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Desouza J, Khan R, Metkari S, Singh K, Narayanaswamy S, Fernandes G, Menon S, Sable N, Pal M, Chaudhari U, Patel V, Patwardhan S, Bakshi G, Sachdeva G. G-protein coupled estrogen receptor 1 (GPER1): A potential target for chemoprevention of prostate cancer. Biochim Biophys Acta Mol Basis Dis 2025:167740. [PMID: 39988180 DOI: 10.1016/j.bbadis.2025.167740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 02/05/2025] [Accepted: 02/16/2025] [Indexed: 02/25/2025]
Abstract
Progression of Prostatic Intra-epithelial Neoplasia (PIN) to Prostate Cancer (PCa) is characterized by a long latency period. This presents several opportunities for intervention. G-Protein coupled Estrogen Receptor 1 (GPER1) has emerged as an attractive target in the field of oncology. Existing data suggest that GPER1 activation inhibits PCa growth. However, the potential of GPER1 as a target for PCa chemoprevention remains unexplored. Analysis of publicly available datasets revealed a significant reduction in the prostatic GPER1 expression in the advanced PCa cases, compared to non-cancerous prostates. This was corroborated by our investigations of human primary PCa samples and the TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mouse model. The frequency of GPER1-positive cells and the expression of GPER1 were significantly higher in the TRAMP prostates presenting High-Grade PIN (HGPIN), compared to control prostates. However, this pattern reversed as HGPIN progressed to PCa. Activation with G1 (an agonist of GPER1) at the HGPIN stage prevented the progression of HGPIN to PCa in TRAMP mice. This effect was abrogated by co-administration of G1 with G15 (an antagonist of GPER1). In vitro activation with G1 inhibited proliferation in LNCaP, PC3, and RWPE-1 cell lines. On the other hand, GPER1-silencing led to a significant increase in in-vitro migration, invasion, and epithelial to mesenchymal transition through miR200a-ZEB2-E-Cadherin loop and by dysregulating the expression of metastasis-associated genes. These observations collectively suggest that GPER1 has a protective role in the context of PCa. Human studies are warranted to assess the potential of GPER1 as a target for PCa chemoprevention.
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Affiliation(s)
- Junita Desouza
- Cell Physiology and Pathology Laboratory, Indian Council of Medical Research-National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), Mumbai 400012, India
| | - Rushda Khan
- Cell Physiology and Pathology Laboratory, Indian Council of Medical Research-National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), Mumbai 400012, India
| | - Siddhanath Metkari
- Experimental Animal Facility, Indian Council of Medical Research-National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), Mumbai 400012, India
| | - Kamlesh Singh
- Department of Urology, Seth G.S. Medical College and King Edward Memorial Hospital, Parel, Mumbai 400012, India
| | - Supradeep Narayanaswamy
- Department of Urology, Seth G.S. Medical College and King Edward Memorial Hospital, Parel, Mumbai 400012, India
| | - Gwendolyn Fernandes
- Department of Pathology, Seth G.S. Medical College and King Edward Memorial Hospital, Parel, Mumbai 400012, India
| | - Santosh Menon
- Department of Pathology, Tata Memorial Hospital (TMH), Parel, Mumbai 400012, India
| | - Nilesh Sable
- Department of Radiology, Tata Memorial Hospital (TMH), Parel, Mumbai 400012, India
| | - Mahendra Pal
- Department of Uro-oncology, Tata Memorial Hospital (TMH), Parel, Mumbai 400012, India
| | - Uddhav Chaudhari
- Cell Physiology and Pathology Laboratory, Indian Council of Medical Research-National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), Mumbai 400012, India
| | - Vainav Patel
- Department of Viral Immunopathogenesis, Indian Council of Medical Research-National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), Mumbai 400012, India
| | - Sujata Patwardhan
- Department of Urology, Seth G.S. Medical College and King Edward Memorial Hospital, Parel, Mumbai 400012, India
| | - Ganesh Bakshi
- Department of Uro-oncology, Tata Memorial Hospital (TMH), Parel, Mumbai 400012, India
| | - Geetanjali Sachdeva
- Cell Physiology and Pathology Laboratory, Indian Council of Medical Research-National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), Mumbai 400012, India.
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Wang Y, Zhang S, Bing J, Li W, Sun L, Wang Y. TP53I11 Functions Downstream of Multiple MicroRNAs to Increase ER Calcium Levels and Inhibits Cancer Cell Proliferation. Int J Mol Sci 2024; 26:31. [PMID: 39795889 PMCID: PMC11719883 DOI: 10.3390/ijms26010031] [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: 12/09/2024] [Revised: 12/21/2024] [Accepted: 12/22/2024] [Indexed: 01/13/2025] Open
Abstract
Cells meticulously regulate free calcium ion (Ca2+) concentrations, with the endoplasmic reticulum (ER) being crucial for Ca2+ homeostasis. Disruptions in ER Ca2+ balance can contribute to various diseases, including cancer. Although considerable research has focused on the direct mechanisms of ER Ca2+ regulation, the role of microRNAs (miRNAs) in this process remains underexplored. Mainly using data from a CRISPR-based genomic screening previously conducted in our laboratory, we identified 33 candidate miRNAs that may regulate ER Ca2+ levels. From these, 10 miRNAs were found to significantly lower basal ER Ca2+ levels. RNA sequencing analysis indicated that these miRNAs downregulate the tumor suppressor tumor protein p53 (TP53)-inducible protein 11 gene (TP53I11), which is a key regulator of ER Ca2+ levels. Functional assays confirmed that TP53I11 influences ER Ca2+ levels and affects cancer cell proliferation. Additionally, the chemotherapeutic agent doxorubicin (DOX) was shown to upregulate TP53I11 and enhance ER Ca2+ accumulation. These findings elucidate the central role of TP53I11 in miRNA-mediated regulation of ER Ca2+ homeostasis and suggest potential therapeutic strategies targeting ER Ca2+ upregulation for cancer intervention.
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Affiliation(s)
- Yiping Wang
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China (J.B.); (W.L.); (L.S.)
| | - Shuai Zhang
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China (J.B.); (W.L.); (L.S.)
| | - Jie Bing
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China (J.B.); (W.L.); (L.S.)
| | - Wanjie Li
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China (J.B.); (W.L.); (L.S.)
| | - Lin Sun
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China (J.B.); (W.L.); (L.S.)
| | - Youjun Wang
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China (J.B.); (W.L.); (L.S.)
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China
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Joghataie P, Ardakani MB, Sabernia N, Salary A, Khorram S, Sohbatzadeh T, Goodarzi V, Amiri BS. The Role of Circular RNA in the Pathogenesis of Chemotherapy-Induced Cardiotoxicity in Cancer Patients: Focus on the Pathogenesis and Future Perspective. Cardiovasc Toxicol 2024; 24:1151-1167. [PMID: 39158829 DOI: 10.1007/s12012-024-09914-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 08/11/2024] [Indexed: 08/20/2024]
Abstract
Cardiotoxicity is a serious challenge cancer patients face today. Various factors are involved in cardiotoxicity. Circular RNAs (circRNAs) are one of the effective factors in the occurrence and prevention of cardiotoxicity. circRNAs can lead to increased proliferation, apoptosis, and regeneration of cardiomyocytes by regulating the molecular pathways, as well as increasing or decreasing gene expression; some circRNAs have a dual role in cardiomyocyte regeneration or death. Identifying each of the pathways related to these processes can be effective on managing patients and preventing cardiotoxicity. In this study, an overview of the molecular pathways involved in cardiotoxicity by circRNAs and their effects on the downstream factors have been discussed.
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Affiliation(s)
- Pegah Joghataie
- Department of Cardiology, School of Medicine, Hazrat-E Rasool General Hospital, Iran University of Medical Sciences, Tehran, Iran
| | | | - Neda Sabernia
- Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | | | - Tooba Sohbatzadeh
- Student Research Committee, School of Medicine, Alborz University of Medical Sciences, Alborz, Iran
| | - Vahid Goodarzi
- Department of Anesthesiology, Rasoul-Akram Medical Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Bahareh Shateri Amiri
- Assistant Professor of Internal Medicine, Department of Internal Medicine, School of Medicine, Hazrat-E Rasool General Hospital, Iran University of Medical Sciences, Tehran, Iran.
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Feng W, Tang Y, Jing R, Ju S, Zong W. Highly expressed B3GALT5-AS1 contributes to gastric cancer progression by recruiting WDR5 to mediate B3GALT5 and regulating β-catenin/ZEB1 axis. J Cell Mol Med 2024; 28:e70061. [PMID: 39224045 PMCID: PMC11369489 DOI: 10.1111/jcmm.70061] [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: 06/12/2024] [Revised: 08/19/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024] Open
Abstract
Long non-coding RNAs (lncRNAs) play an important role in the progression of gastric cancer (GC), but its specific regulatory mechanism remains to be further studied. We previously identified that lncRNA B3GALT5-AS1 was upregulated in GC serum. Here, we investigated the functions and molecular mechanisms of B3GALT5-AS1 in GC tumorigenesis. qRT-PCR was used to detect B3GALT5-AS1 expression in GC. EdU, CCK-8, and colony assays were utilized to assess the proliferation ability of B3GAL5-AS1, and transwell, tube formation assay were used to assess the invasion and metastasis ability. Mechanically, FISH and nuclear plasmolysis PCR identified the subcellular localization of B3GALT5-AS1. RIP and CHIP assays were used to analyse the regulation of B3GALT5-AS1 and B3GALT5. We observed that B3GALT5-AS1 was highly expressed in GC, and silencing B3GALT5-AS1 could inhibit the proliferation, invasion, and migratory capacities of GC. Additionally, B3GALT5-AS1 was bound to WDR5 and modulated the expression of B3GALT5 via regulating the ZEB1/β-catenin pathway. High-expressed B3AGLT5-AS1 promoted GC tumorigenesis and regulated B3GALT5 expression via recruiting WDR5. Our study is expected to provide a new idea for clinical diagnosis and treatment.
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Affiliation(s)
- Wei Feng
- Department of Laboratory MedicineAffiliated Hospital of Nantong UniversityNantongJiangsuChina
- Medical School of Nantong UniversityNantong UniversityNantongJiangsuChina
- Research Center of Clinical MedicineAffiliated Hospital of Nantong UniversityNantongJiangsuChina
| | - Yelan Tang
- Department of Laboratory MedicineAffiliated Hospital of Nantong UniversityNantongJiangsuChina
- Medical School of Nantong UniversityNantong UniversityNantongJiangsuChina
- Research Center of Clinical MedicineAffiliated Hospital of Nantong UniversityNantongJiangsuChina
| | - Rongrong Jing
- Department of Laboratory MedicineAffiliated Hospital of Nantong UniversityNantongJiangsuChina
| | - Shaoqing Ju
- Department of Laboratory MedicineAffiliated Hospital of Nantong UniversityNantongJiangsuChina
| | - Wei Zong
- Department of Laboratory MedicineAffiliated Hospital of Nantong UniversityNantongJiangsuChina
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Xiong T, Wang D, Yang H, Liu B, Li Y, Yu W, Wang J, She Q. miR-194-3p regulates epithelial-mesenchymal transition in embryonic epicardial cells via p120/β-catenin signaling. Acta Biochim Biophys Sin (Shanghai) 2024; 56:717-729. [PMID: 38676398 PMCID: PMC11381220 DOI: 10.3724/abbs.2024051] [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: 04/28/2024] Open
Abstract
The epicardium is integral to cardiac development and facilitates endogenous heart regeneration and repair. While miR-194-3p is associated with cellular migration and invasion, its impact on epicardial cells remains uncharted. In this work we use gain-of-function and loss-of-function methodologies to investigate the function of miR-194-3p in cardiac development. We culture embryonic epicardial cells in vitro and subject them to transforming growth factor β (TGF-β) treatment to induce epithelial-mesenchymal transition (EMT) and monitor miR-194-3p expression. In addition, the effects of miR-194-3p mimics and inhibitors on epicardial cell development and changes in EMT are investigated. To validate the binding targets of miR-194-3p and its ability to recover the target gene-phenotype, we produce a mutant vector p120-catenin-3'UTR-MUT. In epicardial cells, TGF-β-induced EMT results in a notable overexpression of miR-194-3p. The administration of miR-194-3p mimics promotes EMT, which is correlated with elevated levels of mesenchymal markers. Conversely, miR-194-3p inhibitor attenuates EMT. Further investigations reveal a negative correlation between miR-194-3p and p120-catenin, which influences β-catenin level in the cell adhesion pathway. The suppression of EMT caused by the miR-194-3p inhibitor is balanced by silencing of p120-catenin. In conclusion, miR-194-3p directly targets p120-catenin and modulates its expression, which in turn alters β-catenin expression, critically influencing the EMT process in the embryonic epicardial cells via the cell adhesion mechanism.
