has some limitations currently. Screening the most effective ceRNA targets and the clinical application of ceRNA still has many challenges.
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25
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Huang Y, Hong W, Wei X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol 2022; 15:129. [PMID: 36076302 PMCID: PMC9461252 DOI: 10.1186/s13045-022-01347-8] [Citation(s) in RCA: 396] [Impact Index Per Article: 132.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 08/30/2022] [Indexed: 11/10/2022] Open
Abstract
Epithelial–mesenchymal transition (EMT) is an essential process in normal embryonic development and tissue regeneration. However, aberrant reactivation of EMT is associated with malignant properties of tumor cells during cancer progression and metastasis, including promoted migration and invasiveness, increased tumor stemness, and enhanced resistance to chemotherapy and immunotherapy. EMT is tightly regulated by a complex network which is orchestrated with several intrinsic and extrinsic factors, including multiple transcription factors, post-translational control, epigenetic modifications, and noncoding RNA-mediated regulation. In this review, we described the molecular mechanisms, signaling pathways, and the stages of tumorigenesis involved in the EMT process and discussed the dynamic non-binary process of EMT and its role in tumor metastasis. Finally, we summarized the challenges of chemotherapy and immunotherapy in EMT and proposed strategies for tumor therapy targeting EMT.
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Affiliation(s)
- Yuhe Huang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Weiqi Hong
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
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26
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ZEB1: Catalyst of immune escape during tumor metastasis. Biomed Pharmacother 2022; 153:113490. [DOI: 10.1016/j.biopha.2022.113490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/23/2022] [Accepted: 07/27/2022] [Indexed: 11/20/2022] Open
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27
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Panoramic view of microRNAs in regulating cancer stem cells. Essays Biochem 2022; 66:345-358. [PMID: 35996948 DOI: 10.1042/ebc20220007] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 12/17/2022]
Abstract
Cancer stem cells (CSCs) are a subgroup of tumor cells, possessing the abilities of self-renewal and generation of heterogeneous tumor cell lineages. They are believed to be responsible for tumor initiation, metastasis, as well as chemoresistance in human malignancies. MicroRNAs (miRNAs) are small noncoding RNAs that play essential roles in various cellular activities including CSC initiation and CSC-related properties. Mature miRNAs with ∼22 nucleotides in length are generated from primary miRNAs via its precursors by miRNA-processing machinery. Extensive studies have demonstrated that mature miRNAs modulate CSC initiation and stemness features by regulating multiple pathways and targeting stemness-related factors. Meanwhile, both miRNA precursors and miRNA-processing machinery can also affect CSC properties, unveiling a new insight into miRNA function. The present review summarizes the roles of mature miRNAs, miRNA precursors, and miRNA-processing machinery in regulating CSC properties with a specific focus on the related molecular mechanisms, and also outlines the potential application of miRNAs in cancer diagnosis, predicting prognosis, as well as clinical therapy.
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28
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Sundararajan V, Burk UC, Bajdak-Rusinek K. Revisiting the miR-200 Family: A Clan of Five Siblings with Essential Roles in Development and Disease. Biomolecules 2022; 12:biom12060781. [PMID: 35740906 PMCID: PMC9221129 DOI: 10.3390/biom12060781] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/29/2022] [Accepted: 06/01/2022] [Indexed: 12/07/2022] Open
Abstract
Over two decades of studies on small noncoding RNA molecules illustrate the significance of microRNAs (miRNAs/miRs) in controlling multiple physiological and pathological functions through post-transcriptional and spatiotemporal gene expression. Among the plethora of miRs that are essential during animal embryonic development, in this review, we elaborate the indispensable role of the miR-200 family (comprising miR-200a, -200b, 200c, -141, and -429) in governing the cellular functions associated with epithelial homeostasis, such as epithelial differentiation and neurogenesis. Additionally, in pathological contexts, miR-200 family members are primarily involved in tumor-suppressive roles, including the reversal of the cancer-associated epithelial–mesenchymal transition dedifferentiation process, and are dysregulated during organ fibrosis. Moreover, recent eminent studies have elucidated the crucial roles of miR-200s in the pathophysiology of multiple neurodegenerative diseases and tissue fibrosis. Lastly, we summarize the key studies that have recognized the potential use of miR-200 members as biomarkers for the diagnosis and prognosis of cancers, elaborating the application of these small biomolecules in aiding early cancer detection and intervention.
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Affiliation(s)
- Vignesh Sundararajan
- Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore 117599, Singapore;
| | - Ulrike C. Burk
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany;
| | - Karolina Bajdak-Rusinek
- Department of Medical Genetics, Faculty of Medical Sciences, Medical University of Silesia, 40-752 Katowice, Poland
- Correspondence: ; Tel.: +48-32-208-8382
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29
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van Bruggen D, Pohl F, Langseth CM, Kukanja P, Lee H, Albiach AM, Kabbe M, Meijer M, Linnarsson S, Hilscher MM, Nilsson M, Sundström E, Castelo-Branco G. Developmental landscape of human forebrain at a single-cell level identifies early waves of oligodendrogenesis. Dev Cell 2022; 57:1421-1436.e5. [PMID: 35523173 DOI: 10.1016/j.devcel.2022.04.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 03/20/2022] [Accepted: 04/14/2022] [Indexed: 01/06/2023]
Abstract
Oligodendrogenesis in the human central nervous system has been observed mainly at the second trimester of gestation, a much later developmental stage compared to oligodendrogenesis in mice. Here, we characterize the transcriptomic neural diversity in the human forebrain at post-conception weeks (PCW) 8-10. Using single-cell RNA sequencing, we find evidence of the emergence of a first wave of oligodendrocyte lineage cells as early as PCW 8, which we also confirm at the epigenomic level through the use of single-cell ATAC-seq. Using regulatory network inference, we predict key transcriptional events leading to the specification of oligodendrocyte precursor cells (OPCs). Moreover, by profiling the spatial expression of 50 key genes through the use of in situ sequencing (ISS), we identify regions in the human ventral fetal forebrain where oligodendrogenesis first occurs. Our results indicate evolutionary conservation of the first wave of oligodendrogenesis between mice and humans and describe regulatory mechanisms involved in human OPC specification.
