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1
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Dai H, Chen X, Yang J, Loiola RA, Lu A, Cheung KCP. Insights and therapeutic advances in pancreatic cancer: the role of electron microscopy in decoding the tumor microenvironment. Front Cell Dev Biol 2024; 12:1460544. [PMID: 39744013 PMCID: PMC11688199 DOI: 10.3389/fcell.2024.1460544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 09/23/2024] [Indexed: 01/04/2025] Open
Abstract
Pancreatic cancer is one of the most lethal cancers, with a 5-year overall survival rate of less than 10%. Despite the development of novel therapies in recent decades, current chemotherapeutic strategies offer limited clinical benefits due to the high heterogeneity and desmoplastic tumor microenvironment (TME) of pancreatic cancer as well as inefficient drug penetration. Antibody- and nucleic acid-based targeting therapies have emerged as strong contenders in pancreatic cancer drug discovery. Numerous studies have shown that these strategies can significantly enhance drug accumulation in tumors while reducing systemic toxicity. Additionally, electron microscopy (EM) has been a critical tool for high-resolution analysis of the TME, providing insights into the ultrastructural changes associated with pancreatic cancer progression and treatment responses. This review traces the current and technological advances in EM, particularly the development of ultramicrotomy and improvements in sample preparation that have facilitated the detailed visualization of cellular and extracellular components of the TME. This review highlights the contribution of EM in assessing the efficacy of therapeutic agents, from revealing apoptotic changes to characterizing the effects of novel compounds like ionophore antibiotic gramicidin A on cellular ultrastructures. Moreover, the review delves into the potential of EM in studying the interactions between the tumor microbiome and cancer cell migration, as well as in aiding the development of targeted therapies like antibody-drug conjugates (ADCs) and aptamer-drug conjugates (ApDCs).
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Affiliation(s)
- Hong Dai
- Department of Chemistry, The Hong Kong University of Science and Technology, Kowloon, Hong Kong SAR, China
| | - Xingxuan Chen
- Phenome Research Center, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Jiawen Yang
- School of Life Science, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | | | - Aiping Lu
- Phenome Research Center, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Kenneth C. P. Cheung
- Phenome Research Center, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
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2
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Pan D, Long L, Li C, Zhou Y, Liu Q, Zhao Z, Zhao H, Lin W, Zheng Z, Peng L, Li E, Xu L. Splicing factor hnRNPA1 regulates alternative splicing of LOXL2 to enhance the production of LOXL2Δ13. J Biol Chem 2024; 300:107414. [PMID: 38810697 PMCID: PMC11259713 DOI: 10.1016/j.jbc.2024.107414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 05/03/2024] [Accepted: 05/09/2024] [Indexed: 05/31/2024] Open
Abstract
Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family and has the ability to catalyze the cross-linking of extracellular matrix collagen and elastin. High expression of LOXL2 is related to tumor cell proliferation, invasion, and metastasis. LOXL2 contains 14 exons. Previous studies have found that LOXL2 has abnormal alternative splicing and exon skipping in a variety of tissues and cells, resulting in a new alternatively spliced isoform denoted LOXL2Δ13. LOXL2Δ13 lacks LOXL2WT exon 13, but its encoded protein has greater ability to induce tumor cell proliferation, invasion, and metastasis. However, the molecular events that produce LOXL2Δ13 are still unclear. In this study, we found that overexpression of the splicing factor hnRNPA1 in cells can regulate the alternative splicing of LOXL2 and increase the expression of LOXL2Δ13. The exonic splicing silencer exists at the 3' splice site and 5' splice site of LOXL2 exon 13. HnRNPA1 can bind to the exonic splicing silencer and inhibit the inclusion of exon 13. The RRM domain of hnRNPA1 and phosphorylation of hnRNPA1 at S91 and S95 are important for the regulation of LOXL2 alternative splicing. These results show that hnRNPA1 is a splicing factor that enhances the production of LOXL2Δ13.
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Affiliation(s)
- Deyuan Pan
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Lin Long
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Chengyu Li
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Yingxin Zhou
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Qing Liu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China
| | - Ziting Zhao
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Hui Zhao
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Wan Lin
- Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Zhenyuan Zheng
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Liu Peng
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Enmin Li
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China.
| | - Liyan Xu
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong Province, China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong Province, China.
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Calli AO, Kurt K, Narli G, Kocabey DU, Yilmaz A, Ocal I, Yigit S, Yilmaz I. Are micro-RNA 21 and 143 indicative as prognostic biomarkers in dedifferentiated endometrial adenocarcinoma? Mol Biol Rep 2024; 51:756. [PMID: 38874783 DOI: 10.1007/s11033-024-09663-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 05/22/2024] [Indexed: 06/15/2024]
Abstract
AIM Dedifferentiated endometrial adenocarcinoma (DEAC) is a rare, aggressive subtype, accounting for 2% of all endometrial cancers. Poor survival in DEAC prompts the need for effective treatment modalities through better prognostic classification. MicroRNAs (miRNA) have essential roles in tumor angiogenesis, which might enable their use as novel biomarkers. In this study, we aimed to reveal the relationship between the expression of miRNA-21 and miRNA-143, which are associated with angiogenesis, and the prognosis of DEAC. METHOD The study included six cases diagnosed with DEAC. The expression levels of miRNA-21 and miRNA-143 were detected by quantitative real-time PCR. Microvascular density (MVD) was measured by CD34 staining. All data and effects on survival were compared for statistical significance. RESULTS Six cases diagnosed with DEAC were included in the study. The percentage of undifferentiated components ranged from 50 to 90%. The second component of differentiated carcinoma was detected as endometrioid (3/5 grade I, 1/5 grade II, 1/5 grade III) in five cases and serous in one case. The mean MVD was 27 (range 17-44, SD 9.4). In three cases, miRNA-21 expression was down-regulated in neoplastic areas compared to non-neoplastic areas. On the contrary, it was found to be up-regulated in the remaining three cases. MiRNA-143 expression decreased in four cases and increased in two cases. CONCLUSIONS Based on these findings, we found a significant irregular expression of miRNA-21 in DEACs. As in other cancers, angiogenesis is significantly associated with survival in DEACs. This study provides initial data for revealing possible implications of miRNAs as prognostic indicators in DEAC.