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Wu Y, Hao D, Tu Y, Chen L, Yu P, Chen A, Wan Y, Shi L. The role of ZEB1 in regulating tight junctions in antrochoanal polyp. Heliyon 2024; 10:e25653. [PMID: 38370186 PMCID: PMC10869855 DOI: 10.1016/j.heliyon.2024.e25653] [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: 08/09/2023] [Revised: 01/30/2024] [Accepted: 01/31/2024] [Indexed: 02/20/2024] Open
Abstract
Background Antrochoanal polyp (ACP) is a benign nasal mass of unknown etiology. Tight junctions (TJs) are essential to the epithelial barrier that protects the body from external damage. However, the phenotype of tight junction in ACP is currently unclear. Methods The samples were collected from 20 controls, 37 patients with ACP and 45 patients with chronic rhinosinusitis with nasal polyp (CRSwNP). Quantitative Real-Time PCR (qRT-PCR) and immunofluorescence staining (IF) were performed to analyze the expressions of TJs markers (ZO-1, claudin-3 and occludin) and ZEB1. hNEpCs were transfected with ZEB1 small interfering RNA (si-ZEB1) or ZEB1 over-expression plasmid (OE-ZEB1). qRT-PCR and Western blotting were used to determine the levels of TJs-related markers. Primary human nasal epithelial cells (hNECs) were stimulated with IL-17A and si-ZEB1, and the expression of epithelial barrier markers were measured by qRT-PCR and Western blotting. Results Compared to the control group, ACP group showed a significant downregulation in both mRNA and protein levels of ZO-1, occludin, and claudin-3. Furthermore, disease severity correlates positively with the degree of disruption of tight junctions. In addition, higher expression levels of ZEB1, IL-17A, and IFN-γ were observed in the ACP group compared to controls. Overexpression of ZEB1 in hNEpCs led to impairments in the levels of ZO-1, occludin, and claudin-3, while silencing of ZEB1 expression was found to enhance the barrier function of epithelial cells. Finally, IL-17 stimulation of hNECs impaired the expression of TJs-associated molecules (ZO-1, occludin, and claudin-3), which was effectively reversed by the IL-17A + si-ZEB1 group. Conclusions The tight junctions in ACP were extremely damaged and were correlated with the severity of the disease. ZEB1 was involved in the pathogenesis of ACP mediated by IL-17A through regulating tight junctions.
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Affiliation(s)
- Yisha Wu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, China
- Department of Otolaryngology, Head & Neck Surgery, Second Hospital, Shanxi Medical University, Taiyuan, China
| | - Dingqian Hao
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, China
| | - Yanyi Tu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, China
| | - Lin Chen
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, China
| | - Peng Yu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, China
| | - Aiping Chen
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, China
| | - Yuzhu Wan
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, China
| | - Li Shi
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong, China
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Dev A, Vachher M, Prasad CP. β-catenin inhibitors in cancer therapeutics: intricacies and way forward. Bioengineered 2023; 14:2251696. [PMID: 37655825 PMCID: PMC10478749 DOI: 10.1080/21655979.2023.2251696] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 08/19/2023] [Accepted: 08/21/2023] [Indexed: 09/02/2023] Open
Abstract
β-catenin is an evolutionary conserved, quintessential, multifaceted protein that plays vital roles in cellular homeostasis, embryonic development, organogenesis, stem cell maintenance, cell proliferation, migration, differentiation, apoptosis, and pathogenesis of various human diseases including cancer. β-catenin manifests both signaling and adhesive features. It acts as a pivotal player in intracellular signaling as a component of versatile WNT signaling cascade involved in embryonic development, homeostasis as well as in carcinogenesis. It is also involved in Ca2+ dependent cell adhesion via interaction with E-cadherin at the adherens junctions. Aberrant β-catenin expression and its nuclear accumulation promote the transcription of various oncogenes including c-Myc and cyclinD1, thereby contributing to tumor initiation, development, and progression. β-catenin's expression is closely regulated at various levels including its stability, sub-cellular localization, as well as transcriptional activity. Understanding the molecular mechanisms of regulation of β-catenin and its atypical expression will provide researchers not only the novel insights into the pathogenesis and progression of cancer but also will help in deciphering new therapeutic avenues. In the present review, we have summarized the dual functions of β-catenin, its role in signaling, associated mutations as well as its role in carcinogenesis and tumor progression of various cancers. Additionally, we have discussed the challenges associated with targeting β-catenin molecule with the presently available drugs and suggested the possible way forward in designing new therapeutic alternatives against this oncogene.
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Affiliation(s)
- Arundhathi Dev
- Department of Medical Oncology (Laboratory), DR BRAIRCH, All India Institute of Medical Sciences, New Delhi, India
| | - Meenakshi Vachher
- Department of Biochemistry, Institute of Home Economics, University of Delhi, New Delhi, India
| | - Chandra Prakash Prasad
- Department of Medical Oncology (Laboratory), DR BRAIRCH, All India Institute of Medical Sciences, New Delhi, India
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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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Jamal Eddin TM, Nasr SM, Gupta I, Zayed H, Al Moustafa AE. Helicobacter pylori and epithelial mesenchymal transition in human gastric cancers: An update of the literature. Heliyon 2023; 9:e18945. [PMID: 37609398 PMCID: PMC10440535 DOI: 10.1016/j.heliyon.2023.e18945] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/25/2023] [Accepted: 08/03/2023] [Indexed: 08/24/2023] Open
Abstract
Gastric cancer, a multifactorial disease, is considered one of the most common malignancies worldwide. In addition to genetic and environmental risk factors, infectious agents, such as Epstein-Barr virus (EBV) and Helicobacter pylori (H.pylori) contribute to the onset and development of gastric cancer. H. pylori is a type I carcinogen that colonizes the gastric epithelium of approximately 50% of the world's population, thus increasing the risk of gastric cancer development. On the other hand, epithelial mesenchymal transition (EMT) is a fundamental process crucial to embryogenic growth, wound healing, organ fibrosis and cancer progression. Several studies associate gastric pathogen infection of the epithelium with EMT initiation, provoking cancer metastasis in the gastric mucosa through various molecular signaling pathways. Additionally, EMT is implicated in the progression and development of H. pylori-associated gastric cancer. In this review, we recapitulate recent findings elucidating the association between H. pylori infection in EMT promotion leading to gastric cancer progression and metastasis.
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Affiliation(s)
- Tala M. Jamal Eddin
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Shahd M.O. Nasr
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ishita Gupta
- College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Hatem Zayed
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ala-Eddin Al Moustafa
- College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
- Biomedical Research Center, Qatar University, PO Box 2713, Doha, Qatar
- Oncology Department, Faculty of Medicine, McGill University, Montreal, QC, H3G 2M1, Canada
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Akhavanfar R, Shafagh SG, Mohammadpour B, Farahmand Y, Lotfalizadeh MH, Kookli K, Adili A, Siri G, Eshagh Hosseini SM. A comprehensive insight into the correlation between ncRNAs and the Wnt/β-catenin signalling pathway in gastric cancer pathogenesis. Cell Commun Signal 2023; 21:166. [PMID: 37386429 PMCID: PMC10308667 DOI: 10.1186/s12964-023-01092-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 02/26/2023] [Indexed: 07/01/2023] Open
Abstract
During the past decades, gastric cancer (GC) has emerged as one of the most frequent malignancies with a growing rate of prevalence around the world. Despite considerable advances in therapeutic methods, the prognosis and management of patients with gastric cancer (GC) continue to be poor. As one of the candidate molecular targets in the treatment of many types of cancer, the Wnt/β-catenin pathway includes a family of proteins that have important functions in adult tissue homeostasis and embryonic development. The aberrant regulation of Wnt/β-catenin signaling is strongly correlated with the initiation and development of numerous cancers, including GC. Therefore, Wnt/β-catenin signaling has been identified as one of the main targets for extending therapeutic approaches for GC patients. Non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs, are important components of epigenetic mechanisms in gene regulation. They play vital roles in various molecular and cellular processes and regulate many signaling pathways, such as Wnt/β-catenin pathways. Insights into these regulatory molecules involved in GC development may lead to the identification of potential targets for overcoming the limitations of current therapeutic approaches. Consequently, this review aimed to provide a comprehensive overview of ncRNAs interactions involved in Wnt/β-catenin pathway function in GC with diagnostic and therapeutic perspectives. Video Abstract.
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Affiliation(s)
- Roozbeh Akhavanfar
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | | | - Yalda Farahmand
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Keihan Kookli
- International Campus, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Adili
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Goli Siri
- Department of Internal Medicine, Amir Alam Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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Mirzaei S, Gholami MH, Aghdaei HA, Hashemi M, Parivar K, Karamian A, Zarrabi A, Ashrafizadeh M, Lu J. Exosome-mediated miR-200a delivery into TGF-β-treated AGS cells abolished epithelial-mesenchymal transition with normalization of ZEB1, vimentin and Snail1 expression. ENVIRONMENTAL RESEARCH 2023; 231:116115. [PMID: 37178752 DOI: 10.1016/j.envres.2023.116115] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/05/2023] [Accepted: 05/11/2023] [Indexed: 05/15/2023]
Abstract
Exosomes are small extracellular vesicles that can be derived from human cells such as mesenchymal stem cells (MSCs). The size of exosomes is at nano-scale range and owing to their biocompatibility and other characteristics, they have been promising candidates for delivery of bioactive compounds and genetic materials in disease therapy, especially cancer therapy. Gastric cancer (GC) is a leading cause of death among patients and this malignant disease affects gastrointestinal tract that its invasiveness and abnormal migration mediate poor prognosis of patients. Metastasis is an increasing challenge in GC and microRNAs (miRNAs) are potential regulators of metastasis and related molecular pathways, especially epithelial-to-mesenchymal transition (EMT). In the present study, our aim was to explore role of exosomes in miRNA-200a delivery for suppressing EMT-mediated GC metastasis. Exosomes were isolated from MSCs via size exclusion chromatography. The synthetic miRNA-200a mimics were transfected into exosomes via electroporation. AGS cell line exposed to TGF-β for EMT induction and then, these cells cultured with miRNA-200a-loaded exosomes. The transwell assays performed to evaluate GC migration and expression levels of ZEB1, Snail1 and vimentin measured. Exosomes demonstrated loading efficiency of 5.92 ± 4.6%. The TGF-β treatment transformed AGS cells into fibroblast-like cells expressing two stemness markers, CD44 (45.28%) and CD133 (50.79%) and stimulated EMT. Exosomes induced a 14.89-fold increase in miRNA-200a expression in AGS cells. Mechanistically, miRNA-200a enhances E-cadherin levels (P < 0.01), while it decreases expression levels of β-catenin (P < 0.05), vimentin (P < 0.01), ZEB1 (P < 0.0001) and Snail1 (P < 0.01). Leading to EMT inhibition in GC cells. This pre-clinical experiment introduces a new strategy for miRNA-200a delivery that is of importance for preventing migration and invasion of GC cells.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorder Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Molecular and Cellular Sciences, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Science Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kazem Parivar
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Amin Karamian
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences. Tehran, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, 34485, Istanbul, Turkey
| | - Milad Ashrafizadeh
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Jianlin Lu
- Department of Geriatrics, The Fifth People's Hospital of Wujiang District, Suzhou, China.
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12
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Wu S, Sun Z, Guo Z, Li P, Mao Q, Tang Y, Chen H, Peng H, Wang S, Cao Y. The effectiveness of blood-activating and stasis-transforming traditional Chinese medicines (BAST) in lung cancer progression-a comprehensive review. JOURNAL OF ETHNOPHARMACOLOGY 2023; 314:116565. [PMID: 37172918 DOI: 10.1016/j.jep.2023.116565] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/20/2023] [Accepted: 04/29/2023] [Indexed: 05/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Blood-activating and stasis-transforming traditional Chinese medicines (BAST) are a class of herbs that have the effect of dilating blood vessels and dispersing stagnation. Modern pharmaceutical research has demonstrated that they are capable of improving hemodynamics and micro-flow, resist thrombosis and promote blood flow. BAST contain numerous active ingredients, which can theoretically regulate multiple targets at the same time and have a wide range of pharmacological effects in the treatment of diseases including human cancers. Clinically, BAST have minimal side effects and can be used in combination with Western medicine to improve patients' quality of life, lessen adverse effects and minimize the risk of recurrence and metastasis of cancers. AIM OF THE REVIEW We aimed to summarize the research progression of BAST on lung cancer in the past five years and present a prospect for the future. Particularly, this review further analyzes the effects and molecular mechanisms that BAST inhibit the invasion and metastasis of lung cancer. MATERIALS AND METHODS Relevant studies about BSAT were collected from PubMed and Web of science. RESULTS Lung cancer is one of the malignant tumors with the highest mortality rate. Most patients with lung cancer are diagnosed at an advanced stage and are highly susceptible to metastasis. Recent studies have shown that BAST, a class of traditional Chinese medicine (TCM) with the function of opening veins and dispersing blood stasis, significantly improve hemodynamics and microcirculation, prevent thrombosis and promote blood flow, and thereby inhibiting the invasion and metastasis of lung cancer. In the current review, we analyzed 51 active ingredients extracted from BAST. It was found that BAST and their active ingredients contribute to the prevention of invasion and metastasis of lung cancer through multiple mechanisms, such as regulation of EMT process, specific signaling pathway and metastasis-related genes, tumor blood vessel formation, immune microenvironment and inflammatory response of tumors. CONCLUSIONS BSAT and its active ingredients have showed promising anticancer activity and significantly inhibit the invasion and metastasis of lung cancer. A growing number of studies have realized their potential clinical significance in the therapy of lung cancer, which will provide substantial evidences for the development of new TCM for lung cancer therapy.