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Affiliation(s)
- David van Bruggen
- Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, 17177 Stockholm, Sweden
| | - Fabio Pohl
- Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, 17177 Stockholm, Sweden
| | | | - Petra Kukanja
- Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, 17177 Stockholm, Sweden
| | - Hower Lee
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, 171 65, Solna, Sweden
| | - Alejandro Mossi Albiach
- Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, 17177 Stockholm, Sweden
| | - Mukund Kabbe
- Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, 17177 Stockholm, Sweden
| | - Mandy Meijer
- Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, 17177 Stockholm, Sweden
| | - Sten Linnarsson
- Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, 17177 Stockholm, Sweden
| | - Markus M Hilscher
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, 171 65, Solna, Sweden
| | - Mats Nilsson
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, 171 65, Solna, Sweden
| | - Erik Sundström
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, BioClinicum, Solna, Sweden
| | - Gonçalo Castelo-Branco
- Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, 17177 Stockholm, Sweden; Ming Wai Lau Centre for Reparative Medicine, Stockholm node, Karolinska Institutet, Stockholm, Sweden.
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Vilchez Mercedes SA, Bocci F, Ahmed M, Eder I, Zhu N, Levine H, Onuchic JN, Jolly MK, Wong PK. Nrf2 Modulates the Hybrid Epithelial/Mesenchymal Phenotype and Notch Signaling During Collective Cancer Migration. Front Mol Biosci 2022; 9:807324. [PMID: 35480877 PMCID: PMC9037689 DOI: 10.3389/fmolb.2022.807324] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 03/03/2022] [Indexed: 12/12/2022] Open
Abstract
Hybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. It remains a challenge to understand how these cell states, which are mostly non-existent in healthy tissue, become stable phenotypes participating in collective cancer migration. The transcription factor Nrf2, which is associated with tumor progression and resistance to therapy, appears to be central to this process. Here, using a combination of immunocytochemistry, single cell biosensors, and computational modeling, we show that Nrf2 functions as a phenotypic stability factor for hybrid E/M cells by inhibiting a complete epithelial-mesenchymal transition (EMT) during collective cancer migration. We also demonstrate that Nrf2 and EMT signaling are spatially coordinated near the leading edge. In particular, computational analysis of an Nrf2-EMT-Notch network and experimental modulation of Nrf2 by pharmacological treatment or CRISPR/Cas9 gene editing reveal that Nrf2 stabilizes a hybrid E/M phenotype which is maximally observed in the interior region immediately behind the leading edge. We further demonstrate that the Nrf2-EMT-Notch network enhances Dll4 and Jagged1 expression at the leading edge, which correlates with the formation of leader cells and protruding tips. Altogether, our results provide direct evidence that Nrf2 acts as a phenotypic stability factor in restricting complete EMT and plays an important role in coordinating collective cancer migration.
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Affiliation(s)
- Samuel A. Vilchez Mercedes
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, United States
| | - Federico Bocci
- Center for Theoretical Biological Physics, Rice University, Houston, TX, United States
| | - Mona Ahmed
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, United States
| | - Ian Eder
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, United States
| | - Ninghao Zhu
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, United States
| | - Herbert Levine
- Center for Theoretical Biological Physics, Department of Physics and Department of Bioengineering, Northeastern University, Boston, MA, United States
- *Correspondence: Herbert Levine, ; José N. Onuchic, ; Mohit Kumar Jolly, ; Pak Kin Wong,
| | - José N. Onuchic
- Center for Theoretical Biological Physics, Rice University, Houston, TX, United States
- Department of Physics and Astronomy, Department of Chemistry and Department of Biosciences, Rice University, Houston, TX, United States
- *Correspondence: Herbert Levine, ; José N. Onuchic, ; Mohit Kumar Jolly, ; Pak Kin Wong,
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India
- *Correspondence: Herbert Levine, ; José N. Onuchic, ; Mohit Kumar Jolly, ; Pak Kin Wong,
| | - Pak Kin Wong
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, United States
- Department of Mechanical Engineering and Department of Surgery, The Pennsylvania State University, University Park, PA, United States
- *Correspondence: Herbert Levine, ; José N. Onuchic, ; Mohit Kumar Jolly, ; Pak Kin Wong,
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Fan B, Zhang Q, Wang N, Wang G. LncRNAs, the Molecules Involved in Communications With Colorectal Cancer Stem Cells. Front Oncol 2022; 12:811374. [PMID: 35155247 PMCID: PMC8829571 DOI: 10.3389/fonc.2022.811374] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/07/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer stem cells (CRCSCs) can actively self-renew, as well as having multidirectional differentiation and tumor regeneration abilities. Because the high functional activities of CRCSCs are associated with low cure rates in patients with colorectal cancer, efforts have sought to determine the function and regulatory mechanisms of CRCSCs. To date, however, the potential regulatory mechanisms of CRCSCs remain incompletely understood. Many non-coding genes are involved in tumor invasion and spread through their regulation of CRCSCs, with long non-coding RNAs (lncRNAs) being important non-coding RNAs. LncRNAs may be involved in the colorectal cancer development and drug resistance through their regulation of CRCSCs. This review systematically evaluates the latest research on the ability of lncRNAs to regulate CRCSC signaling pathways and the involvement of these lncRNAs in colorectal cancer promotion and suppression. The regulatory network of lncRNAs in the CRCSC signaling pathway has been determined. Further analysis of the potential clinical applications of lncRNAs as novel clinical diagnostic and prognostic biomarkers and therapeutic targets for colorectal cancer may provide new ideas and protocols for the prevention and treatment of colorectal cancer.