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Affiliation(s)
- Aylin Orgen Calli
- Department of Medical Pathology, Ataturk Training and Research Hospital, Katip Celebi University, Izmir, Turkey
| | - Kerem Kurt
- Department of Medical Pathology, Ataturk Training and Research Hospital, Katip Celebi University, Izmir, Turkey.
| | - Gizem Narli
- Department of Medical Pathology, Mengucek Gazi Training and Research Hospital, Binali Yildirim University, Erzincan, Turkey
| | - Duygu Unal Kocabey
- Department of Medical Pathology, Ataturk Training and Research Hospital, Katip Celebi University, Izmir, Turkey
| | - Alpay Yilmaz
- Department of Gynecology and Obstetrics, Ataturk Training and Research Hospital, Katip Celebi University, Izmir, Turkey
| | - Irfan Ocal
- Department of Medical Pathology, Ataturk Training and Research Hospital, Katip Celebi University, Izmir, Turkey
| | - Seyran Yigit
- Department of Medical Pathology, Tinaztepe University, Izmir, Turkey
| | - Ismail Yilmaz
- Department of Medical Pathology, Sultan Abdulhamid Han Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
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Xi S, Oyetunji S, Wang H, Azoury S, Liu Y, Hsiao SH, Zhang M, Carr SR, Hoang CD, Chen H, Schrump DS. Cigarette Smoke Enhances the Malignant Phenotype of Esophageal Adenocarcinoma Cells by Disrupting a Repressive Regulatory Interaction Between miR-145 and LOXL2. J Transl Med 2023; 103:100014. [PMID: 36870293 PMCID: PMC10121750 DOI: 10.1016/j.labinv.2022.100014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/24/2022] [Accepted: 09/19/2022] [Indexed: 01/11/2023] Open
Abstract
Although linked to esophageal carcinogenesis, the mechanisms by which cigarette smoke mediates initiation and progression of esophageal adenocarcinomas (EAC) have not been fully elucidated. In this study, immortalized esophageal epithelial cells and EAC cells (EACCs) were cultured with or without cigarette smoke condensate (CSC) under relevant exposure conditions. Endogenous levels of microRNA (miR)-145 and lysyl-likeoxidase 2 (LOXL2) were inversely correlated in EAC lines/tumors compared with that in immortalized cells/normal mucosa. The CSC repressed miR-145 and upregulated LOXL2 in immortalized esophageal epithelial cells and EACCs. Knockdown or constitutive overexpression of miR-145 activated or depleted LOXL2, respectively, which enhanced or reduced proliferation, invasion, and tumorigenicity of EACC, respectively. LOXL2 was identified as a novel target of miR-145 as well as a negative regulator of this miR in EAC lines/Barrett's epithelia. Mechanistically, CSC induced recruitment of SP1 to the LOXL2 promoter; LOXL2 upregulation coincided with LOXL2 enrichment and concomitant reduction of H3K4me3 levels within the promoter of miR143HG (host gene for miR-145). Mithramycin downregulated LOXL2 and restored miR-145 expression in EACC and abrogated LOXL2-mediated repression of miR-145 by CSC. These findings implicate cigarette smoke in the pathogenesis of EAC and demonstrate that oncogenic miR-145-LOXL2 axis dysregulation is potentially druggable for the treatment and possible prevention of these malignancies.
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Affiliation(s)
- Sichuan Xi
- Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Shakirat Oyetunji
- Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Haitao Wang
- Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Said Azoury
- Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Yi Liu
- Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Shih-Hsin Hsiao
- Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Mary Zhang
- Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Shamus R Carr
- Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Chuong D Hoang
- Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Haobin Chen
- Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - David S Schrump
- Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Liu WJ, Zhao Y, Chen X, Miao ML, Zhang RQ. Epigenetic modifications in esophageal cancer: An evolving biomarker. Front Genet 2023; 13:1087479. [PMID: 36704345 PMCID: PMC9871503 DOI: 10.3389/fgene.2022.1087479] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/19/2022] [Indexed: 01/12/2023] Open
Abstract
Esophageal cancer is a widespread cancer of the digestive system that has two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA). In the diverse range of cancer therapy schemes, the side effects of conventional treatments remain an urgent challenge to be addressed. Therefore, the pursuit of novel drugs with multiple targets, good efficacy, low side effects, and low cost has become a hot research topic in anticancer therapy. Based on this, epigenetics offers an attractive target for the treatment of esophageal cancer, where major mechanisms such as DNA methylation, histone modifications, non-coding RNA regulation, chromatin remodelling and nucleosome localization offer new opportunities for the prevention and treatment of esophageal cancer. Recently, research on epigenetics has remained at a high level of enthusiasm, focusing mainly on translating the basic research into the clinical setting and transforming epigenetic alterations into targets for cancer screening and detection in the clinic. With the increasing emergence of tumour epigenetic markers and antitumor epigenetic drugs, there are also more possibilities for anti-esophageal cancer treatment. This paper focuses on esophageal cancer and epigenetic modifications, with the aim of unravelling the close link between them to facilitate precise and personalized treatment of esophageal cancer.
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Affiliation(s)
- Wen-Jian Liu
- Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yuan Zhao
- Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xu Chen
- School of Basic Medicine, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Man-Li Miao
- School of Basic Medicine, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Ren-Quan Zhang
- Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Wu X, Xu LY, Li EM, Dong G. Molecular dynamics simulation study on the structures of fascin mutants. J Mol Recognit 2023; 36:e2998. [PMID: 36225126 DOI: 10.1002/jmr.2998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/08/2022] [Accepted: 10/10/2022] [Indexed: 02/05/2023]
Abstract
Fascin is a filamentous actin (F-actin) bundling protein, which cross-links F-actin into bundles and becomes an important component of filopodia on the cell surface. Fascin is overexpressed in many types of cancers. The mutation of fascin affects its ability to bind to F-actin and the progress of cancer. In this paper, we have studied the effects of residues of K22, K41, K43, K241, K358, K399, and K471 using molecular dynamics (MD) simulation. For the strong-effect residues, that is, K22, K41, K43, K358, and K471, our results show that the mutation of K to A leads to large values of root mean square fluctuation (RMSF) around the mutated residues, indicating those residues are important for the flexibility and thermal stability. On the other hand, based on residue cross-correlation analysis, alanine mutations of these residues reinforce the correlation between residues. Together with the RMSF data, the local flexibility is extended to the entire protein by the strong correlations to influence the dynamics and function of fascin. By contrast, for the mutants of K241A and K399A those do not affect the function of fascin, the RMSF data do not show significant differences compared with wild-type fascin. These findings are in a good agreement with experimental studies.