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Affiliation(s)
- Siqi Wu
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Zhe Sun
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Zehuai Guo
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Peiqin Li
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Qianqian Mao
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Yang Tang
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Hongyu Chen
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Huiting Peng
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Sisi Wang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Yang Cao
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
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13
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Zarei M, Malekzadeh K, Omidi M, Mousavi P. Clinical significance of long non-coding RNA ZEB2-AS1 and EMT-related markers in ductal and lobular breast cancer. Cancer Rep (Hoboken) 2023; 6:e1826. [PMID: 37088469 PMCID: PMC10172159 DOI: 10.1002/cnr2.1826] [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: 10/07/2022] [Revised: 04/04/2023] [Accepted: 04/10/2023] [Indexed: 04/25/2023] Open
Abstract
BACKGROUND Breast cancer is considered the most prevalent type of cancer in women and accounts for a high rate of death. A body of research has demonstrated that lncRNAs have a regulatory function in human diseases, especially cancers. ZEB2-AS1 is known as an oncogenic lncRNA in various types of cancers, and its deregulation may contribute to cancer development and progression. Therefore, we aimed to reveal the association of ZEB2-AS1 expression with epithelial-mesenchymal transition (EMT) markers, as a hallmark of cancer progression, in a clinical setting. METHODS A recent study suggested that ZEB2-AS1 is significantly involved in EMT. Here we intended to explore the roles of lncRNA ZEB2-AS1 in breast cancer (BC) using bioinformatics tools and laboratory settings. We first evaluated the expression of ZEB2-AS1 mRNA in tumor and healthy control tissues by lnCAR database. Furthermore, ZEB2-AS1 expression level, ZEB2, E-cadherin, and vimentin was measured via qRT-PCR in 30 paired ductal and lobular carcinoma tissues from breast cancer patients and the normal adjacent ones. The correlation between the lncRNA ZEB2-AS1 expression and clinicopathological characteristics of the breast cancer patients was evaluated. RESULTS ZEB2-AS1 showed an upregulation in breast cancer tissues (p = .04) compared to normal adjacent samples. In addition, its level was higher in breast cancer patients with advanced Stages (III & IV) (n = 18) compared to early Stages (I & II) (n = 12) (p = .04). Moreover, ZEB2 (p = .01) and vimentin (p = .02) expression were upregulated in the BC sample, but the expression level of E-cadherin (p = .02) was downregulated when compared with the adjacent normal tissues. By comparison of the expression of EMT-markers between different stages of breast cancer, overexpression of ZEB2 (p = .04) and vimentin (p = .04) and down expression of E-cadherin (p = .03) was observed in advance stages. CONCLUSIONS Collectively, our findings suggest that ZEB2-AS1 expression is significantly upregulated in tumor tissues, especially in advanced stages and ZEB2-AS1 is associated with the aggressiveness of tumors by functioning as putative oncogenic lncRNA. In addition, a combination of ZEB2-AS1 and these EMT markers in breast cancer potentiates these genes as biomarkers for tumor progression.
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Affiliation(s)
- Mahboobeh Zarei
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Kianoosh Malekzadeh
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Mahmoud Omidi
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Pegah Mousavi
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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14
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Lai YH, Liu WL, Lee TY, Kuo CW, Liu YR, Huang CY, Chen YH, Chen IL, Wu SH, Wang SC, Lee PY, Liu CC, Lo J, Chang YC, Kuo HF, Hsieh CC, Li CY, Liu PL. Magnolol regulates miR-200c-3p to inhibit epithelial-mesenchymal transition and retinoblastoma progression by modulating the ZEB1/E-cadherin axis in vitro and in vivo. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 110:154597. [PMID: 36603340 DOI: 10.1016/j.phymed.2022.154597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 11/21/2022] [Accepted: 12/10/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Retinoblastoma, the most common pediatric intraocular malignancy, can develop during embryogenesis, with most children being diagnosed at 3-4 years of age. Multimodal therapies are typically associated with high levels of cytotoxicity and side effects. Therefore, the development of novel treatments with minimal side effects is crucial. Magnolol has a significant anti-tumor effect on various cancers. However, its antitumor effect on retinoblastoma remains unclear. PURPOSE The study aimed to determine the effects of magnolol on the regulation of EMT, migration, invasion, and cancer progression in retinoblastoma and the modulation of miR-200c-3p expression and the Wnt/ zinc finger E-box binding homeobox 1 (ZEB1)/E-cadherin axis in vivo and in vitro. METHODS The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay was used to evaluate magnolol-induced cell toxicity in the Y79 retinoblastoma cell line. Flow cytometry and immunostaining assays were performed to investigate the magnolol-regulated mitochondrial membrane potential and the intracellular and mitochondrial reactive oxygen species levels in Y79 retinoblastoma cells. Orthotopic and subcutaneous xenograft experiments were performed in eight-week-old male null mice to study retinoblastoma progression and metastasis. In situ hybridization and quantitative reverse transcription polymerase chain reaction (RT-qPCR) assays were performed to evaluate the level of the anti-cancer miRNA miR-200c-3p. The mRNA and protein levels of E-cadherin, β-catenin, α-smooth muscle actin (α-SMA), fibronectin-1, and ZEB1 were analyzed using RT-qPCR, immunoblot, immunocytochemistry, and immunohistochemistry assays in vitro and in vivo. RESULTS Magnolol increased E-cadherin levels and reduced the activation of the EMT signaling pathway, EMT, tumor growth, metastasis, and cancer progression in the Y79 retinoblastoma cell line as well as in the orthotopic and subcutaneous xenograft animal models. Furthermore, magnolol increased the expression of miR-200c-3p. Our results demonstrate that miRNA-200c-3p inhibits EMT progression through the Wnt16/β-catenin/ZEB1/E-cadherin axis, and the ZEB1 silencing response shows that miR-200c-3p regulates ZEB1-mediated EMT in retinoblastoma. CONCLUSION Magnolol has an antitumor effect by increasing E-cadherin and miRNA-200c-3p expression to regulate ZEB1-mediated EMT and cancer progression in retinoblastoma. The anti-tumor effect of magnolol by increasing E-cadherin and miRNA-200c-3p expression to regulate ZEB1-mediated EMT and cancer progression in retinoblastoma has been elucidated for the first time.
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Affiliation(s)
- Yu-Hung Lai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Ophthalmology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Wei-Lun Liu
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan; Division of Critical Care Medicine, Department of Emergency and Critical Care Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City 24205, Taiwan
| | - Tsung-Ying Lee
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chung-Wen Kuo
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yu-Ru Liu
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chi-Yuan Huang
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yung-Hsiang Chen
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan; Department of Psychology, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan
| | - I-Ling Chen
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Szu-Hui Wu
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shu-Chi Wang
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Po-Yen Lee
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ching-Chih Liu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Ophthalmology, Chi Mei Medical Center, Tainan 71004, Taiwan
| | - Jung Lo
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Yo-Chen Chang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Ophthalmology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Hsuan-Fu Kuo
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chong-Chao Hsieh
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chia-Yang Li
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan.
| | - Po-Len Liu
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
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15
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Wnt Signaling in the Development of Bone Metastasis. Cells 2022; 11:cells11233934. [PMID: 36497192 PMCID: PMC9739050 DOI: 10.3390/cells11233934] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/24/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Wnt signaling occurs through evolutionarily conserved pathways that affect cellular proliferation and fate decisions during development and tissue maintenance. Alterations in these highly regulated pathways, however, play pivotal roles in various malignancies, promoting cancer initiation, growth and metastasis and the development of drug resistance. The ability of cancer cells to metastasize is the primary cause of cancer mortality. Bone is one of the most frequent sites of metastases that generally arise from breast, prostate, lung, melanoma or kidney cancer. Upon their arrival to the bone, cancer cells can enter a long-term dormancy period, from which they can be reactivated, but can rarely be cured. The activation of Wnt signaling during the bone metastasis process was found to enhance proliferation, induce the epithelial-to-mesenchymal transition, promote the modulation of the extracellular matrix, enhance angiogenesis and immune tolerance and metastasize and thrive in the bone. Due to the complexity of Wnt pathways and of the landscape of this mineralized tissue, Wnt function during metastatic progression within bone is not yet fully understood. Therefore, we believe that a better understanding of these pathways and their roles in the development of bone metastasis could improve our understanding of the disease and may constitute fertile ground for potential therapeutics.
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16
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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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17
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Koparal M, Bozgeyik E, Ceylan O, Ege B, Kurt MY, Yumrutas O, Bozgeyik I. Salivary gland tumors exhibit distinct miRNA signatures involved in Wnt/β-Catenin signaling in formalin fixed paraffin embedded tissue samples. Pathol Res Pract 2022; 238:154119. [PMID: 36137399 DOI: 10.1016/j.prp.2022.154119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/28/2022] [Accepted: 09/06/2022] [Indexed: 10/14/2022]
Abstract
Advances in high-throughput genomic technologies have enabled the identification of numerous selective tumor markers. However, adapting these newly identified markers to clinical practice is not always possible because most RNA molecules, including mRNAs of protein-coding genes and long non-coding RNAs, are not stable under laboratory conditions, making their testing a major challenge. In contrast to long RNA molecules, miRNAs offer a great advantage in that they are relatively stable due to their small size. Accordingly, herein we aimed to determine the expression levels of miRNAs that are involved in Wnt/β-catenin signaling pathway in formalin fixed paraffin embedded (FFPE) tissue samples of patients with salivary gland tumors. A total of 42 patients with salivary gland tumors were included in the study. The miRNA expression signatures were evaluated using the RT-qPCR. As a result, β-catenin positivity was observed in all salivary gland tumors without distinguishing between benign and malignant phenotypes. Remarkably, we found that miR-200a and miR-373 were significantly upregulated whereas miR-30c were downregulated in tissues of patients with salivary gland tumors, compared to adjacent healthy tissue samples. In addition, distinct expression signatures of these miRNAs were significantly associated with the clinicopathological findings of patients such as perineural invasion and lymph node metastasis. Additionally, miR-145 and miR-30a were found to be specifically downregulated in a mucoepidermoid carcinoma. Also, miR-26b was selectively increased in pleomorphic adenomas of the salivary gland. Collectively, our findings suggest that these miRNAs may play chief roles in the differential diagnosis of salivary gland tumors.
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Affiliation(s)
- Mehtap Koparal
- Department of Otorhinolaryngology, Adiyaman University Education and Training Hospital, Adiyaman, Turkey.
| | - Esra Bozgeyik
- Department of Medical Services and Techniques, Vocational School of Health Services, Adiyaman University, Adiyaman, Turkey
| | - Onur Ceylan
- Department of Pathology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Bilal Ege
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Adiyaman University, Adiyaman, Turkey
| | - Muhammed Yusuf Kurt
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Adiyaman University, Adiyaman, Turkey
| | - Onder Yumrutas
- Department of Medical Biology, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey
| | - Ibrahim Bozgeyik
- Department of Medical Biology, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey
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18
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Huang Z, Zhang Z, Zhou C, Liu L, Huang C. Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities. MedComm (Beijing) 2022; 3:e144. [PMID: 35601657 PMCID: PMC9115588 DOI: 10.1002/mco2.144] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 02/05/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT) is a program wherein epithelial cells lose their junctions and polarity while acquiring mesenchymal properties and invasive ability. Originally defined as an embryogenesis event, EMT has been recognized as a crucial process in tumor progression. During EMT, cell–cell junctions and cell–matrix attachments are disrupted, and the cytoskeleton is remodeled to enhance mobility of cells. This transition of phenotype is largely driven by a group of key transcription factors, typically Snail, Twist, and ZEB, through epigenetic repression of epithelial markers, transcriptional activation of matrix metalloproteinases, and reorganization of cytoskeleton. Mechanistically, EMT is orchestrated by multiple pathways, especially those involved in embryogenesis such as TGFβ, Wnt, Hedgehog, and Hippo, suggesting EMT as an intrinsic link between embryonic development and cancer progression. In addition, redox signaling has also emerged as critical EMT modulator. EMT confers cancer cells with increased metastatic potential and drug resistant capacity, which accounts for tumor recurrence in most clinic cases. Thus, targeting EMT can be a therapeutic option providing a chance of cure for cancer patients. Here, we introduce a brief history of EMT and summarize recent advances in understanding EMT mechanisms, as well as highlighting the therapeutic opportunities by targeting EMT in cancer treatment.
