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Mansour RM, El-Sayyad GS, Abulsoud AI, Hemdan M, Faraag AHI, Ali MA, Elsakka EGE, Abdelmaksoud NM, Abdallah AK, Mahdy A, Ashraf A, Zaki MB, Elrebehy MA, Mohammed OA, Abdel-Reheim MA, Abdel Mageed SS, Alam Eldein KM, Doghish AS. The role of miRNAs in pathogenesis, diagnosis, and therapy of Helicobacter pylori infection, gastric cancer-causing bacteria: Special highlights on nanotechnology-based therapy. Microb Pathog 2025; 205:107646. [PMID: 40348207 DOI: 10.1016/j.micpath.2025.107646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/24/2025] [Accepted: 04/28/2025] [Indexed: 05/14/2025]
Abstract
Helicobacter pylori (H. pylori) infection and consequent inflammation in the stomach are widely recognized as major contributors to gastric cancer (GC) development. Recent investigations have placed considerable emphasis on uncovering the controlling influence of small RNA molecules known as microRNAs (miRNAs) in H. pylori-related diseases, particularly gastric cancer. This review aims to offer a comprehensive understanding of the intricate roles fulfilled by miRNAs in conditions associated with H. pylori infection. Exploring miRNA biogenesis pathways reveals their intimate connection with H. pylori infection, shedding light on the underlying molecular mechanisms driving disease progression and identifying potential intervention targets. An examination of epidemiological data surrounding H. pylori infection, including prevalence, risk factors, and transmission routes, underscores the imperative for preventive measures and targeted interventions. Incorporating insights from miRNA-related research into these strategies holds promise for enhancing their efficacy in controlling H. pylori spread. The symptoms, underlying mechanisms, and virulent characteristics of the bacteria highlight the intricate relationship between H. pylori and host cells, influencing the course of diseases. Within this complex web, miRNAs play pivotal roles, regulating various facets of H. pylori's development. MicroRNAs intricately involved in directing the immune response against H. pylori infection serve as key players in molding host defense mechanisms and impacting the bacterium's evasion tactics. Utilizing this knowledge holds the potential to drive forward groundbreaking therapeutic strategies. The diagnostic and prognostic capabilities of miRNAs in H. pylori infection highlight their effectiveness as non-invasive indicators for identifying diseases and evaluating risk. Integration of miRNA signatures into diagnostic algorithms holds promise for enhancing early detection and management of H. pylori-related diseases. MiRNA-based therapeutics offer a promising avenue for combatting H. pylori-induced gastric cancer, targeting specific molecular pathways implicated in tumorigenesis. H. pylori infection induces dysregulation of several miRNAs that contribute to antibiotic resistance, inflammation, and gastric cancer progression, including downregulation of tumor-suppressive miR-7 and miR-153 and upregulation of oncogenic miR-671-5p and miR-155-5p, which promote carcinogenesis and inflammation. Additionally, H. pylori manipulates host immune responses by upregulating miRNAs such as let-7f-5p, let-7i-5p, miR-146b-5p, and miR-185-5p that suppress HLA class II expression and antigen presentation, facilitating immune evasion and chronic gastritis that predispose to gastric cancer. Future research endeavors should focus on refining these therapeutic modalities and identifying novel targets to optimize clinical outcomes. By elucidating the multifaceted roles of miRNAs in H. pylori infection, this review provides invaluable insights into disease pathogenesis, diagnostics, and therapeutics, and the role of some nanoparticles in combating the H. pylori infection. Continued research efforts are imperative for translating these insights into clinical practice and addressing the global burden of H. pylori-related diseases.
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Affiliation(s)
- Reda M Mansour
- Zoology and Entomology Department, Faculty of Science, Helwan University, Helwan, 11795, Egypt; Molecular Biology and Biotechnology Department, School of Biotechnology, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
| | - Gharieb S El-Sayyad
- Department of Medical Analysis Technology, Faculty of Applied Health Sciences Technology, Badr University in Cairo (BUC), Cairo, Egypt; Drug Microbiology Lab., Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt.
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11231, Egypt; Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt.
| | - Mohamed Hemdan
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
| | - Ahmed H I Faraag
- Botany and Microbiology Department, Faculty of Science, Helwan University, Helwan, 11795, Egypt; Medical Department, School of Biotechnology, Badr University in Cairo, Badr City, Cairo, 11829, Egypt.
| | - Mohamed A Ali
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11231, Egypt.
| | - Nourhan M Abdelmaksoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt.
| | - Asmaa K Abdallah
- Botany and Microbiology Department, Faculty of Science, Benha University, 13518 Benha, Egypt.
| | - Ahmed Mahdy
- Molecular Biology and Biotechnology Department, School of Biotechnology, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
| | - Alaa Ashraf
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
| | - Mohamed Bakr Zaki
- Biochemistry, Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt; Department of Biochemistry, Faculty of Pharmacy, Menoufia National University, km Cairo-Alexandria Agricultural Road, Menofia, Egypt.
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Galala University, New Galala City, 43713, Suez, Egypt.
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | | | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
| | - Khaled M Alam Eldein
- Molecular Biology and Biotechnology Department, School of Biotechnology, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
| | - Ahmed S Doghish
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11231, Egypt; Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
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2
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Xu H, Huang K, Shi M, Gong H, Han M, Tian W, Wang X, Zhang D. MicroRNAs in Helicobacter pylori-infected gastric cancer: Function and clinical application. Pharmacol Res 2024; 205:107216. [PMID: 38761883 DOI: 10.1016/j.phrs.2024.107216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/10/2024] [Accepted: 05/11/2024] [Indexed: 05/20/2024]
Abstract
Gastric cancer (GC) is the leading cause of cancer-related death worldwide, and it is associated with a combination of genetic, environmental, and microbial risk factors. Helicobacter pylori (H. pylori) is classified as a type I carcinogen, however, the exact regulatory mechanisms underlying H. pylori-induced GC are incompletely defined. MicroRNAs (miRNAs), one of small non-coding RNAs, negatively regulate gene expression through binding to their target genes. Dysregulation of miRNAs is crucial in human cancer. A noteworthy quantity of aberrant miRNAs induced by H. pylori through complex regulatory networks have been identified. These miRNAs substantially affect genetic instability, cell proliferation, apoptosis, invasion, metastasis, autophagy, chemoresistance, and the tumor microenvironment, leading to GC development and progression. Importantly, some H. pylori-associated miRNAs hold promise as therapeutic tools and biomarkers for GC prevention, diagnosis, and prognosis. Nonetheless, clinical application of miRNAs remains in its infancy with multiple issues, including sensitivity and specificity, stability, reliable delivery systems, and off-target effects. Additional research on the specific molecular mechanisms and more clinical data are still required. This review investigated the biogenesis, regulatory mechanisms, and functions of miRNAs in H. pylori-induced GC, offering novel insights into the potential clinical applications of miRNA-based therapeutics and biomarkers.
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Affiliation(s)
- Huimei Xu
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Ke Huang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing, School of Stomatology, Lanzhou University, Lanzhou 730030, China
| | - Mingxuan Shi
- Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing, School of Stomatology, Lanzhou University, Lanzhou 730030, China
| | - Hang Gong
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Mengyu Han
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Wenji Tian
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Xiaoying Wang
- Department of Emergency, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.
| | - Dekui Zhang
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.
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Kashyap D, Rele S, Bagde PH, Saini V, Chatterjee D, Jain AK, Pandey RK, Jha HC. Comprehensive insight into altered host cell-signaling cascades upon Helicobacter pylori and Epstein-Barr virus infections in cancer. Arch Microbiol 2023; 205:262. [PMID: 37310490 DOI: 10.1007/s00203-023-03598-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/14/2023]
Abstract
Cancer is characterized by mutagenic events that lead to disrupted cell signaling and cellular functions. It is one of the leading causes of death worldwide. Literature suggests that pathogens, mainly Helicobacter pylori and Epstein-Barr virus (EBV), have been associated with the etiology of human cancer. Notably, their co-infection may lead to gastric cancer. Pathogen-mediated DNA damage could be the first and crucial step in the carcinogenesis process that modulates numerous cellular signaling pathways. Altogether, it dysregulates the metabolic pathways linked with cell growth, apoptosis, and DNA repair. Modulation in these pathways leads to abnormal growth and proliferation. Several signaling pathways such RTK, RAS/MAPK, PI3K/Akt, NFκB, JAK/STAT, HIF1α, and Wnt/β-catenin are known to be altered in cancer. Therefore, this review focuses on the oncogenic roles of H. pylori, EBV, and its associated signaling cascades in various cancers. Scrutinizing these signaling pathways is crucial and may provide new insights and targets for preventing and treating H. pylori and EBV-associated cancers.
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Affiliation(s)
- Dharmendra Kashyap
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | - Samiksha Rele
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | - Pranit Hemant Bagde
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | - Vaishali Saini
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | | | | | - Rajan Kumar Pandey
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177, Solna, Sweden
| | - Hem Chandra Jha
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India.
- Centre for Rural Development and Technology, Indian Institute of Technology Indore, Madhya Pradesh, 453552, Indore, India.
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4
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Gu NX, Guo YR, Lin SE, Wang YH, Lin IH, Chen YF, Yen Y. Frizzled 7 modulates goblet and Paneth cell fate, and maintains homeostasis in mouse intestine. Development 2023; 150:287020. [PMID: 36691900 PMCID: PMC10112897 DOI: 10.1242/dev.200932] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 01/17/2023] [Indexed: 01/25/2023]
Abstract
Intestinal homeostasis depends on interactions between the intestinal epithelium, the immune system and the microbiota. Because of these complicated connections, there are many problems that need to be solved. Current research has indicated that genes targeted by Wnt signaling are responsible for controlling intestinal stem cell fate and for modulating intestinal homeostasis. Our data show that loss of frizzled 7 (Fzd7), an important element in Wnt signaling, interrupts the differentiation of mouse intestinal stem cells into absorptive progenitors instead of secretory progenitors (precursors of goblet and Paneth cells). The alteration in canonical Wnt and Notch signaling pathways interrupts epithelial homeostasis, resulting in a decrease in physical protection in the intestine. Several phenotypes in our Fzd7-deleted model were similar to the features of enterocolitis, such as shortened intestines, decreased numbers of goblet cells and Paneth cells, and severe inflammation. Additionally, loss of Fzd7 exacerbated the defects in a chemical-induced colitis model and could initiate tumorigenesis. These findings may provide important information for the discovery of efficient therapeutic methods to treat enterocolitis and related cancers in the intestines.