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Affiliation(s)
- Boyang Fan
- Department of Colorectal Cancer Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qian Zhang
- Department of Colorectal Surgery, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Ning Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Guiyu Wang
- Department of Colorectal Cancer Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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32
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Mortoglou M, Buha Djordjevic A, Djordjevic V, Collins H, York L, Mani K, Valle E, Wallace D, Uysal-Onganer P. Role of microRNAs in response to cadmium chloride in pancreatic ductal adenocarcinoma. Arch Toxicol 2022; 96:467-485. [PMID: 34905088 PMCID: PMC8837568 DOI: 10.1007/s00204-021-03196-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/10/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal and aggressive malignancies with a 5-year survival rate less than 9%. Early detection is particularly difficult due to the lack of symptoms even in advanced stages. microRNAs (miRs/miRNAs) are small (~ 18-24 nucleotides), endogenous, non-coding RNAs, which are involved in the pathogenesis of several malignancies including PDAC. Alterations of miR expressions can lead to apoptosis, angiogenesis, and metastasis. The role of environmental pollutants such as cadmium (Cd) in PDAC has been suggested but not fully understood. This study underlines the role of miRs (miR-221, miR-155, miR-126) in response to cadmium chloride (CdCl2) in vitro. Lethal concentration (LC50) values for CdCl2 resulted in a toxicity series of AsPC-1 > HPNE > BxPC-3 > Panc-1 = Panc-10.5. Following the treatment with CdCl2, miR-221 and miR-155 were significantly overexpressed, whereas miR-126 was downregulated. An increase in epithelial-mesenchymal transition (EMT) via the dysregulation of mesenchymal markers such as Wnt-11, E-cadherin, Snail, and Zeb1 was also observed. Hence, this study has provided evidence to suggest that the environmental pollutant Cd can have a significant role in the development of PDAC, suggesting a significant correlation between miRs and Cd exposure during PDAC progression. Further studies are needed to investigate the precise role of miRs in PDAC progression as well as the role of Cd and other environmental pollutants.
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Affiliation(s)
- Maria Mortoglou
- Cancer Research Group, School of Life Sciences, University of Westminster, London, W1W 6UW UK
| | | | | | - Hunter Collins
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Lauren York
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Katherine Mani
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Elizabeth Valle
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - David Wallace
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Pinar Uysal-Onganer
- Cancer Research Group, School of Life Sciences, University of Westminster, London, W1W 6UW UK
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Colangelo T, Carbone A, Mazzarelli F, Cuttano R, Dama E, Nittoli T, Albanesi J, Barisciano G, Forte N, Palumbo O, Graziano P, di Masi A, Colantuoni V, Sabatino L, Bianchi F, Mazzoccoli G. Loss of circadian gene Timeless induces EMT and tumor progression in colorectal cancer via Zeb1-dependent mechanism. Cell Death Differ 2022; 29:1552-1568. [PMID: 35034102 PMCID: PMC9345857 DOI: 10.1038/s41418-022-00935-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 01/05/2022] [Accepted: 01/07/2022] [Indexed: 12/13/2022] Open
Abstract
The circadian gene Timeless (TIM) provides a molecular bridge between circadian and cell cycle/DNA replication regulatory systems and has been recently involved in human cancer development and progression. However, its functional role in colorectal cancer (CRC), the third leading cause of cancer-related deaths worldwide, has not been fully clarified yet. Here, the analysis of two independent CRC patient cohorts (total 1159 samples) reveals that loss of TIM expression is an unfavorable prognostic factor significantly correlated with advanced tumor stage, metastatic spreading, and microsatellite stability status. Genome-wide expression profiling, in vitro and in vivo experiments, revealed that TIM knockdown induces the activation of the epithelial-to-mesenchymal transition (EMT) program. Accordingly, the analysis of a large set of human samples showed that TIM expression inversely correlated with a previously established gene signature of canonical EMT markers (EMT score), and its ectopic silencing promotes migration, invasion, and acquisition of stem-like phenotype in CRC cells. Mechanistically, we found that loss of TIM expression unleashes ZEB1 expression that in turn drives the EMT program and enhances the aggressive behavior of CRC cells. Besides, the deranged TIM-ZEB1 axis sets off the accumulation of DNA damage and delays DNA damage recovery. Furthermore, we show that the aggressive and genetically unstable 'CMS4 colorectal cancer molecular subtype' is characterized by a lower expression of TIM and that patients with the combination of low-TIM/high-ZEB1 expression have a poorer outcome. In conclusion, our results as a whole suggest the engagement of an unedited TIM-ZEB1 axis in key pathological processes driving malignant phenotype acquisition in colorectal carcinogenesis. Thus, TIM-ZEB1 expression profiling could provide a robust prognostic biomarker in CRC patients, supporting targeted therapeutic strategies with better treatment selection and patients' outcomes.