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Affiliation(s)
- Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041 China
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041 China
| | - Chengwei Zhou
- Department of Thoracic Surgery the Affiliated Hospital of Medical School of Ningbo University Ningbo China
| | - Lin Liu
- Department of Thoracic Surgery the Affiliated Hospital of Medical School of Ningbo University Ningbo China
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041 China
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19
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Exosome-derived miR-200a promotes esophageal cancer cell proliferation and migration via the mediating Keap1 expression. Mol Cell Biochem 2022; 477:1295-1308. [PMID: 35137328 DOI: 10.1007/s11010-022-04353-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 01/06/2022] [Indexed: 12/18/2022]
Abstract
Previous studies have reported that exosomes bearing certain microRNAs (miRNAs) are related to the physiological functions of different types of cancer cells. Our study aimed to elucidate the role of miR-200a in esophageal squamous cell carcinoma (ESCC). We observed that miR-200a expression is higher in esophageal carcinoma cells, tissues, and exosomes than in normal cells and healthy tissues. We showed that exosome-shuttled miR-200a promotes the proliferation, migration, and invasion of esophageal cells and inhibits apoptosis, thereby leading to the progression of ESCC. We showed that miR-200a exerts its effects through its interaction with Keap1, thus altering the Keap1/Nrf2 signaling pathway. Our results suggest that exosome-shuttled miR-200a might be useful as a biomarker for prognosis in patients with ESCC.
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Gharbi S, Mohammadi Z, Dezaki MS, Dokanehiifard S, Dabiri S, Korsching E. Characterization of the first microRNA in human CDH1 that affects cell cycle and apoptosis and indicates breast cancers progression. J Cell Biochem 2022; 123:657-672. [PMID: 34997630 DOI: 10.1002/jcb.30211] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/26/2021] [Accepted: 12/21/2021] [Indexed: 11/12/2022]
Abstract
The E-cadherin protein (Cadherin 1, gene: CDH1), a master regulator of the human epithelial homeostasis, contributes to the epithelial-mesenchymal transition (EMT) which confers cell migratory features to the cells. The EMT is central to many pathophysiological changes in cancer. Therefore, a better understanding of this regulatory scenario is beneficial for therapeutic regiments. The CDH1 gene is approximately 100 kbp long and consists of 16 exons with a relatively large second intron. Since none microRNA (miRNA) has been identified in CDH1 up to now we screened the CDH1 gene for promising miRNA hairpin structures in silico. Out of the 27 hairpin structures we identified, one stable RNA fold with a promising sequence motive was selected for experimental verification. The exogenous validation of the hairpin sequence was performed by transfection of HEK293T cells and the mature miRNA sequences could be verified by quantitative polymerase chain reaction. The endogenous expression of the mature miRNA provisionally named CDH1-i2-miR-1 could be confirmed in two normal (HEK293T, HUVEK) and five cancer cell lines (MCF7, MDA-MB-231, SW480, HT-29, A549). The functional characterization by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed a suppression of HEK293T cell proliferation. A flow cytometry-based approach showed the ability of CDH1-i2-miR-1 to arrest transfected cells on a G2/M state while annexin staining exemplified an apoptotic effect. BAX and PTEN expression levels were affected following the overexpression with the new miRNA. The in vivo expression level was assessed in 35 breast tumor tissues and their paired nonmalignant marginal part. A fourfold downregulation in the tumor specimens compared to their marginal controls could be observed. It can be concluded that the sequence of the hub gene CDH1 harbors at least one miRNA but eventually even more relevant for the pathophysiology of breast cancer.
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Affiliation(s)
- Sedigheh Gharbi
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Zahra Mohammadi
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Maryam Saedi Dezaki
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Sadat Dokanehiifard
- Department of Human Genetics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Shahriar Dabiri
- Department of Pathology, Pathology and Stem Cell Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Eberhard Korsching
- Institute of Bioinformatics, Faculty of Medicine, University of Münster, Münster, Germany
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21
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Identifying Differentially Expressed tRNA-Derived Small Fragments as a Biomarker for the Progression and Metastasis of Colorectal Cancer. DISEASE MARKERS 2022; 2022:2646173. [PMID: 35035608 PMCID: PMC8758288 DOI: 10.1155/2022/2646173] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 11/17/2021] [Accepted: 12/06/2021] [Indexed: 12/29/2022]
Abstract
Objectives. The epithelial-to-mesenchymal transition (EMT) is one key step for the invasion and metastasis of colorectal cancer (CRC). Up until now, the underlying mechanism of EMT in CRC is still unpromising. Thus, it is essential to have a better understanding of its carcinogenesis. The transfer RNA-derived small fragments (tsRNAs) are a new group of small noncoding RNAs (sncRNAs), including tRNA-derived stress-induced RNAs (tiRNAs) and tRNA-derived fragments (tRFs), which have been observed to play an important role in many cancers. However, the relationship between tRFs and EMT in CRC is still unknown. Herein, we aimed to investigate the involvement of tRFs in EMT and its contribution to CRC development. Methods. We identified the differentially expressed tsRNAs in colorectal cancer cell line HT29 treated with TGF-β compared with control cells by using high-throughput sequencing and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). QRT-PCR was conducted to validate the differentially expressed fragments in 68 CRC tumor samples (22 women and 46 men) and adjacent nontumor samples. The association of the expression of tRFs with CRC metastasis and clinical stage was analyzed. Meanwhile, the correlation between tRF expression and overall survival (OS) was also analyzed. TargetScan and miRanda and multiple bioinformatic approaches were used to predict the possible target genes of tsRNAs and analyze possible functions of the tRFs. Results. A series of differentially expressed tsRNAs were identified in TGF-β-treated HT29 cells compared with control cells. tRF-phe-GAA-031 and tRF-VAL-TCA-002 were found to be significantly upregulated in CRC tissues compared to adjacent nontumor tissues. They were significantly correlated with distant metastasis and clinical stage. We compared the differences between tumor samples and nontumor tissues from the ROC curves. The area under the ROC curve (AUC) was up to 0.7554 (95% confidence interval: 0.6739 to 0.8369,
) for tRF-Phe-GAA-031 and up to 0.7313 (95% confidence interval: 0.6474 to 0.8151,
) for tRF-VAL-TCA-002. For OS analysis, higher tRF-phe-GAA-031 and tRF-VAL-TCA-002 expressions were associated with shorter survival for CRC patients. Conclusion. A series of differentially expressed tsRNAs are identified in the EMT process of CRC. And tRF-phe-GAA-031 and tRF-VAL-TCA-002 are higher expressed in CRC tissues, and they might play an important role in the metastasis of CRC. Meanwhile, they may be potential biomarkers and intervention targets in the clinical treatment of CRC.
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Metastatic EMT Phenotype Is Governed by MicroRNA-200-Mediated Competing Endogenous RNA Networks. Cells 2021; 11:cells11010073. [PMID: 35011635 PMCID: PMC8749983 DOI: 10.3390/cells11010073] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022] Open
Abstract
Epithelial–mesenchymal transition (EMT) is a fundamental physiologically relevant process that occurs during morphogenesis and organ development. In a pathological setting, the transition from epithelial toward mesenchymal cell phenotype is hijacked by cancer cells, allowing uncontrolled metastatic dissemination. The competing endogenous RNA (ceRNA) hypothesis proposes a competitive environment resembling a large-scale regulatory network of gene expression circuits where alterations in the expression of both protein-coding and non-coding genes can make relevant contributions to EMT progression in cancer. The complex regulatory diversity is exerted through an array of diverse epigenetic factors, reaching beyond the transcriptional control that was previously thought to single-handedly govern metastatic dissemination. The present review aims to unravel the competitive relationships between naturally occurring ceRNA transcripts for the shared pool of the miRNA-200 family, which play a pivotal role in EMT related to cancer dissemination. Upon acquiring more knowledge and clinical evidence on non-genetic factors affecting neoplasia, modulation of the expression levels of diverse ceRNAs may allow for the development of novel prognostic/diagnostic markers and reveal potential targets for the disruption of cancer-related EMT.
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23
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Nowak E, Bednarek I. Aspects of the Epigenetic Regulation of EMT Related to Cancer Metastasis. Cells 2021; 10:3435. [PMID: 34943943 PMCID: PMC8700111 DOI: 10.3390/cells10123435] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/28/2021] [Accepted: 12/03/2021] [Indexed: 12/11/2022] Open
Abstract
Epithelial to mesenchymal transition (EMT) occurs during the pathological process associated with tumor progression and is considered to influence and promote the metastatic cascade. Characterized by loss of cell adhesion and apex base polarity, EMT enhances cell motility and metastasis. The key markers of the epithelial to mesenchymal transition are proteins characteristic of the epithelial phenotype, e.g., E-cadherin, cytokeratins, occludin, or desmoplakin, the concentration and activity of which are reduced during this process. On the other hand, as a result of acquiring the characteristics of mesenchymal cells, an increased amount of N-cadherin, vimentin, fibronectin, or vitronectin is observed. Importantly, epithelial cells undergo partial EMT where some of the cells show both epithelial and mesenchymal characteristics. The significant influence of epigenetic regulatory mechanisms is observed in the gene expression involved in EMT. Among the epigenetic modifications accompanying incorrect genetic reprogramming in cancer are changes in the level of DNA methylation within the CpG islands and posttranslational covalent changes of histone proteins. All observed modifications, which are stable but reversible changes, affect the level of gene expression leading to the development and progression of the disease, and consequently affect the uncontrolled growth of the population of cancer cells.
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Affiliation(s)
- Ewa Nowak
- Department of Biotechnology and Genetic Engineering, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland;
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24
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Emerging Role of miR-345 and Its Effective Delivery as a Potential Therapeutic Candidate in Pancreatic Cancer and Other Cancers. Pharmaceutics 2021; 13:pharmaceutics13121987. [PMID: 34959269 PMCID: PMC8707074 DOI: 10.3390/pharmaceutics13121987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis. Dysregulated miRNAs are associated with molecular pathways involved in tumor development, metastasis, and chemoresistance in PDAC, as well as other cancers. Targeted treatment strategies that alter miRNA levels in cancers have promising potential as therapeutic interventions. miRNA-345 (miR-345) plays a critical role in tumor suppression and is differentially expressed in various cancers, including pancreatic cancer (PC). The underlying mechanism(s) and delivery strategies of miR-345 have been investigated by us previously. Here, we summarize the potential therapeutic roles of miR-345 in different cancers, with emphasis on PDAC, for miRNA drug discovery, development, status, and implications. Further, we focus on miRNA nanodelivery system(s), based on different materials and nanoformulations, specifically for the delivery of miR-345.
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25
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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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26
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Chen D, Yan Y, Wang X, Li S, Liu Y, Yu D, He Y, Deng R, Liu Y, Xu M, Luo J, Gao H, Wang S. Chronic alcohol exposure promotes HCC stemness and metastasis through β-catenin/miR-22-3p/TET2 axis. Aging (Albany NY) 2021; 13:14433-14455. [PMID: 34019487 PMCID: PMC8202861 DOI: 10.18632/aging.203059] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 03/13/2021] [Indexed: 04/16/2023]
Abstract
Hepatocellular Carcinoma (HCC) patients usually have a high rate of relapse and metastasis. Alcohol, a risk factor for HCC, promotes the aggressiveness of HCC. However, the basic mechanism is still unclear. We used HCC cells and an orthotopic liver tumor model of HCC-LM3 cells for BALB/C nude mice to study the mechanism of alcohol-induced HCC progression. We showed that chronic alcohol exposure promoted HCC cells metastasis and pulmonary nodules formation. First, we identified miR-22-3p as an oncogene in HCC, which promoted HCC cells stemness, tumor growth, and metastasis. Further, we found that miR-22-3p directly targeted TET2 in HCC. TET2, a dioxygenase involved in cytosine demethylation, has pleiotropic roles in hematopoietic stem cells self-renewal. In clinic HCC specimen, TET2 expression was not only decreased by alcohol consumption, but also inversely correlated with miR-22-3p levels. Then, we demonstrated that TET2 depletion promoted HCC cells stemness, tumor growth and metastasis. Furthermore, we identified that β-catenin was an upstream activator of miR-22-3p. In conclusion, this study suggests that chronic alcohol exposure promotes HCC progression and β-catenin/miR-22-3p/TET2 regulatory axis plays an important role in alcohol-promoted HCC malignancy.
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Affiliation(s)
- Danlei Chen
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, Anhui, China
| | - Yan Yan
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
| | - Xinyi Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
- Department of Pulmonary Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Fengtai, Beijing 100071, China
| | - Suzhi Li
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
| | - Yan Liu
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
| | - Dandan Yu
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
| | - Yongjing He
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
| | - Ruiqing Deng
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
| | - Yakun Liu
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, College of Medicine, Lexington, KY 40536, USA
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Hongjun Gao
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
- Department of Pulmonary Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Fengtai, Beijing 100071, China
| | - Siying Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
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27
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Targeting Wnt Signaling in Endometrial Cancer. Cancers (Basel) 2021; 13:cancers13102351. [PMID: 34068065 PMCID: PMC8152465 DOI: 10.3390/cancers13102351] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/03/2021] [Accepted: 05/08/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Wnt has diverse regulatory roles at multiple cellular levels and numerous targeting points, and aberrant Wnt signaling has crucial roles in carcinogenesis, metastasis, cancer recurrence, and chemotherapy resistance; based on these facts, Wnt represents an appealing therapeutic target for cancer treatment. Although preclinical data supports a role for the Wnt signaling pathway in uterine carcinogenesis, this area remains understudied. In this review, we identify the functions of several oncogenes of the Wnt/β-catenin signaling pathway in tumorigenesis and address the translation approach with potent Wnt inhibitors that have already been established or are being investigated to target key components of the pathway. Further research is likely to expand the potential for both biomarker and cancer drug development. There is a scarcity of treatment choices for advanced and recurrent endometrial cancer; investigating the sophisticated connections of Wnt signaling networks in endometrial cancer could address the unmet need for new therapeutic targets. Abstract This review presents new findings on Wnt signaling in endometrial carcinoma and implications for possible future treatments. The Wnt proteins are essential mediators in cell signaling during vertebrate embryo development. Recent biochemical and genetic studies have provided significant insight into Wnt signaling, in particular in cell cycle regulation, inflammation, and cancer. The role of Wnt signaling is well established in gastrointestinal and breast cancers, but its function in gynecologic cancers, especially in endometrial cancers, has not been well elucidated. Development of a subset of endometrial carcinomas has been attributed to activation of the APC/β-catenin signaling pathway (due to β-catenin mutations) and downregulation of Wnt antagonists by epigenetic silencing. The Wnt pathway also appears to be linked to estrogen and progesterone, and new findings implicate it in mTOR and Hedgehog signaling. Therapeutic interference of Wnt signaling remains a significant challenge. Herein, we discuss the Wnt-activating mechanisms in endometrial cancer and review the current advances and challenges in drug discovery.