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Affiliation(s)
- Nai-Xin Gu
- The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11529, Taiwan
| | - Yu-Ru Guo
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Sey-En Lin
- Department of Anatomic Pathology, New Taipei Municipal Tucheng Hospital, Chang Gung Memorial Hospital and Chang Gung University, New Taipei City 236017, Taiwan
| | - Yen-Hsin Wang
- Graduate Institute of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - I-Hsuan Lin
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yi-Fan Chen
- The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11529, Taiwan
- Graduate Institute of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031 , Taiwan
| | - Yun Yen
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Cancer Center, Taipei Municipal WanFang Hospital, Taipei 116081 , Taiwan
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5
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Tong T, Zhou Y, Huang Q, Xiao C, Bai Q, Deng B, Chen L. The regulation roles of miRNAs in Helicobacter pylori infection. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023:10.1007/s12094-023-03094-9. [PMID: 36781601 DOI: 10.1007/s12094-023-03094-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 01/17/2023] [Indexed: 02/15/2023]
Abstract
Helicobacter pylori is a kind of Gram-negative bacteria that parasitizes on human gastric mucosa. Helicobacter pylori infection is very common in human beings, which often causes gastrointestinal diseases, including chronic gastritis, duodenal ulcer and gastric cancer. MicroRNAs are a group of endogenous non-coding single stranded RNAs, which play an important role in cell proliferation, differentiation, autophagy, apoptosis and inflammation. In recent years, relevant studies have found that the expression of microRNA is changed after Helicobacter pylori infection, and then regulate the biological process of host cells. This paper reviews the regulation role of microRNAs on cell biological behavior through different signal pathways after Helicobacter pylori infection.
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Affiliation(s)
- Ting Tong
- Department of Public Health Laboratory Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hengyang Engineering Technology Research Center, Hengyang, 421001, Hunan, China
| | - You Zhou
- Department of Public Health Laboratory Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hengyang Engineering Technology Research Center, Hengyang, 421001, Hunan, China
| | - Qiaoling Huang
- Department of Public Health Laboratory Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hengyang Engineering Technology Research Center, Hengyang, 421001, Hunan, China
| | - Cui Xiao
- Department of Public Health Laboratory Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hengyang Engineering Technology Research Center, Hengyang, 421001, Hunan, China
| | - Qinqin Bai
- Department of Public Health Laboratory Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hengyang Engineering Technology Research Center, Hengyang, 421001, Hunan, China
| | - Bo Deng
- Department of Public Health Laboratory Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,Hengyang Engineering Technology Research Center, Hengyang, 421001, Hunan, China
| | - Lili Chen
- Department of Public Health Laboratory Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,Hunan Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,Hengyang Engineering Technology Research Center, Hengyang, 421001, Hunan, China.
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6
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Ding Y, Chen Y, Yang X, Xu P, Jing J, Miao Y, Mao M, Xu J, Wu X, Lu Z. An integrative analysis of the lncRNA-miRNA-mRNA competitive endogenous RNA network reveals potential mechanisms in the murine hair follicle cycle. Front Genet 2022; 13:931797. [DOI: 10.3389/fgene.2022.931797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 10/11/2022] [Indexed: 11/13/2022] Open
Abstract
Alopecia is a common progressive disorder associated with abnormalities of the hair follicle cycle. Hair follicles undergo cyclic phases of hair growth (anagen), regression (catagen), and rest (telogen), which are precisely regulated by various mechanisms. However, the specific mechanism associated with hair follicle cycling, which includes noncoding RNAs and regulation of competitive endogenous RNA (ceRNA) network, is still unclear. We obtained data from publicly available databases and performed real-time quantitative polymerase chain reaction validations. These analyses revealed an increase in the expression of miRNAs and a decrease in the expression of target mRNAs and lncRNAs from the anagen to telogen phase of the murine hair follicle cycle. Subsequently, we constructed the ceRNA networks and investigated their functions using enrichment analysis. Furthermore, the androgenetic alopecia (AGA) microarray data analysis revealed that several novel alopecia-related genes were identified in the ceRNA networks. Lastly, GSPT1 expression was detected using immunohistochemistry. Our analysis revealed 11 miRNAs (miR-148a-3p, miR-146a-5p, miR-200a-3p, miR-30e-5p, miR-30a-5p, miR-27a-3p, miR-143-3p, miR-27b-3p, miR-126a-3p, miR-378a-3p, and miR-22-3p), 9 target mRNAs (Atp6v1a, Cdkn1a, Gadd45a, Gspt1, Mafb, Mitf, Notch1, Plk2, and Slc7a5), and 2 target lncRNAs (Neat1 and Tug1) were differentially expressed in hair follicle cycling. The ceRNA networks were made of 12 interactive miRNA-mRNA pairs and 13 miRNA-lncRNA pairs. The functional enrichment analysis revealed the enrichment of hair growth–related signaling pathways. Additionally, GSPT1 was downregulated in androgenetic alopecia patients, possibly associated with alopecia progression. The ceRNA network identified by our analysis could be involved in regulating the hair follicle cycle.
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Chen C, Luo L, Xu C, Yang X, Liu T, Luo J, Shi W, Yang L, Zheng Y, Yang J. Tumor specificity of WNT ligands and receptors reveals universal squamous cell carcinoma oncogenes. BMC Cancer 2022; 22:790. [PMID: 35850748 PMCID: PMC9295300 DOI: 10.1186/s12885-022-09898-2] [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: 01/22/2022] [Accepted: 07/11/2022] [Indexed: 11/10/2022] Open
Abstract
Background The WNT signal pathway has myriad family members, which are broadly involved in embryonic development and human cancer. Over-activation of WNT-β-Catenin signaling promotes cancer cell proliferation and survival. However, how diverse components of WNT signaling specifically engaged in distinct tumor types remains incompletely understood. Methods We analyzed the transcriptomic profiling of WNT ligands and receptors/co-receptors among 26 different tumor types to identify their expression pattern, and further verified these results using clinical oral squamous cell carcinoma (OSCC) and lung squamous cell carcinoma (LUSC) samples. At the same time, we also detected WNT7B expression in oral inflammation and carcinoma, and constructed stable WNT7B knockdown OSCC cell lines to study the effects of WNT7B on the cell migration and invasion ability. Results We found a group of tumor-specific WNT members, including a panel of squamous cell carcinomas (SCCs) specific upregulated WNT ligands and receptors, WNT5A, WNT7B, FZD7 and GPC1. We further revealed a significant correlation between these protein expression characteristics and clinical outcomes of OSCC and LUSC patients. Moreover, WNT7B was demonstrated to contribute to the development of oral chronic inflammation and OSCC, partly due to promoting the invasion ability of tumor cells. Conclusions These results demonstrate that the function of WNT ligands and receptors in specific tumors depends on the origination of tumor tissue type. Collectively, they support the use of WNT components as a highly specific target for pan-tissue-type originated tumors. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09898-2.
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Affiliation(s)
- Cheng Chen
- Department of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610054, China.,School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Lunan Luo
- Department of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610054, China.,School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Changling Xu
- Department of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610054, China.,School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Xia Yang
- Department of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610054, China.,School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Ting Liu
- Department of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610054, China.,School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Jingyue Luo
- Department of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610054, China.,School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Wen Shi
- Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing, 100191, China
| | - Lu Yang
- Department of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610054, China.,School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Yi Zheng
- Department of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610054, China. .,School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China.
| | - Jing Yang
- Department of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610054, China. .,School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China.
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8
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Larasati Y, Boudou C, Koval A, Katanaev VL. Unlocking the Wnt pathway: Therapeutic potential of selective targeting FZD 7 in cancer. Drug Discov Today 2021; 27:777-792. [PMID: 34915171 DOI: 10.1016/j.drudis.2021.12.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/09/2021] [Accepted: 12/09/2021] [Indexed: 02/08/2023]
Abstract
The Wnt signaling is of paramount pathophysiological importance. Despite showing promising anticancer activities in pre-clinical studies, current Wnt pathway inhibitors face complications in clinical trials resulting from on-target toxicity. Hence, the targeting of pathway component(s) that are essential for cancer but dispensable for normal physiology is key to the development of a safe Wnt signaling inhibitor. Frizzled7 (FZD7) is a Wnt pathway receptor that is redundant in healthy tissues but crucial in various cancers. FZD7 modulates diverse aspects of carcinogenesis, including cancer growth, metastasis, maintenance of cancer stem cells, and chemoresistance. In this review, we describe state-of-the-art knowledge of the functions of FZD7 in carcinogenesis and adult tissue homeostasis. Next, we overview the development of small molecules and biomolecules that target FZD7. Finally, we discuss challenges and possibilities in developing FZD7-selective antagonists.
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Affiliation(s)
- Yonika Larasati
- Department of Cell Physiology and Metabolism, Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
| | - Cédric Boudou
- Department of Cell Physiology and Metabolism, Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
| | - Alexey Koval
- Department of Cell Physiology and Metabolism, Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
| | - Vladimir L Katanaev
- Department of Cell Physiology and Metabolism, Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; School of Biomedicine, Far Eastern Federal University, 690922 Vladivostok, Russia.
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9
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Zheng L, Wu Y, Shen L, Liang X, Yang Z, Li S, Li T, Shang W, Shao W, Wang Y, Liu F, Ma L, Jia J. Mechanisms of JARID1B Up-Regulation and Its Role in Helicobacter pylori-Induced Gastric Carcinogenesis. Front Oncol 2021; 11:757497. [PMID: 34778074 PMCID: PMC8581301 DOI: 10.3389/fonc.2021.757497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 10/07/2021] [Indexed: 11/13/2022] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Helicobacter pylori infection can induce GC through a serial cascade of events, with emerging evidence suggesting the important role of epigenetic alterations in the development and progression of the disease. Here, we report on mechanisms responsible for Jumonji AT-rich interactive domain1B (JARID1B) upregulation in GC and its role in the malignant transformation induced by H. pylori infection. We found that upregulation of JARID1B was associated with poorer prognosis, greater tumor purity, and less immune cell infiltration into the tumor. Mechanistically, we showed that the upregulation of JARID1B in human GC was attributed to JARID1B amplification and its induction by H. pylori infection. Furthermore, we identified miR-29c as a negative regulator of JARID1B in GC. H. pylori caused downregulation of miR-29c in human GC and thereby contributed to JARID1B upregulation through relieving posttranscriptional regulation. Functionally, we showed that knockdown of JARID1B reduced GC cell proliferation induced by H. pylori infection. Subsequently, cyclinD1 (CCND1), a key molecule in GC, was shown to be a target gene of JARID1B. In conclusion, these results suggest that JARID1B may be an oncogene upregulated in human GC and could represent a novel therapeutic target to prevent malignant transformation induced by H. pylori infection.