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Affiliation(s)
- Tommaso Colangelo
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Biomarkers Unit, Viale Padre Pio 7, 71013, San Giovanni Rotondo, (FG), Italy
| | - Annalucia Carbone
- Fondazione IRCCS Casa Sollievo della Sofferenza, Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Viale Cappuccini snc, 71013, San Giovanni Rotondo, (FG), Italy
| | - Francesco Mazzarelli
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Biomarkers Unit, Viale Padre Pio 7, 71013, San Giovanni Rotondo, (FG), Italy
| | - Roberto Cuttano
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Biomarkers Unit, Viale Padre Pio 7, 71013, San Giovanni Rotondo, (FG), Italy
| | - Elisa Dama
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Biomarkers Unit, Viale Padre Pio 7, 71013, San Giovanni Rotondo, (FG), Italy
| | - Teresa Nittoli
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Biomarkers Unit, Viale Padre Pio 7, 71013, San Giovanni Rotondo, (FG), Italy
| | - Jacopo Albanesi
- Department of Sciences, Roma Tre University, Viale G. Marconi, 446, 00154, Rome, (RM), Italy
| | - Giovannina Barisciano
- Department of Sciences and Technologies, University of Sannio, Via Traiano, 3, 82100, Benevento, (BN), Italy
| | - Nicola Forte
- UOC- Patologia Clinica-Settore Anatomia Patologica, Ospedale Fatebenefratelli, Viale Principe di Napoli, 14/A, 82100, Benevento, (BN), Italy
| | - Orazio Palumbo
- Fondazione IRCCS Casa Sollievo della Sofferenza, Division of Medical Genetics, Viale Padre Pio, 7d, 71013, San Giovanni Rotondo, (FG), Italy
| | - Paolo Graziano
- Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini snc, 71013, San Giovanni Rotondo, (FG), Italy
| | - Alessandra di Masi
- Department of Sciences, Roma Tre University, Viale G. Marconi, 446, 00154, Rome, (RM), Italy
| | - Vittorio Colantuoni
- Department of Sciences and Technologies, University of Sannio, Via Traiano, 3, 82100, Benevento, (BN), Italy
| | - Lina Sabatino
- Department of Sciences and Technologies, University of Sannio, Via Traiano, 3, 82100, Benevento, (BN), Italy
| | - Fabrizio Bianchi
- Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Biomarkers Unit, Viale Padre Pio 7, 71013, San Giovanni Rotondo, (FG), Italy.
| | - Gianluigi Mazzoccoli
- Fondazione IRCCS Casa Sollievo della Sofferenza, Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Viale Cappuccini snc, 71013, San Giovanni Rotondo, (FG), Italy.
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The Transcription Factors Zeb1 and Snail Induce Cell Malignancy and Cancer Stem Cell Phenotype in Prostate Cells, Increasing Androgen Synthesis Capacity and Therapy Resistance. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1393:51-64. [PMID: 36587301 DOI: 10.1007/978-3-031-12974-2_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Prostate cancer (PCa) incidence has increased during the last decades, becoming one of the leading causes of death by cancer in men worldwide. During an extended period of prostate cancer, malignant cells are androgen-sensitive being testosterone the main responsible for tumor growth. Accordingly, treatments blocking production and action of testosterone are mostly used. However, during disease progression, PCa cells become androgen insensitive producing a castration-resistant stage with a worse prognosis. Overcoming castration-resistant prostate cancer (CRPC) has become a great challenge in the management of this disease. In the search for molecular pathways leading to therapy resistance, the epithelial-mesenchymal transition (EMT), and particularly the transcription factors zinc finger E-box-binding homeobox 1 (Zeb1) and zinc finger protein SNAI1 (Snail), master genes of the EMT, have shown to have pivotal roles. Also, the discovery that cancer stem cells (CSCs) can be generated de novo from their non-CSCs counterpart has led to the question whereas these EMT transcription factors could be implicated in this dynamic conversion between non-CSC and CSC. In this review, we analyze evidence supporting the idea that Zeb1 and Snail induce cell malignancy and cancer stem cell phenotype in prostate cells, increasing androgen synthesis capacity and therapy resistance.
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Cavallari I, Ciccarese F, Sharova E, Urso L, Raimondi V, Silic-Benussi M, D’Agostino DM, Ciminale V. The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers. Cancers (Basel) 2021; 13:5874. [PMID: 34884985 PMCID: PMC8656820 DOI: 10.3390/cancers13235874] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers.
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Affiliation(s)
- Ilaria Cavallari
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Francesco Ciccarese
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Evgeniya Sharova
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Loredana Urso
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
| | - Vittoria Raimondi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Micol Silic-Benussi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Donna M. D’Agostino
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Biomedical Sciences, University of Padua, 35131 Padova, Italy
| | - Vincenzo Ciminale
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
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36
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MicroRNAs in Pancreatic Cancer and Chemoresistance. Pancreas 2021; 50:1334-1342. [PMID: 35041330 DOI: 10.1097/mpa.0000000000001934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading malignancies affecting human health, largely because of the development of resistance to chemotherapy/radiotherapy. There are many mechanisms that mediate the development of drug resistance, such as the transport of antineoplastic agents into cells, shifts in energy metabolism and environment, antineoplastic agent-induced DNA damage, and genetic mutations. MicroRNAs are short, noncoding RNAs that are 20 to 24 nucleotides in length and serve several biological functions. They bind to the 3'-untranslated regions of target genes and induce target degradation or translational inhibition. MicroRNAs can regulate several target genes and mediate PDAC chemotherapy/radiotherapy resistance. The detection of novel microRNAs would not only reveal the molecular mechanisms of PDAC and resistance to chemotherapy/radiotherapy but also provide new approaches to PDAC therapy. MicroRNAs are thus potential therapeutic targets for PDAC and might be essential in uncovering new mechanisms of the disease.
