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Zhong Y, He JW, Huang CX, Lai HZ, Li XK, Zheng C, Fu X, You FM, Ma Q. The NcRNA/Wnt axis in lung cancer: oncogenic mechanisms, remarkable indicators and therapeutic targets. J Transl Med 2025; 23:326. [PMID: 40087753 PMCID: PMC11907837 DOI: 10.1186/s12967-025-06326-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/27/2025] [Indexed: 03/17/2025] Open
Abstract
Early diagnosis of lung cancer (LC) is challenging, treatment options are limited, and treatment resistance leads to poor prognosis and management in most patients. The Wnt/β-catenin signaling pathway plays a vital role in the occurrence, progression, and therapeutic response of LC. Recent studies indicate that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) function as epigenetic regulators that can promote or inhibit Wnt/β-catenin signaling by interacting with Wnt proteins, receptors, signaling transducers, and transcriptional effectors, thereby affecting LC cell proliferation, metastasis, invasion, and treatment resistance. Deepening our understanding of the regulatory network between ncRNAs and the Wnt/β-catenin signaling pathway will help overcome the limitations of current LC diagnosis and treatment methods. This article comprehensively reviews the regulatory mechanisms related to the functions of ncRNAs and the Wnt/β-catenin pathway in LC, examining their potential as diagnostic and prognostic biomarkers and therapeutic targets, aiming to offer new promising perspectives for LC diagnosis and treatment.
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Affiliation(s)
- Yang Zhong
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China
| | - Jia-Wei He
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China
| | - Chun-Xia Huang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China
| | - Heng-Zhou Lai
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China
| | - Xue-Ke Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China
| | - Chuan Zheng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China.
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China.
| | - Xi Fu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China.
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China.
| | - Feng-Ming You
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China.
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China.
| | - Qiong Ma
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610072, China.
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Jayawickrama SM, Ranaweera PM, Pradeep RGGR, Jayasinghe YA, Senevirathna K, Hilmi AJ, Rajapakse RMG, Kanmodi KK, Jayasinghe RD. Developments and future prospects of personalized medicine in head and neck squamous cell carcinoma diagnoses and treatments. Cancer Rep (Hoboken) 2024; 7:e2045. [PMID: 38522008 PMCID: PMC10961052 DOI: 10.1002/cnr2.2045] [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: 08/28/2023] [Revised: 02/07/2024] [Accepted: 03/05/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Precision healthcare has entered a new era because of the developments in personalized medicine, especially in the diagnosis and treatment of head and neck squamous cell carcinoma (HNSCC). This paper explores the dynamic landscape of personalized medicine as applied to HNSCC, encompassing both current developments and future prospects. RECENT FINDINGS The integration of personalized medicine strategies into HNSCC diagnosis is driven by the utilization of genetic data and biomarkers. Epigenetic biomarkers, which reflect modifications to DNA that can influence gene expression, have emerged as valuable indicators for early detection and risk assessment. Treatment approaches within the personalized medicine framework are equally promising. Immunotherapy, gene silencing, and editing techniques, including RNA interference and CRISPR/Cas9, offer innovative means to modulate gene expression and correct genetic aberrations driving HNSCC. The integration of stem cell research with personalized medicine presents opportunities for tailored regenerative approaches. The synergy between personalized medicine and technological advancements is exemplified by artificial intelligence (AI) and machine learning (ML) applications. These tools empower clinicians to analyze vast datasets, predict patient responses, and optimize treatment strategies with unprecedented accuracy. CONCLUSION The developments and prospects of personalized medicine in HNSCC diagnosis and treatment offer a transformative approach to managing this complex malignancy. By harnessing genetic insights, biomarkers, immunotherapy, gene editing, stem cell therapies, and advanced technologies like AI and ML, personalized medicine holds the key to enhancing patient outcomes and ushering in a new era of precision oncology.
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Affiliation(s)
| | | | | | | | - Kalpani Senevirathna
- Centre for Research in Oral Cancer, Faculty of Dental SciencesUniversity of PeradeniyaKandySri Lanka
| | | | | | - Kehinde Kazeem Kanmodi
- School of DentistryUniversity of RwandaKigaliRwanda
- Faculty of DentistryUniversity of PuthisastraPhnom PenhCambodia
- Cephas Health Research Initiative IncIbadanNigeria
- School of Health and Life SciencesTeesside UniversityMiddlesbroughUK
| | - Ruwan Duminda Jayasinghe
- Centre for Research in Oral Cancer, Faculty of Dental SciencesUniversity of PeradeniyaKandySri Lanka
- Faculty of DentistryUniversity of PuthisastraPhnom PenhCambodia
- School of Health and Life SciencesTeesside UniversityMiddlesbroughUK
- Department of Oral Medicine and Periodontology, Faculty of Dental SciencesUniversity of PeradeniyaKandySri Lanka
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Tolue Ghasaban F, Maharati A, Zangouei AS, Zangooie A, Moghbeli M. MicroRNAs as the pivotal regulators of cisplatin resistance in head and neck cancers. Cancer Cell Int 2023; 23:170. [PMID: 37587481 PMCID: PMC10428558 DOI: 10.1186/s12935-023-03010-9] [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: 01/31/2023] [Accepted: 07/28/2023] [Indexed: 08/18/2023] Open
Abstract
Although, there is a high rate of good prognosis in early stage head and neck tumors, about half of these tumors are detected in advanced stages with poor prognosis. A combination of chemotherapy, radiotherapy, and surgery is the treatment option in head and neck cancer (HNC) patients. Although, cisplatin (CDDP) as the first-line drug has a significant role in the treatment of HNC patients, CDDP resistance can be observed in a large number of these patients. Therefore, identification of the molecular mechanisms involved in CDDP resistance can help to reduce the side effects and also provides a better therapeutic management. MicroRNAs (miRNAs) as the post-transcriptional regulators play an important role in drug resistance. Therefore, in the present review we investigated the role of miRNAs in CDDP response of head and neck tumors. It has been reported that the miRNAs exerted their roles in CDDP response by regulation of signaling pathways such as WNT, NOTCH, PI3K/AKT, TGF-β, and NF-kB as well as apoptosis, autophagy, and EMT process. The present review paves the way to suggest a non-invasive miRNA based panel marker for the prediction of CDDP response among HNC patients. Therefore, such diagnostic miRNA based panel marker reduces the CDDP side effects and improves the clinical outcomes of these patients following an efficient therapeutic management.
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Affiliation(s)
- Faezeh Tolue Ghasaban
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Sadra Zangouei
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Zangooie
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
- Student research committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Hu W, Wong JYY, Dai Y, Ren D, Blechter B, Duan H, Niu Y, Xu J, Fu W, Meliefste K, Zhou B, Yang J, Ye M, Jia X, Meng T, Bin P, Rahman ML, Dean Hosgood H, Vermeulen RC, Silverman DT, Zheng Y, Lan Q, Rothman N. Occupational exposure to diesel engine exhaust and serum levels of microRNAs in a cross-sectional molecular epidemiology study in China. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2023; 64:159-166. [PMID: 36762959 DOI: 10.1002/em.22533] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/29/2023] [Accepted: 02/08/2023] [Indexed: 05/03/2023]
Abstract
Diesel engine exhaust (DEE) is an established lung carcinogen, but the biological mechanisms of diesel-induced lung carcinogenesis are not well understood. MicroRNAs (miRNAs) are small noncoding RNAs that play a potentially important role in regulating gene expression related to lung cancer. We conducted a cross-sectional molecular epidemiology study to evaluate whether serum levels of miRNAs are altered in healthy workers occupationally exposed to DEE compared to unexposed controls. We conducted a two-stage study, first measuring 405 miRNAs in a pilot study of six DEE-exposed workers exposed and six controls. In the second stage, 44 selected miRNAs were measured using the Fireplex circulating miRNA assay that profiles miRNAs directly from biofluids of 45 workers exposed to a range of DEE (Elemental Carbon (EC), median, range: 47.7, 6.1-79.7 μg/m3 ) and 46 controls. The relationship between exposure to DEE and EC with miRNA levels was analyzed using linear regression adjusted for potential confounders. Serum levels of four miRNAs were significantly lower (miR-191-5p, miR-93-5p, miR-423-3p, miR-122-5p) and one miRNA was significantly higher (miR-92a-3p) in DEE exposed workers compared to controls. Of these miRNAs, miR-191-5p (ptrend = .001, FDR = 0.04) and miR-93-5p (ptrend = .009, FDR = 0.18) showed evidence of an inverse exposure-response with increasing EC levels. Our findings suggest that occupational exposure to DEE may affect circulating miRNAs implicated in biological processes related to carcinogenesis, including immune function.
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Affiliation(s)
- Wei Hu
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Jason Y Y Wong
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Yufei Dai
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Dianzhi Ren
- Chaoyang Center for Disease Control and Prevention, Chaoyang, China
| | - Batel Blechter
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Huawei Duan
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yong Niu
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Jun Xu
- School of Public Health, The University of Hong Kong, Hong Kong, China
| | - Wei Fu
- Chaoyang Center for Disease Control and Prevention, Chaoyang, China
| | - Kees Meliefste
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
| | | | - Jufang Yang
- Chaoyang Center for Disease Control and Prevention, Chaoyang, China
| | - Meng Ye
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xiaowei Jia
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Tao Meng
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Ping Bin
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Mohammad L Rahman
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - H Dean Hosgood
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
- Division of Epidemiology, Albert Einstein College of Medicine, The Bronx, New York, USA
| | - Roel C Vermeulen
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
| | - Debra T Silverman
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Yuxin Zheng
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China
- School of Public Health, Qingdao University, Qingdao, China
| | - Qing Lan
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Nathaniel Rothman
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
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Xu X, Cai B, Liu Y, Liu R, Li J. MIR503HG silencing promotes endometrial stromal cell progression and metastasis and suppresses apoptosis in adenomyosis by activating the Wnt/β‑catenin pathway via targeting miR‑191. Exp Ther Med 2023; 25:117. [PMID: 36815970 PMCID: PMC9934002 DOI: 10.3892/etm.2023.11816] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 12/16/2022] [Indexed: 02/03/2023] Open
Abstract
MIR503HG is a 786 bp long lncRNA located on chromosome Xq26.3, and it can regulate diverse cellular processes. The pathogenesis of adenomyosis (AD) is associated with endometrial stromal cells (ESCs). The present study investigated the specific role of MIR503HG in AD pathogenesis and progression using ESCs derived from the endometrium of patients with AD as a model. Expression of MIR503HG and microRNA (miR)-191 were assessed using reverse transcription-quantitative PCR. An immunocytochemistry assay was used to detect cytokeratin- or vimentin-positive ESCs. Transfections of ESCs with MIR503HG overexpression plasmid, short hairpin-MIR503HG and miR-191 inhibitor were performed. ESC viability, migration, invasion and apoptosis were evaluated using Cell Counting Kit-8, Transwell and flow cytometry assays. The association between MIR503HG and miR-191 was predicted by StarBase and confirmed using a dual-luciferase reporter assay. Expression of epithelial-mesenchymal transition-related markers (E-cadherin and N-cadherin) and Wnt/β-catenin pathway-related molecules (β-catenin) in ESCs were analyzed by western blotting. The isolated ESCs were vimentin-positive and cytokeratin-negative. MIR503HG was lowly expressed in the endometrial tissues derived from patients with AD. MIR503HG overexpression hindered ESC viability, migration and invasion while enhancing the apoptosis and downregulating miR-191 expression. MIR503HG knockdown induced the opposite effects, accompanied by downregulation of the E-cadherin expression and upregulation of N-cadherin and β-catenin levels. MIR503HG directly targeted miR-191 that was highly expressed in endometrial tissues derived from patients with AD. In ESCs, downregulation of miR-191 inhibited the viability, migration and invasion and the expression of N-cadherin and β-catenin levels while enhancing the apoptosis and E-cadherin expression in ESCs. Moreover, downregulation of miR-191 partially reversed the effect of MIR503HG knockdown. Collectively, overexpressed MIR503HG impeded the proliferation and migration of ESCs derived from endometrium of patients with AD, while promoting apoptosis via inhibition of the Wnt/β-catenin pathway via targeting miR-191.