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Affiliation(s)
- Xiaodong Wu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, People's Republic of China
| | - Li-Yan Xu
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, People's Republic of China
- Cancer Research Center, Shantou University Medical College, Shantou, People's Republic of China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, People's Republic of China
| | - En-Min Li
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, People's Republic of China
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, People's Republic of China
| | - Geng Dong
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, People's Republic of China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, People's Republic of China
- Medical Informatics Research Center, Shantou University Medical College, Shantou, People's Republic of China
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7
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Mbatha S, Hull R, Dlamini Z. Exploiting the Molecular Basis of Oesophageal Cancer for Targeted Therapies and Biomarkers for Drug Response: Guiding Clinical Decision-Making. Biomedicines 2022; 10:biomedicines10102359. [PMID: 36289620 PMCID: PMC9598679 DOI: 10.3390/biomedicines10102359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/24/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
Worldwide, oesophageal cancer is the sixth leading cause of deaths related to cancer and represents a major health concern. Sub-Saharan Africa is one of the regions of the world with the highest incidence and mortality rates for oesophageal cancer and most of the cases of oesophageal cancer in this region are oesophageal squamous cell carcinoma (OSCC). The development and progression of OSCC is characterized by genomic changes which can be utilized as diagnostic or prognostic markers. These include changes in the expression of various genes involved in signaling pathways that regulate pathways that regulate processes that are related to the hallmarks of cancer, changes in the tumor mutational burden, changes in alternate splicing and changes in the expression of non-coding RNAs such as miRNA. These genomic changes give rise to characteristic profiles of altered proteins, transcriptomes, spliceosomes and genomes which can be used in clinical applications to monitor specific disease related parameters. Some of these profiles are characteristic of more aggressive forms of cancer or are indicative of treatment resistance or tumors that will be difficult to treat or require more specialized specific treatments. In Sub-Saharan region of Africa there is a high incidence of viral infections such as HPV and HIV, which are both risk factors for OSCC. The genomic changes that occur due to these infections can serve as diagnostic markers for OSCC related to viral infection. Clinically this is an important distinction as it influences treatment as well as disease progression and treatment monitoring practices. This underlines the importance of the characterization of the molecular landscape of OSCC in order to provide the best treatment, care, diagnosis and screening options for the management of OSCC.
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Affiliation(s)
- Sikhumbuzo Mbatha
- SAMRC Precision Oncology Research Unit (PORU), SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa
- Department of Surgery, Faculty of Health Sciences, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa
- Correspondence: (S.M.); (Z.D.)
| | - Rodney Hull
- SAMRC Precision Oncology Research Unit (PORU), SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa
- Correspondence: (S.M.); (Z.D.)
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MicroRNA-143 act as a tumor suppressor microRNA in human lung cancer cells by inhibiting cell proliferation, invasion, and migration. Mol Biol Rep 2022; 49:7637-7647. [PMID: 35717476 DOI: 10.1007/s11033-022-07580-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 04/30/2022] [Accepted: 05/06/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND/AIM MicroRNAs play crucial roles in controlling cellular biological processes. miR-143 expression is usually downregulated in different cancers. In this study, we focused on exploring the role of miR143 in NSCLC development. METHODS Bioinformatics analyses were used to detect the expression level of miR-143 in lung tumors. The cells were transfected by pCMV-miR-143 vectors. The efficacy of transfection was verified by Flow cytometry. The influence of miR-143 replacement on NSCLC cells migration, proliferation, and apoptosis was detected using wound-healing assay, MTT assay, and DAPI staining, respectively. RESULTS MTT assay revealed that overexpression of miR143 inhibited cell growth and proliferation. Scratch assay results demonstrated that restoration of miR143 suppressed cell migration. The qRT-PCR assay was further used to detect the assumed relationship between miR143 and apoptotic and metastatic-related genes. CONCLUSION The findings showed that miR-143 could reduce cell proliferation, invasion, and migration by reducing CXCR4, Vimentin, MMP-1, Snail-1, C-myc expression level, and increasing E-cadherin expression levels in lung cancer cells and might be a potential target in NSCLC's targeted therapy.
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9
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Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
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Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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10
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Wu X, Wen B, Lin L, Shi W, Li D, Cheng Y, Xu LY, Li EM, Dong G. New insights into the function of Fascin in actin bundling: A combined theoretical and experimental study. Int J Biochem Cell Biol 2021; 139:106056. [PMID: 34390855 DOI: 10.1016/j.biocel.2021.106056] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 08/04/2021] [Accepted: 08/07/2021] [Indexed: 02/05/2023]
Abstract
Fascin, one of actin bundling proteins, plays an important role in the cross-linking of actin filaments (F-actin). Phosphorylation of Fascin is an important posttranslational modification to affect its structure and function. For example, a phosphomimetic mutation of Fascin-S39D decrease its bundling ability with F-actin significantly. In this paper, we studied the actin-bundling activity of Fascin by using molecular dynamics (MD) simulations and biochemical methods. All single-site mutations from serine/threonine to aspartic acid were mimicked by MD simulations. For five mutants (S146D, S156D, S218D, T239D and S259D), the mutated residues in domain 2 of Fascin were found to form salt-bridge interactions with an adjacent residue, indicating that mutations of these residues could potentially reduce actin-bundling activity. Further, F-actin-bundling assays and immunofluorescence technique showed S146D and T239D to have a strong effect on Fascin bundling with F-actin. Finally, we show that single-site mutations do not change the general shape of Fascin, but local structures near the mutated residues in Fascin-S146D and T239D become unstable, thereby affecting the ability of Fascin to bind with F-actin. These findings suggest that targeting domain 2 of Fascin would be very useful for the drug design. In addition, our study indicates that MD simulation is a useful method to screening which residues on Fascin are important.