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37
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Miao L, Feng G, Yuan H. CircRNAs: a family number of miRNA regulatory transcriptome in laryngeal carcinoma. J Clin Lab Anal 2021; 35:e24038. [PMID: 34617636 PMCID: PMC8605118 DOI: 10.1002/jcla.24038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 01/22/2023] Open
Abstract
Laryngeal carcinoma (LC) is a common head and neck cancer, which is the result of mutational changes due to gene dysregulation and etiological factors such as tobacco and smoking. A large number of patients received a poor prognosis due to diagnosis at an advanced stage. This highlights the need for definitive, early, and efficient diagnoses. With rapid development of high‐throughput sequencing, circular RNA (circRNA) has been reported to play a pivotal role in cancer. CircRNA functions as a microRNA (miRNA) sponge in the regulation of mRNA expression, forming circRNA‐miRNA regulatory axis. In this review, we described the axis in LC. The result indicated that CDR1as, hsa_circ_0042823, hsa_circ_0023028, circPARD3, hsa_circ_103862, hsa_circ_0000218, circMYLK, circCORO1C, hsa_circ_100290, circ‐CCND1, hsa_circ_0057481, circFLAN, and circRASSF2 expressed higher in LC, whereas, hsa_circ_0036722 and hsa_circ_0042666 expressed lower. The circRNAs regulated the target genes by sponging miRNAs and contributed to the pathogenesis of LC.
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Affiliation(s)
- Limin Miao
- Department of Geriatric Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
| | - Guanying Feng
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Oral and Maxillofacial, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Hua Yuan
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Oral and Maxillofacial, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
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Brabletz S, Schuhwerk H, Brabletz T, Stemmler MP. Dynamic EMT: a multi-tool for tumor progression. EMBO J 2021; 40:e108647. [PMID: 34459003 PMCID: PMC8441439 DOI: 10.15252/embj.2021108647] [Citation(s) in RCA: 417] [Impact Index Per Article: 104.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/14/2021] [Accepted: 06/29/2021] [Indexed: 12/20/2022] Open
Abstract
The process of epithelial-mesenchymal transition (EMT) is fundamental for embryonic morphogenesis. Cells undergoing it lose epithelial characteristics and integrity, acquire mesenchymal features, and become motile. In cancer, this program is hijacked to confer essential changes in morphology and motility that fuel invasion. In addition, EMT is increasingly understood to orchestrate a large variety of complementary cancer features, such as tumor cell stemness, tumorigenicity, resistance to therapy and adaptation to changes in the microenvironment. In this review, we summarize recent findings related to these various classical and non-classical functions, and introduce EMT as a true tumorigenic multi-tool, involved in many aspects of cancer. We suggest that therapeutic targeting of the EMT process will-if acknowledging these complexities-be a possibility to concurrently interfere with tumor progression on many levels.
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Affiliation(s)
- Simone Brabletz
- Department of Experimental Medicine 1Nikolaus‐Fiebiger Center for Molecular MedicineFriedrich‐Alexander University of Erlangen‐NürnbergErlangenGermany
| | - Harald Schuhwerk
- Department of Experimental Medicine 1Nikolaus‐Fiebiger Center for Molecular MedicineFriedrich‐Alexander University of Erlangen‐NürnbergErlangenGermany
| | - Thomas Brabletz
- Department of Experimental Medicine 1Nikolaus‐Fiebiger Center for Molecular MedicineFriedrich‐Alexander University of Erlangen‐NürnbergErlangenGermany
| | - Marc P. Stemmler
- Department of Experimental Medicine 1Nikolaus‐Fiebiger Center for Molecular MedicineFriedrich‐Alexander University of Erlangen‐NürnbergErlangenGermany
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39
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Garrido-Cano I, Pattanayak B, Adam-Artigues A, Lameirinhas A, Torres-Ruiz S, Tormo E, Cervera R, Eroles P. MicroRNAs as a clue to overcome breast cancer treatment resistance. Cancer Metastasis Rev 2021; 41:77-105. [PMID: 34524579 PMCID: PMC8924146 DOI: 10.1007/s10555-021-09992-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 09/02/2021] [Indexed: 12/31/2022]
Abstract
Breast cancer is the most frequent cancer in women worldwide. Despite the improvement in diagnosis and treatments, the rates of cancer relapse and resistance to therapies remain higher than desirable. Alterations in microRNAs have been linked to changes in critical processes related to cancer development and progression. Their involvement in resistance or sensitivity to breast cancer treatments has been documented by different in vivo and in vitro experiments. The most significant microRNAs implicated in modulating resistance to breast cancer therapies are summarized in this review. Resistance to therapy has been linked to cellular processes such as cell cycle, apoptosis, epithelial-to-mesenchymal transition, stemness phenotype, or receptor signaling pathways, and the role of microRNAs in their regulation has already been described. The modulation of specific microRNAs may modify treatment response and improve survival rates and cancer patients' quality of life. As a result, a greater understanding of microRNAs, their targets, and the signaling pathways through which they act is needed. This information could be useful to design new therapeutic strategies, to reduce resistance to the available treatments, and to open the door to possible new clinical approaches.
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Affiliation(s)
| | | | | | - Ana Lameirinhas
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain
| | | | - Eduardo Tormo
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain.,Center for Biomedical Network Research On Cancer, CIBERONC-ISCIII, 28029, Madrid, Spain
| | | | - Pilar Eroles
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain. .,Center for Biomedical Network Research On Cancer, CIBERONC-ISCIII, 28029, Madrid, Spain. .,Department of Physiology, University of Valencia, 46010, Valencia, Spain.