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Affiliation(s)
- Xiaoping Xu
- Department of Gynecology, People's Hospital of Deyang City, Deyang, Sichuan 618000, P.R. China,Correspondence to: Dr Xiaoping Xu, Department of Gynecology, People's Hospital of Deyang City, 173 Section 1 Taishan North Road, Jingyang, Deyang, Sichuan 618000, P.R. China
| | - Bin Cai
- Department of Gynecology, People's Hospital of Deyang City, Deyang, Sichuan 618000, P.R. China
| | - Yang Liu
- Department of Gynecology, People's Hospital of Deyang City, Deyang, Sichuan 618000, P.R. China
| | - Ruiqian Liu
- Department of Gynecology, People's Hospital of Deyang City, Deyang, Sichuan 618000, P.R. China
| | - Jia Li
- Department of Gynecology, Guizhou Province Maternal and Child Health Hospital, Guiyang, Guizhou 550000, P.R. China
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Nail AN, Ferragut Cardoso AP, Montero LK, States JC. miRNAs and arsenic-induced carcinogenesis. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2023; 96:203-240. [PMID: 36858773 PMCID: PMC10184182 DOI: 10.1016/bs.apha.2022.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Arsenic-induced carcinogenesis is a worldwide health problem. Identifying the molecular mechanisms responsible for the induction of arsenic-induced cancers is important for developing treatment strategies. MicroRNA (miRNA) dysregulation is known to affect development and progression of human cancer. Several studies have identified an association between altered miRNA expression in cancers from individuals chronically exposed to arsenic and in cell models for arsenic-induced carcinogenesis. This chapter provides a comprehensive review for miRNA dysregulation in arsenic-induced cancer.
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Affiliation(s)
- Alexandra N Nail
- Department of Pharmacology and Toxicology, Center for Integrative Environmental Health Science, University of Louisville, Louisville, KY, United States
| | - Ana P Ferragut Cardoso
- Department of Pharmacology and Toxicology, Center for Integrative Environmental Health Science, University of Louisville, Louisville, KY, United States
| | - Lakyn K Montero
- Department of Pharmacology and Toxicology, Center for Integrative Environmental Health Science, University of Louisville, Louisville, KY, United States
| | - J Christopher States
- Department of Pharmacology and Toxicology, Center for Integrative Environmental Health Science, University of Louisville, Louisville, KY, United States.
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Ye Q, Li Z, Li Y, Li Y, Zhang Y, Gui R, Cui Y, Zhang Q, Qian L, Xiong Y, Yu Y. Exosome-Derived microRNA: Implications in Melanoma Progression, Diagnosis and Treatment. Cancers (Basel) 2022; 15:cancers15010080. [PMID: 36612077 PMCID: PMC9818028 DOI: 10.3390/cancers15010080] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 12/19/2022] [Indexed: 12/25/2022] Open
Abstract
Melanoma is a malignant and aggressive cancer, and its progression is greatly affected by interactions between melanoma cells and their surroundings. Exploration on mechanism of melanoma and improved diagnostic and therapeutic strategies are becoming increasingly important. Unlike extracellular messengers that mainly work on targeted cells through corresponding receptors, exosomes are essential intercellular messengers that deliver biologically active substances such as nucleic acids and proteins to target cells for cell-cell communication. Of them, microRNAs (miRNAs) are common and important exosomal components that can regulate the expression of a wide range of target genes. Accordingly, exosome-derived miRNAs play a significant role in melanoma progression, including invasion and metastasis, microenvironment establishment, angiogenesis, and immune escape. MiRNA signatures of exosomes are specific in melanoma patients compared to healthy controls, thus circulating miRNAs, especially exosomal miRNAs, become potential diagnostic markers and therapeutic targets for melanoma. This review aims to summarize recent studies on the role of exosomal miRNAs in melanoma as well as ongoing efforts in melanoma treatment.
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Affiliation(s)
- Qiang Ye
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Zi Li
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Yang Li
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Yirong Li
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Yan Zhang
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Runlin Gui
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Yue Cui
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Qi Zhang
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Lu Qian
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Department of Endocrinology, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi’an 710069, China
| | - Yuyan Xiong
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
- Correspondence: (Y.X.); (Y.Y.)
| | - Yi Yu
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
- Correspondence: (Y.X.); (Y.Y.)
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Kudelova E, Holubekova V, Grendar M, Kolkova Z, Samec M, Vanova B, Mikolajcik P, Smolar M, Kudela E, Laca L, Lasabova Z. Circulating miRNA expression over the course of colorectal cancer treatment. Oncol Lett 2021; 23:18. [PMID: 34868358 PMCID: PMC8630815 DOI: 10.3892/ol.2021.13136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 07/20/2021] [Indexed: 11/06/2022] Open
Abstract
Colorectal cancer (CRC) is the third-most common cancer type in males and the second-most common cancer type in females, and has the second-highest overall mortality rate worldwide. Approximately 50% of patients in stage I–III develop metastases, mostly localized to the liver. All physiological conditions occurring in the organism are also reflected in the levels of circulating microRNAs (miRNAs/miRs) in patients. miRNAs are a class of small, non-coding, single-stranded RNAs consisting of 18–25 nucleotides, which have important roles in various cellular processes. The aim of the present study was to evaluate a panel of seven circulating miRNAs (miR-106a-5p, miR-210-5p, miR-155-5p, miR-21-5p, miR-103a-3p, miR-191-5p and miR-16-5p) as biomarkers for monitoring patients undergoing adjuvant treatment of CRC. Total RNA was extracted from the plasma of patients with CRC prior to surgery, in the early post-operative period (n=60) and 3 months after surgery (n=14). The levels of the selected circulating miRNAs were measured with the miRCURY LNA miRNA PCR system and fold changes were calculated using the standard ∆∆Cq method. DIANA-miRPath analysis was used to evaluate the role of significantly deregulated miRNAs. The results indicated significant upregulation of miR-155-5p, miR-21-5p and miR-191-5p, and downregulation of miR-16-5p directly after the surgery. In paired follow-up samples, the most significant upregulation was detected for miR-106a-5p and miR-16-5p, and the most significant downregulation was for miR-21-5p. Pathway analysis outlined the role of the differentially expressed miRNAs in cancer development, but the same pathways are also involved in wound healing and regeneration of intestinal epithelium. It may be suggested that these processes should also be considered in studies investigating sensitive and easily detectable circulating biomarkers for recurrence in patients.
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Affiliation(s)
- Eva Kudelova
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Veronika Holubekova
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Marian Grendar
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Zuzana Kolkova
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Marek Samec
- Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Barbora Vanova
- Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Peter Mikolajcik
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Marek Smolar
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Erik Kudela
- Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Ludovit Laca
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
| | - Zora Lasabova
- Department of Molecular Biology and Genomics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin SK-03601, Slovak Republic
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Huang B, Yan X, Li Y. Cancer Stem Cell for Tumor Therapy. Cancers (Basel) 2021; 13:cancers13194814. [PMID: 34638298 PMCID: PMC8508418 DOI: 10.3390/cancers13194814] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/13/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Although many methods have been applied in clinical treatment for tumors, they still always show a poor prognosis. Molecule targeted therapy has revolutionized tumor therapy, and a proper target must be found urgently. With a crucial role in tumor development, metastasis and recurrence, cancer stem cells have been found to be a feasible and potential target for tumor therapy. We list the unique biological characteristics of cancer stem cells and summarize the recent strategies to target cancer stem cells for tumor therapy, through which we hope to provide a comprehensive understanding of cancer stem cells and find a better combinational strategy to target cancer stem cells for tumor therapy. Abstract Tumors pose a significant threat to human health. Although many methods, such as operations, chemotherapy and radiotherapy, have been proposed to eliminate tumor cells, the results are unsatisfactory. Targeting therapy has shown potential due to its specificity and efficiency. Meanwhile, it has been revealed that cancer stem cells (CSCs) play a crucial role in the genesis, development, metastasis and recurrence of tumors. Thus, it is feasible to inhibit tumors and improve prognosis via targeting CSCs. In this review, we provide a comprehensive understanding of the biological characteristics of CSCs, including mitotic pattern, metabolic phenotype, therapeutic resistance and related mechanisms. Finally, we summarize CSCs targeted strategies, including targeting CSCs surface markers, targeting CSCs related signal pathways, targeting CSC niches, targeting CSC metabolic pathways, inducing differentiation therapy and immunotherapy (tumor vaccine, CAR-T, oncolytic virus, targeting CSCs–immune cell crosstalk and immunity checkpoint inhibitor). We highlight the potential of immunity therapy and its combinational anti-CSC therapies, which are composed of different drugs working in different mechanisms.
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Affiliation(s)
- Binjie Huang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
| | - Xin Yan
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
- Correspondence: ; Tel.: +86-138-9361-5421
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10
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Wang L, Liu LZ, Jiang BH. Dysregulation of microRNAs in metal-induced angiogenesis and carcinogenesis. Semin Cancer Biol 2021; 76:279-286. [PMID: 34428550 DOI: 10.1016/j.semcancer.2021.08.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs) are small endogenous non-coding RNAs that regulate cancer initiation, development, angiogenesis, and therapeutic resistance. Metal exposure widely occurs through air, water, soil, food, and industrial contaminants. Hundreds of millions of people may have metal exposure associated with toxicity, serious health problems, and cancer occurrence. Metal exposure is found to induce oxidative stress, DNA damage and repair, and activation of multiple signaling pathways. However, molecular mechanisms of metal-induced carcinogenesis remain to be elucidated. Recent studies demonstrated that the exposure of metals such as arsenic, hexavalent chromium, cadmium, and nickel caused dysregulation of microRNAs that are implicated to play an important role in cell transformation, tumor growth and angiogenesis. This review focuses on the recent studies that show metal-induced miRNA dysregulation and underlined mechanisms in cell malignant transformation, angiogenesis and tumor growth.
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Affiliation(s)
- Lin Wang
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, China; Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, United States
| | - Ling-Zhi Liu
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, United States.
| | - Bing-Hua Jiang
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, United States.
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11
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Kabzinski J, Maczynska M, Majsterek I. MicroRNA as a Novel Biomarker in the Diagnosis of Head and Neck Cancer. Biomolecules 2021; 11:844. [PMID: 34198889 PMCID: PMC8228566 DOI: 10.3390/biom11060844] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 02/07/2023] Open
Abstract
Head and neck squamous cell carcinoma is the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths in 2018, and although the survival statistics for some patient groups are improving, there is still an urgent need to find a fast and reliable biomarker that allows early diagnosis. This niche can be filled by microRNA, small single-stranded non-coding RNA molecules, which are expressed in response to specific events in the body. This article presents the potential use of microRNAs in the diagnosis of HNSCC, compares the advances in this field to other diseases, especially other cancers, and discusses the detailed use of miRNA as a biomarker in profiling and predicting the treatment outcome with radiotherapy and immunotherapy. Potential problems and difficulties related to the development of this promising technology, and areas on which future research should be focused in order to overcome these difficulties, were also indicated.
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Affiliation(s)
| | | | - Ireneusz Majsterek
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, al. Kościuszki 4, 90-419 Łódź, Poland; (J.K.); (M.M.)
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12
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Li W, Wu L, Sun Q, Yang Q, Xue J, Shi M, Tang H, Zhang J, Liu Q. MicroRNA-191 blocking the translocation of GLUT4 is involved in arsenite-induced hepatic insulin resistance through inhibiting the IRS1/AKT pathway. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 215:112130. [PMID: 33743404 DOI: 10.1016/j.ecoenv.2021.112130] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 06/12/2023]
Abstract
Environmental exposure to arsenic can cause a variety of health problems. Epidemiological and experimental studies have established a diabetogenic role for arsenic, but the mechanisms responsible for arsenic-induced impairment of insulin action are unclear. MicroRNAs (miRNAs) are involved in various metabolic disorders, particularly in the development of insulin resistance. The present study investigated whether arsenite, an active form of arsenic, induces hepatic insulin resistance and the mechanisms underlying it. After male C57BL/6J mice were exposed to arsenite (0 or 20 ppm) in drinking water for 12 months, intraperitoneal glucose tolerance tests (IPGTTs) and insulin tolerance tests (ITTs) revealed an arsenite-induced glucose metabolism disorder. Hepatic glycogen levels were lower in arsenite-exposed mice. Further, for livers of mice exposed to arsenite, miR-191 levels were higher, and protein levels of insulin receptor substrate 1 (IRS1), p-IRS1, and phospho-protein kinase B (p-AKT) were lower. Further, glucose transporter 4 (GLUT4) had lower levels on the plasma membrane. For insulin-treated L-02 cells, arsenite decreased glucose consumption and glycogen levels, increased miR-191 levels, and inhibited the IRS1/AKT pathway and the translocation of GLUT4 from the cytoplasm to the plasma membrane. For insulin-treated L-02 cells, the decreases of glucose consumption, glycogen levels, GLUT4 on the plasma membrane, and p-AKT levels induced by arsenite were reversed by SC79 (agonist of AKT) and an miR-191 inhibitor; these effects caused by miR-191 inhibitor were restored by IRS1 siRNA. In insulin-treated L-02 cells, miR-191, via IRS1, was involved in the arsenite-induced decreases of glucose consumption and glycogen levels and in inhibition of the translocation of GLUT4. Thus, miR-191 blocking the translocation of GLUT4 was involved in arsenite-induced hepatic insulin resistance through inhibiting the IRS1/AKT pathway. Our study reveals a mechanism for arsenite-induced hepatic insulin resistance, which provides clues for discovering biomarkers for the development of type 2 diabetes and for prevention and treatment of arsenic poisoning.