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28
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Zhang Y, Zhu L, Wang X. NEM-Tar: A Probabilistic Graphical Model for Cancer Regulatory Network Inference and Prioritization of Potential Therapeutic Targets From Multi-Omics Data. Front Genet 2021; 12:608042. [PMID: 33968127 PMCID: PMC8100334 DOI: 10.3389/fgene.2021.608042] [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: 09/18/2020] [Accepted: 03/22/2021] [Indexed: 11/13/2022] Open
Abstract
Targeted therapy has been widely adopted as an effective treatment strategy to battle against cancer. However, cancers are not single disease entities, but comprising multiple molecularly distinct subtypes, and the heterogeneity nature prevents precise selection of patients for optimized therapy. Dissecting cancer subtype-specific signaling pathways is crucial to pinpointing dysregulated genes for the prioritization of novel therapeutic targets. Nested effects models (NEMs) are a group of graphical models that encode subset relations between observed downstream effects under perturbations to upstream signaling genes, providing a prototype for mapping the inner workings of the cell. In this study, we developed NEM-Tar, which extends the original NEMs to predict drug targets by incorporating causal information of (epi)genetic aberrations for signaling pathway inference. An information theory-based score, weighted information gain (WIG), was proposed to assess the impact of signaling genes on a specific downstream biological process of interest. Subsequently, we conducted simulation studies to compare three inference methods and found that the greedy hill-climbing algorithm demonstrated the highest accuracy and robustness to noise. Furthermore, two case studies were conducted using multi-omics data for colorectal cancer (CRC) and gastric cancer (GC) in the TCGA database. Using NEM-Tar, we inferred signaling networks driving the poor-prognosis subtypes of CRC and GC, respectively. Our model prioritized not only potential individual drug targets such as HER2, for which FDA-approved inhibitors are available but also the combinations of multiple targets potentially useful for the design of combination therapies.
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Affiliation(s)
- Yuchen Zhang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Lina Zhu
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Xin Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.,Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute, City University of Hong Kong, Shenzhen, China
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29
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Zhang H, Li M, Kaboli PJ, Ji H, Du F, Wu X, Zhao Y, Shen J, Wan L, Yi T, Wen Q, Li X, Cho CH, Li J, Xiao Z. Identification of cluster of differentiation molecule-associated microRNAs as potential therapeutic targets for gastrointestinal cancer immunotherapy. Int J Biol Markers 2021; 36:22-32. [PMID: 33788641 DOI: 10.1177/17246008211005473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Cluster of differentiation molecules are markers of immune cells that have been identified as a potential immunotherapeutic target for cancer treatment. MicroRNAs are small non-coding RNAs that act as tumor suppressors or oncogenes whose importance in diagnosis, prognosis, and treatment of gastric and colorectal cancers has been widely reported. However, their association with cluster of differentiation molecules in gastrointestinal cancers has not been well studied. Therefore, our study aimed to analyze the relationship between microRNAs and cluster of differentiation molecules in gastrointestinal cancers, and to identify cluster of differentiation molecule-associated microRNAs as prognostic biomarkers for gastrointestinal cancer patients. METHODS Targetscan, Starbase, DIANA microT, and miRDB were used to investigate microRNA profiles that might be correlated with cluster of differentiation molecules in gastrointestinal cancers. Moreover, The Cancer Genome Atlas data analysis was used to investigate the association between cluster of differentiation molecules and microRNA expression in patients with gastric, colon, rectal, pancreatic, and esophageal cancers. The Kaplan-Meier plotter was used to identify the association between overall survival and cluster of differentiation molecule-associated microRNA expression in gastrointestinal cancer patients. RESULTS miR-200a, miR-559, and miR-1236 were negatively associated with CD86, CD81, and CD160, respectively, in almost all types of gastrointestinal cancers, which were further verified in the in vitro studies by transfecting microRNA mimics in gastric cancer, colon cancer, pancreatic, and esophageal cell lines. CONCLUSION Our study showed that miR-200a, miR-1236, and miR-559 are identified as cluster of differentiation-associated microRNAs in gastrointestinal cancers, providing a novel perspective to identify new therapeutic targets for cancer immunotherapy in gastrointestinal cancer patients.
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Affiliation(s)
- Hanyu Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Parham Jabbarzadeh Kaboli
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Huijiao Ji
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Lin Wan
- Department of Hematology and Oncology, The Children's Hospital of Soochow, Suzhou, Jiangsu, China
| | - Tao Yi
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan, PR China
| | - Xiang Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
| | - Jing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China.,Department of Oncology and Hematology, Hospital (T.C.M.) Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institution for Translational Medicine, Luzhou, Sichuan, PR China
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30
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Shen M, Zhang W, Wang B. The Effect of LncRNA Zinc Finger E-Box-Binding Homeobox 1 Antisense 1 on the Biological Characteristics of Gastric Cancer Cells by Regulating the MiR-200b/Wnt1 Axis. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In recent decades, most gastric cancer patients are diagnosed in the advanced disease stage with poor prognosis, and more than half of the advanced-stage patients will relapse. This research explores lncRNA ZEB1-AS1’s effect on gastric cancer cell proliferation, invasion, apoptosis
via regulating the miR-200b/Wnt1 molecular axis. ZEB1-AS1 and miR-200b expressions in BGC-803, SGC-7901, MKN-45, and AGS cells were measured by qRT-PCR. ZEB1-AS1 siRNA, miR-200b mimics, and miR-200b mimics + pcDNA3.1-ZEB1-AS1 were transfected into BGC-803 cells to study their respective effect
on cell proliferation, invasion, apoptosis using CCK-8 and Transwell assays and flow cytometry, respectively. Dual-luciferase reporter gene assay is used to detect the luciferase activity of ZEB1-AS1 WT or MUT and Wnt1 WT or MUT after co-transfecting with miR-200b mimics. The expression of
miR-200b in BGC-803 cells with knocked down or overexpressed ZEB1-AS1 was quantified with qRT-PCR. Western blot analysis was used to detect the protein level of Wnt1 in BGC-803 cells with upregulated or downregulated miR-200b expression. Data showed that ZEB1-AS1 expression was significantly
raised when miR-200b expression was reduced (P < 0.05). BGC-803 cells were selected for follow-up experiments. ZEB1-AS1, Wnt1, and miR-200b were found to have a targeted regulatory relationship. The knockdown of ZEB1-AS1 and upregulation of miR-200b can hinder BGC-803 cell proliferation
and invasion and expedite apoptosis. ZEB1-AS1 and miR-200b overexpression can reverse the effect of miR-200b upregulation on BGC-803 cell proliferation, invasion, and apoptosis. Therefore, lncRNA ZEB1-AS1 could impede gastric cancer cell proliferation and invasion and accelerate apoptosis
via the regulation of the miR-200b/Wnt1 molecular axis.
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Affiliation(s)
- Minghai Shen
- Department of General Surgury, Xixi Hospital of Hangzhou, Hangzhou 310023, Zhejiang, PR China
| | - Weidong Zhang
- Department of General Surgury, Xixi Hospital of Hangzhou, Hangzhou 310023, Zhejiang, PR China
| | - Bei Wang
- Department of Division of Hepatobiliary and Pancreatic Surgery, First Affifiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, PR China
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Emami Nejad A, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M, Nedaeinia R, Haghjooy Javanmard S, Taherian M, Ahmadlou M, Salehi R, Sadeghi B, Manian M. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int 2021; 21:62. [PMID: 33472628 PMCID: PMC7816485 DOI: 10.1186/s12935-020-01719-5] [Citation(s) in RCA: 335] [Impact Index Per Article: 83.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 12/11/2020] [Accepted: 12/16/2020] [Indexed: 12/13/2022] Open
Abstract
Hypoxia is a common feature of solid tumors, and develops because of the rapid growth of the tumor that outstrips the oxygen supply, and impaired blood flow due to the formation of abnormal blood vessels supplying the tumor. It has been reported that tumor hypoxia can: activate angiogenesis, thereby enhancing invasiveness and risk of metastasis; increase survival of tumor, as well as suppress anti-tumor immunity and hamper the therapeutic response. Hypoxia mediates these effects by several potential mechanisms: altering gene expression, the activation of oncogenes, inactivation of suppressor genes, reducing genomic stability and clonal selection. We have reviewed the effects of hypoxia on tumor biology and the possible strategiesto manage the hypoxic tumor microenvironment (TME), highlighting the potential use of cancer stem cells in tumor treatment.
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Affiliation(s)
- Asieh Emami Nejad
- Department of Biology, Payame Noor University (PNU), P.O.Box 19395-3697, Tehran, Iran
| | - Simin Najafgholian
- Department of Emergency Medicine, School of Medicine , Arak University of Medical Sciences, Arak, Iran
| | - Alireza Rostami
- Department of Surgery, School of Medicine Amiralmomenin Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Alireza Sistani
- Department of Emergency Medicine, School of Medicine Valiasr Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Samaneh Shojaeifar
- Department of Midwifery, Faculty of Nursing and Midwifery , Arak University of Medical Sciences , Arak, Iran
| | - Mojgan Esparvarinha
- Department of Immunology, School of Medicine , Tabriz University of Medical Sciences , Tabriz, Iran
| | - Reza Nedaeinia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease , Isfahan University of Medical Sciences , Isfahan, Iran
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences , Isfahan, Iran
| | - Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Ahmadlou
- Sciences Medical of University Arak, Hospital Amiralmomenin, Center Development Research Clinical, Arak, Iran
| | - Rasoul Salehi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease , Isfahan University of Medical Sciences , Isfahan, Iran.,Department of Genetics and Molecular Biology, School of Medicine , Isfahan University of Medical Sciences , Isfahan, Iran
| | - Bahman Sadeghi
- Department of Health and Community Medicine, School of Medicine, Arak University of Medical Sciences, Arak, 3848176341, Iran.
| | - Mostafa Manian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. .,Department of Medical Laboratory Science, Faculty of Medical Science Kermanshah Branch, Islamic Azad University, Imam Khomeini Campus, Farhikhtegan Bld., Shahid J'afari St., Kermanshah, 3848176341, Iran.
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Liu B, Li J, Li JM, Liu GY, Wang YS. HOXC-AS2 mediates the proliferation, apoptosis, and migration of non-small cell lung cancer by combining with HOXC13 gene. Cell Cycle 2021; 20:236-246. [PMID: 33427025 DOI: 10.1080/15384101.2020.1868161] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the highest incidence and mortality of malignant tumors worldwide and has become a global public health problem. Long non-coding RNAs (LncRNAs) are expected to participate in the progression of NSCLC. This study aims to explore the effects and underlying mechanisms of LncRNA HOXC-AS2 on NSCLC cell proliferation, apoptosis, and migration. The Cell Counting Kit-8 (CCK-8) and clone formation assay were used to measure the A549 and HCC827 cell proliferation. The cell apoptosis and migration was respectively analyzed by flow cytometry and transwell assay. RNA immunoprecipitation (RIP) was used to detect the interaction between HOXC-AS2 and HOXC13. The expression of β-catenin, α-SMA, MMP-1, MMP-2 expression, E-cadherin, and Ki-67 expression were determined by Western blot or immunohistochemistry (IHC) assay. We found that HOXC-AS2 was significantly up-regulated in NSCLC tissues. Knockdown of HOXC-AS2 expression resulted in significant decreases in NSCLC cell proliferation, migration, and epithelial-mesenchymal transition (EMT) process marker proteins, simultaneously activated A549 and HCC827 cell apoptosis. RIP assay suggested that HOXC13 was a functional target for HOXC-AS2. And HOXC-AS2 and HOXC13 could positively regulate each other. Compared with the normal tissues, the mRNA level of HOXC13 was increased in NSCLC tissues. HOXC13 silencing counteracted increases of A549 and HCC827 cell proliferation and migration, as well as a decrease of cell apoptosis induced by HOXC-AS2 overexpression. Moreover, HOXC-AS2 silencing reduced tumor growth rate and Ki-67 expression in vivo. Taken together, HOXC-AS2 knockdown inhibited NSCLC cell proliferation and migration, as well as stimulated NSCLC cell apoptosis through regulation of HOXC13 expression.