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Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers. Cancers (Basel) 2021; 13:cancers13184550. [PMID: 34572776 PMCID: PMC8472624 DOI: 10.3390/cancers13184550] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers. HCC is associated with multiple risk factors and is characterized by a marked tumor heterogeneity that makes its molecular classification difficult to apply in the clinics. The lack of circulating biomarkers for the diagnosis, prognosis, and prediction of response to treatments further undermines the possibility of developing personalized therapies. Accumulating evidence affirms the involvement of cancer stem cells (CSCs) in tumor heterogeneity, recurrence, and drug resistance. Owing to the contribution of CSCs to treatment failure, there is an urgent need to develop novel therapeutic strategies targeting, not only the tumor bulk, but also the CSC subpopulation. Clarification of the molecular mechanisms influencing CSC properties, and the identification of their functional roles in tumor progression, may facilitate the discovery of novel CSC-based therapeutic targets to be used alone, or in combination with current anticancer agents, for the treatment of HCC. Here, we review the driving forces behind the regulation of liver CSCs and their therapeutic implications. Additionally, we provide data on their possible exploitation as prognostic and predictive biomarkers in patients with HCC.
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41
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Interaction between Ras and Src clones causes interdependent tumor malignancy via Notch signaling in Drosophila. Dev Cell 2021; 56:2223-2236.e5. [PMID: 34324859 DOI: 10.1016/j.devcel.2021.07.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/31/2021] [Accepted: 07/02/2021] [Indexed: 02/07/2023]
Abstract
Cancer tissue often comprises multiple tumor clones with distinct oncogenic alterations such as Ras or Src activation, yet the mechanism by which tumor heterogeneity drives cancer progression remains elusive. Here, we show in Drosophila imaginal epithelium that clones of Ras- or Src-activated benign tumors interact with each other to mutually promote tumor malignancy. Mechanistically, Ras-activated cells upregulate the cell-surface ligand Delta while Src-activated cells upregulate its receptor Notch, leading to Notch activation in Src cells. Elevated Notch signaling induces the transcriptional repressor Zfh1/ZEB1, which downregulates E-cadherin and cell death gene hid, leading to Src-activated invasive tumors. Simultaneously, Notch activation in Src cells upregulates the cytokine Unpaired/IL-6, which activates JAK-STAT signaling in neighboring Ras cells. Elevated JAK-STAT signaling upregulates the BTB-zinc-finger protein Chinmo, which downregulates E-cadherin and thus generates Ras-activated invasive tumors. Our findings provide a mechanistic explanation for how tumor heterogeneity triggers tumor progression via cell-cell interactions.
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42
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Liao C, Wang Q, An J, Long Q, Wang H, Xiang M, Xiang M, Zhao Y, Liu Y, Liu J, Guan X. Partial EMT in Squamous Cell Carcinoma: A Snapshot. Int J Biol Sci 2021; 17:3036-3047. [PMID: 34421348 PMCID: PMC8375241 DOI: 10.7150/ijbs.61566] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
In the process of cancer EMT, some subgroups of cancer cells simultaneously exhibit both mesenchymal and epithelial characteristics, a phenomenon termed partial EMT (pEMT). pEMT is a plastic state in which cells coexpress epithelial and mesenchymal markers. In squamous cell carcinoma (SCC), pEMT is regulated, and the phenotype is maintained via the HIPPO pathway, NOTCH pathway and TGF-β pathways and by microRNAs, lncRNAs and the cancer microenvironment (CME); thus, SCC exhibits aggressive tumorigenic properties and high stemness, which leads collective migration and therapy resistance. Few studies have reported therapeutic interventions to address cells that have undergone pEMT, and this approach may be an effective way to inhibit the plasticity, drug resistance and metastatic potential of SCC.
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Affiliation(s)
- Chengcheng Liao
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi 563000, China
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Qian Wang
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
- Microbial Resources and Drug Development Key Laboratory of Guizhou Tertiary Institution, Life Sciences Institute, Zunyi Medical University, Zunyi 563006, China
| | - Jiaxing An
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Qian Long
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi 563000, China
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Hui Wang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Meiling Xiang
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Mingli Xiang
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Yujie Zhao
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi 563000, China
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Yulin Liu
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi 563000, China
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Jianguo Liu
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi 563000, China
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Xiaoyan Guan
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi 563000, China
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43
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Edwards A, Brennan K. Notch Signalling in Breast Development and Cancer. Front Cell Dev Biol 2021; 9:692173. [PMID: 34295896 PMCID: PMC8290365 DOI: 10.3389/fcell.2021.692173] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/07/2021] [Indexed: 12/22/2022] Open
Abstract
The Notch signalling pathway is a highly conserved developmental signalling pathway, with vital roles in determining cell fate during embryonic development and tissue homeostasis. Aberrant Notch signalling has been implicated in many disease pathologies, including cancer. In this review, we will outline the mechanism and regulation of the Notch signalling pathway. We will also outline the role Notch signalling plays in normal mammary gland development and how Notch signalling is implicated in breast cancer tumorigenesis and progression. We will cover how Notch signalling controls several different hallmarks of cancer within epithelial cells with sections focussed on its roles in proliferation, apoptosis, invasion, and metastasis. We will provide evidence for Notch signalling in the breast cancer stem cell phenotype, which also has implications for therapy resistance and disease relapse in breast cancer patients. Finally, we will summarise the developments in therapeutic targeting of Notch signalling, and the pros and cons of this approach for the treatment of breast cancer.