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Affiliation(s)
- Xiaodong Wu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, PR China
| | - Bing Wen
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, PR China
| | - Lirui Lin
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, PR China; Medical Informatics Research Center, Shantou University Medical College, Shantou, 515041, PR China
| | - Wenqi Shi
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, PR China; Cancer Research Center, Shantou University Medical College, Shantou, 515041, PR China
| | - Dajia Li
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, PR China; Cancer Research Center, Shantou University Medical College, Shantou, 515041, PR China
| | - Yinwei Cheng
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, PR China; Cancer Research Center, Shantou University Medical College, Shantou, 515041, PR China
| | - Li-Yan Xu
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, PR China; Cancer Research Center, Shantou University Medical College, Shantou, 515041, PR China.
| | - En-Min Li
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, PR China; Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, PR China.
| | - Geng Dong
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, PR China; Medical Informatics Research Center, Shantou University Medical College, Shantou, 515041, PR China.
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11
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Zhang HJ, Chen G, Chen SW, Fu ZW, Zhou HF, Feng ZB, Mo JX, Li CB, Liu J. Overexpression of cyclin-dependent kinase 1 in esophageal squamous cell carcinoma and its clinical significance. FEBS Open Bio 2021; 11:3126-3141. [PMID: 34586751 PMCID: PMC8564100 DOI: 10.1002/2211-5463.13306] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 09/04/2021] [Accepted: 09/28/2021] [Indexed: 12/25/2022] Open
Abstract
Cyclin‐dependent kinase 1 (CDK1) plays a significant role in certain malignancies. However, it remains unclear whether CDK1 plays a role in esophageal squamous cell carcinoma (ESCC). The aim of this study was to analyze the expression and clinical value of CDK1 in ESCC. CDK1 protein in 151 ESCC tissues and 138 normal esophageal tissues was detected by immunohistochemistry. RNA‐seq of eight pairs of ESCC and adjacent esophageal specimens was performed to evaluate the levels of CDK1 mRNA. Microarray and external RNA‐seq data from 664 cases of ESCC and 1733 cases of control tissues were used to verify the difference in CDK1 expression between the two groups. A comprehensive analysis of all data was performed to evaluate the difference in CDK1 between ESCC tissues and control tissues. Further, functional enrichment analyses were performed based on differentially expressed genes (DEGs) of ESCC and co‐expressed genes (CEGs) of CDK1. In addition, a lncRNA‐miRNA‐CDK1 network was constructed. The expression of CDK1 protein was obviously increased in ESCC tissues (3.540 ± 2.923 vs. 1.040 ± 1.632, P < 0.001). RNA‐seq indicated that the mRNA level of CDK1 was also highly expressed in ESCC tissues (5.261 ± 0.703 vs. 2.229 ± 1.161, P < 0.0001). Comprehensive analysis revealed consistent up‐regulation of CDK1 (SMD = 1.41; 95% CI 1.00–1.83). Further, functional enrichment analyses revealed that the functions of these genes were mainly concentrated in the cell cycle. A triple regulatory network of PVT1‐hsa‐miR‐145‐5p/hsa‐miR‐30c‐5p‐CDK1 was constructed using in silico analysis. In summary, overexpression of CDK1 is closely related to ESCC tumorigenesis.
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Affiliation(s)
- Han-Jie Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shang-Wei Chen
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zong-Wang Fu
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hua-Fu Zhou
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhen-Bo Feng
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jun-Xian Mo
- Department of Cardio-Thoracic Surgery, The Seventh Affiliated Hospital of Guangxi Medical University, Wuzhou, China.,Wuzhou Gongren Hospital, Wuzhou, China
| | - Chang-Bo Li
- Department of Cardio-Thoracic Surgery, The Seventh Affiliated Hospital of Guangxi Medical University, Wuzhou, China.,Wuzhou Gongren Hospital, Wuzhou, China
| | - Jun Liu
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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12
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Chen X, Su X, Lin M, Fu B, Zhou C, Ling C, Qian Z, Yao Y. Expression of miR-192-5p in colon cancer serum and its relationship with clinicopathologic features. Am J Transl Res 2021; 13:9371-9376. [PMID: 34540055 PMCID: PMC8430106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/09/2021] [Indexed: 06/13/2023]
Abstract
Colon cancer has a poor prognosis due to a lack of biomarkers for early diagnosis and prognosis. The present study analyzed serum miR-192-5p expression levels in colon cancer patients and their correlations with clinicopathologic features. Relative mRNA expression was assessed by real-time fluorescence-based quantitative PCR in the serum of 164 colon cancer patients and 60 healthy controls. Patients were enrolled in a high or low miR-192-5p group according to the cutoff value determined by ROC curve analysis. The Kaplan-Meier method and univariate and multivariate Cox regression models were applied to analyze the risk factors influencing the postoperative survival of colon cancer patients. miR-192-5p mRNA expression in the colon cancer group was significantly reduced compared with the control group (P<0.01). Low miR-192-5p expression was significantly associated with a poor differentiation degree, lymphatic metastasis, vascular invasion, and high TNM stage (P=0.027, 0.001, 0.010, and <0.001, respectively). Colon cancer patients in the low miR-192-5p group exhibited a low survival rate (P<0.001). The independent risk factors for postoperative survival included lymphatic metastasis, a high TNM stage, and miR-192-5p<1.16 (P=0.017, 0.025, and 0.008, respectively). miR-192-5p may represent a promising biomarker for early diagnosis and prognosis in colon cancer patients.