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Affiliation(s)
- Lixin Zheng
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Yujiao Wu
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Li Shen
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Xiuming Liang
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Zongcheng Yang
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Shuyan Li
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Tongyu Li
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Wenjing Shang
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Wei Shao
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Yue Wang
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Fen Liu
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Lin Ma
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Jihui Jia
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Infection and Immunology, School of Basic Medical Sciences, Shandong University, Jinan, China
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10
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Smith AJ, Sompel KM, Elango A, Tennis MA. Non-Coding RNA and Frizzled Receptors in Cancer. Front Mol Biosci 2021; 8:712546. [PMID: 34671643 PMCID: PMC8521042 DOI: 10.3389/fmolb.2021.712546] [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: 05/20/2021] [Accepted: 08/30/2021] [Indexed: 12/18/2022] Open
Abstract
Frizzled receptors have been long recognized for their role in Wnt/β-catenin signaling, a pathway known for its tumorigenic effects. More recent studies of frizzled receptors include efforts to understand non-coding RNA (ncRNA) regulation of these receptors in cancer. It has become increasingly clear that ncRNA molecules are important for regulating the expression of both oncogenic and tumor-suppressive proteins. The three most commonly described ncRNA molecules are microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Here, we review ncRNA molecules that directly or indirectly affect frizzled protein expression and downstream signaling. Exploring these interactions highlights the potential of incorporating ncRNA molecules into cancer prevention and therapy strategies that target frizzled receptors. Previous investigations of frizzled receptors and ncRNA have established strong promise for a role in cancer progression, but additional studies are needed to provide the substantial pre-clinical evidence required to translate findings to clinical applications.
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11
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Khalili-Tanha G, Moghbeli M. Long non-coding RNAs as the critical regulators of doxorubicin resistance in tumor cells. Cell Mol Biol Lett 2021; 26:39. [PMID: 34425750 PMCID: PMC8381522 DOI: 10.1186/s11658-021-00282-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 08/17/2021] [Indexed: 12/16/2022] Open
Abstract
Resistance against conventional chemotherapeutic agents is one of the main reasons for tumor relapse and poor clinical outcomes in cancer patients. Various mechanisms are associated with drug resistance, including drug efflux, cell cycle, DNA repair and apoptosis. Doxorubicin (DOX) is a widely used first-line anti-cancer drug that functions as a DNA topoisomerase II inhibitor. However, DOX resistance has emerged as a large hurdle in efficient tumor therapy. Furthermore, despite its wide clinical application, DOX is a double-edged sword: it can damage normal tissues and affect the quality of patients’ lives during and after treatment. It is essential to clarify the molecular basis of DOX resistance to support the development of novel therapeutic modalities with fewer and/or lower-impact side effects in cancer patients. Long non-coding RNAs (lncRNAs) have critical roles in the drug resistance of various tumors. In this review, we summarize the state of knowledge on all the lncRNAs associated with DOX resistance. The majority are involved in promoting DOX resistance. This review paves the way to introducing an lncRNA panel marker for the prediction of the DOX response and clinical outcomes for cancer patients.
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Affiliation(s)
- Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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12
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Wang C, Hu Y, Yang H, Wang S, Zhou B, Bao Y, Huang Y, Luo Q, Yang C, Xie X, Yang S. Function of Non-coding RNA in Helicobacter pylori-Infected Gastric Cancer. Front Mol Biosci 2021; 8:649105. [PMID: 34046430 PMCID: PMC8144459 DOI: 10.3389/fmolb.2021.649105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is a common malignant tumor of the digestive system. Its occurrence and development are the result of a combination of genetic, environmental, and microbial factors. Helicobacter pylori infection is a chronic infection that is closely related to the occurrence of gastric tumorigenesis. Non-coding RNA has been demonstrated to play a very important role in the organism, exerting a prominent role in the carcinogenesis, proliferation, apoptosis, invasion, metastasis, and chemoresistance of tumor progression. H. pylori infection affects the expression of non-coding RNA at multiple levels such as genetic polymorphisms and signaling pathways, thereby promoting or inhibiting tumor progression or chemoresistance. This paper mainly introduces the relationship between H. pylori-infected gastric cancer and non-coding RNA, providing a new perspective for gastric cancer treatment.
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Affiliation(s)
- Chao Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yiyang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Huan Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Sumin Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Bo Zhou
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yulu Bao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yu Huang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Qiang Luo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Chuan Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Xia Xie
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
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13
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Ouyang J, Xie Z, Lei X, Tang G, Gan R, Yang X. Clinical crosstalk between microRNAs and gastric cancer (Review). Int J Oncol 2021; 58:7. [PMID: 33649806 PMCID: PMC7895535 DOI: 10.3892/ijo.2021.5187] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
Globally, there were over 1 million new gastric cancer (GC) patients in 2018 and GC has become the sixth most common cancer worldwide. GC caused 783,000 deaths worldwide in 2018, making it the third most deadly cancer type. miRNAs are short (~22 nucleotides in length) non‑coding RNA molecules, which can regulate gene expression passively at a post‑transcriptional level. There are more and more in‑depth studies on miRNAs. There are numerous conclusive evidences that there is an inseparable link between miRNAs and GC. miRNAs can affect the entire process of GC, including the oncogenesis, development, diagnosis, treatment and prognosis of GC. Although many miRNAs have been linked to GC, few can be applied to clinical practice. This review takes the clinical changes of GC as a clue and summarizes the miRNAs related to GC that have confirmed the mechanism of action in the past three years. Through in‑depth study and understanding of the mechanism of those miRNAs, we predict their possible clinical uses, and suggest some new insights to overcome GC.
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Affiliation(s)
- Jing Ouyang
- Institute of Pharmacy and Pharmacology, University of South China
| | - Zhizhong Xie
- Institute of Pharmacy and Pharmacology, University of South China
| | - Xiaoyong Lei
- Institute of Pharmacy and Pharmacology, University of South China
| | - Guotao Tang
- Institute of Pharmacy and Pharmacology, University of South China
| | - Runliang Gan
- Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaoyan Yang
- Institute of Pharmacy and Pharmacology, University of South China
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14
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Cui Y, Huang S, Cao J, Ye J, Huang H, Liao D, Yang Y, Chen W, Pu R. Combined targeting of vascular endothelial growth factor C (VEGFC) and P65 using miR-27b-3p agomir and lipoteichoic acid in the treatment of gastric cancer. J Gastrointest Oncol 2021; 12:121-132. [PMID: 33708430 DOI: 10.21037/jgo-21-12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Gastric cancer is the second leading cancer-related mortality worldwide and more effective treatment strategies are urgently needed to combat the disease. Using lipoteichoic acid (LTA) and miR-27b-3p agomir, we aimed to assess the efficacy of this combination of therapies in treating gastric cancer. Methods The RNA levels of miR-27b-3p, FOXO3, MET, KRAS, vascular endothelial growth factor C (VEGFC), TSC1, and P65 were analyzed by quantified-PCR (Q-PCR) and the cell viability of AGS cells was analyzed by MTT. Confirm Luciferase reporter assays were used to explore the putative miR-27b-3p binding sites and Western blot analyzed the protein level of GAPDH, VEGFC, P65, AKT, and phosphorylated-AKT (p-AKT). The level of P65 in both the cytoplasm and nucleus of AGS cells was visualized by immunofluorescence assay. Subcutaneous xenograft models of gastric cancer were established, and mice were treated with miR-27b-3p agomir, LTA, or both. Hematoxylin-eosin staining and Ki-67 immunohistochemistry analysis of tumor tissues were then performed. Results The results showed that the decreased expression of miR-27b-3p in gastric cancer cell lines inhibited the viability of AGS cells, and VEGFC was confirmed as the target of miR-27b-3p. In addition, ectopic expression of miR-27b-3p significantly inhibited the AKT pathway in AGS and N87 cells, and LTA suppressed the proliferation of gastric cancer cells by inhibiting the NF-κB pathway. In an established xenograft model, both miR-27b-3p agomir alone and LTA treatment alone inhibited tumor growth and treatment which combined the two showed an even stronger inhibitory effect. Conclusions Taken together, the combined use of LTA and miR-27b-3p agomir exhibited a synergistic effect in the treatment of gastric cancer.
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Affiliation(s)
- Yejia Cui
- Department of Clinical Laboratory, SSL Central Hospital of Dongguan City, Dongguan Third Clinical Hospital of Guangdong Medical University, Dongguan, China
| | - Shaolong Huang
- Department of Clinical Laboratory, SSL Central Hospital of Dongguan City, Dongguan Third Clinical Hospital of Guangdong Medical University, Dongguan, China.,Department of Clinical Laboratory, Binhaiwan Central Hospital of Dongguan, Dongguan, China
| | - Jin Cao
- Department of Clinical Laboratory, SSL Central Hospital of Dongguan City, Dongguan Third Clinical Hospital of Guangdong Medical University, Dongguan, China
| | - Jinjun Ye
- Department of Clinical Laboratory, SSL Central Hospital of Dongguan City, Dongguan Third Clinical Hospital of Guangdong Medical University, Dongguan, China
| | - Haohai Huang
- Department of Clinical Pharmacy, SSL Central Hospital of Dongguan City, Dongguan Third Clinical Hospital of Guangdong Medical University, Dongguan, China
| | - Dan Liao
- Department of Gynecology and Obstetrics, SSL Central Hospital of Dongguan City, Dongguan Third Clinical Hospital of Guangdong Medical University, Dongguan, China
| | - Yufeng Yang
- Department of Pathology, SSL Central Hospital of Dongguan City, Dongguan Third Clinical Hospital of Guangdong Medical University, Dongguan, China
| | - Wanchan Chen
- Department of Clinical Laboratory, SSL Central Hospital of Dongguan City, Dongguan Third Clinical Hospital of Guangdong Medical University, Dongguan, China
| | - Rong Pu
- Department of Clinical Laboratory, SSL Central Hospital of Dongguan City, Dongguan Third Clinical Hospital of Guangdong Medical University, Dongguan, China
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15
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Dai Y, Cheng Z, Fricke DR, Zhao H, Huang W, Zhong Q, Zhu P, Zhang W, Wu Z, Lin Q, Zhu H, Liu Y, Qian T, Fu L, Cui L, Zeng T. Prognostic role of Wnt and Fzd gene families in acute myeloid leukaemia. J Cell Mol Med 2021; 25:1456-1467. [PMID: 33417298 PMCID: PMC7875934 DOI: 10.1111/jcmm.16233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 01/18/2023] Open
Abstract
Wnt-Fzd signalling pathway plays a critical role in acute myeloid leukaemia (AML) progression and oncogenicity. There is no study to investigate the prognostic value of Wnt and Fzd gene families in AML. Our study screened 84 AML patients receiving chemotherapy only and 71 also undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) from the Cancer Genome Atlas (TCGA) database. We found that some Wnt and Fzd genes had significant positive correlations. The expression levels of Fzd gene family were independent of survival in AML patients. In the chemotherapy group, AML patients with high Wnt2B or Wnt11 expression had significantly shorter event-free survival (EFS) and overall survival (OS); high Wnt10A expressers had significantly longer OS than the low expressers (all P < .05), whereas, in the allo-HSCT group, the expression levels of Wnt gene family were independent of survival. We further found that high expression of Wnt10A and Wnt11 had independent prognostic value, and the patients with high Wnt10A and low Wnt11 expression had the longest EFS and OS in the chemotherapy group. Pathway enrichment analysis showed that genes related to Wnt10A, Wnt11 and Wnt 2B were mainly enriched in 'cell morphogenesis involved in differentiation', 'haematopoietic cell lineage', 'platelet activation, signalling and aggregation' and 'mitochondrial RNA metabolic process' signalling pathways. Our results indicate that high Wnt2B and Wnt11 expression predict poor prognosis, and high Wnt10A expression predicts favourable prognosis in AML, but their prognostic effects could be neutralized by allo-HSCT. Combined Wnt10A and Wnt11 may be a novel prognostic marker in AML.