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Affiliation(s)
- Bin Liu
- Department of Thoracic Oncology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University , Chengdu, China.,Department of Medical Oncology, Sichuan Cancer Hospital &institute & School of Medicine, University of Electronic Science and Technology of China , Chengdu, China
| | - Jing Li
- Department of General Internal Medicine, Sichuan Cancer Hospital &institute & School of Medicine, University of Electronic Science and Technology of China , Chengdu, China
| | - Ji-Man Li
- Department of Pathology, Sichuan Cancer Hospital &institute & School of Medicine, University of Electronic Science and Technology of China , Chengdu, China
| | - Guang-Yuan Liu
- Ward 1, Department of Thoracic Surgery, Sichuan Cancer Hospital &institute & School of Medicine, University of Electronic Science and Technology of China , Chengdu, China
| | - Yong-Sheng Wang
- Department of Thoracic Oncology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University , Chengdu, China
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Singh S, Raza W, Parveen S, Meena A, Luqman S. Flavonoid display ability to target microRNAs in cancer pathogenesis. Biochem Pharmacol 2021; 189:114409. [PMID: 33428895 DOI: 10.1016/j.bcp.2021.114409] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/01/2021] [Accepted: 01/05/2021] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are non-coding, conserved, single-stranded nucleotide sequences involved in physiological and developmental processes. Recent evidence suggests an association between miRNAs' deregulation with initiation, promotion, progression, and drug resistance in cancer cells. Besides, miRNAs are known to regulate the epithelial-mesenchymal transition, angiogenesis, autophagy, and senescence in different cancer types. Previous reports proposed that apart from the antioxidant potential, flavonoids play an essential role in miRNAs modulation associated with changes in cancer-related proteins, tumor suppressor genes, and oncogenes. Thus, flavonoids can suppress proliferation, help in the development of drug sensitivity, suppress metastasis and angiogenesis by modulating miRNAs expression. In the present review, we summarize the role of miRNAs in cancer, drug resistance, and the chemopreventive potential of flavonoids mediated by miRNAs. The potential of flavonoids to modulate miRNAs expression in different cancer types demonstrate their selectivity and importance as regulators of carcinogenesis. Flavonoids as chemopreventive agents targeting miRNAs are extensively studied in vitro, in vivo, and pre-clinical studies, but their efficiency in targeting miRNAs in clinical studies is less investigated. The evidence presented in this review highlights the potential of flavonoids in cancer prevention/treatment by regulating miRNAs, although further investigations are required to validate and establish their clinical usefulness.
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Affiliation(s)
- Shilpi Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Waseem Raza
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Jawahar Lal Nehru University, New Delhi 110067, India
| | - Shahnaz Parveen
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India.
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Circ_0001247 functions as a miR-1270 sponge to accelerate cervical cancer progression by up-regulating ZEB2 expression level. Biotechnol Lett 2021; 43:745-755. [PMID: 33386495 DOI: 10.1007/s10529-020-03059-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND There is increasing evidence that circular RNA (circRNA) disorders have an impact on the progression of various malignancies. The expression characteristics, function and underlying mechanism of circ_0001247 in cervical cancer (CC) have not been confirmed. METHODS GSE147483 datasets of circRNAs expression in CC cell line and normal cervical cell line were retrieved from GEO database, and the circRNA with significant difference was selected; circ_0001247, miR-1270, and Zinc finger E-box binding homeobox 2 (ZEB2) expressions in CC tissues and cell lines were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) assay; cell counting kit-8 (CCK-8) assay and BrdU assay were applied to monitor the proliferative ability of CC cells; Transwell assay was conducted to examine the migration and invasion of CC cells, and flow cytometry was used to evaluate the apoptosis; Western blot assay was adopted to detect ZEB2 protein expressions; dual-luciferase report gene assay was used to verify the targeting relationship between circ_0001247 and miR-1270, and miR-1270 and the 3'UTR of ZEB2. RESULTS Analysis of GSE147483 suggested that circ_0001247 could probably be an oncogenic circRNA in CC. Compared with that in adjacent tissues and normal cervical epithelial cells, circ_0001247 expression in CC tissues and cell lines was significantly increased; knocking down circ_0001247 expression could inhibit the proliferation and metastasis of CC cells, and promote apoptosis, while circ_0001247 overexpression worked oppositely; circ_0001247 sponged miR-1270 in CC cells; miR-1270 diminished the promoting effect of circ_0001247 by inactivating the ZEB2. CONCLUSION Circ_0001247 promotes progression of CC by sponging miR-1270 to upregulate ZEB2 expression level.
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Yang D, Li Q, Shang R, Yao L, Wu L, Zhang M, Zhang L, Xu M, Lu Z, Zhou J, Huang L, Huang X, Cheng D, Yang Y, Yu H. WNT4 secreted by tumor tissues promotes tumor progression in colorectal cancer by activation of the Wnt/β-catenin signalling pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:251. [PMID: 33222684 PMCID: PMC7682076 DOI: 10.1186/s13046-020-01774-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 11/09/2020] [Indexed: 01/02/2023]
Abstract
BACKGROUND Wingless and Int-related protein (Wnt) ligands are aberrantly expressed in patients with colorectal cancer (CRC). However, the aberrant level of Wnt ligands in serum have not been explored. Here, we aimed to identify the levels of WNT4 in serum and explored its oncogenic role in CRC. METHODS The Oncomine database was used to analyze the relationship between WNT4 and the prognosis of CRC. ELISA was performed to measure WNT4 levels in serum and conditioned medium from fresh CRC tissues and adjacent normal tissues. Western blot and immunohistochemistry were carried out to measure the expression of WNT4 in human CRC tissues and adjacent normal tissues. The migration and invasion of CRC cells were determined by trans-well assay, and the effects of WNT4 on CRC invasion and metastasis in vivo were verified by tumor xenograft in nude mice. Cancer-associated fibroblasts (CAFs) and angiogenesis in subcutaneous nodules were detected by immunofluorescence (IF). In addition, the suspended spheres formation and tube formation assay were performed to explore the effects of WNT4 on CAFs and angiogenesis respectively. RESULTS WNT4 was significantly upregulated in serum of CRC patients, and CRC tissues were identified as an important source of elevated WNT4 levels in CRC patients. Interestingly, elevated levels of WNT4 in serum were downregulated after tumor resection. Furthermore, we found that WNT4 contributed to epithelial-to-mesenchymal transition (EMT) and activated fibroblasts by activating the WNT4/β-catenin pathway in vitro and in vivo. Moreover, angiogenesis was induced via the WNT4/β-catenin/Ang2 pathway. Those effects could be reversed by ICG-001, a β-catenin/TCF inhibitor. CONCLUSION Our findings indicated that serum levels of WNT4 may be a potential biomarker for CRC. WNT4 secreted by colorectal cancer tissues promote the progression of CRC by inducing EMT, activate fibroblasts and promote angiogenesis through the canonical Wnt/β-catenin signalling pathway.
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Affiliation(s)
- Dongmei Yang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Qing Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Renduo Shang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Liwen Yao
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Lianlian Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Mengjiao Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Lihui Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Ming Xu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Zihua Lu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Jie Zhou
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Li Huang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Xiaodong Huang
- Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Du Cheng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China
| | - Yanning Yang
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, Hubei, 430060, People's Republic of China.
| | - Honggang Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. .,Hubei Key Laboratory of Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China. .,Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Jiefang Rd. 238, Wuhan, 430060, China.
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Ma Y, Pan C, Tang X, Zhang M, Shi H, Wang T, Zhang Y. MicroRNA-200a represses myocardial infarction-related cell death and inflammation by targeting the Keap1/Nrf2 and β-catenin pathways. Hellenic J Cardiol 2020; 62:139-148. [PMID: 33197602 DOI: 10.1016/j.hjc.2020.10.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Acute myocardial infarction (MI) is a main cause of emergency death in the world. MicroRNAs (miRs/miRNAs) are a series of small non-coding RNA molecules, which regulate cardiovascular disorders that involve MI. In this study, we explored the function of miR-200a in MI treatment. METHODS We observed down-regulation of miR-200a levels and up-regulation of Keap1 and β-catenin levels in H2O2-treated newborn murine ventricular cardiomyocytes (NMVCs) and the infarcted heart tissues of MI mouse models, compared to the non-treated NMVCs and normal heart tissues of healthy mice. RESULTS CCK-8 and colony formation assays indicated the reduction in NMVC vitality due to H2O2 treatment and the recovery of cell vitality due to miR-200a overexpression, respectively. Flow cytometry with Annexin and PI staining indicated the inhibition of H2O2-triggered cell apoptosis through ectopically expressed miR-200a. Western blotting and ELISA analyses that detected pro-inflammatory cell factors [interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α] confirmed that miR-200a prevented H2O2-induced NMVC inflammation. Moreover, miR-200a inhibited up-regulation of Keap1 and β-catenin expression in H2O2-treated NMVCs by directly binding with the 3'-UTR regions of both Keap1 and β-catenin. Furthermore, overexpression of Keap1 and β-cateninin in H2O2-treated NMVCs with recovered miR-200a elevated inflammation and apoptosis, respectively. CONCLUSION The results showed that miR-200a expression was inhibited in murine cardiomyocytes due to H2O2 stress in MI cardiac tissues and overexpressed miR-200a could protect the cells from death by regulating the Keap1/Nrf2 and β-catenin signal transduction pathways.
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Affiliation(s)
- Yi Ma
- Department of Radiology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213164, China.
| | - Changjie Pan
- Department of Radiology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213164, China.
| | - Xiaoqiang Tang
- Department of Radiology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213164, China.
| | - Ming Zhang
- Department of Radiology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213164, China.
| | - Haifeng Shi
- Department of Radiology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213164, China.
| | - Tao Wang
- Department of Radiology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213164, China.
| | - Yong Zhang
- Department of Radiology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213164, China.
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BTXA regulates the epithelial-mesenchymal transition and autophagy of keloid fibroblasts via modulating miR-1587/miR-2392 targeted ZEB2. Biosci Rep 2020; 39:220731. [PMID: 31652445 PMCID: PMC6822502 DOI: 10.1042/bsr20190679] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 09/10/2019] [Accepted: 09/30/2019] [Indexed: 12/23/2022] Open
Abstract
Keloids are very resistant to treatment in dermatology and plastic surgical practice. The present study aimed to explore the underlying mechanism of botulinum toxin A (BTXA) treated human skin keloid fibroblasts (HSFBs) proving some new insights into keloids treatment. Expression of miR-1587 and miR-2392 were significantly down-regulated in keloid tissues and HSFBs, while the ZEB2 was a target of both and up-regulated in keloid tissues and HSFBs compared with the normal controls. BTXA could significantly increase the expression of miR-1587 and miR-2392 but decrease the expression of ZEB2. BTXA could significantly inhibit the proliferation, cell cycle, and migration and promote apoptosis and autophagy of HSFBs; however, miR-1587 and miR-2392 inhibitors could reverse these effects of BTXA on HSFBs. Silencing ZEB2 could significantly attenuate the effects of miR-1587 and miR-2392 inhibitors in promoting cell proliferation and migration and suppressing apoptosis and autophagy of HSFBs after treating with BTXA. BTXA could suppress the proliferation and migration and promote apoptosis and autophagy of HSFBs via modulating miR-1587/miR-2392 targeted ZEB2.
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Ghazi T, Nagiah S, Dhani S, Chuturgoon AA. Fusaric acid-induced epigenetic modulation of hepatic H3K9me3 triggers apoptosis in vitro and in vivo. Epigenomics 2020; 12:955-972. [PMID: 32762452 DOI: 10.2217/epi-2019-0284] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Aim: To determine the effect of the food-borne mycotoxin, fusaric acid (FA) on miR-200a, SUV39H1-mediated H3K9me3, genome integrity and apoptosis in human liver (HepG2) cells and C57BL/6 mice livers. Materials & methods: MiR-200a, Sirt1, SUV39H1-mediated H3K9me3, genome integrity and apoptosis was measured in HepG2 cells and C57BL/6 mice livers using qPCR, western blot, DNA electrophoresis and luminometry. Results: FA: upregulated miR-200a and decreased Sirt1 expression in HepG2 cells and mice livers; decreased expression of SUV39H1 and KDM4B, thus decreasing H3K9me3 and increasing H3K9me1; increased cell mortality via apoptosis. Conclusion: FA induced apoptosis by upregulating miR-200a and decreasing SUV39H1-mediated H3K9me3 in HepG2 cells and mice livers.