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Affiliation(s)
- Xu Chen
- Center of Clinical Laboratory, First Affiliated Hospital of Soochow UniversitySuzhou 215006, People’s Republic of China
| | - Xiandu Su
- Department of Clinical Laboratory, People’s Hospital of DanzhouDanzhou 571700, People’s Republic of China
| | - Mingli Lin
- Department of Clinical Laboratory, People’s Hospital of DanzhouDanzhou 571700, People’s Republic of China
| | - Buyuan Fu
- Department of Clinical Laboratory, People’s Hospital of DanzhouDanzhou 571700, People’s Republic of China
| | - Cong Zhou
- Department of Surgical Oncology, People’s Hospital of DanzhouDanzhou 571700, People’s Republic of China
| | - Chen Ling
- Center of Clinical Laboratory, First Affiliated Hospital of Soochow UniversitySuzhou 215006, People’s Republic of China
| | - Zhongping Qian
- Center of Clinical Laboratory, First Affiliated Hospital of Soochow UniversitySuzhou 215006, People’s Republic of China
| | - Yanping Yao
- Department of Pharmacy, Suzhou Xiangcheng People’s HospitalSuzhou 215006, People’s Republic of China
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13
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Ma Y, Cao X, Shi G, Shi T. MiRNA-145 and Its Direct Downstream Targets in Digestive System Cancers: A Promising Therapeutic Target. Curr Pharm Des 2021; 27:2264-2273. [PMID: 33121400 DOI: 10.2174/1381612826666201029095702] [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: 04/29/2020] [Accepted: 09/24/2020] [Indexed: 11/22/2022]
Abstract
MicroRNAs (miRNAs) play a vital role in the onset and development of many diseases, including cancers. Emerging evidence shows that numerous miRNAs have the potential to be used as diagnostic biomarkers for cancers, and miRNA-based therapy may be a promising therapy for the treatment of malignant neoplasm. MicroRNA-145 (miR-145) has been considered to play certain roles in various cellular processes, such as proliferation, differentiation and apoptosis, via modulating the expression of direct target genes. Recent reports show that miR-145 participates in the progression of digestive system cancers, and plays crucial and novel roles in cancer treatment. In this review, we summarize the recent knowledge concerning the function of miR-145 and its direct targets in digestive system cancers. We discuss the potential role of miR-145 as a valuable biomarker for digestive system cancers and how miR-145 regulates these digestive system cancers via different targets to explore the potential strategy of targeting miR-145.
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Affiliation(s)
- Yini Ma
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Xiu Cao
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Guojuan Shi
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Tianlu Shi
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
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14
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Bhat AA, Nisar S, Maacha S, Carneiro-Lobo TC, Akhtar S, Siveen KS, Wani NA, Rizwan A, Bagga P, Singh M, Reddy R, Uddin S, Grivel JC, Chand G, Frenneaux MP, Siddiqi MA, Bedognetti D, El-Rifai W, Macha MA, Haris M. Cytokine-chemokine network driven metastasis in esophageal cancer; promising avenue for targeted therapy. Mol Cancer 2021; 20:2. [PMID: 33390169 PMCID: PMC7780621 DOI: 10.1186/s12943-020-01294-3] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 12/06/2020] [Indexed: 02/08/2023] Open
Abstract
Esophageal cancer (EC) is a disease often marked by aggressive growth and poor prognosis. Lack of targeted therapies, resistance to chemoradiation therapy, and distant metastases among patients with advanced disease account for the high mortality rate. The tumor microenvironment (TME) contains several cell types, including fibroblasts, immune cells, adipocytes, stromal proteins, and growth factors, which play a significant role in supporting the growth and aggressive behavior of cancer cells. The complex and dynamic interactions of the secreted cytokines, chemokines, growth factors, and their receptors mediate chronic inflammation and immunosuppressive TME favoring tumor progression, metastasis, and decreased response to therapy. The molecular changes in the TME are used as biological markers for diagnosis, prognosis, and response to treatment in patients. This review highlighted the novel insights into the understanding and functional impact of deregulated cytokines and chemokines in imparting aggressive EC, stressing the nature and therapeutic consequences of the cytokine-chemokine network. We also discuss cytokine-chemokine oncogenic potential by contributing to the Epithelial-Mesenchymal Transition (EMT), angiogenesis, immunosuppression, metastatic niche, and therapeutic resistance development. In addition, it discusses the wide range of changes and intracellular signaling pathways that occur in the TME. Overall, this is a relatively unexplored field that could provide crucial insights into tumor immunology and encourage the effective application of modulatory cytokine-chemokine therapy to EC.
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Affiliation(s)
- Ajaz A Bhat
- Functional and Molecular Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Sabah Nisar
- Functional and Molecular Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Selma Maacha
- Research Department, Sidra Medicine, Doha, Qatar
| | | | - Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | | | - Nissar A Wani
- Department of Biotechnology, Central University of Kashmir, Ganderbal, Jammu and Kashmir, India
| | - Arshi Rizwan
- Department of Nephrology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Puneet Bagga
- Diagnostic Imaging, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Mayank Singh
- Dr. B. R. Ambedkar Institute Rotary Cancer Hospital (BRAIRCH), AIIMS, New Delhi, India
| | - Ravinder Reddy
- Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | | | - Gyan Chand
- Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | | | - Mushtaq A Siddiqi
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Jammu & Kashmir, India
| | - Davide Bedognetti
- Laboratory of Cancer Immunogenomics, Cancer Research Department, Sidra Medicine, Doha, Qatar
- Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Wael El-Rifai
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Jammu & Kashmir, India.
| | - Mohammad Haris
- Functional and Molecular Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar.
- Laboratory Animal Research Center, Qatar University, Doha, Qatar.
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15
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Shi L, Chen Q, Ge X. Long intergenic non-coding RNA 00337 confers progression of esophageal cancer by mediating microrna-145-dependent fscn1. FASEB J 2020; 34:11431-11443. [PMID: 32654289 DOI: 10.1096/fj.202000470] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 04/30/2020] [Indexed: 11/11/2022]
Abstract
Long non-coding RNAs (lncRNAs) have been highlighted as prominent genetic modulators involved in multiple important biological processes of cancer cells, especially in esophageal cancer (EC). We tried to elucidate the potential role of LINC00337 in the progression of EC. Based on TCGA database analysis and Reverse transcription quantitative polymerase chain reaction determination, high expression of LINC00337 and FSCN1 was detected, while miR-145 exhibited a low expression in EC. LINC00337 was identified to bind to miR-145 to impair the miR-145-dependent FSCN1 inhibition. The underlying regulatory mechanisms were evaluated by transfection with LINC00337 overexpression plasmid, siRNA against LINC00337, miR-145 mimic, or anta-miR-145. Downregulation of LINC00337 results in increased Bax level, decreased FSCN1, Bcl-2, VEGF, and p53 levels, in addition to diminished cell proliferation, migration, invasion and tumor growth, with accelerated cell apoptosis by upregulating miR-145. Taken together, the findings obtained provided evidence suggesting that LINC00337 acts as a tumor promoter in EC, providing insight and advancements for EC treatment.