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Affiliation(s)
- Yifeng Dai
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhiheng Cheng
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Doerte R Fricke
- Department of Genetics, LSU Health Sciences Center, New Orleans, LA, USA
| | - Hongyou Zhao
- Institute of Engineering Medicine, Beijing Institute of Technology, Beijing, China
| | - Wenhui Huang
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qingfu Zhong
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Pei Zhu
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenjuan Zhang
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhihua Wu
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qing Lin
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Huoyan Zhu
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yan Liu
- Translational Medicine Center, Huaihe Hospital of Henan University, Kaifeng, China
| | - Tingting Qian
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lin Fu
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.,Department of Hematology, Huaihe Hospital of Henan University, Kaifeng, China.,Guangdong Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumor Microenvironment, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Longzhen Cui
- Translational Medicine Center, Huaihe Hospital of Henan University, Kaifeng, China
| | - Tiansheng Zeng
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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16
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Ghafouri-Fard S, Vafaee R, Shoorei H, Taheri M. MicroRNAs in gastric cancer: Biomarkers and therapeutic targets. Gene 2020; 757:144937. [PMID: 32640300 DOI: 10.1016/j.gene.2020.144937] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/09/2020] [Accepted: 07/01/2020] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are a group of non-coding RNAs that have critical roles in regulation of expression of genes. They can inhibit or decrease expression of target genes mostly via interaction with 3' untranslated region of their targets. Their crucial roles in the regulation of expression of tumor suppressor genes and oncogenes have potentiated them as contributors in tumorigenesis. Moreover, their stability in body fluids has enhanced their potential as cancer biomarkers. In the present review article, we describe the role of miRNAs in the pathogenesis of gastric cancer and advances in application of miRNAs as biomarkers and therapeutic targets in this kind of malignancy.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Vafaee
- Proteomics Research Center, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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17
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Koushyar S, Powell AG, Vincan E, Phesse TJ. Targeting Wnt Signaling for the Treatment of Gastric Cancer. Int J Mol Sci 2020; 21:E3927. [PMID: 32486243 PMCID: PMC7311964 DOI: 10.3390/ijms21113927] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/27/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023] Open
Abstract
The Wnt signaling pathway is evolutionarily conserved, regulating both embryonic development and maintaining adult tissue homeostasis. Wnt signaling controls several fundamental cell functions, including proliferation, differentiation, migration, and stemness. It therefore plays an important role in the epithelial homeostasis and regeneration of the gastrointestinal tract. Often, both hypo- or hyper-activation of the pathway due to genetic, epigenetic, or receptor/ligand alterations are seen in many solid cancers, such as breast, colorectal, gastric, and prostate. Gastric cancer (GC) is the fourth commonest cause of cancer worldwide and is the second leading cause of cancer-related death annually. Although the number of new diagnoses has declined over recent decades, prognosis remains poor, with only 15% surviving to five years. Geographical differences in clinicopathological features are also apparent, with epidemiological and genetic studies revealing GC to be a highly heterogeneous disease with phenotypic diversity as a result of etiological factors. The molecular heterogeneity associated with GC dictates that a single 'one size fits all' approach to management is unlikely to be successful. Wnt pathway dysregulation has been observed in approximately 50% of GC tumors and may offer a novel therapeutic target for patients who would otherwise have a poor outcome. This mini review will highlight some recent discoveries involving Wnt signaling in GC.
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Affiliation(s)
- Sarah Koushyar
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff CF24 4HQ, UK; (S.K.); (A.G.P.)
| | - Arfon G. Powell
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff CF24 4HQ, UK; (S.K.); (A.G.P.)
- Division of Cancer & Genetics, Cardiff University, Cardiff CF14 4XW, UK
| | - Elizabeth Vincan
- Victorian Infectious Diseases Reference Laboratory, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia;
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth WA 6102, Australia
| | - Toby J. Phesse
- The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne VIC 3000, Australia
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18
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Flanagan DJ, Vincan E, Phesse TJ. Wnt Signaling in Cancer: Not a Binary ON:OFF Switch. Cancer Res 2019; 79:5901-5906. [PMID: 31431458 PMCID: PMC7616966 DOI: 10.1158/0008-5472.can-19-1362] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/16/2019] [Accepted: 08/07/2019] [Indexed: 11/16/2022]
Abstract
In the March 1 issue of Cancer Research, we identified the Wnt receptor Fzd7 as an attractive therapeutic target for the treatment of gastric cancer. In summary, we showed that pharmacological inhibition of Wnt receptors, or genetic deletion of Fzd7, blocks the initiation and growth of gastric tumors. Inhibiting Fzd receptors, specifically Fzd7, inhibits the growth of gastric cancer cells even in the presence of adenomatous polyposis coli (Apc) mutation. Apc is located in the cytoplasm downstream of Fzd7 in the Wnt signaling cascade and APC mutations activate Wnt/β-catenin signaling, therefore, this result seems counterintuitive. Here, we analyze this result in greater detail in the context of current knowledge of Wnt signaling and discuss the wider implications of this aspect of Wnt signaling in other cancers.
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Affiliation(s)
| | - Elizabeth Vincan
- University of Melbourne and Victorian Infectious Diseases Reference Laboratory, Doherty Institute of Infection and Immunity, Melbourne, Australia.
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Australia
| | - Toby J Phesse
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, United Kingdom.
- Doherty Institute of Infection and Immunity, Melbourne, Australia
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19
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Parizadeh SM, Jafarzadeh-Esfehani R, Avan A, Ghandehari M, Goldani F, Parizadeh SM. The Prognostic and Predictive Value of microRNAs in Patients with H. pylori-positive Gastric Cancer. Curr Pharm Des 2019; 24:4639-4645. [PMID: 30636577 DOI: 10.2174/1381612825666190110144254] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/24/2018] [Accepted: 12/24/2018] [Indexed: 01/19/2023]
Abstract
Gastric cancer (GC) has a high mortality rate with a poor 5-year survival. Helicobacter pylori (H. pylori) is present as part of the normal flora of stomach. It is found in the gastric mucosa of more than half of the world population. This bacterium is involved in developing H. pylori-induced GC due to the regulation of different micro ribonucleic acid (miRNA or miR). miRNAs are small noncoding RNAs and are recognized as prognostic biomarkers for GC that may control gene expression. miRNAs may function as tumor suppressors, or oncogenes. In this review, we evaluated studies that investigated the ectopic expression of miRNAs in the prognosis of H. pylori positive and negative GC.
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Affiliation(s)
| | - Reza Jafarzadeh-Esfehani
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Ghandehari
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Islamic Azad University, Mashhad Branch, Mashhad, Iran
| | - Fatemeh Goldani
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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20
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Silva-García O, Valdez-Alarcón JJ, Baizabal-Aguirre VM. Wnt/β-Catenin Signaling as a Molecular Target by Pathogenic Bacteria. Front Immunol 2019; 10:2135. [PMID: 31611869 PMCID: PMC6776594 DOI: 10.3389/fimmu.2019.02135] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/27/2019] [Indexed: 12/31/2022] Open
Abstract
The Wnt/β-catenin signaling pathway is crucial to regulate cell proliferation and polarity, cell determination, and tissue homeostasis. The activation of Wnt/β-catenin signaling is based on the interaction between Wnt glycoproteins and seven transmembrane receptors-Frizzled (Fzd). This binding promotes recruitment of the scaffolding protein Disheveled (Dvl), which results in the phosphorylation of the co-receptor LRP5/6. The resultant molecular complex Wnt-Fzd-LRP5/6-Dvl forms a structural region for Axin interaction that disrupts Axin-mediated phosphorylation/degradation of the transcriptional co-activator β-catenin, thereby allowing it to stabilize and accumulate in the nucleus where it activates the expression of Wnt-dependent genes. Due to the prominent physiological function, the Wnt/β-catenin signaling must be strictly controlled because its dysregulation, which is caused by different stimuli, may lead to alterations in cell proliferation, apoptosis, and inflammation-associated cancer. The virulence factors from pathogenic bacteria such as Salmonella enterica sv Typhimurium, Helicobacter pylori, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Citrobacter rodentium, Clostridium difficile, Bacteroides fragilis, Escherichia coli, Haemophilus parasuis, Lawsonia intracellularis, Shigella dysenteriae, and Staphylococcus epidermidis employ a variety of molecular strategies to alter the appropriate functioning of diverse signaling pathways. Among these, Wnt/β-catenin has recently emerged as an important target of several virulence factors produced by bacteria. The mechanisms used by these factors to interfere with the activity of Wnt/β-catenin is diverse and include the repression of Wnt inhibitors' expression by the epigenetic modification of histones, blocking Wnt-Fzd ligand binding, activation or inhibition of β-catenin nuclear translocation, down- or up-regulation of Wnt family members, and inhibition of Axin-1 expression that promotes β-catenin activity. Such a variety of mechanisms illustrate an evolutionary co-adaptation of eukaryotic molecular signaling to a battery of soluble or structural components synthesized by pathogenic bacteria. This review gathers the recent efforts to elucidate the mechanistic details through which bacterial virulence factors modulate Wnt/β-catenin signaling and its physiological consequences concerning the inflammatory response and cancer.
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Affiliation(s)
| | - Juan J Valdez-Alarcón
- Centro Multidisciplinario de Estudios en Biotecnología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Mexico
| | - Víctor M Baizabal-Aguirre
- Centro Multidisciplinario de Estudios en Biotecnología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Mexico
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The Function of Lgr5+ Cells in the Gastric Antrum Does Not Require Fzd7 or Myc In Vivo. Biomedicines 2019; 7:biomedicines7030050. [PMID: 31288403 PMCID: PMC6783992 DOI: 10.3390/biomedicines7030050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/02/2019] [Accepted: 07/05/2019] [Indexed: 12/15/2022] Open
Abstract
The extreme chemical and mechanical forces endured by the gastrointestinal tract drive a constant renewal of the epithelial lining. Stem cells of the intestine and stomach, marked by the cell surface receptor Lgr5, preserve the cellular status-quo of their respective tissues through receipt and integration of multiple cues from the surrounding niche. Wnt signalling is a critical niche component for gastrointestinal stem cells and we have previously shown that the Wnt receptor, Frizzled-7 (Fzd7), is required for gastric homeostasis and the function of Lgr5+ intestinal stem cells. Additionally, we have previously shown a requirement for the Wnt target gene Myc in intestinal homeostasis, regeneration and tumourigenesis. However, it is unknown whether Fzd7 or Myc have conserved functions in gastric Lgr5+ stem cells. Here we show that gastric Lgr5+ stem cells do not require Fzd7 or Myc and are able to maintain epithelial homeostasis, highlighting key differences in the way Wnt regulates homeostasis and Lgr5+ stem cells in the stomach compared to the intestinal epithelium. Furthermore, deletion of Myc throughout the epithelium of the gastric antrum has no deleterious effects suggesting therapeutic targeting of Myc in gastric cancer patients will be well tolerated by the surrounding normal tissue.