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Affiliation(s)
- Terisha Ghazi
- Discipline of Medical Biochemistry & Chemical Pathology, School of Laboratory Medicine & Medical Science, College of Health Sciences, Howard College Campus, University of KwaZulu-Natal, Durban 4041, South Africa
| | - Savania Nagiah
- Discipline of Medical Biochemistry & Chemical Pathology, School of Laboratory Medicine & Medical Science, College of Health Sciences, Howard College Campus, University of KwaZulu-Natal, Durban 4041, South Africa
| | - Shanel Dhani
- Discipline of Medical Biochemistry & Chemical Pathology, School of Laboratory Medicine & Medical Science, College of Health Sciences, Howard College Campus, University of KwaZulu-Natal, Durban 4041, South Africa
| | - Anil A Chuturgoon
- Discipline of Medical Biochemistry & Chemical Pathology, School of Laboratory Medicine & Medical Science, College of Health Sciences, Howard College Campus, University of KwaZulu-Natal, Durban 4041, South Africa
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Zhou F, Du C, Xu D, Lu J, Zhou L, Wu C, Wu B, Huang J. Knockdown of ubiquitin‑specific protease 51 attenuates cisplatin resistance in lung cancer through ubiquitination of zinc‑finger E‑box binding homeobox 1. Mol Med Rep 2020; 22:1382-1390. [PMID: 32468048 PMCID: PMC7339607 DOI: 10.3892/mmr.2020.11188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 12/17/2019] [Indexed: 12/29/2022] Open
Abstract
Lung cancer is a devastating cancer with high morbidity and mortality. Ubiquitin‑specific protease (USP) is a type of deubiquitinating enzyme (DUB) that has been implicated in numerous cancers, including colorectal, myeloma and breast. In the present study, the expression of USP51 was determined in the lung cancer cell line A549 and cisplatin (also known as DDP)‑resistant lung cancer strain A549/DDP. The expression of zinc‑finger E‑box binding homeobox 1 (ZEB1), a transcriptional repressor, was also examined. The effects of USP51 knockdown or overexpression on proliferation and apoptosis, as well as the impact of ZEB1 overexpression and USP51 interference on apoptosis and ubiquitination were then assessed. Notably, increased expression of USP51 and ZEB1 in A549/DDP cells was observed, and treatment with DDP significantly inhibited proliferation in A549/DDP cells. In addition, knockdown of USP51 in A549/DDP cells significantly induced apoptosis, decreased ZEB1 expression and increased cleaved poly ADP‑ribose polymerase 1 (PARP1) and cleaved caspase‑3 levels. Consistently, USP51 overexpression in A549 cells displayed the opposite effects and potently attenuated DDP‑induced apoptosis. Notably, overexpression of ZEB1 in A549/DDP cells potently attenuated the effects of USP51 knockdown on apoptosis, and co‑IP experiments further demonstrated interaction between USP51 and ZEB. Lastly, knockdown of USP51 promoted ZEB1 ubiquitination, leading to ZEB1 degradation. Collectively, the present findings demonstrated that USP51 inhibition attenuated DDP resistance in A549/DDP cells via ubiquitin‑mediated degradation of ZEB1. Hence, targeting USP51 may serve as a novel therapeutic target for DDP resistance in lung cancer.
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Affiliation(s)
- Feng Zhou
- Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
- Department of Respiratory Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201700, P.R. China
| | - Chunling Du
- Department of Respiratory Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201700, P.R. China
| | - Donghui Xu
- Department of Respiratory Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201700, P.R. China
| | - Jinchang Lu
- Department of Respiratory Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201700, P.R. China
| | - Lei Zhou
- Department of Respiratory Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201700, P.R. China
| | - Chaomin Wu
- Department of Respiratory Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201700, P.R. China
| | - Bo Wu
- Department of Respiratory Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201700, P.R. China
| | - Jianan Huang
- Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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40
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Shao Z, Gao D, Chen L, Ding W, Yu Q. Non‑coding RNAs that regulate the Wnt/β‑catenin signaling pathway in gastric cancer: Good cop, bad cop? (Review). Oncol Rep 2020; 44:1314-1321. [PMID: 32945460 DOI: 10.3892/or.2020.7705] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 07/13/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most common causes of cancer‑related mortality worldwide. Despite remarkable progress in the diagnosis and treatment of GC, a large number of cases are diagnosed as advanced GC, and treatment failure occurs. Emerging evidence has shown that non‑coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non‑coding RNAs (lncRNAs), play a vital role in the tumorigenesis and development of GC. Moreover, the pathogenesis of GC is closely related to aberrant activation of the Wnt (Wingless‑type MMTV integration site family) signaling pathway. ncRNAs serve as potential novel biomarkers in the clinical examination, prognosis and therapeutic targeting of GC. Furthermore, dysregulation of ncRNAs has been demonstrated to affect tumor initiation, epithelial‑mesenchymal transition (EMT), angiogenesis, tumor development, invasion, metastasis and resistance to therapy via the Wnt/β‑catenin signaling pathway. This review focuses on the role of ncRNAs in modulating the Wnt/β‑catenin signaling pathway in the pathogenesis of GC, which may provide a reference for the clinical diagnosis and treatment of GC.
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Affiliation(s)
- Zhaozhao Shao
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Dian Gao
- Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Li Chen
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wenjie Ding
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Qiongfang Yu
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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41
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Liu X, Zhang Y, Wang Y, Bian C, Wang F. Long non-coding RNA KCNQ1OT1 up-regulates CTNND1 by sponging miR-329-3p to induce the proliferation, migration, invasion, and inhibit apoptosis of colorectal cancer cells. Cancer Cell Int 2020; 20:340. [PMID: 32760218 PMCID: PMC7379774 DOI: 10.1186/s12935-020-01425-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 07/14/2020] [Indexed: 12/11/2022] Open
Abstract
Background Long non-coding RNAs (lncRNAs) have been certified to be involved in the occurrence and growth of diverse cancers, including CRC. The purpose of the research was to explore the effects of lncRNA KCNQ1 overlapping transcript 1 (KCNQ1OT1) on proliferation, migration, invasion, and apoptosis in CRC cells and its mechanism. Methods The levels of KCNQ1OT1 and miR-329-3p were examined by quantitative real-time polymerase chain reaction (qRT-PCR) in CRC tissues and cells. The mRNA and protein levels of catenin delta-1 (CTNND1) were measured by qRT-PCR and western blot analysis, respectively. The targets of KCNQ1OT1 and miR-329-3p were predicted by online software and confirmed by luciferase reporter assay. The cell proliferation, migration, invasion, and apoptosis were examined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), transwell, and apoptosis assay. The expression levels of CyclinD1, Bcl-2, MMP9, Cleaved-casp-3, and E-cadherin in SW480 and LS1034 cells were gauged by western blot analysis. Xenograft tumor model was structured to prove the biological role of KCNQ1OT1 of CRC in vivo. Results The levels of KCNQ1OT1 and CTNND1 were significantly increased in CRC tissues and cells. Knockdown of KCNQ1OT1 suppressed proliferation, migration, invasion, and induced apoptosis in CRC cells. Conversely, CTNND1 overexpression reversed the impact of KCNQ1OT1 knockdown on CRC cells. Moreover, CTNND1 was verified as a direct target of miR-329-3p, and miR-329-3p could specially bind to KCNQ1OT1. Also, the down-regulation of KCNQ1OT1 triggered the CRC progress by up-regulating CTNND1 expression in CRC cells. Besides, KCNQ1OT1 knockdown inhibited CRC tumor growth through the miR-329-3p/CTNND1 axis in vivo. Conclusion Our results indicated that KCNQ1OT1 could positively regulate CTNND1 expression by sponging miR-329-3p, thereby boosting the progression of CRC. Our findings provided the underlying therapy targets for CRC.
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Affiliation(s)
- Xing Liu
- Department of Anorectal Surgery, Jining NO. 1 People's Hospital, Jining, 272000 Shandong China
| | - Yexiang Zhang
- Department of Surgery, Second People's Hospital, Rencheng District, Jining, 272061 Shandong China
| | - Yan Wang
- Department of Acupuncture and Physiotherapy, Jining NO. 1, People's Hospital, Jining, 272000 Shandong China
| | - Chao Bian
- Department of Acupuncture and Physiotherapy, Jining NO. 1, People's Hospital, Jining, 272000 Shandong China
| | - Fengji Wang
- Department of General Surgery, Shandong Institute of Parasitic Diseases, Shandong First Medical University and Shandong Academy of Medical Sciences, No. 11 Taibaizhong Road, Jining, 272033 Shandong China
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42
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Lei Y, Chen L, Zhang G, Shan A, Ye C, Liang B, Sun J, Liao X, Zhu C, Chen Y, Wang J, Zhang E, Deng L. MicroRNAs target the Wnt/β‑catenin signaling pathway to regulate epithelial‑mesenchymal transition in cancer (Review). Oncol Rep 2020; 44:1299-1313. [PMID: 32700744 PMCID: PMC7448411 DOI: 10.3892/or.2020.7703] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 06/24/2020] [Indexed: 12/11/2022] Open
Abstract
Epithelial‑mesenchymal transition (EMT), during which cancer cells lose the epithelial phenotype and gain the mesenchymal phenotype, has been verified to result in tumor migration and invasion. Numerous studies have shown that dysregulation of the Wnt/β‑catenin signaling pathway gives rise to EMT, which is characterized by nuclear translocation of β‑catenin and E‑cadherin suppression. Wnt/β‑catenin signaling was confirmed to be affected by microRNAs (miRNAs), several of which are down‑ or upregulated in metastatic cancer cells, indicating their complex roles in Wnt/β‑catenin signaling. In this review, we demonstrated the targets of various miRNAs in altering Wnt/β‑catenin signaling to promote or inhibit EMT, which may elucidate the underlying mechanism of EMT regulation by miRNAs and provide evidence for potential therapeutic targets in the treatment of invasive tumors.
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Affiliation(s)
- Yuhe Lei
- Department of Pharmacy, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518000, P.R. China
| | - Lei Chen
- Department of Pharmacy, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518000, P.R. China
| | - Ge Zhang
- Department of Big Data Research of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China
| | - Aiyun Shan
- Department of Pharmacy, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518000, P.R. China
| | - Chunfeng Ye
- Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Bin Liang
- Formula Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Jiayu Sun
- Department of Pharmacy, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518000, P.R. China
| | - Xin Liao
- Department of Pharmacy, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518000, P.R. China
| | - Changfeng Zhu
- Department of Pharmacy, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518000, P.R. China
| | - Yueyue Chen
- Formula Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Jing Wang
- Formula Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Enxin Zhang
- Department of Oncology, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518000, P.R. China
| | - Lijuan Deng
- Formula Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
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43
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MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy. Biomolecules 2020; 10:biom10071040. [PMID: 32664703 PMCID: PMC7407563 DOI: 10.3390/biom10071040] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 02/07/2023] Open
Abstract
Molecular signaling pathways involved in cancer have been intensively studied due to their crucial role in cancer cell growth and dissemination. Among them, zinc finger E-box binding homeobox-1 (ZEB1) and -2 (ZEB2) are molecules that play vital roles in signaling pathways to ensure the survival of tumor cells, particularly through enhancing cell proliferation, promoting cell migration and invasion, and triggering drug resistance. Importantly, ZEB proteins are regulated by microRNAs (miRs). In this review, we demonstrate the impact that miRs have on cancer therapy, through their targeting of ZEB proteins. MiRs are able to act as onco-suppressor factors and inhibit the malignancy of tumor cells through ZEB1/2 down-regulation. This can lead to an inhibition of epithelial-mesenchymal transition (EMT) mechanism, therefore reducing metastasis. Additionally, miRs are able to inhibit ZEB1/2-mediated drug resistance and immunosuppression. Additionally, we explore the upstream modulators of miRs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as these regulators can influence the inhibitory effect of miRs on ZEB proteins and cancer progression.
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44
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Ahadi A. Dysregulation of miRNAs as a signature for diagnosis and prognosis of gastric cancer and their involvement in the mechanism underlying gastric carcinogenesis and progression. IUBMB Life 2020; 72:884-898. [DOI: 10.1002/iub.2259] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 02/08/2020] [Indexed: 02/06/2023]
Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of MedicineShahid Beheshti University of Medical Sciences Tehran Iran
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45
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Chen G, Hu C, Song Y, Xiu M, Zhang Y, Lai P, Li Y, Liu X, Huang P. Relationship between Aurora-A V57I Polymorphism and the Risk of Cancer: A Meta-Analysis and Trial Sequential Analysis. J Cancer 2020; 11:3225-3234. [PMID: 32231728 PMCID: PMC7097942 DOI: 10.7150/jca.40567] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 01/21/2020] [Indexed: 02/06/2023] Open
Abstract
Background: It is still conflicting for the correlation between cancer susceptibility and Aurora-A V57I (rs1047972) gene variant from the published researches. This meta-analysis was performed to access the correlation between cancer susceptibility and Aurora-A rs1047972 gene polymorphism by using meta-analysis methods. Methods: Eligible studies published before Nov 1, 2019 were systematically searched in PMC, PubMed, EMBASE, Web of Science, Cochrane Library Database, China National Knowledge Infrastructure, Wanfang databases, in order to collect qualified case-control or cohort studies. The odds ratio (OR) and its 95% confidence interval (95%CI) were used to evaluate the correlation between Aurora-A rs1047972 gene polymorphism and cancer risk. Sensitivity analysis was used to examine the stability of the results; Egger's test and Begg's funnel chart were used to assess possible publication bias. Trial sequential analysis (TSA) was used to access whether the sample size of our meta-analysis was sufficient. Results: The sample set extracted from 24 case-control studies involving 35,926 subjects (14,639 cases and 21,287 controls) for the association of Aurora-A rs1047972 gene polymorphism with cancer susceptibility. In our meta-analysis, Aurora-A rs1047972 polymorphism was associated with an increased risk of cancer susceptibility in overall populations (GA+GG vs. AA: P=0.039, OR=1.106; 95% CI 1.005-1.218; AA vs. GG: P=0.003, OR= 0.814; 95% CI, 0.710-0.934), and the GA/GG variant might be a risk factor for cancer susceptibility. In the stratified analysis by ethnicity, we found a significant association between Aurora-A rs1047972 variant and the susceptibility of the cancer in Caucasian population. In a subgroup analysis by cancer type, we observed a significantly increased susceptibility of lung cancer. In addition, an increased risk was found between Aurora-A rs1047972 polymorphism and cancer susceptibility in MALDI-TOF group and among population-based study (PB) patients. Our results were in a sufficiently large number of participants according to TSA and did not require more studies to confirm such association. Conclusion: Our meta-analysis revealed that the susceptibility of cancer was associated with Aurora-A rs1047972 polymorphism, especially in Caucasians. And the GA/GG variant might be a risk factor for cancer susceptibility.