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Affiliation(s)
- Lixia Shi
- Department of General Surgery, Linyi People's Hospital, Linyi, P.R. China
| | - Qing Chen
- Department of General Surgery, Linyi People's Hospital, Linyi, P.R. China
| | - Xiaofen Ge
- Infectious Diseases Clinic, Linyi People's Hospital, Linyi, P.R. China
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16
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Jia A, Wu Y, Ren W, Han P, Shao Y. Genetic variations of CARMN affect risk of esophageal cancer in northwest China. Gene 2020; 748:144680. [DOI: 10.1016/j.gene.2020.144680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 04/04/2020] [Accepted: 04/14/2020] [Indexed: 01/02/2023]
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17
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Zhou SN. Role of non-coding RNAs in esophageal carcinoma. Shijie Huaren Xiaohua Zazhi 2020; 28:453-459. [DOI: 10.11569/wcjd.v28.i12.453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In recent years, the research on the role of non-coding RNAs (ncRNAs) in tumors has received more and more attention. Although research on the role of ncRNAs in the early diagnosis, disease monitoring, treatment guidance, and prognosis prediction of esophageal carcinoma has been gradually carried out, there are still many problems that need to be addressed. In the current paper, I review the progress in the research of ncRNAs in esophageal carcinoma, with an aim to help provide new strategies for the prevention and treatment of esophageal carcinoma.
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Affiliation(s)
- Su-Na Zhou
- Department of Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
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18
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Tian YQ, Fan ZJ, Liu S, Wu YJ, Liu SY. Value of microRNAs in diagnosis and prognosis of colorectal cancer. Shijie Huaren Xiaohua Zazhi 2019; 27:1278-1284. [DOI: 10.11569/wcjd.v27.i20.1278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Some new treatment methods have been explored to delay the recurrence of colorectal cancer (CRC). Early diagnosis plays an important role in the improvement of curative effect. The conventional methods used to diagnose and monitor CRC are fecal occult blood test (FOBT) and colonoscopy. However, FOBT has an unsatisfactory sensitivity, while colonoscopy is expensive and invasive. As new biomarkers, microRNAs, which can be detected in CRC tissues, cells, and body fluid as tumor suppressors or oncogenes, can be used in early diagnosis, the monitoring of metastasis and treatment, as well prognostic evaluation of CRC. This article reviews the diagnostic and prognostic value of microRNAs in CRC.
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Affiliation(s)
- Ya-Qiong Tian
- Third Central Hospital of Tianjin, Tianjin Key Laboratory of Artificial Cell, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin 300170, China
| | - Zhi-Juan Fan
- Third Central Hospital of Tianjin, Tianjin Key Laboratory of Artificial Cell, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin 300170, China
| | - Shuang Liu
- Third Central Hospital of Tianjin, Tianjin Key Laboratory of Artificial Cell, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin 300170, China
| | - Yu-Jing Wu
- Third Central Hospital of Tianjin, Tianjin Key Laboratory of Artificial Cell, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin 300170, China
| | - Shu-Ye Liu
- Third Central Hospital of Tianjin, Tianjin Key Laboratory of Artificial Cell, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin 300170, China
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19
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Taniguchi K, Wada SI, Ito Y, Hayashi J, Inomata Y, Lee SW, Tanaka T, Komura K, Akao Y, Urata H, Uchiyama K. α-Aminoisobutyric Acid-Containing Amphipathic Helical Peptide-Cyclic RGD Conjugation as a Potential Drug Delivery System for MicroRNA Replacement Therapy in Vitro. Mol Pharm 2019; 16:4542-4550. [PMID: 31596588 DOI: 10.1021/acs.molpharmaceut.9b00680] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Replacement therapy with tumor suppressive microRNA (TS-miRNA) might be the next-generation oligonucleotide therapy; however, a novel drug delivery system (DDS) is required. Recently, we developed the cell-penetrating peptide, model amphipathic peptide with α-aminoisobutyric acid (MAP(Aib)), as a carrier for oligonucleotide delivery to cells. In this study, we examined whether a modified MAP(Aib) analogue, MAP(Aib)-cRGD, could be a DDS for TS-miRNA replacement therapy. MIR145-5p, a representative TS-miRNA especially in colorectal cancer, was selected. The MAP(Aib)-cRGD dose was adjusted for MIR145-5p delivery to cells using peripheral blood mononuclear cells and degradation analysis. AlexaFluor488-labeled MIR145-5p incorporation into cells and negative regulation of MIR145-5p-targeting genes demonstrated MAP(Aib)-cRGD's functionality as a miRNA DDS. Treating MIR145-5p with MAP(Aib)-cRGD also revealed various anticancer effects, such as cell viability, invasion inhibition, and apoptosis induction in WiDr cells. Altogether, these findings suggest that MAP(Aib)-cRGD could be a DDS for TS-miRNA replacement therapy, but in vivo investigations are required.