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miR-27b-mediated suppression of aquaporin-11 expression in hepatocytes reduces HCV genomic RNA levels but not viral titers. Virol J 2019; 16:58. [PMID: 31046802 PMCID: PMC6498629 DOI: 10.1186/s12985-019-1160-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 04/08/2019] [Indexed: 02/07/2023] Open
Abstract
Background MicroRNAs (miRNAs) have gained much attention as cellular factors regulating hepatitis C virus (HCV) infection. miR-27b has been shown to regulate HCV infection in the hepatocytes via various mechanisms that have not been fully elucidated. In this study, therefore, we examined the mechanisms of miR-27b-mediated regulation of HCV infection. Methods In silico screening analysis, transfection with miR-27b mimic, and a cell-based reporter assay were performed to identify miR-27b target genes. Cell cultured-derived HCV (HCVcc) was added to Huh7.5.1 cells knocked down for aquaporin (AQP) 11 (AQP11) and overexpressing AQP11. HCV replication levels were evaluated by real-time RT-PCR analysis of HCVcc genome. Results Infection of Huh7.5.1 cells with HCVcc resulted in significant elevation in miR-27b expression levels. In silico analysis revealed that AQP11, which is an AQP family member and is mainly localized in the endoplasmic reticulum (ER), was a candidate for a target gene of miR-27b. Transfection of a miR-27b mimic significantly reduced AQP11 expression, but a cell-based reporter assay demonstrated that miR-27b did not suppress the expression of a reporter gene containing the 3′-untranslated region of the AQP11 gene, suggesting that miR-27b indirectly suppressed AQP11 expression. AQP11 expression levels were significantly reduced by infection with HCVcc in Huh7.5.1 cells. Knockdown and over-expression of AQP11 significantly reduced and increased HCVcc genome levels in the cells following infection, respectively, however, AQP11 knockdown did not show significant effects on the HCVcc titers in the culture supernatants. Conclusions These results indicated that HCV infection induced a miR-27b-mediated reduction in AQP11 expression, leading to a modest reduction in HCV genome levels in the cells, not HCV titers in the culture supernatants.
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Zou D, Xu L, Li H, Ma Y, Gong Y, Guo T, Jing Z, Xu X, Zhang Y. Role of abnormal microRNA expression in Helicobacter pylori associated gastric cancer. Crit Rev Microbiol 2019; 45:239-251. [PMID: 30776938 DOI: 10.1080/1040841x.2019.1575793] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epidemiological studies have shown that Helicobacter pylori (HP) infection is a risk factor for gastric cancer (GC). HP infection may induce the release of pro-inflammatory mediators, and abnormally increase the level of reactive oxygen species (ROS), nitric oxide (NO), and cytokines in mucosal epithelial cells of the stomach. However, the specific mechanism underlying the pathogenesis of HP-associated GC is still poorly understood. Recent studies have revealed that abnormal microRNA expression may affect the proliferation, differentiation, and apoptosis of mucosal epithelial cells of the stomach to further influence GC occurrence, development, and metastasis. Herein, we summarize the role of abnormal microRNAs in the regulation of HP-associated GC progression. Abnormal microRNA expression in HP-positive GC may be a biomarker for GC diagnosis, occurrence, and development as well as its targeted treatment and prognosis.
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Affiliation(s)
- Dan Zou
- a The First laboratory of cancer institute , First Hospital of China Medical University , Shenyang , China
| | - Ling Xu
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China
| | - Heming Li
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China.,c Department of Oncology , Affiliated Zhongshan Hospital of Dalian University , Dalian , China
| | - Yanju Ma
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China.,d Department of Medical Oncology , Cancer Hospital of China Medical University , Shenyang , China
| | - Yuehua Gong
- e Department of Tumor Etiology and Screening Department of Cancer Institute and General Surgery, First Hospital of China Medical University , Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department , Shenyang , China
| | - Tianshu Guo
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China
| | - Zhitao Jing
- f Department of Neurosurgery , First Hospital of China Medical University , Shenyang , China
| | - Xiuying Xu
- g Department of Gastroenterology , First Hospital of China Medical University , Shenyang , China
| | - Ye Zhang
- a The First laboratory of cancer institute , First Hospital of China Medical University , Shenyang , China
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Mechanisms of Inflammasome Signaling, microRNA Induction and Resolution of Inflammation by Helicobacter pylori. Curr Top Microbiol Immunol 2019; 421:267-302. [PMID: 31123893 DOI: 10.1007/978-3-030-15138-6_11] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammasome-controlled transcription and subsequent cleavage-mediated activation of mature IL-1β and IL-18 cytokines exemplify a crucial innate immune mechanism to combat intruding pathogens. Helicobacter pylori represents a predominant persistent infection in humans, affecting approximately half of the population worldwide, and is associated with the development of chronic gastritis, peptic ulcer disease, and gastric cancer. Studies in knockout mice have demonstrated that the pro-inflammatory cytokine IL-1β plays a central role in gastric tumorigenesis. Infection by H. pylori was recently reported to stimulate the inflammasome both in cells of the mouse and human immune systems. Using mouse models and in vitro cultured cell systems, the bacterial pathogenicity factors and molecular mechanisms of inflammasome activation have been analyzed. On the one hand, it appears that H. pylori-stimulated IL-1β production is triggered by engagement of the immune receptors TLR2 and NLRP3, and caspase-1. On the other hand, microRNA hsa-miR-223-3p is induced by the bacteria, which controls the expression of NLRP3. This regulating effect by H. pylori on microRNA expression was also described for more than 60 additionally identified microRNAs, indicating a prominent role for inflammatory and other responses. Besides TLR2, TLR9 becomes activated by H. pylori DNA and further TLR10 stimulated by the bacteria induce the secretion of IL-8 and TNF, respectively. Interestingly, TLR-dependent pathways can accelerate both pro- and anti-inflammatory responses during H. pylori infection. Balancing from a pro-inflammation to anti-inflammation phenotype results in a reduction in immune attack, allowing H. pylori to persistently colonize and to survive in the gastric niche. In this chapter, we will pinpoint the role of H. pylori in TLR- and NLRP3 inflammasome-dependent signaling together with the differential functions of pro- and anti-inflammatory cytokines. Moreover, the impact of microRNAs on H. pylori-host interaction will be discussed, and its role in resolution of infection versus chronic infection, as well as in gastric disease development.
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25
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Quan H, Li B, Yang J. MicroRNA-504 functions as a tumor suppressor in hepatocellular carcinoma through inhibiting Frizzled-7-mediated-Wnt/β-catenin signaling. Biomed Pharmacother 2018; 107:754-762. [PMID: 30142536 DOI: 10.1016/j.biopha.2018.07.150] [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: 05/10/2018] [Revised: 07/11/2018] [Accepted: 07/30/2018] [Indexed: 02/06/2023] Open
Abstract
Accumulating evidence suggests that microRNAs (miRNAs) are critical regulators in the development and progression of various malignant tumors, including hepatocellular carcinoma (HCC). Multiple findings have indicated that miRNA-504 (miR-504) is dysregulated in several types of cancers, functioning as an oncogenic miRNA or a tumor suppressive miRNA. However, the role of miR-504 in HCC remains unknown. In this study, we aimed to detect the expression pattern of miR-504 in HCC tissues and cell lines and investigate the precise biological function in HCC cells. Our results showed that miR-504 expression levels were frequently downregulated in both HCC tissues and cell lines. Gain-of-function experiments demonstrated that miR-504 overexpression inhibited the proliferation and invasion in HCC cell lines. By contrast, miR-504 inhibition had the opposite effect. Interestingly, bioinformatics analysis predicted that Frizzled-7 (FZD7) was a potential target gene of miR-504. Dual-luciferase reporter assays confirmed that miR-504 directly targeted the 3'-untranslated region of FZD7 mRNA. In addition, our results showed that miR-504 negatively regulated the mRNA and protein expression of FZD7 in HCC cell lines. Moreover, miR-540 overexpression inhibited the cellular expression of β-catenin and blocked the activation of Wnt signaling in HCC cells. Notably, restoration of FZD7 expression significantly reversed the inhibitory effect of miR-504 on proliferation, invasion, and Wnt/β-catenin signaling in HCC cells. In conclusion, our results demonstrate that miR-504 functions as a tumor suppressive miRNA that inhibits the proliferation and invasion of HCC cells by targeting FZD7 and inhibiting Wnt/β-catenin signaling. Our study provides evidence that miR-504-meidated FZD7/Wnt/β-catenin signaling pathway plays an important role in HCC development and progression and suggests miR-504 as a novel future therapeutic target for treatment of HCC.
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Affiliation(s)
- Hui Quan
- Department of Interventional Vascular Surgery, Baoji Central Hospital, Baoji, Shaanxi Province 721008, China
| | - Bo Li
- Department of Interventional Radiology, Traditional Chinese Medical Hospital of Baoji City, Baoji, Shaanxi Province 721001, China
| | - Jianjun Yang
- Department of Infectious Diseases, Baoji Central Hospital, No. 8 Jiangtan Road, Weibin District, Baoji, Shaanxi Province 721008, China.