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Affiliation(s)
- Wenqi Li
- Center for Global Health, The Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Lu Wu
- Center for Global Health, The Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Qian Sun
- Center for Global Health, The Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, Guangdong, People's Republic of China
| | - Qianlei Yang
- Center for Global Health, The Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Junchao Xue
- Center for Global Health, The Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Ming Shi
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Huanwen Tang
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Jingshu Zhang
- Center for Global Health, The Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Safety Assessment and Research Center for Drug, Pesticide, and Veterinary Drug, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
| | - Qizhan Liu
- Center for Global Health, The Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
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El Founini Y, Chaoui I, Dehbi H, El Mzibri M, Abounader R, Guessous F. MicroRNAs: Key Regulators in Lung Cancer. Microrna 2021; 10:109-122. [PMID: 34047262 DOI: 10.2174/2211536610666210527102522] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 04/11/2021] [Accepted: 04/14/2021] [Indexed: 12/24/2022]
Abstract
Noncoding RNAs have emerged as key regulators of the genome upon gene expression profiling and genome-wide sequencing. Among these noncoding RNAs, microRNAs are short noncoding RNAs that regulate a plethora of functions, biological processes and human diseases by targeting the messenger RNA stability through 3'UTR binding, leading to either mRNA cleavage or translation repression, depending on microRNA-mRNA complementarity degree. Additionally, strong evidence has suggested that dysregulation of miRNAs contribute to the etiology and progression of human cancers, such as lung cancer, the most common and deadliest cancer worldwide. Indeed, by acting as oncogenes or tumor suppressors, microRNAs control all aspects of lung cancer malignancy, including cell proliferation, survival, migration, invasion, angiogenesis, cancer stem cells, immune-surveillance escape, and therapy resistance; and their expressions are often associated with clinical parameters. Moreover, several deregulated microRNAs in lung cancer are carried by exosomes, microvesicles and secreted in body fluids, mainly the circulation where they conserve their stable forms. Subsequently, seminal efforts have been focused on extracellular microRNAs levels as noninvasive diagnostic and prognostic biomarkers in lung cancer. In this review, focusing on recent literature, we summarize the deregulation, mechanisms of action, functions and highlight clinical applications of miRNAs for better management and design of future lung cancer targeted therapies.
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Affiliation(s)
- Younes El Founini
- Unit of Biology and Medical Research, National Center of Energy, Sciences and Nuclear Techniques, Rabat, Morocco.,Laboratory of Genetics and Molecular Pathology, Medical School, University Hassan II, Casablanca, Morocco
| | - Imane Chaoui
- Unit of Biology and Medical Research, National Center of Energy, Sciences and Nuclear Techniques, Rabat, Morocco
| | - Hind Dehbi
- Laboratory of Genetics and Molecular Pathology, Medical School, University Hassan II, Casablanca, Morocco
| | - Mohammed El Mzibri
- Unit of Biology and Medical Research, National Center of Energy, Sciences and Nuclear Techniques, Rabat, Morocco
| | - Roger Abounader
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, United States
| | - Fadila Guessous
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, United States.,Department of Biological Sciences, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco
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14
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Fitriana M, Hwang WL, Chan PY, Hsueh TY, Liao TT. Roles of microRNAs in Regulating Cancer Stemness in Head and Neck Cancers. Cancers (Basel) 2021; 13:cancers13071742. [PMID: 33917482 PMCID: PMC8038798 DOI: 10.3390/cancers13071742] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/14/2022] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are epithelial malignancies with 5-year overall survival rates of approximately 40-50%. Emerging evidence indicates that a small population of cells in HNSCC patients, named cancer stem cells (CSCs), play vital roles in the processes of tumor initiation, progression, metastasis, immune evasion, chemo-/radioresistance, and recurrence. The acquisition of stem-like properties of cancer cells further provides cellular plasticity for stress adaptation and contributes to therapeutic resistance, resulting in a worse clinical outcome. Thus, targeting cancer stemness is fundamental for cancer treatment. MicroRNAs (miRNAs) are known to regulate stem cell features in the development and tissue regeneration through a miRNA-target interactive network. In HNSCCs, miRNAs act as tumor suppressors and/or oncogenes to modulate cancer stemness and therapeutic efficacy by regulating the CSC-specific tumor microenvironment (TME) and signaling pathways, such as epithelial-to-mesenchymal transition (EMT), Wnt/β-catenin signaling, and epidermal growth factor receptor (EGFR) or insulin-like growth factor 1 receptor (IGF1R) signaling pathways. Owing to a deeper understanding of disease-relevant miRNAs and advances in in vivo delivery systems, the administration of miRNA-based therapeutics is feasible and safe in humans, with encouraging efficacy results in early-phase clinical trials. In this review, we summarize the present findings to better understand the mechanical actions of miRNAs in maintaining CSCs and acquiring the stem-like features of cancer cells during HNSCC pathogenesis.
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Affiliation(s)
- Melysa Fitriana
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Otorhinolaryngology Head and Neck Surgery Department, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Wei-Lun Hwang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 11221, Taiwan
- Cancer Progression Center of Excellence, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Pak-Yue Chan
- School of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (P.-Y.C.); (T.-Y.H.)
| | - Tai-Yuan Hsueh
- School of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (P.-Y.C.); (T.-Y.H.)
| | - Tsai-Tsen Liao
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Correspondence: ; Tel.: +886-2736-1661 (ext. 3435)
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15
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Gomari MM, Farsimadan M, Rostami N, Mahmoudi Z, Fadaie M, Farhani I, Tarighi P. CD44 polymorphisms and its variants, as an inconsistent marker in cancer investigations. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2021; 787:108374. [PMID: 34083044 DOI: 10.1016/j.mrrev.2021.108374] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 12/23/2020] [Accepted: 03/18/2021] [Indexed: 12/24/2022]
Abstract
Among cell surface markers, CD44 is considered the main marker for identifying and isolating the cancer stem cells (CSCs) among other cells and has attracted significant attention in a variety of research areas. Many studies have shown the essential roles of CD44 in initiation, metastasis, and tumorigenesis in different types of cancer; however, the validity of CD44 as a therapeutic or diagnostic target has not been fully confirmed in some other studies. Whereas the association of specific single nucleotide polymorphisms (SNPs) in the CD44 gene and related variants with cancer risk have been observed in clinical investigations, the significance of these findings remains controversial. Here, we aimed to provide an up-to-date overview of recent studies on the association of CD44 polymorphisms and its variants with different kinds of cancer to determine whether or not it can be used as an appropriate candidate for cancer tracking.
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Affiliation(s)
- Mohammad Mahmoudi Gomari
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Marziye Farsimadan
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Neda Rostami
- Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran
| | - Zahra Mahmoudi
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahmood Fadaie
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ibrahim Farhani
- Department of Medical Biotechnology, Faculty of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Golestan, Iran
| | - Parastoo Tarighi
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.
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16
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Colak DK, Egeli U, Eryilmaz IE, Aybastier O, Malyer H, Cecener G, Tunca B. The Anticancer Effect of Inula viscosa Methanol Extract by miRNAs' Re-regulation: An in vitro Study on Human Malignant Melanoma Cells. Nutr Cancer 2021; 74:211-224. [PMID: 33570434 DOI: 10.1080/01635581.2020.1869791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Alternative and natural therapies are needed for malignant melanoma (MM), the most deadly skin cancer type due to chemotherapy's limited effect. In the present study, we evaluated the anticancer potentials of Inula viscosa methanol and water extracts (IVM and IVW) on MM cells, A2058 and MeWo, and normal fibroblasts. After the chromatographic and antioxidant activity analysis, their antiproliferative effects were determined with the increasing doses for 24-72 h. IVM induced more cell death in a dose and time-dependent manner in MM cells compared to IVW. This effect was probably due to the higher amount of phenolics in it. IVM significantly induced more apoptotic death in MM cells than fibroblasts (p < 0.01), which was also supported morphologically. IVM also caused cell cycle arrest at G0/G1 and G2/M phases in A2058 and MeWo, respectively, and suppressed the migration ability of MM cells (p < 0.01). Additionally, IVM was found to have significant potential in regulating MM-related miRNAs, upregulating miR-579 and miR-524, and downregulating miR-191 and miR-193, in MM cells (p < 0.05, p < 0.01). As a result, the anticancer effect of IVM via regulating miRNAs' expression has been demonstrated for the first time. Thus, IVM, with these potentials, may be a promising candidate for MM treatment.
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Affiliation(s)
| | - Unal Egeli
- Medical Biology Department, Bursa Uludag University, Bursa, Turkey
| | | | - Onder Aybastier
- Analytical Chemistry Department, Bursa Uludag University, Bursa, Turkey
| | - Hulusi Malyer
- Biology Department, Bursa Uludag University, Bursa, Turkey
| | - Gulsah Cecener
- Medical Biology Department, Bursa Uludag University, Bursa, Turkey
| | - Berrin Tunca
- Medical Biology Department, Bursa Uludag University, Bursa, Turkey
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BASP1 Suppresses Cell Growth and Metastasis through Inhibiting Wnt/ β-Catenin Pathway in Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8628695. [PMID: 33426068 PMCID: PMC7775134 DOI: 10.1155/2020/8628695] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 11/27/2020] [Accepted: 12/08/2020] [Indexed: 02/06/2023]
Abstract
Objective Our research is designed to explore the function of brain acid soluble protein 1 (BASP1) in the progression of gastric cancer (GC) and its underlying molecular mechanisms. Methods In this study, the expression of BASP1 was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in both GC tissue and GC cells. The cell cloning, proliferation, apoptosis, migration, and invasion potential of AGS and HGC-27 cells were, respectively, determined using colony formation assay, 5-ethynyl-20-deoxyuridine (EDU) assay, flow cytometry, and Transwell assay. The protein expressions of Bax, caspase-3, Bcl-2, matrix metalloproteinases 2 (MMP-2), MMP-9, Wilms tumor 1 (WT1), Wnt, and β-catenin in AGS and HGC-27 cells were measured by western blot. In addition, the mRNA expressions of WT1, Wnt, and β-catenin in AGS and HGC-27 cells were detected by qRT-PCR. Results BASP1 expression was significantly downregulated in both GC tissue and GC cells. BASP1 overexpression markedly repressed proliferation, migration, and invasion and facilitated apoptosis in AGS and HGC-27 cells. In addition, BASP1 overexpression notably promoted the protein expression of Bax and caspase-3 in AGS and HGC-27 cells and inhibited the expression of Bcl-2, MMP-2, and MMP-9. Moreover, BASP1 overexpression significantly inhibited the mRNA and protein expression of WT1, Wnt, and β-catenin in AGS and HGC-27 cells. Conclusion BASP1 could significantly suppress cell proliferation, migration, and invasion and promote apoptosis through inhibiting the activation of the Wnt/β-catenin pathway in GC.
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Wu S, Tseng IC, Huang WC, Su CW, Lai YH, Lin C, Lee AYL, Kuo CY, Su LY, Lee MC, Hsu TC, Yu CH. Establishment of an Immunocompetent Metastasis Rat Model with Hepatocyte Cancer Stem Cells. Cancers (Basel) 2020; 12:cancers12123721. [PMID: 33322441 PMCID: PMC7764036 DOI: 10.3390/cancers12123721] [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: 10/22/2020] [Revised: 11/30/2020] [Accepted: 12/09/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. Cancer stem cells (CSCs) are responsible for the maintenance, metastasis, and relapse of various tumors. The effects of CSCs on the tumorigenesis of HCC are still not fully understood, however. We have recently established two new rat HCC cell lines HTC and TW-1, which we isolated from diethylnitrosamine-induced rat liver cancer. Results showed that TW-1 expressed the genetic markers of CSCs, including CD133, GSTP1, CD44, CD90, and EpCAM. Moreover, TW-1 showed higher tolerance to sorafenib than HTC did. In addition, tumorigenesis and metastasis were observed in nude mice and wild-type rats with TW-1 xenografts. Finally, we combined highly expressed genes in TW-1/HTC with well-known biomarkers from recent HCC studies to predict HCC-related biomarkers and able to identify HCC with AUCs > 0.9 after machine learning. These results indicated that TW-1 was a novel rat CSC line, and the mice or rat models we established with TW-1 has great potential on HCC studies in the future.