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Affiliation(s)
| | - Shun-Ichi Wada
- Department of Bioorganic Chemistry , Osaka University of Pharmaceutical Sciences , 4-20-1 Nasahara , Takatsuki , Osaka 569-1094 , Japan
| | | | - Junsuke Hayashi
- Department of Bioorganic Chemistry , Osaka University of Pharmaceutical Sciences , 4-20-1 Nasahara , Takatsuki , Osaka 569-1094 , Japan
| | | | | | | | | | - Yukihiro Akao
- United Graduate School of Drug Discovery and Medical Information Sciences , Gifu University , 1-1 Yanagido , Gifu 501-1193 , Japan
| | - Hidehito Urata
- Department of Bioorganic Chemistry , Osaka University of Pharmaceutical Sciences , 4-20-1 Nasahara , Takatsuki , Osaka 569-1094 , Japan
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20
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Chen Q, Hou J, Wu Z, Zhao J, Ma D. miR-145 Regulates the sensitivity of esophageal squamous cell carcinoma cells to 5-FU via targeting REV3L. Pathol Res Pract 2019; 215:152427. [PMID: 31072625 DOI: 10.1016/j.prp.2019.04.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 03/28/2019] [Accepted: 04/26/2019] [Indexed: 12/24/2022]
Abstract
Aberrant expression of miR-145 was associated with chemotherapy in multitype cancers. However, the underlying role and molecular mechanism of miR-145 in the sensitivity of esophageal squamous cell carcinoma (ESCC) to 5-FU remained largely unknown. Cell viability was determined by Cell Counting Kit-8 (CCK-8) assay. Gene expression levels were detected by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Protein expression levels were evaluated by Western blot. TargetScan was used for the prediction of binding sites for miRNA in mRNAs. The interaction between mRNA 3' UTR and miRNA was verified by dual luciferase reporter assay. The results showed that miR-145 was downregulated in ESCC tumor tissues and cells, while REV3L was upregulated in ESCC tumor tissues. Overexpression of miR-145 decreased REV3L mRNA and protein level in ESCC cell line KYSE150, while decreased miR-145 increased REV3L mRNA and protein level in esophageal epithelium cell line (HEEC). In addition, the luciferase activity of ESCC cells was decreased after the treatment of miR-145 mimic and mRNA 3'UTR-WT. Overexpressed miR-145 significantly inhibited cell viability and elevated cell apoptosis rate upon 5-FU treatment. Additionally, transfection of miR-145 mimic further altered expression of key genes involved in cell apoptosis (Bcl-2, Bax, Caspase3) in ESCC cells treated with 5-FU. miR-145 might be a therapeutic target for the treatment of ESCC.
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Affiliation(s)
- Qing Chen
- Department of Oncology, Jingjiang Peoples' Hospital, Jingjiang, 214500, China
| | - Juan Hou
- Department of Oncology, Jingjiang Peoples' Hospital, Jingjiang, 214500, China
| | - Zhiwei Wu
- Department of Oncology, Jingjiang Peoples' Hospital, Jingjiang, 214500, China
| | - Jie Zhao
- Department of Oncology, Jingjiang Peoples' Hospital, Jingjiang, 214500, China
| | - De Ma
- Department of Oncology, Jingjiang Peoples' Hospital, Jingjiang, 214500, China.
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21
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Hernández R, Sánchez-Jiménez E, Melguizo C, Prados J, Rama AR. Downregulated microRNAs in the colorectal cancer: diagnostic and therapeutic perspectives. BMB Rep 2019. [PMID: 30158023 PMCID: PMC6283029 DOI: 10.5483/bmbrep.2018.51.11.116] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Colorectal cancer (CRC), the third most common cancer in the world, has no specific biomarkers that facilitate its diagnosis and subsequent treatment. The miRNAs, small single-stranded RNAs that repress the mRNA translation and trigger the mRNA degradation, show aberrant levels in the CRC, by which these molecules have been related with the initiation, progression, and drug-resistance of this cancer type. Numerous studies show the microRNAs influence the cellular mechanisms related to the cell cycle, differentiation, apoptosis, and migration of the cancer cells through the post-transcriptionally regulated gene expression. Specific patterns of the upregulated and down-regulated miRNA have been associated with the CRC diagnosis, prognosis, and therapeutic response. Concretely, the downregulated miRNAs represent attractive candidates, not only for the CRC diagnosis, but for the targeted therapies via the tumor-suppressing microRNA replacement. This review shows a general overview of the potential uses of the miRNAs in the CRC diagnosis, prognosis, and treatment with a special focus on the downregulated ones. [BMB Reports 2018; 51(11): 563-571].
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Affiliation(s)
- Rosa Hernández
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100; Biosanitary Institute of Granada (ibs. GRANADA), SAS-Universidad de Granada, Granada 18100; Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada 18100, Spain
| | - Ester Sánchez-Jiménez
- Proteomics Laboratory CSIC/UAB, Institute of Biomedical Research, Barcelona 08036, Spain
| | - Consolación Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100; Biosanitary Institute of Granada (ibs. GRANADA), SAS-Universidad de Granada, Granada 18100; Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada 18100, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100; Biosanitary Institute of Granada (ibs. GRANADA), SAS-Universidad de Granada, Granada 18100; Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada 18100, Spain
| | - Ana Rosa Rama
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100; Department of Health Science, University of Jaén, Jaén 23071, Spain
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22
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Ye D, Shen Z, Zhou S. Function of microRNA-145 and mechanisms underlying its role in malignant tumor diagnosis and treatment. Cancer Manag Res 2019; 11:969-979. [PMID: 30774425 PMCID: PMC6349084 DOI: 10.2147/cmar.s191696] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
miRNAs are single-stranded small RNAs that do not encode proteins. They can combine complementarily with the 3′-UTRs of target gene mRNA molecules to promote targeted mRNA degradation or inhibit mRNA translation, thereby regulating gene expression at the post-transcriptional level. MiRNAs participate in regulation of cell cycling, growth, apoptosis, differentiation, and stress responses. MiRNA-145 (miR-145) is a tumor suppressor that targets various tumor-specific genes and proteins, thereby influencing related signaling pathways. MiR-145 not only regulates tumor growth, invasion, and metastasis, but is also important for tumor angiogenesis and tumor stem cell proliferation. Here, we review the roles and mechanisms of miR-145 in the diagnosis and treatment of malignant tumors. Published data confirm that miR-145 expression in various tumors is significantly lower than that in normal tissues and that overexpression of miR-145 inhibits the growth of different tumor cells, significantly reduces the ability of tumors to spread, and improves sensitivity to chemotherapeutic drugs. We conclude that miR-145 is a potential marker for use in the early diagnosis and prognostic evaluation of patients with cancer, has a role as a tumor suppressor, and is a promising cancer treatment target candidate.