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26
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Xu Y, Han YF, Ye B, Zhang YL, Dong JD, Zhu SJ, Chen J. miR-27b-3p is Involved in Doxorubicin Resistance of Human Anaplastic Thyroid Cancer Cells via Targeting Peroxisome Proliferator-Activated Receptor Gamma. Basic Clin Pharmacol Toxicol 2018; 123:670-677. [PMID: 29924913 DOI: 10.1111/bcpt.13076] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/14/2018] [Indexed: 12/22/2022]
Abstract
Chemotherapy is one of the most effective forms of cancer treatment. It has been widely used in the treatment of various malignant tumours. To investigate molecular mechanisms responsible for the chemoresistance of anaplastic thyroid cancer (ATC), we established the doxorubicin (Dox) resistance of human ATC SW1736 and 8305C cells and named them SW1736/Dox and 8305C/Dox, respectively. We evaluated the expression of various micro-RNAs (miRNAs) between control and Dox-resistant ATC cells and found that the expression of miR-27b-3p was significantly increased in Dox-resistant ATC cells. Targeted inhibition of miR-27b can increase the sensitivity of SW1736/Dox and 8305C/Dox cells. Bioinformatics analysis revealed that miR-27b can directly target peroxisome proliferator-activated receptor gamma (PPARγ) within the 3' untranslated region (UTR). This was proved by the results that miR-27b-3p down-regulated the protein and mRNA levels of PPARγ. While the mutant in the core binding sites of PPARγ abolished miR-27b-3p-induced down-regulation of luciferase activity. Over-expression of PPARγ can increase the Dox sensitivity of SW1736/Dox and 8305C/Dox cells. Basic fibroblast growth factor (bFGF) might be involved in miR-27b-3p/PPARγ-regulated Dox resistance of ATC cells. The activation of p65 nuclear factor-κB (NF-κB) regulated the up-regulation of miR-27b-3p in Dox-resistant ATC cells. Collectively, our data revealed that miR-27b-3p/PPARγ is involved in the Dox resistance of human ATC cells. It suggested that targeted inhibition of miR-27b-3p might be helpful to overcome the drug resistance of ATC cells.
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Affiliation(s)
- Yuan Xu
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.,Department of Neck Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yi-Fan Han
- Department of Neck Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Bing Ye
- Department of Neck Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yin-Long Zhang
- Department of Neck Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jian-Da Dong
- Department of Neck Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shao-Jun Zhu
- Department of Neck Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jiong Chen
- Department of General Surgery, Anhui Provincial Hospital, Hefei, Anhui, China
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miRNAs reshape immunity and inflammatory responses in bacterial infection. Signal Transduct Target Ther 2018; 3:14. [PMID: 29844933 PMCID: PMC5968033 DOI: 10.1038/s41392-018-0006-9] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 11/20/2017] [Accepted: 12/10/2017] [Indexed: 12/15/2022] Open
Abstract
Pathogenic bacteria cause various infections worldwide, especially in immunocompromised and other susceptible individuals, and are also associated with high infant mortality rates in developing countries. MicroRNAs (miRNAs), small non-coding RNAs with evolutionarily conserved sequences, are expressed in various tissues and cells that play key part in various physiological and pathologic processes. Increasing evidence implies roles for miRNAs in bacterial infectious diseases by modulating inflammatory responses, cell penetration, tissue remodeling, and innate and adaptive immunity. This review highlights some recent intriguing findings, ranging from the correlation between aberrant expression of miRNAs with bacterial infection progression to their profound impact on host immune responses. Harnessing of dysregulated miRNAs in bacterial infection may be an approach to improving the diagnosis, prevention and therapy of infectious diseases. Changes in production of tiny cellular RNAs in response to bacterial infection could guide the development of better diagnostics and therapies. MicroRNAs regulate other genes by binding to messenger RNA strands and controlling their translation into proteins. Xikun Zhou, Min Wu and colleagues of the University of North Dakota have now reviewed current knowledge about how microRNA levels shift during infection with various bacterial pathogens. These microRNAs can modulate the immune response as well as pathways that influence metabolic activity and cell survival. Increasing studies have indicated that shifts in microRNA levels in response to different infections could provide a potential bacterial ‘fingerprint’ for achieving accurate diagnosis. With deeper insight into how different microRNAs influence infection, it might one day day become possible to target these molecules with ‘antisense’ or ‘agonist’ drugs that modulate their activity.
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28
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Frizzled Receptors as Potential Therapeutic Targets in Human Cancers. Int J Mol Sci 2018; 19:ijms19051543. [PMID: 29789460 PMCID: PMC5983605 DOI: 10.3390/ijms19051543] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 05/12/2018] [Accepted: 05/19/2018] [Indexed: 12/14/2022] Open
Abstract
Frizzled receptors (FZDs) are a family of seven-span transmembrane receptors with hallmarks of G protein-coupled receptors (GPCRs) that serve as receptors for secreted Wingless-type (WNT) ligands in the WNT signaling pathway. Functionally, FZDs play crucial roles in regulating cell polarity, embryonic development, cell proliferation, formation of neural synapses, and many other processes in developing and adult organisms. In this review, we will introduce the basic structural features and review the biological function and mechanism of FZDs in the progression of human cancers, followed by an analysis of clinical relevance and therapeutic potential of FZDs. We will focus on the development of antibody-based and small molecule inhibitor-based therapeutic strategies by targeting FZDs for human cancers.
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29
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Flanagan DJ, Austin CR, Vincan E, Phesse TJ. Wnt Signalling in Gastrointestinal Epithelial Stem Cells. Genes (Basel) 2018; 9:genes9040178. [PMID: 29570681 PMCID: PMC5924520 DOI: 10.3390/genes9040178] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 03/16/2018] [Accepted: 03/19/2018] [Indexed: 02/06/2023] Open
Abstract
Wnt signalling regulates several cellular functions including proliferation, differentiation, apoptosis and migration, and is critical for embryonic development. Stem cells are defined by their ability for self-renewal and the ability to be able to give rise to differentiated progeny. Consequently, they are essential for the homeostasis of many organs including the gastrointestinal tract. This review will describe the huge advances in our understanding of how stem cell functions in the gastrointestinal tract are regulated by Wnt signalling, including how deregulated Wnt signalling can hijack these functions to transform cells and lead to cancer.
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Affiliation(s)
- Dustin J Flanagan
- Molecular Oncology Laboratory, Victorian Infectious Diseases Reference Laboratory and the Doherty Institute, University of Melbourne, Melbourne, VIC 3000, Australia.
| | - Chloe R Austin
- Cancer and Cell Signalling Laboratory, European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff CF24 4HQ, Wales, UK.
| | - Elizabeth Vincan
- Molecular Oncology Laboratory, Victorian Infectious Diseases Reference Laboratory and the Doherty Institute, University of Melbourne, Melbourne, VIC 3000, Australia.
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, WA 6102, Australia.
| | - Toby J Phesse
- Cancer and Cell Signalling Laboratory, European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff CF24 4HQ, Wales, UK.
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30
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Guo J, Zhang CD, An JX, Xiao YY, Shao S, Zhou NM, Dai DQ. Expression of miR-634 in gastric carcinoma and its effects on proliferation, migration, and invasion of gastric cancer cells. Cancer Med 2018; 7:776-787. [PMID: 29464926 PMCID: PMC5852365 DOI: 10.1002/cam4.1204] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 08/24/2017] [Accepted: 08/25/2017] [Indexed: 12/18/2022] Open
Abstract
This study aims to observe the expression of microRNA (miR)‐634 in different gastric cancer cell lines and tissues, and to study the effects of miR‐634 on the proliferation, migration, and invasion of the gastric cancer cells. The miR‐634 mimics and miR‐634 inhibitors were transfected by lentivirus into human gastric cancer SGC‐7901 and MGC‐803 cells, and the miR‐634 cells without transfection were used as the control group (NC group). The expression of miR‐634 in the transfected cells was detected by qRT‐PCR. Cell viability was measured by the CCK8 assay. The migration and invasion ability of the cells were detected by scratch assays and Transwell® chamber assays, respectively, and the luciferase assay verified the binding of miR‐634 to the target gene JAG1. The expression level of miR‐634 in gastric cancer tissues and cell lines was significantly lower than that in normal adjacent tissues and control cells. The survival of cells was significantly decreased, and number of cells migrating and invading was decreased in the miR‐634 mimics group. However, in the miR‐634 inhibitor group, the opposite results were observed. Over‐expression of miR‐634 inhibited the proliferation, migration, and invasion of gastric cancer cell lines, and the miR‐634 target gene was JAG1.
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Affiliation(s)
- Jiao Guo
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Chun-Dong Zhang
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Jia-Xiang An
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Yun-Yun Xiao
- Department of Obstetrics and Gynecology, the Shengjing Affiliated Hospital of China Medical University, Shenyang, 110004, China
| | - Shuai Shao
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Nuo-Ming Zhou
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Dong-Qiu Dai
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China.,Cancer Center, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
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31
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Li G, Su Q, Liu H, Wang D, Zhang W, Lu Z, Chen Y, Huang X, Li W, Zhang C, He Y, Fu L, Bi J. Frizzled7 Promotes Epithelial-to-mesenchymal Transition and Stemness Via Activating Canonical Wnt/β-catenin Pathway in Gastric Cancer. Int J Biol Sci 2018; 14:280-293. [PMID: 29559846 PMCID: PMC5859474 DOI: 10.7150/ijbs.23756] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 01/06/2018] [Indexed: 12/25/2022] Open
Abstract
Aberrant activation of Wnt signaling is a crucial event in tumor development and metastasis. Wnt signaling is commonly divided into canonical and non-canonical signaling pathways based on whether β-catenin is activated (canonical). The two signaling pathways are initiated by Wnt ligand binding to the surface Frizzled (FZD) receptors, and regulate cancer stem cell self-renewal and epithelial-mesenchymal transition (EMT). Frizzled 7 (FZD7), a member of Frizzled family, promotes cell proliferation and invasiveness in many cancers, suggesting that FZD7 transmitting Wnt signaling is important for driving cancer growth. FZD7 expression has been reported to be up-regulated in human primary gastric cancer tissues. However, the molecular mechanism by which FZD7 promotes gastric cancer(GC) development and progression is not fully understood. Our present study showed that FZD7 was overexpressed in clinical GC samples, and thus was correlated with tumor invasion, lymphatic and organ metastasis, late TNM stages and poor patient survival. The endogenous expression of FZD7 was significantly increased in cancer stem cell-enriched spheres compared with adherent cells. Furthermore, RNA interference-mediated silencing of FZD7 inhibited proliferation, migration and invasion in gastric cancer cells. Moreover, ablation of FZD7 down-regulated EMT and the expression levels of cancer stem cell markers, and these inhibitions were associated with attenuated canonical Wnt/β-catenin signaling. The results suggest that Wnt canonical pathway may contribute to tumorigenesis and metastasis, indicating that FZD7 could be a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Guanman Li
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Qiao Su
- Animal Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Haibo Liu
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510000, Guangdong, China
| | - Dong Wang
- Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Wenhui Zhang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Zhenhai Lu
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China
| | - Yu Chen
- Department of Immunity, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Xiaohui Huang
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Wen Li
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Changhua Zhang
- Gastrointestinal Surgery Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Yulong He
- Gastrointestinal Surgery Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Li Fu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Cancer Research Centre, School of Medicine, Shenzhen University, Shenzhen, China
| | - Jiong Bi
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
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32
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Driehuis E, Clevers H. WNT signalling events near the cell membrane and their pharmacological targeting for the treatment of cancer. Br J Pharmacol 2017; 174:4547-4563. [PMID: 28244067 PMCID: PMC5727251 DOI: 10.1111/bph.13758] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 02/16/2017] [Accepted: 02/18/2017] [Indexed: 12/16/2022] Open
Abstract
WNT signalling is an essential signalling pathway for all multicellular animals. Although first described more than 30 years ago, new components and regulators of the pathway are still being discovered. Considering its importance in both embryonic development and adult homeostasis, it is not surprising that this pathway is often deregulated in human diseases such as cancer. Recently, it became clear that in addition to cytoplasmic components such as β-catenin, other, membrane-bound or extracellular, components of the WNT pathway are also altered in cancer. This review gives an overview of the recent discoveries on WNT signalling events near the cell membrane. Furthermore, membrane-associated components of the WNT pathway, which are more accessible for therapeutic intervention, as well therapeutic approaches that already target those components will be discussed. In this way, we hope to stimulate the development of effective anti-cancer therapies that target this fascinating pathway. LINKED ARTICLES This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.