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Affiliation(s)
- Guangyuan Chen
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Cong Hu
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Yuxuan Song
- Department of Urology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Mengxi Xiu
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Yiling Zhang
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Penghui Lai
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Yunyan Li
- The Second Clinical Medical School, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Xiaoqiang Liu
- Department of Urology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Peng Huang
- Center for Evidence-based Medicine, School of Public Health, Nanchang University, Nanchang 330006, China.,Jiangxi Province Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang 330006, China
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46
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Methodology to analyze gene expression patterns of early mammary development in pig models. Mol Biol Rep 2020; 47:3241-3248. [PMID: 32219771 DOI: 10.1007/s11033-020-05362-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 02/27/2020] [Indexed: 12/28/2022]
Abstract
In mammary gland development, normal stem cell activity occurs in the embryonic stage and postnatally. Research supports that certain breast cancers contain a small sub-population of cells that mimic stem-like activity. It is believed stem cell activation in the mutated mature human mammary tissue is what drives quiescent epithelial cells to convert to mesenchymal states initiating migration, invasion, and metastasis in breast cancer. The goal of the work reported herein was to investigate early mammary development gene expression in the postnatal pig using fine needle biopsy methods in order to establish a reliable model for human breast cancer detection. Tissue samples were collected from pig mammary glands beginning at Day 11 of age through Day 39 in order to capture early postnatal-growth gene expression. Based on the initial clustering analysis, two distinct clusters of gene expression profiles occurred before and after Day 25 of mammary development. Gene set enrichment analysis (GSEA) ontology indicated the cellular processes that changed after Day 25, and many of these processes were implicated in epithelial-mesenchymal transition (EMT) signaling events. Gene expression in the postnatal pig was compared with the Epithelial-Mesenchymal Transition gene database (dbEMT) confirming the presence of EMT activity in this early developmental program. Information from this study will provide insight into early postnatal mammary gland development. In addition, mechanisms exploited by mutated mammary epithelial cells leading to cancer initiation and growth may be detected considering that mutated mammary epithelial cells can reactivate early developmental signals.
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47
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SNHG16 regulates invasion and migration of bladder cancer through induction of epithelial-to-mesenchymal transition. Hum Cell 2020; 33:737-749. [PMID: 32207096 DOI: 10.1007/s13577-020-00343-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 02/28/2020] [Indexed: 12/15/2022]
Abstract
Bladder cancer (BCa) is one of the most common urinary malignancies in the world. Growing evidence suggests that epithelial-to-mesenchymal transition (EMT) is a major contributor for BCa metastasis. lncRNA small nucleolar RNA host gene 16 (SNHG16) has been reported as a tumor promoter in many cancers. This study aims to investigate the function and mechanism of SNHG16 on EMT in BCa. Quantitative RT-PCR (qRT-PCR) was used to determine the expression of SNHG16 in human BCa tissues and TGF-β-induced cells. Western blot (WB) was performed to evaluate the expression of EMT-related proteins. Transwell assay was exerted to assess the migration and invasion ability of SNHG16 in BCa. RNA pull-down assay was conducted to confirm the RNA-RNA interaction. The precise mechanism by which SNHG16 regulated EMT process in BCa was also explored. SNHG16 was found up-regulated in TGF-β-induced BCa cells and BCa tissues. Transwell assay showed that overexpression of SNHG16 significantly promoted the migration and invasion of BCa cells, whereas knock-down of SNHG16 caused the opposite effects. Then, the interaction between SNHG16 and miR-200a-3p was verified by dual-luciferase reporter assay and RNA pull-down assay. And the effects of knock-down or overexpression of SNHG16 on migration and invasion were reversed by co-transfecting miR-200a-3p inhibitors or mimics. This study first demonstrated that SNHG16 was responsible for EMT of BCa cells via miR-200a-3p/ ZEB1/ZEB2 axis. These results provided a potential therapeutic strategy for BCa treatment, especially in metastatic BCa.
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48
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Deng S, Zhang X, Qin Y, Chen W, Fan H, Feng X, Wang J, Yan R, Zhao Y, Cheng Y, Wei Y, Fan X, Ashktorab H, Smoot D, Meltzer SJ, Li S, Li K, Peng Y, Jin Z. miRNA-192 and -215 activate Wnt/β-catenin signaling pathway in gastric cancer via APC. J Cell Physiol 2020; 235:6218-6229. [PMID: 32091625 DOI: 10.1002/jcp.29550] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 01/09/2020] [Indexed: 12/13/2022]
Abstract
Although great progress has been made in surgical techniques, traditional radiotherapy, and chemotherapy, gastric cancer (GC) is still the most common malignant tumor and has a high mortality, which highlights the importance of novel diagnostic markers. Emerging studies suggest that different microRNAs (miRNAs) are involved in tumorigenesis of GC. In this study, we found that miRNA-192 and -215 are significantly upregulated in GC and promote cell proliferation and migration. Adenomatous polyposis coli (APC), a well-known negative regulator in Wnt signaling, has been proved to be a target of miRNA-192 and -215. Inhibition of miRNA-192 or -215 reduced the Topflash activities and repressed the expression of Wnt signaling pathway proteins, while APC small interfering RNAs reversed the inhibitory effects, suggesting that miRNA-192 and -215 activate Wnt signaling via APC. In addition, APC mediates the cell proliferation and migration regulated by miRNA-192 and -215. Furthermore, APC is downregulated in GC tissues and negatively correlated with the expression of miRNA-192 and -215. In summary, miRNA-192 and -215 target APC and function as oncogenic miRNAs by activating Wnt signaling in GC, revealing to be potential therapeutic targets.
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Affiliation(s)
- Shiqi Deng
- Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Xiaojing Zhang
- Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China.,Department of Pathology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Health Science Center, Shenzhen University, Shenzhen, China.,Department of Pathology, Guangdong Province Key Laboratory of Molecular Oncologic Pathology, Guangdong, China
| | - Ying Qin
- Department of Gastrointestinal Surgery, Shenzhen Second People's Hospital, Shenzhen, Guangdong, China
| | - Wangchun Chen
- Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Hu Fan
- Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Xianling Feng
- Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Jian Wang
- Department of Pathology and Pathophysiology, The Guangzhou Medical University, Guangzhou, China
| | - Ruibin Yan
- Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, The Shenzhen Graduate School of Peking University, Shenzhen, Guangdong, China
| | - Yanqiu Zhao
- Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, The Shenzhen Graduate School of Peking University, Shenzhen, Guangdong, China
| | - Yulan Cheng
- Department of Medicine/GI Division, The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Yanjie Wei
- Center for High Performance Computing, Shenzhen Institutes of Advanced Technology, Shenzhen, Guangdong, China
| | - Xinmin Fan
- Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Hassan Ashktorab
- Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington DC
| | - Duane Smoot
- Department of Medicine, Meharry Medical Center, Nashville, Tennessee
| | - Stephen J Meltzer
- Department of Medicine/GI Division, The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Song Li
- Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, The Shenzhen Graduate School of Peking University, Shenzhen, Guangdong, China
| | - Kuan Li
- Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Yin Peng
- Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China.,Department of Pathology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Health Science Center, Shenzhen University, Shenzhen, China
| | - Zhe Jin
- Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China.,Department of Pathology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Health Science Center, Shenzhen University, Shenzhen, China
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Pham TT, Ban J, Hong Y, Lee J, Vu TH, Truong AD, Lillehoj HS, Hong YH. MicroRNA gga-miR-200a-3p modulates immune response via MAPK signaling pathway in chicken afflicted with necrotic enteritis. Vet Res 2020; 51:8. [PMID: 32014061 PMCID: PMC6998359 DOI: 10.1186/s13567-020-0736-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/27/2019] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that contribute to host immune response as post-transcriptional regulation. The current study investigated the biological role of the chicken (Gallus gallus) microRNA-200a-3p (gga-miR-200a-3p), using 2 necrotic enteritis (NE) afflicted genetically disparate chicken lines, 6.3 and 7.2, as well as the mechanisms underlying the fundamental signaling pathways in chicken. The expression of gga-miR-200a-3p in the intestinal mucosal layer of NE-induced chickens, was found to be upregulated during NE infection in the disease-susceptible chicken line 7.2. To validate the target genes, we performed an overexpression analysis of gga-miR-200a-3p using chemically synthesized oligonucleotides identical to gga-miR-200a-3p, reporter gene analysis including luciferase reporter assay, and a dual fluorescence reporter assay in cultured HD11 chicken macrophage cell lines. Gga-miR-200a-3p was observed to be a direct transcriptional repressor of ZAK, MAP2K4, and TGFβ2 that are involved in mitogen-activated protein kinase (MAPK) pathway by targeting the 3′-UTR of their transcripts. Besides, gga-miR-200a-3p may indirectly affect the expression of protein kinases including p38 and ERK1/2 at both transcriptional and translational levels, suggesting that this miRNA may function as an important regulator of the MAPK signaling pathway. Proinflammatory cytokines consisting of IL-1β, IFN-γ, IL-12p40, IL-17A, and LITAF belonging to Th1 and Th17-type cytokines, were upregulated upon gga-miR-200a-3p overexpression. These findings have enhanced our knowledge of the immune function of gga-miR-200a-3p mediating the chicken immune response via regulation of the MAPK signaling pathway and indicate that this miRNA may serve as an important biomarker of diseases in domestic animals.
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Affiliation(s)
- Thu Thao Pham
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea.,Key Laboratory of Animal Cell Biotechnology, National Institute of Animal Science, 9 Tan Phong, Thuy Phuong, Bac Tu Liem, Hanoi, 100000, Viet Nam
| | - Jihye Ban
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Yeojin Hong
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Jiae Lee
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Thi Hao Vu
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Anh Duc Truong
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea.,Department of Biochemistry and Immunology, National Institute of Veterinary Research, 86 Truong Chinh, Dong Da, Hanoi, 100000, Viet Nam
| | - Hyun S Lillehoj
- Animal Biosciences and Biotechnology Laboratory, Agricultural Research Services, United States Department of Agriculture, Beltsville, MD, 20705, USA
| | - Yeong Ho Hong
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea.
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50
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Yang J, Tao Q, Zhou Y, Chen Q, Li L, Hu S, Liu Y, Zhang Y, Shu J, Zhang X, Zhang L, Zhang L. MicroRNA-708 represses hepatic stellate cells activation and proliferation by targeting ZEB1 through Wnt/β-catenin pathway. Eur J Pharmacol 2020; 871:172927. [PMID: 31962101 DOI: 10.1016/j.ejphar.2020.172927] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 01/12/2020] [Accepted: 01/13/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is caused by a sustained wound healing response to chronic liver injury, and the activation of insubstantial hepatic stellate cells (HSCs) is the key process involved. The progression of liver fibrosis may be attenuated by suppressing activation and proliferation of the HSCs. MicroRNA (miRNA) have emerged as major players in governing fundamental biological processes through multiple mechanisms MiR-708 is known to inhibit the development of hepatocellular carcinoma. However, whether miR-708 can function as a transcriptional regulator in liver fibrosis remains unclear. Our study demonstrated that miR-708 expression was inhibited in fibrotic liver tissues and in activated HSCs, accompanied by an increase of the Zinc finger E-box binding homeobox 1 (ZEB1) level. Besides, overexpression of miR-708 and silencing of ZEB1 inhibited the activation and proliferation of LX-2 cells. While knockdown of miR-708 or overexpression of ZEB1 showed reversed results. Further, dual luciferase reporter assays showed that miR-708 directly targeted ZEB1 in vitro. Interestingly, ZEB1 was found to be involved in HSCs by regulating Wnt/β-catenin signaling pathway. Together, our data showed that miR-708 may be a potential therapeutic target in liver fibrosis therapy.
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Affiliation(s)
- Junfa Yang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Qing Tao
- Department of Pathogen Biology, Anhui Medical University, China
| | - Yiwen Zhou
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Qingfeng Chen
- Clinic Medical College of Anhui Medical University, Hefei, 230032, China
| | - Liangyun Li
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Shuang Hu
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Yumin Liu
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Yu Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Jinling Shu
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Xianzheng Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Lei Zhang
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China.
| | - Lingling Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
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