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Affiliation(s)
- Semon Wu
- Department of Life Science, Chinese Culture University, Taipei 11114, Taiwan;
- Correspondence: (S.W.); (C.-H.Y.); Tel.: +886-2-2861-0511(ext. 26234) (S.W.); +886-2-66289779 (C.-H.Y.); Fax: +886-2-2862-3724 (S.W.); +886-2-66289009 (C.-H.Y.)
| | - I-Chieh Tseng
- Department of Life Science, Chinese Culture University, Taipei 11114, Taiwan;
| | - Wen-Cheng Huang
- License Biotech, Co., Ltd., Taipei 10690, Taiwan; (W.-C.H.); (C.-W.S.)
| | - Cheng-Wen Su
- License Biotech, Co., Ltd., Taipei 10690, Taiwan; (W.-C.H.); (C.-W.S.)
| | - Yu-Heng Lai
- Department of Chemistry, Chinese Culture University, Taipei 11114, Taiwan;
| | - Che Lin
- Department of Electrical Engineering and Graduate Institute of Communication Engineering, National Taiwan University, Taipei 10617, Taiwan;
| | - Alan Yueh-Luen Lee
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan;
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan; (C.-Y.K.); (L.-Y.S.); (M.-C.L.)
| | - Li-Yu Su
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan; (C.-Y.K.); (L.-Y.S.); (M.-C.L.)
| | - Ming-Cheng Lee
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan; (C.-Y.K.); (L.-Y.S.); (M.-C.L.)
| | - Te-Cheng Hsu
- Department of Electrical Engineering, National Tsing Hua University, Hsinchu, Taipei 30013, Taiwan;
| | - Chun-Hsien Yu
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan
- Department of Pediatrics, School of Medicine, Tzu Chi University, Hualien 97071, Taiwan
- Correspondence: (S.W.); (C.-H.Y.); Tel.: +886-2-2861-0511(ext. 26234) (S.W.); +886-2-66289779 (C.-H.Y.); Fax: +886-2-2862-3724 (S.W.); +886-2-66289009 (C.-H.Y.)
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Jaikumarr Ram A, Girija As S, Jayaseelan VP, Arumugam P. Overexpression of BASP1 Indicates a Poor Prognosis in Head and Neck Squamous Cell Carcinoma. Asian Pac J Cancer Prev 2020; 21:3435-3439. [PMID: 33247706 PMCID: PMC8033119 DOI: 10.31557/apjcp.2020.21.11.3435] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Indexed: 01/04/2023] Open
Abstract
Objective: Brain abundant membrane attached signal protein 1 (BASP1) was originally identified as a membrane and cytoplasmic protein. Recent studies have shown that BASP1 highly expressed in cancer and promoted the proliferation of cancer. However, the role of BASP1 in head and neck squamous cell carcinoma (HNSCC) is largely unknown. Here, we performed a systematic data analysis to examine whether BASP1 can function as prognostic marker in HNSCC. Methods: In this study, we used Oncomine, and UALCAN, databases to analyze the expression of BASP1 in HNSCC. We used Kaplan-Meier plotter to evaluate the effect of BASP1 on clinical prognosis. In addition, we also analyzed genetic alterations, interaction network, and functional enrichment of BASP1. Results: BASP1 mRNA expression level was remarkably increased in HNSCC than in normal tissues (P=1.624e-12). Moreover, high BASP1 expression was significantly related to poor survival (p=0.00056) in HNSCC patients. In addition, BASP1 gene amplified in 5% of HNSCC patients which contributes to the overexpression of BASP1. Conclusions: These findings suggest that BASP1 was frequently amplified which contributes to the overexpression of BASP1, thereby promoting HNSCC progression. Thus, these results indicate that BASP1 might serve as a biomarker to predict the progression and prognosis of HNSCC patients.
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Affiliation(s)
- Ashwin Jaikumarr Ram
- Department of Microbiology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Smiline Girija As
- Department of Microbiology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | | | - Paramasivam Arumugam
- BRULAC-DRC, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
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20
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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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21
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Khosravi N, Mokhtarzadeh A, Baghbanzadeh A, Hajiasgharzadeh K, Shahgoli VK, Hemmat N, Safarzadeh E, Baradaran B. Immune checkpoints in tumor microenvironment and their relevance to the development of cancer stem cells. Life Sci 2020; 256:118005. [PMID: 32593711 DOI: 10.1016/j.lfs.2020.118005] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/14/2020] [Accepted: 06/22/2020] [Indexed: 02/06/2023]
Abstract
Cancer is the second cause of mortality in the world after cardiovascular disease. Various studies attribute the emergence of therapeutic resistance in tumors to the presence of cancer stem cells or cancer-initiating cells (CSC/CIC). These relatively rare cells because of their typical stemness features, are responsible for tumor cell progression and recurrence. Moreover, CSCs have immunomodulatory capabilities and through orchestrating, some immunological profiles can stay safe from host anticancer immunity, and provide immunotherapy resistance in cancer patients. Many studies have shown that CSCs by producing immune system inhibitory factors and interacting with immune checkpoint molecules like CD47, PDL-1, CTLA4, Tim3, and LAG3, are able to communicate with tumor microenvironment (TME) components and protect cancer cells from immune clearance. In this review, we summarize the CSCs immunological mechanisms and comprehensively discuss interactions between these cells and factors that are present in the TME to repress immune system responses and enhance tumor survival. Therefore, it seems that further studies on this topic will open new doors to improve the therapeutic approaches of malignant cancers.
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Affiliation(s)
- Neda Khosravi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Vahid Khaze Shahgoli
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Safarzadeh
- Department of Microbiology & Immunology, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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22
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Ladak SS, Roebuck E, Powell J, Fisher AJ, Ward C, Ali S. The Role of miR-200b-3p in Modulating TGF-β1-induced Injury in Human Bronchial Epithelial Cells. Transplantation 2020; 103:2275-2286. [PMID: 31283671 DOI: 10.1097/tp.0000000000002845] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Dysregulation of microRNAs (miRNAs) has been implicated in airway diseases where transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition (EMT) may contribute to pathophysiology. Our study investigated the role of miRNA-200b in TGF-β1-induced EMT in human bronchial epithelial cells. METHODS NanoString nCounter miRNA assay was used to profile miRNA in control versus TGF-β1 (1, 4, and 24 h) stimulated BEAS-2B cells. Immortalized primary bronchial epithelial cell line (BEAS-2B cells), human primary bronchial epithelial cells (PBECs), and PBECs derived post-lung transplant were transfected with miR-200b-3p mimics and EMT marker expression was examined at RNA and protein level. miRNA target studies were performed and validated using computational tools and luciferase assay. In situ hybridization was done on normal lung tissue to localize miR-200b-3p in airway epithelium. RESULTS miR-200b-3p was downregulated post-TGF-β1 treatment compared with control in BEAS-2B. miR-200b-3p mimic transfection before TGF-β1 stimulation maintained epithelial marker expression and downregulated mesenchymal cell markers at RNA and protein level in BEAS-2B cells and PBECs. Furthermore, miR-200b-3p mimics reversed established TGF-β1-induced EMT in BEAS-2B cells. miR-200b-3p targets, ZNF532, and ZEB2 were validated as direct targets using luciferase assay. miR-200b-3p mimics suppress TGF-β1-induced EMT via inhibition of ZNF532 and ZEB2. In situ hybridization showed that miR-200b-3p is expressed in the normal lung epithelium. Additionally, miR-200b-3p mimics inhibit EMT in the presence of TGF-β1 in PBECs derived from lung allograft. CONCLUSIONS We provide proof of concept that miR-200b-3p protects airway epithelial cells from EMT. Manipulating miR-200b-3p expression may represent a novel therapeutic modulator in airway pathophysiology.
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Affiliation(s)
- Shameem S Ladak
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Eliott Roebuck
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Jason Powell
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.,Department of Otolaryngology, Head and Neck Surgery, Freeman Hospital, Newcastle upon Tyne, United Kingdom
| | - Andrew J Fisher
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.,Institute of Transplantation, Newcastle Upon Tyne Hospitals, Newcastle upon Tyne, United Kingdom
| | - Chris Ward
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Simi Ali
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
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23
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Liu Y, Liu X, Ye P, Zhang X, Schilling AF, Yonezawa T, Gao G, Cui X. MicroRNA-191 regulates differentiation and migration of mesenchymal stem cells and their paracrine effect on angiogenesis. Biotechnol Lett 2020; 42:1777-1788. [PMID: 32436119 DOI: 10.1007/s10529-020-02907-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 05/05/2020] [Indexed: 01/08/2023]
Abstract
MicroRNAs (miRNAs) are critical regulators in organ development. Among them, miR-191 is known to be regulated in early embryogenesis and dysregulated in cancer. This role in undifferentiated tissues suggests a possible part of miR-191 also in bone marrow derived mesenchymal stem cells (BMSCs) physiology. Here, we report that miR-191 decreased MMP expression and migration of BMSCs. Conditioned media of miR-191 overexpressing BMSCs block VEGF expression, and inhibit angiogenesis of HUVECs. Under osteogenic culture conditions, inhibition of miR-191 significantly induces bone formation. Moreover, our studies showed miR-191 might influence chondrogenesis of BMSCs by directly targeting CCAAT Enhancer Binding Protein Beta (CEBPB). Taken together, here we demonstrate the role of miR-191 in differentiation, migration and paracrine function of BMSCs.
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Affiliation(s)
- Yuanxing Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, 310003, Zhejiang Province, China
| | - Xi Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, 310003, Zhejiang Province, China
| | - Pengxiang Ye
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, Hubei Province, China
| | - Xiafei Zhang
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, Hubei Province, China
| | - Arndt F Schilling
- Clinic for Trauma Surgery, Orthopaedic Surgery and Plastic Surgery, University Medical Center Göttingen, Robert Koch Strasse 40, 37075, Göttingen, Germany
| | - Tomo Yonezawa
- Center for Therapeutic Innovation, Gene Research Center for Frontier Life Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-14 Sakamoto, Nagasaki, 852-8523- 0022, Japan
| | - Guifang Gao
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, Hubei Province, China. .,Department of Plastic Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Xiaofeng Cui
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, Hubei Province, China.
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24
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Zhang Y, Roth JA, Yu H, Ye Y, Xie K, Zhao H, Chang DW, Huang M, Li H, Qu J, Wu X. A 5-microRNA signature identified from serum microRNA profiling predicts survival in patients with advanced stage non-small cell lung cancer. Carcinogenesis 2020; 40:643-650. [PMID: 30428030 DOI: 10.1093/carcin/bgy132] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 11/11/2018] [Indexed: 12/19/2022] Open
Abstract
Circulating microRNAs (miRNAs) are potential biomarkers for cancer diagnosis, screening and prognosis. This study aimed to identify serum miRNAs as predictors of survival in patients with advanced non-small cell lung cancer (NSCLC). We profiled serum miRNAs in a pilot set of four patients with good survival (>24 months) and four patients with poor survival (<6 months). We selected 140 stably detectable miRNAs and 42 miRNAs reported in literature for further analysis. Expression of these 182 miRNAs was measured using high-throughput polymerase chain reaction assay, and their association with 3-year survival in the discovery (n = 345) and validation (n = 177) cohorts was assessed. Five serum miRNAs (miR-191, miR-28-3p, miR-145, miR-328 and miR-18a) were significantly associated with 3-year overall survival in both cohorts. A combined 5-miRNA risk score was created to assess the cumulative impact of these miRNAs on risk of death. Quartile analysis of the risk score showed significant association with 3-year death risk, with a 4.6-, 6.8- and 9.3-month reduction in median survival time for the second, third and fourth quartiles, respectively. Survival tree analysis also identified distinct risk groups with different 3-year survival durations. Data from The Cancer Genome Atlas revealed all five miRNAs were differentially expressed (P < 0.0001) in paired tumor and normal tissues. Pathway analysis indicated that target genes of these five miRNAs were mainly enriched in inflammatory/immune response pathways and pathways implicated in resistance to chemoradiotherapy and/or targeted therapy. Our results suggested that the 5-miRNA signature could serve as a prognostic predictor in patients with advanced NSCLC.