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Affiliation(s)
- Abigail Edwards
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Keith Brennan
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
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44
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Hsieh PL, Huang CC, Yu CC. Emerging Role of MicroRNA-200 Family in Dentistry. Noncoding RNA 2021; 7:35. [PMID: 34208375 PMCID: PMC8293310 DOI: 10.3390/ncrna7020035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/30/2021] [Accepted: 06/03/2021] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenous non-coding RNAs ~22 nucleotides in length, which have been shown to participate in various biological processes. As one of the most researched miRNAs, the miR-200 family has been found to regulate several factors that are associated with the epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs) behavior. In this review, we briefly summarize the background of the miR-200 family and their implication in various dental diseases. We focus on the expression changes, biological functions, and clinical significance of the miR-200 family in oral cancer; periodontitis; oral potentially malignant disorder; gingival overgrowth; and other periodontal diseases. Additionally, we discuss the use of the miR-200 family as molecular biomarkers for diagnosis, prognostic, and therapeutic application.
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Affiliation(s)
- Pei-Ling Hsieh
- Department of Anatomy, School of Medicine, China Medical University, Taichung 404333, Taiwan;
| | - Chun-Chung Huang
- Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan;
| | - Cheng-Chia Yu
- Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan;
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
- School of Dentistry, Chung Shan Medical University, Taichung 40201, Taiwan
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45
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Yoshida K, Yamamoto Y, Ochiya T. miRNA signaling networks in cancer stem cells. Regen Ther 2021; 17:1-7. [PMID: 33598508 PMCID: PMC7848775 DOI: 10.1016/j.reth.2021.01.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/06/2021] [Indexed: 12/20/2022] Open
Abstract
Cancer stem cells (CSCs) are a small cell subpopulation in many cancer types and are involved in various processes of tumor progression, such as initiation, metastasis and recurrence. The distinguished features of CSCs include a variety of biological properties, including self-renewal, multidifferentiation, stemness marker expression, and resistance to chemotherapy and radiotherapy. Despite their great potential of clinical importance, the CSC signaling pathways are not well understood at the molecular level. MicroRNAs (miRNAs) are a class of endogenous noncoding RNAs that play an important role in the regulation of several cellular, physiological, and developmental processes. Aberrant miRNA expression is associated with many human diseases, including cancer. miRNAs have been implicated in the regulation of CSC properties; therefore, a better understanding of miRNA-induced modulation of CSC gene expression could aid in the identification of promising biomarkers and therapeutic targets. In the present review, we summarize the major findings of the impacts of miRNAs on CSC signaling networks; we then discuss the recent advances that have improved our understanding of CSC regulation by miRNA-mediated signaling networks and that may lead to the development of miRNA therapeutics specifically targeting CSCs.
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Affiliation(s)
- Kosuke Yoshida
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yusuke Yamamoto
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
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46
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Keyvani-Ghamsari S, Khorsandi K, Rasul A, Zaman MK. Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance. Clin Epigenetics 2021; 13:120. [PMID: 34051847 PMCID: PMC8164819 DOI: 10.1186/s13148-021-01107-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 05/19/2021] [Indexed: 12/13/2022] Open
Abstract
At present, after extensive studies in the field of cancer, cancer stem cells (CSCs) have been proposed as a major factor in tumor initiation, progression, metastasis, and recurrence. CSCs are a subpopulation of bulk tumors, with stem cell-like properties and tumorigenic capabilities, having the abilities of self-renewal and differentiation, thereby being able to generate heterogeneous lineages of cancer cells and lead to resistance toward anti-tumor treatments. Highly resistant to conventional chemo- and radiotherapy, CSCs have heterogeneity and can migrate to different organs and metastasize. Recent studies have demonstrated that the population of CSCs and the progression of cancer are increased by the deregulation of different epigenetic pathways having effects on gene expression patterns and key pathways connected with cell proliferation and survival. Further, epigenetic modifications (DNA methylation, histone modifications, and RNA methylations) have been revealed to be key drivers in the formation and maintenance of CSCs. Hence, identifying CSCs and targeting epigenetic pathways therein can offer new insights into the treatment of cancer. In the present review, recent studies are addressed in terms of the characteristics of CSCs, the resistance thereof, and the factors influencing the development thereof, with an emphasis on different types of epigenetic changes in genes and main signaling pathways involved therein. Finally, targeted therapy for CSCs by epigenetic drugs is referred to, which is a new approach in overcoming resistance and recurrence of cancer.
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Affiliation(s)
| | - Khatereh Khorsandi
- Department of Photodynamic, Medical Laser Research Center, Yara Institute, ACECR, Tehran, Iran.
| | - Azhar Rasul
- Department of Zoology, Government College University Faisalabad, Faisalabad, 38000, Pakistan
| | - Muhammad Khatir Zaman
- Department of Biotechnology, Abdul Wali Khan University Mardan (AWKUM), Mardan, 23200, Pakistan
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Taki M, Abiko K, Ukita M, Murakami R, Yamanoi K, Yamaguchi K, Hamanishi J, Baba T, Matsumura N, Mandai M. Tumor Immune Microenvironment during Epithelial-Mesenchymal Transition. Clin Cancer Res 2021; 27:4669-4679. [PMID: 33827891 DOI: 10.1158/1078-0432.ccr-20-4459] [Citation(s) in RCA: 190] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 01/31/2021] [Accepted: 03/22/2021] [Indexed: 11/16/2022]
Abstract
Epithelial-mesenchymal transition (EMT) has been shown to play a critical role in tumor development from initiation to metastasis. EMT could be regarded as a continuum, with intermediate hybrid epithelial and mesenchymal phenotypes having high plasticity. Classical EMT is characterized by the phenotype change of epithelial cells to cells with mesenchymal properties, but EMT is also associated with multiple other molecular processes, including tumor immune evasion. Some previous studies have shown that EMT is associated with the cell number of immunosuppressive cells, such as myeloid-derived suppressor cells, and the expression of immune checkpoints, such as programmed cell death-ligand 1, in several cancer types. At the molecular level, EMT transcriptional factors, including Snail, Zeb1, and Twist1, produce or attract immunosuppressive cells or promote the expression of immunosuppressive checkpoint molecules via chemokine production, leading to a tumor immunosuppressive microenvironment. In turn, immunosuppressive factors induce EMT in tumor cells. This feedback loop between EMT and immunosuppression promotes tumor progression. For therapy directly targeting EMT has been challenging, the elucidation of the interactive regulation of EMT and immunosuppression is desirable for developing new therapeutic approaches in cancer. The combination of immune checkpoint inhibitors and immunotherapy targeting immunosuppressive cells could be a promising therapy for EMT.