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Affiliation(s)
- Else Driehuis
- Hubrecht InstituteRoyal Netherlands Academy of Arts and Sciences (KNAW)UtrechtThe Netherlands
- University medical center (UMC)UtrechtThe Netherlands
| | - Hans Clevers
- Hubrecht InstituteRoyal Netherlands Academy of Arts and Sciences (KNAW)UtrechtThe Netherlands
- University medical center (UMC)UtrechtThe Netherlands
- Princess Maxime Center (PMC)UtrechtThe Netherlands
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33
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MicroRNA in gastrointestinal cell signalling. Inflammopharmacology 2017; 26:1-14. [PMID: 29110118 DOI: 10.1007/s10787-017-0414-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 10/28/2017] [Indexed: 12/17/2022]
Abstract
Our gut forms an important organ and its formation, functioning and homeostasis are maintained by several factors including cell signalling pathways and commensal microflora. These factors affect pathological, physiological and immunological parameters to maintain gut health and prevent its inflammation. Among these, different intracellular signalling pathways play an important role in regulating gut homeostasis. These pathways are in turn regulated by various microRNAs that play a key role in maintaining the balance between tolerance and inflammation. This review highlights the importance of various cell signalling pathways in modulating gut homeostasis and the role specific miRNAs play in their regulation.
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Jia YJ, Liu ZB, Wang WG, Sun CB, Wei P, Yang YL, You MJ, Yu BH, Li XQ, Zhou XY. HDAC6 regulates microRNA-27b that suppresses proliferation, promotes apoptosis and target MET in diffuse large B-cell lymphoma. Leukemia 2017; 32:703-711. [PMID: 29135973 DOI: 10.1038/leu.2017.299] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 09/01/2017] [Accepted: 09/12/2017] [Indexed: 12/22/2022]
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Histone deacetylase 6 (HDAC6) is frequently altered in DLBCL and inhibition of HDAC6 has potent anti-tumor effects in vitro and in vivo. We profiled miRNAs that altered in the HDAC6 knockdown DLBCL cells with NanoString nCounter assay and identified microRNA-27b (miR-27b) as the most significantly increased miRNA. We validated decreased expression of miR-27b in DLBCL tissues, and we found that low expression of miR-27b was associated with poor overall survival of patients with DLBCL. In addition, forced expression of miR-27b suppressed DLBCL cell viability and proliferation in vitro, and inhibited tumor growth in vivo. Mechanistically, Rel A/p65 is found to negatively regulate miR-27b expression, and its acetylation and block of nuclear translocalization caused by HDAC6 inhibition significantly elevates miR-27b expression. Furthermore, miR-27b targets MET and thus represses the MET/PI3K/AKT pathway. These findings highlight an important role of miR-27b in the development of DLBCL and uncover a HDAC6-Rel A/p65-miR-27b-MET signaling pathway. Elevating miR-27b through HDAC6 inhibition would be a promising strategy for DLBCL treatment.
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Affiliation(s)
- Y J Jia
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Z B Liu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China.,Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - W G Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - C B Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - P Wei
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Y L Yang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - M J You
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,The University of Texas MD Anderson Cancer Center, UT Health Graduate School of Biomedical Sciences, Houston, TX, USA
| | - B H Yu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - X Q Li
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - X Y Zhou
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
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35
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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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Song H, Nan Y, Wang X, Zhang G, Zong S, Kong X. MicroRNA‑613 inhibits proliferation and invasion of renal cell carcinoma cells through targeting FZD7. Mol Med Rep 2017; 16:4279-4286. [PMID: 29067457 DOI: 10.3892/mmr.2017.7076] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 05/18/2017] [Indexed: 11/05/2022] Open
Abstract
MicroRNAs (miRNAs) have emerged as critical regulators in cancer progression. miR‑613 has been reported as a tumor suppressor gene in many types of human cancers. However, the function of miR‑613 in renal cell carcinoma (RCC) remains unclear. In the present study, the authors aimed to detect the expression of miR‑613 and its function in RCC cell lines. miR‑613 was reported to be significantly downregulated RCC cell lines. Functional analyses demonstrated that overexpression of miR‑613 significantly decreased RCC cell proliferation and invasion. Bioinformatics analysis showed that Frizzled7 (FZD7) was a predicted target of miR‑613, which was verified by dual‑luciferase reporter assay, reverse transcription quantitative‑polymerase chain reaction and western blot analysis. Restoration of FZD7 significantly reversed the suppressive effects of miR‑613 on RCC cell proliferation and invasion. Taken together, the results of the present study indicated that miR‑613 functions as a tumor suppressor that inhibits RCC cell proliferation and invasion by targeting and inhibiting FZD7, providing novel insight into RCC pathogenesis and a potential therapeutic target for RCC.
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Affiliation(s)
- Haitao Song
- Department of Urinary Surgery, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yonghao Nan
- Department of Urinary Surgery, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Xinsheng Wang
- Department of Urinary Surgery, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Gang Zhang
- Department of Urinary Surgery, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Shi Zong
- Department of Urinary Surgery, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Xiangbo Kong
- Department of Urinary Surgery, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
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MicroRNA-27b inhibits cell proliferation in oral squamous cell carcinoma by targeting FZD7 and Wnt signaling pathway. Arch Oral Biol 2017; 83:92-96. [PMID: 28735227 DOI: 10.1016/j.archoralbio.2017.07.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 06/29/2017] [Accepted: 07/11/2017] [Indexed: 12/21/2022]
Abstract
This study intended to investigate the role of microRNA-27b (miR-27b) in proliferation of oral squamous cell carcinoma (OSCC) cells and to explore the potential molecular mechanism. Cell proliferation was detected by MTT assay. The expression levels of miR-27b, Frizzled7 (FZD7), cyclin D1 and c-myc were detected by quantitative real time polymerase chain reaction (qRT-PCR). The protein expression level of FZD7 was detected by western blot analysis. The relationship between miR-27b and FZD7, and the activity of Wnt signaling pathway were determined using luciferase reporter assay. The miR-27b expression in OSCC cell lines was significantly decreased compared with control. Overexpression of miR-27b remarkably inhibited OSCC cell proliferation. Additionally, miR-27b could target and inhibit FZD7 expression and decrease the activity of Wnt signaling pathway.miR-27b could inhibit OSCC cell proliferation through inhibiting FZD7 and FZD7-mediated Wnt signaling pathway.
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38
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Wu J, Li J, Ren J, Zhang D. MicroRNA-485-5p represses melanoma cell invasion and proliferation by suppressing Frizzled7. Biomed Pharmacother 2017; 90:303-310. [DOI: 10.1016/j.biopha.2017.03.064] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 03/21/2017] [Accepted: 03/21/2017] [Indexed: 12/18/2022] Open
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Ding L, Ni J, Yang F, Huang L, Deng H, Wu Y, Ding X, Tang J. Promising therapeutic role of miR-27b in tumor. Tumour Biol 2017; 39:1010428317691657. [PMID: 28351320 DOI: 10.1177/1010428317691657] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs are small nonprotein-encoding RNAs ranging from 18 to 25 nucleotides in size and regulate multiple biological pathways via directly targeting a variety of associated genes in cancers. MicroRNA-27b is a highly conserved MicroRNA throughout vertebrates and there are two homologs (hsa-miR-27a and hsa-miR-27b) in humans. MicroRNA-27b is an intragenic microRNA located on chromosome 9q22.1 within the C9orf3 gene, clustering with miR-23b and miR-24-1 in human. As a frequently dysregulated microRNA in human cancers, microRNA-27b could function as a tumor suppressor or an oncogenic microRNA. More and more studies indicate that microRNA-27b is involved in affecting various biological processes, such as angiogenesis, proliferation, metastasis, and drug resistance, and thus may act as a promising therapeutic target in human cancers. In this review, we discuss the role of microRNA-27b in detail and offer novel insights into molecular targeting therapy for cancers.
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Affiliation(s)
- Li Ding
- 1 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. China.,2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China
| | - Jie Ni
- 2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China.,3 The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, P.R. China
| | - Fan Yang
- 2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China
| | - Lingli Huang
- 2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China
| | - Heng Deng
- 4 The Graduate School, AnHui University of Traditional Chinese Medicine, Hefei, P.R. China
| | - Yang Wu
- 2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China
| | - Xuansheng Ding
- 1 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. China
| | - Jinhai Tang
- 2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China.,5 Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, P.R. China
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40
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Zhou H, Liu Y, Xiao L, Hu Z, Xia K. Overexpression of MicroRNA-27b Inhibits Proliferation, Migration, and Invasion via Suppression of MET Expression. Oncol Res 2017; 25:147-154. [PMID: 28081743 PMCID: PMC7840835 DOI: 10.3727/096504016x14732772150505] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
MicroRNA-27b (miR-27b) was recently found to be significantly downregulated in different human cancers. However, evidence of the function of miR-27b in non-small cell lung cancer (NSCLC) remains limited. In this study, we aimed to investigate novel miR-27b-mediated targets or signaling pathways associated with the tumorigenesis and metastasis of NSCLC. Real-time (RT) PCR was performed to examine miR-27b expression in NSCLC specimens. MTT assay, wound-healing assay, and Transwell assay were used to determine cell proliferation, migration, and invasion. Our data indicated that the miR-27b levels were significantly decreased in NSCLC specimens and cell lines (SK-MES-1, H358, H460, A549, and H1229) when compared to matched normal adjacent tissues and normal human lung epithelial cell lines, respectively. Restoration of miR-27b significantly inhibited the proliferation, migration, and invasion of A549 cells. We then conducted in silico analysis and luciferase reporter gene assay and identified MET, a receptor tyrosine kinase, as a direct target of miR-27b in NSCLC cells. Moreover, overexpression of MET rescued the suppressive effect of miR-27b on the proliferation, migration, and invasion of A549 cells, suggesting that MET acts as a downstream effecter of miR-27b in NSCLC cells. In summary, our study identified a novel miR-27b/MET signaling pathway involved in the cell proliferation, migration, and invasion of NSCLC, and identification of miR-27b-mediated novel signaling pathways may help reveal the molecular mechanism underlying the development and malignant progression of this disease.