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Affiliation(s)
- Yajie Zhang
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jack A Roth
- Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hao Yu
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yuanqing Ye
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kunlin Xie
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hua Zhao
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David W Chang
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Maosheng Huang
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hecheng Li
- Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jieming Qu
- Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xifeng Wu
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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25
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Hartl M, Puglisi K, Nist A, Raffeiner P, Bister K. The brain acid-soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin. Mol Oncol 2020; 14:625-644. [PMID: 31944520 PMCID: PMC7053243 DOI: 10.1002/1878-0261.12636] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 12/16/2019] [Accepted: 01/09/2020] [Indexed: 12/13/2022] Open
Abstract
The MYC protein is a transcription factor with oncogenic potential controlling fundamental cellular processes such as cell proliferation, metabolism, differentiation, and apoptosis. The MYC gene is a major cancer driver, and elevated MYC protein levels are a hallmark of most human cancers. We have previously shown that the brain acid-soluble protein 1 gene (BASP1) is specifically downregulated by the v-myc oncogene and that ectopic BASP1 expression inhibits v-myc-induced cell transformation. The 11-amino acid effector domain of the BASP1 protein interacts with the calcium sensor calmodulin (CaM) and is mainly responsible for this inhibitory function. We also reported recently that CaM interacts with all MYC variant proteins and that ectopic CaM increases the transactivation and transformation potential of the v-Myc protein. Here, we show that the presence of excess BASP1 or of a synthetic BASP1 effector domain peptide leads to displacement of v-Myc from CaM. The protein stability of v-Myc is decreased in cells co-expressing v-Myc and BASP1, which may account for the inhibition of v-Myc. Furthermore, suppression of v-Myc-triggered transcriptional activation and cell transformation is compensated by ectopic CaM, suggesting that BASP1-mediated withdrawal of CaM from v-Myc is a crucial event in the inhibition. In view of the tumor-suppressive role of BASP1 which was recently also reported for human cancer, small compounds or peptides based on the BASP1 effector domain could be used in drug development strategies aimed at tumors with high MYC expression.
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Affiliation(s)
- Markus Hartl
- Institute of Biochemistry and Center for Molecular Biosciences (CMBI)University of InnsbruckAustria
| | - Kane Puglisi
- Institute of Biochemistry and Center for Molecular Biosciences (CMBI)University of InnsbruckAustria
| | - Andrea Nist
- Institute of Biochemistry and Center for Molecular Biosciences (CMBI)University of InnsbruckAustria
- Present address:
Genomics Core FacilityPhilipps University of MarburgGermany
| | - Philipp Raffeiner
- Institute of Biochemistry and Center for Molecular Biosciences (CMBI)University of InnsbruckAustria
- Present address:
Department of Molecular MedicineScripps ResearchLa JollaCAUSA
| | - Klaus Bister
- Institute of Biochemistry and Center for Molecular Biosciences (CMBI)University of InnsbruckAustria
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26
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Satheesh NJ, Samuel SM, Büsselberg D. Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells. Biomolecules 2020; 10:biom10010079. [PMID: 31947879 PMCID: PMC7022456 DOI: 10.3390/biom10010079] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/24/2019] [Accepted: 12/26/2019] [Indexed: 12/13/2022] Open
Abstract
Cancer remains one of the most feared and dreaded diseases in this era of modern medicine, claiming the lives of many, and affecting the quality of life of several others around the globe despite major advances in the diagnosis, treatment, palliative care and the immense resources invested into cancer research. While research in cancer has largely focused on the neoplasm/tumor and the cancerous cells that make up the tumor, more recently, the existence, proliferation, differentiation, migration and invasion of cancer stem cells (CSCs) and the role that CSCs play in tumor initiation, progression, metastasis, drug resistance and relapse/recurrence of the disease has gained widespread interest in cancer research. Although the conventional therapeutic approaches such as surgery, chemotherapy and radiation therapy are effective cancer treatments, very often these treatment modalities fail to target the CSCs, which then later become the source of disease recurrence. A majority of the anti-cancer agents target rapidly dividing cancer cells and normal cells and hence, have side effects that are not expected. Targeting CSCs remains a challenge due to their deviant nature with a low proliferation rate and increased drug resistance mechanism. Ascorbic acid/Vitamin C (Vit.C), a potent antioxidant, is a cofactor for several biosynthetic and gene regulatory enzymes and a vital contributor to immune defense of the body, and was found to be deficient in patients with advanced stages of cancer. Vit.C has gained importance in the treatment of cancer due to its ability to modulate the redox status of the cell and influence epigenetic modifications and significant roles in HIF1α signaling. Studies have reported that intravenous administration of Vit.C at pharmacological doses selectively kills tumor cells and targets CSCs when administered along with chemotherapeutic drugs. In the current article, we provide an in-depth review of how Vit.C plays an important role in targeting CSCs and its possible use as an adjuvant, neoadjuvant or co-treatment in the treatment of cancers.
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27
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Nasr MA, Salah RA, Abd Elkodous M, Elshenawy SE, El-Badri N. Dysregulated MicroRNA Fingerprints and Methylation Patterns in Hepatocellular Carcinoma, Cancer Stem Cells, and Mesenchymal Stem Cells. Front Cell Dev Biol 2019; 7:229. [PMID: 31681762 PMCID: PMC6811506 DOI: 10.3389/fcell.2019.00229] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 09/26/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the top causes of cancer mortality worldwide. Although HCC has been researched extensively, there is still a need for novel and effective therapeutic interventions. There is substantial evidence that initiation of carcinogenesis in liver cirrhosis, a leading cause of HCC, is mediated by cancer stem cells (CSCs). CSCs were also shown to be responsible for relapse and chemoresistance in several cancers, including HCC. MicroRNAs (miRNAs) constitute important epigenetic markers that regulate carcinogenesis by acting post-transcriptionally on mRNAs, contributing to the progression of HCC. We have previously shown that co-culture of cancer cells with mesenchymal stem cells (MSCs) could induce the reprogramming of MSCs into CSC-like cells. In this review, we evaluate the available data concerning the epigenetic regulation of miRNAs through methylation and the possible role of this regulation in stem cell and somatic reprogramming in HCC.
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Affiliation(s)
- Mohamed A Nasr
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Radwa Ayman Salah
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - M Abd Elkodous
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Shimaa E Elshenawy
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
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28
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Qu Z, Feng J, Pan H, Jiang Y, Duan Y, Fa Z. Exosomes derived from HCC cells with different invasion characteristics mediated EMT through TGF-β/Smad signaling pathway. Onco Targets Ther 2019; 12:6897-6905. [PMID: 31692540 PMCID: PMC6711569 DOI: 10.2147/ott.s209413] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 07/27/2019] [Indexed: 12/22/2022] Open
Abstract
Background Exosomes are nano-sized biological vesicles released by many kinds of cells, which play an important role in tumor metastasis through transporting cytokines, RNAs and proteins. However, the molecular mechanisms of exosomes in hepatocellular carcinoma (HCC) metastasis are not completely understood. Materials and methods Exosomes derived from hepatoma cell lines with different invasion characteristics. Exosome characteristics, cell migration and invasion, and effects on major signal transduction pathways deregulated in cancer cells were analyzed by transmission electron microscopy (TEM), wound-healing assay, Trans-well invasion assay and Western blot-based assays, respectively. Moreover, exosomes effects on tumor metastasis in vivo were investigated by subcutaneous transplantation tumor model of athymic nude mice. Results Exosomes derived from hepatoma cells can promote the migration and invasion of recipient cells, induce the decrease of E-cadherin expression, increase the expression of Vimentin and promote epithelial-mesenchymal transition (EMT) in cells. Moreover, highly invasive hepatoma-cells-derived exosomes effects are stronger than low-invasive hepatoma cells and normal liver cells exosomes. Mechanistic studies showed that the biological alterations in recipient HCC cells treated with MHCC97H and MHCC97L-derived exosomes were caused by inducing EMT via TGF-β/Smad signaling pathway. In vivo experiments also suggest that highly invasive hepatoma cells derived exosomes are more likely to promote lung metastasis of HCC in nude mice. Conclusion Our results reveal the important role of tumor-derived exosomes in the migration and invasion of recipient cells and exosomes may be the novel therapeutic and prognostic targets for HCC patients.
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Affiliation(s)
- Zhen Qu
- Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Changzhou, the Third Hospital Affiliated to Soochow University, Changzhou, Jiangsu, People's Republic of China
| | - Jiawei Feng
- Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Changzhou, the Third Hospital Affiliated to Soochow University, Changzhou, Jiangsu, People's Republic of China
| | - Hua Pan
- Department of Hepatobiliary Surgery, The People's Hospital of Liyang, Liyang, Jiangsu, People's Republic of China
| | - Yong Jiang
- Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Changzhou, the Third Hospital Affiliated to Soochow University, Changzhou, Jiangsu, People's Republic of China
| | - Yunfei Duan
- Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Changzhou, the Third Hospital Affiliated to Soochow University, Changzhou, Jiangsu, People's Republic of China
| | - Zhenzhong Fa
- Department of Hepatobiliary Surgery, Changzhou Wujin People's Hospital, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu, People's Republic of China
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29
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Hartl M, Schneider R. A Unique Family of Neuronal Signaling Proteins Implicated in Oncogenesis and Tumor Suppression. Front Oncol 2019; 9:289. [PMID: 31058089 PMCID: PMC6478813 DOI: 10.3389/fonc.2019.00289] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 03/29/2019] [Indexed: 12/20/2022] Open
Abstract
The neuronal proteins GAP43 (neuromodulin), MARCKS, and BASP1 are highly expressed in the growth cones of nerve cells where they are involved in signal transmission and cytoskeleton organization. Although their primary structures are unrelated, these signaling proteins share several structural properties like fatty acid modification, and the presence of cationic effector domains. GAP43, MARCKS, and BASP1 bind to cell membrane phospholipids, a process reversibly regulated by protein kinase C-phosphorylation or by binding to the calcium sensor calmodulin (CaM). GAP43, MARCKS, and BASP1 are also expressed in non-neuronal cells, where they may have important functions to manage cytoskeleton architecture, and in case of MARCKS and BASP1 to act as cofactors in transcriptional regulation. During neoplastic cell transformation, the proteins reveal differential expression in normal vs. tumor cells, and display intrinsic tumor promoting or tumor suppressive activities. Whereas GAP43 and MARCKS are oncogenic, tumor suppressive functions have been ascribed to BASP1 and in part to MARCKS depending on the cell type. Like MARCKS, the myristoylated BASP1 protein is localized both in the cytoplasm and in the cell nucleus. Nuclear BASP1 participates in gene regulation converting the Wilms tumor transcription factor WT1 from an oncoprotein into a tumor suppressor. The BASP1 gene is downregulated in many human tumor cell lines particularly in those derived from leukemias, which display elevated levels of WT1 and of the major cancer driver MYC. BASP1 specifically inhibits MYC-induced cell transformation in cultured cells. The tumor suppressive functions of BASP1 and MARCKS could be exploited to expand the spectrum of future innovative therapeutic approaches to inhibit growth and viability of susceptible human tumors.
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Affiliation(s)
- Markus Hartl
- Center of Molecular Biosciences (CMBI), Institute of Biochemistry, University of Innsbruck, Innsbruck, Austria
| | - Rainer Schneider
- Center of Molecular Biosciences (CMBI), Institute of Biochemistry, University of Innsbruck, Innsbruck, Austria
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Chen XY, Zhang J, Hou LD, Zhang R, Chen W, Fan HN, Huang YX, Liu H, Zhu JS. Upregulation of PD-L1 predicts poor prognosis and is associated with miR-191-5p dysregulation in colon adenocarcinoma. Int J Immunopathol Pharmacol 2018; 32:2058738418790318. [PMID: 30045644 PMCID: PMC6073840 DOI: 10.1177/2058738418790318] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Targeting of the programmed cell-death 1 ligand 1 (PD-L1) signal pathway is a
promising treatment strategy in several cancers. The purpose of this study was
to evaluate the clinical significance of PD-L1 in patients with colon
adenocarcinoma (COAD). A total of 240 patients who were diagnosed with COAD from
The Cancer Genome Atlas (TCGA) RNA-sequencing data and another cohort for
pair-matched COAD samples (n = 40) in tissue microarray (TMA) were enrolled in
this study. The correlation of PD-L1 or miR-191-5p expression with
clinicopathological features and prognosis in patients with COAD was further
analyzed using TCGA data and TMA. The Cox proportional hazard regression model
was used to evaluate the association of PD-L1 or miR-191-5p expression with
overall survival (OS) and tumor recurrence in patients with COAD. The microRNAs
(miRNAs) that target PD-L1 gene were identified by bioinformatics and Spearman
correlation analysis. We found that PD-L1 expression was increased in COAD
tissues and was correlated with poor survival and tumor recurrence in patients
with COAD. The increased expression of PD-L1 was attributed to the dysregulation
of miR-191-5p expression rather than its genetic or epigenetic alterations.
Moreover, the expression of miR-191-5p presented the negative correlation with
PD-L1 expression and acted as an independent prognostic factor of OS in patients
with COAD. Therefore, PD-L1 may predict poor prognosis and is negatively
associated with miR-191-5p expression in patients with COAD.