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Affiliation(s)
- Mana Taki
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
| | - Kaoru Abiko
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
- Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Fushimi-ku, Kyoto, Japan
| | - Masayo Ukita
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Ryusuke Murakami
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Koji Yamanoi
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Ken Yamaguchi
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Junzo Hamanishi
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Tsukasa Baba
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Morioka, Iwate, Japan
| | - Noriomi Matsumura
- Department of Obstetrics and Gynecology, Faculty of Medicine, Kindai University, Osaka-sayama, Osaka, Japan
| | - Masaki Mandai
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
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48
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Raghav PK, Mann Z. Cancer stem cells targets and combined therapies to prevent cancer recurrence. Life Sci 2021; 277:119465. [PMID: 33831426 DOI: 10.1016/j.lfs.2021.119465] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/01/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) control the dynamics of tumorigenesis by self-renewal ability and differentiation potential. These properties contribute towards tumor malignancy, metastasis, cellular heterogeneity, and immune escape, which are regulated by multiple signaling pathways. The CSCs are chemoresistant and cause cancer recurrence, generally recognized as a small side-population that eventually leads to tumor relapse. Despite many treatment options available, none can be considered entirely efficient due to a lack of specificity and dose limitation. This review primarily highlights the processes involved in CSCs development and maintenance. Secondly, the current effective therapies based on stem cells, cell-free therapies that involve exosomes and miRNAs, and photodynamic therapy have been discussed. Also, the inhibitors that specifically target various signaling pathways, which can be used in combination to control CSCs kinetics have been highlighted. Conclusively, this comprehensive review is a detailed study of recently developed novel treatment strategies that will facilitate in coming up with better-targeted approaches against CSCs.
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Affiliation(s)
| | - Zoya Mann
- Independent Researcher, New Delhi, India
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49
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Romano G, Acunzo M, Nana-Sinkam P. microRNAs as Novel Therapeutics in Cancer. Cancers (Basel) 2021; 13:1526. [PMID: 33810332 PMCID: PMC8037786 DOI: 10.3390/cancers13071526] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
In the last 20 years, the functional roles for miRNAs in gene regulation have been well established. MiRNAs act as regulators in virtually all biological pathways and thus have been implicated in numerous diseases, including cancer. They are particularly relevant in regulating the basic hallmarks of cancer, including apoptosis, proliferation, migration, and invasion. Despite the substantial progress made in identifying the molecular mechanisms driving the deregulation of miRNAs in cancer, the clinical translation of these important molecules to therapy remains in its infancy. The paucity of vehicles available for the safe and efficient delivery of miRNAs and ongoing concerns for toxicity remain major obstacles to clinical application. Novel formulations and the development of new vectors have significantly improved the stability of oligonucleotides, increasing the effectiveness of therapy. Furthermore, the use of specific moieties for delivery in target tissues or cells has increased the specificity of treatment. The use of new technologies has allowed small but important steps toward more specific therapeutic delivery in tumor tissues and cells. Although a long road remains, the path ahead holds great potential. Currently, a few miRNA drugs are under investigation in human clinical trials with promising results ahead.
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Affiliation(s)
| | | | - Patrick Nana-Sinkam
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (G.R.); (M.A.)
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50
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Ghafouri-Fard S, Glassy MC, Abak A, Hussen BM, Niazi V, Taheri M. The interaction between miRNAs/lncRNAs and Notch pathway in human disorders. Biomed Pharmacother 2021; 138:111496. [PMID: 33743335 DOI: 10.1016/j.biopha.2021.111496] [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: 02/10/2021] [Revised: 03/07/2021] [Accepted: 03/09/2021] [Indexed: 02/07/2023] Open
Abstract
Notch pathway is a signaling cascade with important impacts on cell proliferation, differentiation, developmental processes and tissue homeostasis. This pathway also regulates stem cell properties, thus being involved in both normal developmental processes and metastatic capacity of cancer cells. Lots of lncRNAs and miRNAs have been recognized that control Notch pathway at some levels or their expression is regulated by this pathway. FOXD2-AS1, MEG3, ANRIL, linc-OIP5, lincRNA-p21, CBR3-AS1, HOTAIR, PVT1 and GAS5 are among lncRNAs that interact with Notch signaling. miR-19, miR-21, miR-33a, miR-8/200, miR-34a, miR-146a, miR-37, miR-100, miR-107 and several other miRNAs have functional interplay with this signaling cascade. In the present review article, we have illuminated the interplay between lncRNAs/miRNAs and Notch pathway in two distinct contexts i.e. cancers and non-neoplastic conditions.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mark C Glassy
- Translational Neuro-Oncology Laboratory, San Diego (UCSD) Moores Cancer Center, University of California, CA, United States
| | - Atefe Abak
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bashdar Mahmud Hussen
- Pharmacognosy Department, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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