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41
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Wu W, Dang S, Feng Q, Liang J, Wang Y, Fan N. MicroRNA-542-3p inhibits the growth of hepatocellular carcinoma cells by targeting FZD7/Wnt signaling pathway. Biochem Biophys Res Commun 2017; 482:100-105. [PMID: 27815069 DOI: 10.1016/j.bbrc.2016.10.136] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 10/28/2016] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNA) are relevant regulators of the tumorigenesis of various cancers, such as hepatocellular carcinoma (HCC). Recent studies have suggested that miR-542-3p is a tumor suppressor gene in numerous cancers. However, the role of miR-542-3p in HCC remains unclear. This study showed that miR-542-3p was downregulated in HCC tissues and cell lines. MTT, colony formation, and cell cycle assays revealed that miR-542-3p overexpression inhibited HCC cell growth, whereas miR-542-3p suppression promoted cell growth. Frizzled7 (FZD7), the most important Wnt receptor involved in cancer development and progression, was identified as a functional target of miR-542-3p through dual-luciferase reporter assay, RT-qPCR, and Western blot. The mRNA expression of FZD7 was inversely correlated with miR-542-3p expression in HCC tissues. miR-542-3p overexpression could significantly decrease the activation of Wnt signaling pathway in HCC cells. FZD7 overexpression could significantly reverse the inhibitory effect of miR-542-3p on HCC cell growth and Wnt signaling pathway. Taken together, our study suggests that miR-542-3p inhibits HCC cell growth by targeting FZD7 and inhibiting Wnt signaling pathway. The decreased miR-542-3p expression may also contribute to the progression of HCC and may represent a novel molecular therapeutic target for HCC.
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Affiliation(s)
- Wenhua Wu
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Shuangsuo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
| | - Qinhui Feng
- Department of Infectious Diseases, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Junrong Liang
- Department of Gastroenterology Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Yuan Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Na Fan
- Department of Respiratory Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
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42
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Onco-GPCR signaling and dysregulated expression of microRNAs in human cancer. J Hum Genet 2016; 62:87-96. [PMID: 27734836 DOI: 10.1038/jhg.2016.124] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 08/27/2016] [Accepted: 09/09/2016] [Indexed: 02/07/2023]
Abstract
The G-protein-coupled receptor (GPCR) family is the largest family of cell-surface receptors involved in signal transduction. Aberrant expression of GPCRs and G proteins are frequently associated with prevalent human diseases, including cancer. In fact, GPCRs represent the therapeutic targets of more than a quarter of the clinical drugs currently on the market. MiRNAs (miRNAs) are also aberrantly expressed in many human cancers, and they have significant roles in the initiation, development and metastasis of human malignancies. Recent studies have revealed that dysregulation of miRNAs and their target genes expression are associated with cancer progression. The emerging information suggests that miRNAs play an important role in the fine tuning of many signaling pathways, including GPCR signaling. We summarize our current knowledge of the individual functions of miRNAs regulated by GPCRs and GPCR signaling-associated molecules, and miRNAs that regulate the expression and activity of GPCRs, their endogenous ligands and their coupled heterotrimeric G proteins in human cancer.
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Sun XF, Sun JP, Hou HT, Li K, Liu X, Ge QX. MicroRNA-27b exerts an oncogenic function by targeting Fbxw7 in human hepatocellular carcinoma. Tumour Biol 2016; 37:15325-15332. [PMID: 27704356 DOI: 10.1007/s13277-016-5444-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 09/23/2016] [Indexed: 10/20/2022] Open
Abstract
Aberrant expression of microRNAs (miRNAs) plays fundamental effect on the pathogenesis of hepatocellular carcinoma (HCC). MiR-27b was previously found to play important roles in human cancers. However, its expression status, clinical significance, and biological functions in HCC remain largely unclear. The expression status of miR-27b in HCC specimens and cells were determined with qRT-PCR. MTT, 5-bromodeoxyuridine (BrdU) proliferation assays, and flow cytometry analysis were carried out to assay proliferation, cell cycle, and apoptosis. A subcutaneous model was used to evaluated the HCC tumor growth in vivo. The putative target gene of miR-27b was disclosed by TargetScan and a luciferase reporter assay. The levels of miR-27b were overexpressed in HCC. Overexpression of miR-27b was correlated with adverse prognostic features and reduced survival rate. Inhibition of miR-27b in SMMC-7721 cells remarkably suppressed proliferative ability and cell-cycle progression while enhanced apoptosis. In contrast, miR-27b overexpression resulted in prominent increased proliferation and process of cell cycle and reduced apoptosis of Hep3B cells. In vivo studies showed that knockdown of miR-27b inhibited the in vivo growth of SMMC-7721 cells in mouse xenograft model. Furthermore, we confirmed that Fbxw7 was directly regulated by miR-27b and mediated the roles of miR-27b in HCC. We suggest that miR-27b serves as an oncogenic miRNA in HCC by modulating proliferation, cell-cycle progression, and apoptosis, and its oncogenic effect is mediated by its downstream target gene, Fbxw7.
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Affiliation(s)
- Xin-Fang Sun
- Department of Gastroenterology, Huaihe Hospital, Henan University, No. 8 Baobei Road, Kaifeng, Henan Province, 475000, China
| | - Jin-Ping Sun
- Department of Gastroenterology, Huaihe Hospital, Henan University, No. 8 Baobei Road, Kaifeng, Henan Province, 475000, China
| | - Hong-Tao Hou
- Department of Gastroenterology, Huaihe Hospital, Henan University, No. 8 Baobei Road, Kaifeng, Henan Province, 475000, China
| | - Ke Li
- Department of Gastroenterology, Huaihe Hospital, Henan University, No. 8 Baobei Road, Kaifeng, Henan Province, 475000, China
| | - Xin Liu
- Department of Gastroenterology, Huaihe Hospital, Henan University, No. 8 Baobei Road, Kaifeng, Henan Province, 475000, China
| | - Quan-Xing Ge
- Department of Gastroenterology, Huaihe Hospital, Henan University, No. 8 Baobei Road, Kaifeng, Henan Province, 475000, China.
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44
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Fang Q, Chen X, Zhi X. Long Non-Coding RNA (LncRNA) Urothelial Carcinoma Associated 1 (UCA1) Increases Multi-Drug Resistance of Gastric Cancer via Downregulating miR-27b. Med Sci Monit 2016; 22:3506-3513. [PMID: 27694794 PMCID: PMC5051552 DOI: 10.12659/msm.900688] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND In this study, we aimed to investigate the association between UCA1 and miR-27b in gastric cancer and further study their involvement in multi-drug resistance (MDR) of gastric cancer. MATERIAL AND METHODS The microarray data of dysregulated lncRNAs in gastric cancer tissues was retrieved in the GEO dataset. QRT-PCR analysis was performed to assess UCA1 expression based on 28 paired cancerous and peritumoral normal tissues. The human gastric cancer cell line SGC-7901, and SGC-7901 derived Adriamycin (doxorubicin) resistant SGC-7901/ADR, cisplatin resistant SGC-7901/DDP, and 5-FU resistant SGC-7901/FU cells were used as in vitro cell models to assess the effect of UCA1 and miR-27b on MDR. RESULTS UCA1 was significantly upregulated in the cancerous tissues and its expression was negatively correlated with miR-27b expression level. Inhibition of UCA1 significantly restored miR-27b expression in MDR gastric cancer cells. UCA1 knockdown and miR-27b overexpression reduced IC50 of ADR, DDP, and 5-FU in SGC-7901/ADR cells and increased ADR induced cell apoptosis. UCA1 overexpression and miR-27b inhibition increased the IC50 of ADR, DDP, and 5-FU in SGC-7901 cells and reduced ADR induced cell apoptosis. Western blot analysis showed that UCA1 knockdown and miR-27b overexpression also decreased anti-apoptotic protein BCL-2 and increased apoptotic protein cleaved caspase-3. CONCLUSIONS UCA1 is negatively correlated with miR-27b expression in gastric cancer tissue. Knockdown of UCA1 restored miR-27b expression in gastric cancer cells. The UCA1-miR-27b axis was involved in regulation of chemosensitivity of gastric cancer cells.
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Affiliation(s)
- Qun Fang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - XiaoYan Chen
- Department of Emergency, Yidu Central Hospital of Weifang, Weifang, China (mainland)
| | - XuTing Zhi
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China (mainland)
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45
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Zhang M, Du X. Noncoding RNAs in gastric cancer: Research progress and prospects. World J Gastroenterol 2016; 22:6610-6618. [PMID: 27547004 PMCID: PMC4970485 DOI: 10.3748/wjg.v22.i29.6610] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/26/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Noncoding RNAs (ncRNAs) have attracted much attention in cancer research field. They are involved in cellular development, proliferation, differentiation and apoptosis. The dysregulation of ncRNAs has been reported in tumor initiation, progression, invasion and metastasis in various cancers, including gastric cancer (GC). In the past few years, an accumulating body of evidence has deepened our understanding of ncRNAs, and several emerging ncRNAs have been identified, such as PIWI-interacting RNAs (piRNAs) and circular RNAs (circRNAs). The competing endogenous RNA (ceRNA) networks include mRNAs, microRNAs, long ncRNAs (lncRNAs) and circRNAs, which play critical roles in the tumorigenesis of GC. This review summarizes the recent hotspots of ncRNAs involved in GC pathobiology and their potential applications in GC. Finally, we briefly discuss the advances in the ceRNA network in GC.
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Frizzled7: A Promising Achilles' Heel for Targeting the Wnt Receptor Complex to Treat Cancer. Cancers (Basel) 2016; 8:cancers8050050. [PMID: 27196929 PMCID: PMC4880867 DOI: 10.3390/cancers8050050] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 05/03/2016] [Accepted: 05/09/2016] [Indexed: 02/07/2023] Open
Abstract
Frizzled7 is arguably the most studied member of the Frizzled family, which are the cognate Wnt receptors. Frizzled7 is highly conserved through evolution, from Hydra through to humans, and is expressed in diverse organisms, tissues and human disease contexts. Frizzled receptors can homo- or hetero-polymerise and associate with several co-receptors to transmit Wnt signalling. Notably, Frizzled7 can transmit signalling via multiple Wnt transduction pathways and bind to several different Wnt ligands, Frizzled receptors and co-receptors. These promiscuous binding and functional properties are thought to underlie the pivotal role Frizzled7 plays in embryonic developmental and stem cell function. Recent studies have identified that Frizzled7 is upregulated in diverse human cancers, and promotes proliferation, progression and invasion, and orchestrates cellular transitions that underscore cancer metastasis. Importantly, Frizzled7 is able to regulate Wnt signalling activity even in cancer cells which have mutations to down-stream signal transducers. In this review we discuss the various aspects of Frizzled7 signalling and function, and the implications these have for therapeutic targeting of Frizzled7 in cancer.
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