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Affiliation(s)
- Xiao-Yu Chen
- 1 Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Zhang
- 1 Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Li-Dan Hou
- 2 Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Rui Zhang
- 1 Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Chen
- 1 Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hui-Ning Fan
- 1 Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yan-Xia Huang
- 1 Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hui Liu
- 1 Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jin-Shui Zhu
- 1 Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
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Yang Q, Cui Y, Luo F, Liu X, Wang Q, Bai J, Dong F, Sun Q, Lu L, Xu H, Xue J, Chen C, Xiang Q, Liu Q, Zhang Q. MicroRNA-191, acting via the IRS-1/Akt signaling pathway, is involved in the hepatic insulin resistance induced by cigarette smoke extract. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2018; 25:22400-22407. [PMID: 28963693 DOI: 10.1007/s11356-017-0277-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 09/19/2017] [Indexed: 06/07/2023]
Abstract
Cigarette smoke causes insulin resistance, which is associated with type 2 diabetes mellitus (T2DM). However, the mechanism by which this occurs remains poorly understood. Because the involvement of microRNAs (miRNAs) in the development of insulin resistance is largely unknown, we investigated, in hepatocytes, the roles of miR-191 in cigarette smoke extract (CSE)-induced insulin resistance. In L-02 cells, CSE not only decreased glucose uptake and glycogen levels but also reduced levels of insulin receptor substrate-1 (IRS-1) and Akt activation, effects that were blocked by SC79, an activator of Akt. CSE also increased miR-191 levels in L-02 cells. Furthermore, the inhibition of miR-191 blocked the decreases of IRS-1 and p-Akt levels, which antagonized the decreases of glucose uptake and glycogen levels in L-02 cells induced by CSE. These results reveal a mechanism by which miR-191 is involved in CSE-induced hepatic insulin resistance via the IRS-1/Akt signaling pathway, which helps to elucidate the mechanism for cigarette smoke-induced T2DM.
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Affiliation(s)
- Qianlei Yang
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Yan Cui
- School of Public Health, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Fei Luo
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Xinlu Liu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Qiushi Wang
- Jiangsu Center for Disease Control and Prevention, Nanjing, 210009, Jiangsu, People's Republic of China
| | - Jun Bai
- School of Public Health, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Faqin Dong
- Key Laboratory of Solid Waste Treatment and the Resource Recycle, Southwest University of Science and Technology, Mianyan, 621010, Sichuan, People's Republic of China
| | - Qian Sun
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Lu Lu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Hui Xu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Junchao Xue
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Chao Chen
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Quanyong Xiang
- Jiangsu Center for Disease Control and Prevention, Nanjing, 210009, Jiangsu, People's Republic of China
| | - Qizhan Liu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China.
| | - Qingbi Zhang
- School of Public Health, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China.
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Gu S, Sun D, Dai H, Zhang Z. N6-methyladenosine mediates the cellular proliferation and apoptosis via microRNAs in arsenite-transformed cells. Toxicol Lett 2018; 292:1-11. [DOI: 10.1016/j.toxlet.2018.04.018] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 04/12/2018] [Accepted: 04/16/2018] [Indexed: 12/21/2022]
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Mitchell KA, Zingone A, Toulabi L, Boeckelman J, Ryan BM. Comparative Transcriptome Profiling Reveals Coding and Noncoding RNA Differences in NSCLC from African Americans and European Americans. Clin Cancer Res 2018; 23:7412-7425. [PMID: 29196495 DOI: 10.1158/1078-0432.ccr-17-0527] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 06/26/2017] [Accepted: 09/08/2017] [Indexed: 12/19/2022]
Abstract
Purpose: To determine whether racial differences in gene and miRNA expression translates to differences in lung tumor biology with clinical relevance in African Americans (AAs) and European Americans (EAs).Experimental Design: The NCI-Maryland Case Control Study includes seven Baltimore City hospitals and is overrepresented with AA patients (∼40%). Patients that underwent curative NSCLC surgery between 1998 and 2014 were enrolled. Comparative molecular profiling used mRNA (n = 22 AAs and 19 EAs) and miRNA (n = 42 AAs and 55 EAs) expression arrays to track differences in paired fresh frozen normal tissues and lung tumor specimens from AAs and EAs. Pathway enrichment, predicted drug response, tumor microenvironment infiltration, cancer immunotherapy antigen profiling, and miRNA target enrichment were assessed.Results: AA-enriched differential gene expression was characterized by stem cell and invasion pathways. Differential gene expression in lung tumors from EAs was primarily characterized by cell proliferation pathways. Population-specific gene expression was partly driven by population-specific miRNA expression profiles. Drug susceptibility predictions revealed a strong inverse correlation between AA resistance and EA sensitivity to the same panel of drugs. Statistically significant differences in M1 and M2 macrophage infiltration were observed in AAs (P < 0.05); however, PD-L1, PD-L2 expression was similar between both.Conclusions: Comparative transcriptomic profiling revealed clear differences in lung tumor biology between AAs and EAs. Increased participation by AAs in lung cancer clinical trials are needed to integrate, and leverage, transcriptomic differences with other clinical information to maximize therapeutic benefit in both AAs and EAs. Clin Cancer Res; 23(23); 7412-25. ©2017 AACR.
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Affiliation(s)
- Khadijah A Mitchell
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Adriana Zingone
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Leila Toulabi
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Jacob Boeckelman
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Bríd M Ryan
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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Yang Y, Sun Y, Wu Y, Tang D, Ding X, Xu W, Su B, Gao W. Downregulation of miR-3127-5p promotes epithelial-mesenchymal transition via FZD4 regulation of Wnt/β-catenin signaling in non-small-cell lung cancer. Mol Carcinog 2018; 57:842-853. [PMID: 29566281 DOI: 10.1002/mc.22805] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 03/11/2018] [Accepted: 03/20/2018] [Indexed: 12/31/2022]
Abstract
MiR-3127-5p has been implicated as a tumor-suppressive microRNA (miRNA) in non-small-cell lung cancer (NSCLC) and its expression was associated with tumor recurrence and poor prognosis. The aim of this study was to determine whether miR-3127-5p regulates epithelial-mesenchymal transition (EMT) in NSCLC, and to investigate the underlying mechanisms. Using qRT-PCR, we examined the expression levels of miR-3127-5p in a cohort of primary NSCLC specimens with and without distant metastasis. We further performed a series of in vitro and in vivo experiments to investigate the effects and underlying mechanism of miR-3127-5p on EMT, cell migration, invasion, and adhesion in NSCLC. We found that metastatic NSCLC tissues showed markedly downregulated miR-3127-5p expression. Transforming growth factor-β1 (TGF-β1) treatment induced EMT in A549 and H1299 cells, and downregulation of miR-3127-5p could result in the similar effect. Mechanically, we demonstrated that frizzled-4 (FZD4) is a target gene and miR-3127-5p exerts its effects by regulating the Wnt/β-catenin signaling. In addition, the expression levels of FZD4 and miR-3127-5p were also negatively associated in both clinical and xenografted tumors. Overall, these findings suggest that downregulation of miR-3127-5p promotes EMT through activating the Wnt/FZD4/β-catenin signaling pathway and may represent a therapeutic target for NSCLC metastasis.
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Affiliation(s)
- Yang Yang
- Department of Thoracic Surgery, Huadong Hospital Affiliated to FuDan University, Shanghai, China.,Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yifeng Sun
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yun Wu
- Department of Thoracic Surgery, Huadong Hospital Affiliated to FuDan University, Shanghai, China
| | - Dongfang Tang
- Department of Thoracic Surgery, Huadong Hospital Affiliated to FuDan University, Shanghai, China
| | - Xi Ding
- Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wen Xu
- Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bo Su
- Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wen Gao
- Department of Thoracic Surgery, Huadong Hospital Affiliated to FuDan University, Shanghai, China
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Chen P, Pan X, Zhao L, Jin L, Lin C, Quan J, He T, Zhou L, Wu X, Wang Y, Ni L, Yang S, Lai Y. MicroRNA-191-5p exerts a tumor suppressive role in renal cell carcinoma. Exp Ther Med 2018; 15:1686-1693. [PMID: 29434754 PMCID: PMC5774385 DOI: 10.3892/etm.2017.5581] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 08/10/2017] [Indexed: 02/05/2023] Open
Abstract
Renal cell carcinoma (RCC) is a common tumor of the urinary system. Previously, miR-191-5p has been reported to be associated with various types of cancer; however, its specific functions in RCC have not been investigated to date. In the present study, the expression of miR-191-5p in the 786-O and ACHN cell lines was detected in vitro by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results of RT-qPCR revealed that miR-191-5p was significantly downregulated in the two cell lines compared with the 293T cell line. miR-191-5p was also significantly downregulated in RCC tissue compared with paired normal tissue. In addition, the effects of miR-191-5p on cell proliferation, migration, invasion and apoptosis were examined by CCK-8, MTT, wound scratch, Transwell and flow cytometry assays. Downregulation of miR-191-5p was observed to promote cell proliferation, migration and invasion, as well as to repress the cell apoptosis of 786-O and ACHN cells. Therefore, the current study suggests that miR-191-5p functions as a tumor suppressor in RCC. Further studies are required to uncover the underlying signaling pathway of miR-191-5p and its potential role as a biomarker for early detection and prognosis prediction, and as a therapeutic target of RCC.
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Affiliation(s)
- Peijie Chen
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Department of Urology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Xiang Pan
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Liwen Zhao
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Lu Jin
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Canbin Lin
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Department of Urology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Jing Quan
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Tao He
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Liang Zhou
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Xueling Wu
- Department of Urology, Longgang District Central Hospital of Shenzhen, Shenzhen, Guangdong 518116, P.R. China
| | - Yong Wang
- Department of Reproduction, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Liangchao Ni
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Shangqi Yang
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Yongqing Lai
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
- Correspondence to: Professor Yongqing Lai, Department of Urology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, Guangdong 518036, P.R. China, E-mail:
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Chen C, Yang Q, Wang D, Luo F, Liu X, Xue J, Yang P, Xu H, Lu J, Zhang A, Liu Q. MicroRNA-191, regulated by HIF-2α, is involved in EMT and acquisition of a stem cell-like phenotype in arsenite-transformed human liver epithelial cells. Toxicol In Vitro 2017; 48:128-136. [PMID: 29277653 DOI: 10.1016/j.tiv.2017.12.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 12/20/2017] [Accepted: 12/22/2017] [Indexed: 02/06/2023]
Abstract
Inorganic arsenic is widely distributed in the environment, and epidemiologic data show a strong association between arsenic exposure and risk of liver cancer. An understanding of the mechanisms underlying development of liver cancer and metastasis would be useful in reducing the incidence and mortality of liver cancer. MicroRNAs (miRs) act as regulators in liver cancer. Here, we show that acute or chronic exposure of human liver epithelial L-02 cells to arsenite increased expression of miR-191. There were decreased levels of BASP-1 and E-cadherin and increased levels of WT-1 and N-cadherin, indicating that arsenite induced epithelial-mesenchymal transition (EMT). Moreover, arsenite increased EpCAM and CD90 mRNA levels, showing the acquisition of stem cell-like properties by these cells. Suppression of miR-191 resulted in repression of EMT and reduced expression of stem-cell markers. Further, a miR-191 inhibitor blocked spheroid formation and production of side population cells. Luciferase reporter assays indicated that miR-191 was a target of HIF-2α, and inhibition of miR-191 decreased the neoplastic and metastatic properties of arsenite-transformed L-02 cells. Thus, in arsenite-transformed liver epithelial cells, transcriptional activation of the miR-191 promoter by HIF-2α is involved in EMT and in the acquisition of a stem cell-like phenotype.
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Affiliation(s)
- Chao Chen
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Qianlei Yang
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Dapeng Wang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, People's Republic of China
| | - Fei Luo
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Xinlu Liu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Junchao Xue
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Ping Yang
- The School of Public Health, Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China
| | - Hui Xu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Jiachun Lu
- The School of Public Health, Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China
| | - Aihua Zhang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, People's Republic of China.
| | - Qizhan Liu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
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Gao X, Xie Z, Wang Z, Cheng K, Liang K, Song Z. Overexpression of miR-191 Predicts Poor Prognosis and Promotes Proliferation and Invasion in Esophageal Squamous Cell Carcinoma. Yonsei Med J 2017; 58:1101-1110. [PMID: 29047233 PMCID: PMC5653474 DOI: 10.3349/ymj.2017.58.6.1101] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 07/25/2017] [Accepted: 07/27/2017] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Accumulating evidence has shown that dysregulation of microRNA-191 (miR-191) is closely associated with tumorigenesis and progression in a wide range of cancers. This study aimed to explore the potential role of miR-191 in esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS miR-191 expression was assessed in 93 ESCC tissue specimens by real-time polymerase chain reaction, and survival analysis was performed via Kaplan-Meier and Cox regression analyses. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, plate colony-forming, BrdU, and Transwell assays were conducted to observe the effect of miR-191 on ESCC proliferation and invasion. Luciferase reporter and western blot assays were taken to identify target genes of miR-191. RESULTS miR-191 was overexpressed in 93 cases of ESCC, compared with adjacent normal tissues, and miR-191 expression was significantly related to differentiation, depth of invasion, TNM stage, lymph node metastasis, and distant metastasis of tumor. Kaplan-Meier and Cox regression analyses demonstrated that overexpression of miR-191 was an independent and significant predictor of ESCC prognosis. Both gain-of-function and loss-of-function experiments showed that miR-191 promoted ESCC cell proliferation and invasion activities in vitro. Early growth response 1 (EGR1), a tumor suppressor, was predicted as a direct target of miR-191. Luciferase reporter and western blot assays proved that miR-191 reduced EGR1 expression by directly binding its 3' untranslated region. Moreover, EGR1 knockdown by siRNA enhanced ESCC cell growth and invasion. CONCLUSION Our findings provide specific biological roles of miR-191 in ESCC survival and progression. Targeting the novel miR-191/EGR1 axis represents a potential new therapeutic way to block ESCC development.
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Affiliation(s)
- Xiaotian Gao
- Department of Cardiac Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhanqiang Xie
- Department of Cardiothoracic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhigang Wang
- Department of Cardiothoracic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Keluo Cheng
- Department of Cardiothoracic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ke Liang
- Department of Cardiothoracic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zeqing Song
- Department of Internal Medicine, Guangdong Medical University Affiliated Longhua Central Hospital, Shenzhen, China.
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Tang H, Wang Y, Zhang B, Xiong S, Liu L, Chen W, Tan G, Li H. High brain acid soluble protein 1(BASP1) is a poor prognostic factor for cervical cancer and promotes tumor growth. Cancer Cell Int 2017; 17:97. [PMID: 29089860 PMCID: PMC5655910 DOI: 10.1186/s12935-017-0452-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 09/09/2017] [Indexed: 12/16/2022] Open
Abstract
Background The aim of this study was to determine whether brain abundant membrane attached signal protein 1 (BASP1) is a valuable prognostic biomarker for cervical cancer and whether BASP1 regulates the progression of cervical cancer. Methods Quantitative real-time PCR, western blotting, and immunohistochemistry were used to determined BASP1 levels. Statistical analyses were used to examine whether BASP1 was a prognostic factor for patients with cervical cancer. The MTT assay, colony formation assay, cell cycle assay, anchorage-independent growth assay, and a tumor xenograft model were used to determine the role of BASP1 in the proliferation and tumorigenicity of cervical cancer. Results Brain abundant membrane attached signal protein 1 was upregulated in cervical cancer tissues and cells, and BASP1 expression levels were higher in patients that had died during follow-up compared with those that survived. There was a positive correlation between BASP1 expression and clinical stage (p < 0.001), T classification (p < 0.001), N classification (p < 0.05), and survival or mortality (p < 0.05). Patients with higher BASP1 expression had a shorter overall survival time. Cox regression analysis shown BSAP1 was an unfavorable prognostic factor for patients with cervical cancer. Overexpression of BASP1 promoted the proliferation of cervical cancer and its colony formation ability, accelerated cell cycle progression, and enhanced tumorgenicity. BASP1 knockdown inhibited the proliferation of cervical cancer and its colony formation ability, suppressed cell cycle progression, and decreased tumorgenicity. Conclusions The results showed that BASP1 not only is a novel prognostic factor for patients with cervical cancer, but also promotes the proliferation and tumorigenicity of cervical cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12935-017-0452-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Huiru Tang
- Department of Gynecology & Obstetrics, Peking University Shenzhen Hospital, Shenzhen, 518036 People's Republic of China.,Shenzhen Key Laboratory of Gynecological Diagnostic Technology Research, Shenzhen, 518036 People's Republic of China
| | - Yan Wang
- Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 People's Republic of China
| | - Bing Zhang
- Department of Nuclear Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 People's Republic of China
| | - Shiqiu Xiong
- Department of Biochemistry, University of Leicester, Leicester, LE1 7RH UK
| | - Liangshuai Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 People's Republic of China
| | - Wei Chen
- Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 People's Republic of China
| | - Guosheng Tan
- Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 People's Republic of China.,Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road II, Yuexiu District, Guangzhou, 510080 People's Republic of China
| | - Heping Li
- Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 People's Republic of China.,Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road II, Yuexiu District, Guangzhou, 510080 People's Republic of China
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Kennedy L, Hargrove L, Demieville J, Francis N, Seils R, Villamaria S, Francis H. Recent Advances in Understanding Cholangiocarcinoma. F1000Res 2017; 6:1818. [PMID: 29067165 PMCID: PMC5635438 DOI: 10.12688/f1000research.12118.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/10/2017] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive malignancy that arises from damaged epithelial cells, cholangiocytes, and possibly de-differentiated hepatocytes. CCA has a poor overall survival rate and limited therapeutic options. Based on this data, it is imperative that new diagnostic and therapeutic interventions be developed. Recent work has attempted to understand the pathological mechanisms driving CCA progression. Specifically, recent publications have delved into the role of cancer stem cells (CSCs), mesenchymal stem cells (MSCs), and microRNAs (miRNAs) during CCA pathology. CSCs are a specific subset of cells within the tumor environment that are derived from a cell with stem-like properties and have been shown to influence recurrence and chemoresistance during CCA. MSCs are known for their anti-inflammatory activity and have been postulated to influence malignancy during CCA, but little is known about their exact functions. miRNAs exert various functions via gene regulation at both the transcriptional and the translational levels, giving miRNAs diverse roles in CCA progression. Additionally, current miRNA-based therapeutic approaches are in clinical trials for various liver diseases, giving hope for similar approaches for CCA. However, the interactions among these three factors in the context of CCA are unknown. In this review, we focus on recently published data (within the last 3 years) that discuss the role of CSCs, MSCs, and miRNAs and their possible interactions during CCA pathogenesis.
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Affiliation(s)
- Lindsey Kennedy
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Bryan, TX, USA.,Research, Central Texas Veterans Health Care System, Temple, TX, USA
| | - Laura Hargrove
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Bryan, TX, USA
| | | | - Nicole Francis
- Baylor Scott & White Health Digestive Disease Research Center, Temple, TX, USA
| | - Rowan Seils
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Bryan, TX, USA
| | - Sara Villamaria
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Bryan, TX, USA
| | - Heather Francis
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Bryan, TX, USA.,Research, Central Texas Veterans Health Care System, Temple, TX, USA.,Baylor Scott & White Health Digestive Disease Research Center, Temple, TX, USA
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Liang Z, Lu L, Mao J, Li X, Qian H, Xu W. Curcumin reversed chronic tobacco smoke exposure induced urocystic EMT and acquisition of cancer stem cells properties via Wnt/β-catenin. Cell Death Dis 2017; 8:e3066. [PMID: 28981096 PMCID: PMC5680574 DOI: 10.1038/cddis.2017.452] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 08/03/2017] [Accepted: 08/04/2017] [Indexed: 12/17/2022]
Abstract
Tobacco smoke (TS) is the most important single risk factor for bladder cancer. Epithelial-mesenchymal transition (EMT) is a transdifferentiation process, involved in the initiation of TS-related cancer. Cancer stem cells (CSCs) have an essential role in the progression of many tumors including TS-related cancer. However, the molecular mechanisms of TS exposure induced urocystic EMT and acquisition of CSCs properties remains undefined. Wnt/β-catenin pathway is critical for EMT and the maintenance of CSCs. The aim of our present study was to investigate the role of Wnt/β-catenin pathway in chronic TS exposure induced urocystic EMT, stemness acquisition and the preventive effect of curcumin. Long time TS exposure induced EMT changes and the levels of CSCs' markers were significant upregulated. Furthermore, we demonstrated that Wnt/β-catenin pathway modulated TS-triggered EMT and stemness, as evidenced by the findings that TS elevated Wnt/β-catenin activation, and that TS-mediated EMT and stemness were attenuated by Wnt/β-catenin inhibition. Treatment of curcumin reversed TS-elicited activation of Wnt/β-catenin, EMT and CSCs properties. Collectively, these data indicated the regulatory role of Wnt/β-catenin in TS-triggered urocystic EMT, acquisition of CSCs properties and the chemopreventive effect of curcumin.
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Affiliation(s)
- Zhaofeng Liang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Ling Lu
- Department of Children's Health Care, Women and Children Health Hospital of Zhenjiang, Jiangsu Province, Zhenjiang, China
| | - Jiahui Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xia Li
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hui Qian
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Wenrong Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
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42
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Gu S, Sun D, Li X, Zhang Z. Alterations of miRNAs and Their Potential Roles in Arsenite-Induced Transformation of Human Bronchial Epithelial Cells. Genes (Basel) 2017; 8:genes8100254. [PMID: 28972549 PMCID: PMC5664104 DOI: 10.3390/genes8100254] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 09/24/2017] [Accepted: 09/28/2017] [Indexed: 01/09/2023] Open
Abstract
The alterations of micro RNAs (miRNAs) and their potential roles in arsenite-induced tumorigenesis are still poorly understood. In this study, miRNA Array was used to detect the expression level of miRNAs in human bronchial epithelial (HBE) cells that were transformed by 2.5 μM arsenite for 13 weeks. These cells exhibited a neoplastic phenotype manifested by increased levels of cellular proliferation and migration and clone formation. Subsequently, 191 dysregulated miRNAs were identified to be associated with arsenite-induced transformation by miRNA Array. Among them, six miRNAs were validated by their expression levels with quantitative real-time polymerase chain reaction (qPCR), and 17 miRNAs were further explored via their target genes as well as regulatory network. Three databases, TargetMiner, miRDB, and TarBase, were used to predict the target genes of the 17 miRNAs, and a total of 954 common genes were sorted. Results of Gene Ontology (GO) analyses showed that the 954 genes were involved in diverse terms of GO categories, such as positive regulation of macroautophagy, epithelial cell maturation, and synaptic vesicle clustering. Moreover, results of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that most of these target genes were enriched in various cancer-related pathways, including non-small cell lung cancer, Wnt signaling pathway, cell cycle, and p53 signaling pathway. The miRNA-gene regulatory network, which was constructed by cytoscape software with miRNAs and their target genes, showed that miR-15b-5p, miR-106b-5p, and miR-320d were the core hubs. Collectively, our results provide new insights into miRNA-mediated mechanisms underlying arsenite-induced transformation, although more experimental verification is still needed to prove these predictions.
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Affiliation(s)
- Shiyan Gu
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu 610041, China.
| | - Donglei Sun
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu 610041, China.
| | - Xinyang Li
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu 610041, China.
| | - Zunzhen Zhang
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu 610041, China.
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43
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Peng Y, Zhang X, Feng X, Fan X, Jin Z. The crosstalk between microRNAs and the Wnt/β-catenin signaling pathway in cancer. Oncotarget 2017; 8:14089-14106. [PMID: 27793042 PMCID: PMC5355165 DOI: 10.18632/oncotarget.12923] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 10/21/2016] [Indexed: 12/16/2022] Open
Abstract
Mounting evidence has indicated microRNA (miR) dysregulation and the Wnt/β-catenin signaling pathway jointly drive carcinogenesis, cancer metastasis, and drug-resistance. The current review will focus on the role of the crosstalk between miRs and the Wnt/β-catenin signaling pathway in cancer development. MiRs were found to activate or inhibit the canonical Wnt pathway at various steps. On the other hand, Wnt activation increases expression of miR by directly binding to its promoter and activating transcription. Moreover, there are mutual feedback loops between some miRs and the Wnt/β-catenin signaling pathway. Clinical trials of miR-based therapeutic agents are investigated for solid and hematological tumors, however, challenges concerning low bioavailability and possible side effects must be overcome before the final clinical application. This review will describe current understanding of miR crosstalk with the Wnt/β-catenin signaling cascade. Better understanding of the regulatory network will provide insight into miR-based therapeutic development.
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Affiliation(s)
- Yin Peng
- Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.,Department of Pathology, Wuhan University School of Basic Medical Sciences, Hubei, People's Republic of China
| | - Xiaojing Zhang
- Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.,Shenzhen Key Laboratory of Translational Medicine in Tumors, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Xianling Feng
- Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Xinmim Fan
- Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
| | - Zhe Jin
- Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.,Shenzhen Key Laboratory of Micromolecule Innovatal Drugs, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.,Shenzhen Key Laboratory of Translational Medicine in Tumors, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
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Rapp J, Jaromi L, Kvell K, Miskei G, Pongracz JE. WNT signaling - lung cancer is no exception. Respir Res 2017; 18:167. [PMID: 28870231 PMCID: PMC5584342 DOI: 10.1186/s12931-017-0650-6] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 08/27/2017] [Indexed: 02/07/2023] Open
Abstract
Since the initial discovery of the oncogenic activity of WNT ligands our understanding of the complex roles for WNT signaling pathways in lung cancers has increased substantially. In the current review, the various effects of activation and inhibition of the WNT signaling pathways are summarized in the context of lung carcinogenesis. Recent evidence regarding WNT ligand transport mechanisms, the role of WNT signaling in lung cancer angiogenesis and drug transporter regulation and the importance of microRNA and posttranscriptional regulation of WNT signaling are also reviewed.
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Affiliation(s)
- Judit Rapp
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
| | - Luca Jaromi
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
| | - Krisztian Kvell
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
| | - Gyorgy Miskei
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
| | - Judit E. Pongracz
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
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45
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Liang Z, Wu R, Xie W, Xie C, Wu J, Geng S, Li X, Zhu M, Zhu W, Zhu J, Huang C, Ma X, Xu W, Zhong C, Han H. Effects of Curcumin on Tobacco Smoke-induced Hepatic MAPK Pathway Activation and Epithelial-Mesenchymal Transition In Vivo. Phytother Res 2017; 31:1230-1239. [PMID: 28585748 DOI: 10.1002/ptr.5844] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 05/09/2017] [Accepted: 05/10/2017] [Indexed: 12/11/2022]
Abstract
Tobacco smoke is a major risk factor for hepatic cancer. Epithelial-mesenchymal transition (EMT) induced by tobacco smoke is crucially involved in the initiation and development of cancer. Mitogen-activated protein kinase (MAPK) pathways play important roles in tobacco smoke-associated carcinogenesis including EMT process. The chemopreventive effect of curcumin supplementation against cancers has been reported. In this study, we investigated the effects of tobacco smoke on MAPK pathway activation and EMT alterations, and then the preventive effect of curcumin was examined in the liver of BALB/c mice. Our results indicated that exposure of mice to tobacco smoke for 12 weeks led to activation of ERK1/2, JNK, p38 and ERK5 pathways as well as activator protein-1 (AP-1) proteins in liver tissue. Exposure of mice to tobacco smoke reduced the hepatic mRNA and protein expression of the epithelial markers, while the hepatic mRNA and protein levels of the mesenchymal markers were increased. Treatment of curcumin effectively attenuated tobacco smoke-induced activation of ERK1/2 and JNK MAPK pathways, AP-1 proteins and EMT alterations in the mice liver. Our data suggested the protective effect of curcumin in tobacco smoke-triggered MAPK pathway activation and EMT in the liver of BALB/c mice, thus providing new insights into the chemoprevention of tobacco smoke-associated hepatic cancer. Copyright © 2017 John Wiley & Sons, Ltd.
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Affiliation(s)
- Zhaofeng Liang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Rui Wu
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
- Chongchuanqu Market Supervision Administration, Nantong, 226006, China
| | - Wei Xie
- Institute of Food Safety and Assessment, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 211166, China
| | - Chunfeng Xie
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Jieshu Wu
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Shanshan Geng
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Xiaoting Li
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Mingming Zhu
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Weiwei Zhu
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Jianyun Zhu
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Cong Huang
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Xiao Ma
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Caiyun Zhong
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Hongyu Han
- Department of Clinical Nutrition, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China
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Li H, Zhou ZQ, Yang ZR, Tong DN, Guan J, Shi BJ, Nie J, Ding XT, Li B, Zhou GW, Zhang ZY. MicroRNA-191 acts as a tumor promoter by modulating the TET1-p53 pathway in intrahepatic cholangiocarcinoma. Hepatology 2017; 66:136-151. [PMID: 28194813 DOI: 10.1002/hep.29116] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Accepted: 02/08/2017] [Indexed: 01/20/2023]
Abstract
UNLABELLED Current treatment of intrahepatic cholangiocarcinoma (ICC) remains ineffective because knowledge of ICC carcinogenesis is unclear. Increasing evidence suggests that microRNAs (miRNAs), including miR-191, play an important role in tumorigenesis; but expression and biological functions of miR-191 in ICC remain to be established. This study investigated the functions and underlying mechanisms of miR-191 in ICC. ICC miRNA profiles were generated in five pairs of ICC and matched to normal bile duct tissues by next-generation sequencing technology; ICC miRNA profiles were verified in 18 pairs of ICC tissues and normal bile duct tissues by quantitative RT-PCR. The miR-191-associated mechanisms in ICC were investigated in vitro and in vivo, and clinical outcomes associated with miR-191 were correlated in 84 patients. Our results showed that miR-191 expression was significantly increased in ICC compared with the adjacent normal bile duct tissues (P < 0.001). Overexpression of miR-191 promoted proliferation, invasion, and migration of cholangiocarcinoma cells in vitro and in vivo. The elevated miR-191 expression reduced the expression level of ten-eleven translocation 1 (TET1)-a direct target gene of miR-191 in ICC, which catalyzes demethylation. The reduced TET1 expression level allowed the methylated CpG-rich regions at the p53 gene transcription start site stay methylated, leading to reduced p53 expression level, which compromises p53's anticancer vigor. Finally, miR-191 was found to be an independent risk factor for poor prognosis in patients with ICC (overall survival, hazard ratio = 3.742, 95% confidence interval 2.080-6.733, P < 0.001; disease-free survival, hazard ratio = 2.331, 95% confidence interval 1.346-4.037, P = 0.003). CONCLUSION Our results suggest that overexpressed miR-191 is associated with ICC progression through the miR-191/TET1/p53 pathway. (Hepatology 2017;66:136-151).
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Affiliation(s)
- Hao Li
- Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China
| | - Zun-Qiang Zhou
- Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhang-Ru Yang
- Department of Radiation Oncology, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China
| | - Da-Nian Tong
- Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China
| | - Jiao Guan
- Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China
| | - Bao-Jie Shi
- Department of Surgery, Shanghai Jiao Tong University, Affiliated First People's Hospital, Shanghai, China
| | - Jia Nie
- School of Biomedical Engineering, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai, China.,Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xian-Ting Ding
- School of Biomedical Engineering, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bin Li
- Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Guang-Wen Zhou
- Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China
| | - Zheng-Yun Zhang
- Department of Surgery, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, Shanghai, China
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Guo RS, Yu Y, Chen J, Chen YY, Shen N, Qiu M. Restoration of Brain Acid Soluble Protein 1 Inhibits Proliferation and Migration of Thyroid Cancer Cells. Chin Med J (Engl) 2017; 129:1439-46. [PMID: 27270539 PMCID: PMC4910367 DOI: 10.4103/0366-6999.183434] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Brain acid soluble protein 1 (BASP1) is identified as a novel potential tumor suppressor in several cancers. However, its role in thyroid cancer has not been investigated yet. In the present study, the antitumor activities of BASP1 against the growth and migration of thyroid cancer cells were evaluated. METHODS BASP1 expression in thyroid cancer tissues and normal tissues were examined by immunohistochemical staining and the association between its expression and prognosis was analyzed. pcDNA-BASP1 carrying full length of BASP1 cDNA was constructed to restore the expression of BASP1 in thyroid cancer cell lines (BHT-101 and KMH-2). The cell proliferation in vitro and in vivo was evaluated by WST-1 assay and xenograft tumor models, respectively. Cell cycle distribution after transfection was analyzed using flow cytometry. Cell apoptosis after transfection was examined by annexin V/propidium iodide assay. The migration was examined using transwell assay. RESULTS BASP1 expression was abundant in normal tissues while it is significantly decreased in cancer tissues (P = 0.000). pcDNA-BASP1 restored the expression of BASP1 and significantly inhibited the growth of BHT-101 and KMH-2 cells as well as xenograft tumors in nude mice (P = 0.000). pcDNA-BASP1 induced G1 arrest and apoptosis in BHT-101 and KMH-2 cells. In addition, pcDNA-BASP1 significantly inhibited the cell migration. CONCLUSIONS Downregulation of BASP1 expression may play a role in the tumorigenesis of thyroid cancer. Restoration of BASP1 expression exerted extensive antitumor activities against growth and migration of thyroid cancer cells, which suggested that BASP1 gene might act as a potential therapeutic agent for the treatment of thyroid cancer.
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Affiliation(s)
- Run-Sheng Guo
- Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 201705; Department of General Surgery, Jiading Central Hospital, Shanghai 201822, China
| | - Yue Yu
- Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Jun Chen
- Department of Pathology, Jiading Central Hospital, Shanghai 201822, China
| | - Yue-Yu Chen
- Department of General Surgery, Jiading Central Hospital, Shanghai 201822, China
| | - Na Shen
- Department of Otorhinolaryngology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ming Qiu
- Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 201705, China
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Yu D, Geng H, Liu Z, Zhao L, Liang Z, Zhang Z, Xie D, Wang Y, Zhang T, Min J, Zhong C. Cigarette smoke induced urocystic epithelial mesenchymal transition via MAPK pathways. Oncotarget 2017; 8:8791-8800. [PMID: 28060741 PMCID: PMC5352442 DOI: 10.18632/oncotarget.14456] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 12/06/2016] [Indexed: 02/07/2023] Open
Abstract
Cigarette smoke has been shown to be a major risk factor for bladder cancer. Epithelial-mesenchymal transition (EMT) is a crucial process in cancer development. The role of MAPK pathways in regulating cigarette smoke-triggered urocystic EMT remains to be elucidated. Human normal urothelial cells and BALB/c mice were used as in vitro and in vivo cigarette smoke exposure models. Exposure of human normal urothelial cells to cigarette smoke induced morphological change, enhanced migratory and invasive capacities, reduced epithelial marker expression and increased mesenchymal marker expression, along with the activation of MAPK pathways. Moreover, we revealed that ERK1/2 and p38 inhibitors, but rather JNK inhibitor, effectively attenuated cigarette smoke-induced urocystic EMT. Importantly, the regulatory function of ERK1/2 and p38 pathways in cigarette smoke-triggered urocystic EMT was further confirmed in mice exposed to CS for 12 weeks. These findings could provide new insight into the molecular mechanisms of cigarette smoke-associated bladder cancer development as well as its potential intervention.
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Affiliation(s)
- Dexin Yu
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Hao Geng
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Zhiqi Liu
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Li Zhao
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Zhaofeng Liang
- Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Jiangsu 212013, China
| | - Zhiqiang Zhang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Dongdong Xie
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Yi Wang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Tao Zhang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Jie Min
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Caiyun Zhong
- Department of Toxicology and Nutritional Science, School of Public Health, Nanjing Medical University, Nanjing 210029, China
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Congenital Cataract in Gpr161vl/vl Mice Is Modified by Proximal Chromosome 15. PLoS One 2017; 12:e0170724. [PMID: 28135291 PMCID: PMC5279759 DOI: 10.1371/journal.pone.0170724] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Accepted: 01/10/2017] [Indexed: 11/24/2022] Open
Abstract
The morphology and severity of human congenital cataract varies even among individuals with the same mutation, suggesting that genetic background modifies phenotypic penetrance. The spontaneous mouse mutant, vacuolated lens (vl), arose on the C3H/HeSnJ background. The mutation disrupts secondary lens fiber development by E16.5, leading to full penetrance of congenital cataract. The vl locus was mapped to a frameshift deletion in the orphan G protein-coupled receptor, Gpr161, which is expressed in differentiating lens fiber cells. When Gpr161vl/vl C3H mice are crossed to MOLF/EiJ mice an unexpected rescue of cataract is observed, suggesting that MOLF modifiers affect cataract penetrance. Subsequent QTL analysis mapped three modifiers (Modvl3-5: Modifier of vl) and in this study we characterized Modvl4 (Chr15; LOD = 4.4). A Modvl4MOLF congenic was generated and is sufficient to rescue congenital cataract and the lens fiber defect at E16.5. Additional phenotypic analysis on three subcongenic lines narrowed down the interval from 55 to 15Mb. In total only 18 protein-coding genes and 2 micro-RNAs are in this region. Fifteen of the 20 genes show detectable expression in the E16.5 eye. Subsequent expression studies in Gpr161vl/vl and subcongenic E16.5 eyes, bioinformatics analysis of C3H/MOLF polymorphisms, and the biological relevancy of the genes in the interval identified three genes (Cdh6, Ank and Trio) that likely contribute to the rescue of the lens phenotype. These studies demonstrate that modification of the Gpr161vl/vl cataract phenotype is likely due to genetic variants in at least one of three closely linked candidate genes on proximal Chr15.
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Hashemi ZS, Khalili S, Forouzandeh Moghadam M, Sadroddiny E. Lung cancer and miRNAs: a possible remedy for anti-metastatic, therapeutic and diagnostic applications. Expert Rev Respir Med 2017; 11:147-157. [DOI: 10.1080/17476348.2017.1279403] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Zahra Sadat Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Saeed Khalili
- Department of Clinical Laboratory Sciences, Dezful University of Medical Sciences, Dezful, Iran
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mehdi Forouzandeh Moghadam
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Esmaeil Sadroddiny
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
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