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Affiliation(s)
- Dong Ye
- Department of Otorhinolaryngology - Head and Neck Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China, .,Department of Otorhinolaryngology -Head and Neck Surgery, Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Zhisen Shen
- Department of Otorhinolaryngology -Head and Neck Surgery, Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Shuihong Zhou
- Department of Otorhinolaryngology - Head and Neck Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China,
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Kiuchi J, Komatsu S, Imamura T, Nishibeppu K, Shoda K, Arita T, Kosuga T, Konishi H, Shiozaki A, Okamoto K, Fujiwara H, Ichikawa D, Otsuji E. Low levels of tumour suppressor miR-655 in plasma contribute to lymphatic progression and poor outcomes in oesophageal squamous cell carcinoma. Mol Cancer 2019; 18:2. [PMID: 30609933 PMCID: PMC6320607 DOI: 10.1186/s12943-018-0929-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 12/26/2018] [Indexed: 01/07/2023] Open
Abstract
Recent studies identified that low levels of tumour suppressor microRNAs (miRNAs) in plasma/serum relate to tumour progression and poor outcomes in cancers. We selected six candidates (miR-126, 133b, 143, 203, 338-3p, 655) of tumour suppressor miRNAs in oesophageal squamous cell carcinoma (ESCC) by a systematic review of NCBI database. Of these, miR-655 levels were significantly down-regulated in plasma of ESCC patients compared to healthy volunteers by test- and validation-scale analyses. Low levels of plasma miR-655 were significantly associated with lymphatic invasion, lymph node metastasis and advanced stage. Univariate and multivariate analysis revealed that the low level of plasma miR-655 was an independent risk factor of lymphatic progression and a poor prognostic factor. Overexpression of miR-655 in ESCC cells inhibited cell proliferation, migration, invasion and epithelial-mesenchymal transition. Increased plasma miR-655 levels by the subcutaneous injection significantly inhibited lymph node metastasis in mice. Low levels of miR-655 in plasma relate to lymphatic progression and poor outcomes, and the restoration of the plasma miR-655 levels might inhibit tumour and lymphatic progression in ESCC.
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Affiliation(s)
- Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Katsutoshi Shoda
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Toshiyuki Kosuga
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Daisuke Ichikawa
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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Zhang Q, Gan H, Song W, Chai D, Wu S. MicroRNA-145 promotes esophageal cancer cells proliferation and metastasis by targeting SMAD5. Scand J Gastroenterol 2018; 53:769-776. [PMID: 29852786 DOI: 10.1080/00365521.2018.1476913] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To clarify the relative expression and molecular function of microRNA (miR)-145 in esophageal cancer and understand its mechanistic involvement in this disease. MATERIAL AND METHODS The relative expression of miR-145 in clinical samples was analyzed using the public GSE43732 dataset. The prognostic analysis with respect to miR-145 expression was performed with Kaplan-Meier plot. Cell viability was measured by MTT assay and the anchorage-independent growth was evaluated by soft agar assay. The migration and invasion of esophageal cancer cells were measured using transwell chamber. The regulatory effect of miR-145 on SMAD5 was determined by dual-luciferase reporter assay. The endogenous SMAD5 protein was measured by Western blot. RESULTS We demonstrated high expression of miR-145 associated with late stage and unfavorable prognosis of esophageal cancer. Ectopic expression of miR-145 mimic significantly stimulated cell proliferation and anchorage-independent growth. Furthermore, high level of miR-145 significantly promoted both migration and invasion in vitro. Notably, we identified SMAD5 as direct target of miR-145, the suppressed expression of which consequently led to increased cell proliferation and migration/invasion. CONCLUSION Our study uncovered the crucial role of miR-145/SMAD5 in esophageal cancer and highlighted its target potential for diagnostic and therapeutic purpose.
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Affiliation(s)
- Qiong Zhang
- a Department of Pathology , The First Affiliated Hospital of Bengbu Medical College , Bengbu , China.,b Department of Pathology , Bengbu Medical College , Bengbu , China
| | - Huaiyong Gan
- a Department of Pathology , The First Affiliated Hospital of Bengbu Medical College , Bengbu , China.,b Department of Pathology , Bengbu Medical College , Bengbu , China
| | - Wenqing Song
- a Department of Pathology , The First Affiliated Hospital of Bengbu Medical College , Bengbu , China.,b Department of Pathology , Bengbu Medical College , Bengbu , China
| | - Damin Chai
- a Department of Pathology , The First Affiliated Hospital of Bengbu Medical College , Bengbu , China.,b Department of Pathology , Bengbu Medical College , Bengbu , China
| | - Shiwu Wu
- a Department of Pathology , The First Affiliated Hospital of Bengbu Medical College , Bengbu , China.,b Department of Pathology , Bengbu Medical College , Bengbu , China
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Ishiwata T, Matsuda Y, Yoshimura H, Sasaki N, Ishiwata S, Ishikawa N, Takubo K, Arai T, Aida J. Pancreatic cancer stem cells: features and detection methods. Pathol Oncol Res 2018; 24:797-805. [PMID: 29948612 DOI: 10.1007/s12253-018-0420-x] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Accepted: 05/17/2018] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a high incidence of distant metastasis and recurrence. Cancer stem cells (CSCs), which are pluripotent, self-renewable, and capable of forming tumors, contribute to PDAC initiation and metastasis and are responsible for resistance to chemotherapy and radiation. Three types of experimental methods are commonly used to identify CSCs: CSC-specific marker detection, a sphere-formation assay that reveals cell proliferation under non-adherent conditions, and detection of side-population (SP) cells that possess high intracellular-to-extracellular pump functions. Several CSC-specific markers have been reported in PDACs, including CD133, CD24, CD44, CXCR4, EpCAM, ABCG2, c-Met, ALDH-1, and nestin. There remains controversy regarding which markers are specific to PDAC CSCs and which are expressed alone or in combination in CSCs. Examining characteristics of isolated CSCs and discovering CSC-specific treatment options are important to improve the prognosis of PDAC cases. This review summarizes CSC-detection methods for PDAC, including CSC-marker detection, the sphere-formation assay, and detection of SP cells.
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Affiliation(s)
- Toshiyuki Ishiwata
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
| | - Yoko Matsuda
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, 173-0015, Japan
| | - Hisashi Yoshimura
- Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, 180-0022, Japan
| | - Norihiko Sasaki
- Research Team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan
| | - Shunji Ishiwata
- Division of Medical Pharmaceutics & Therapeutics, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, Japan
| | - Naoshi Ishikawa
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Kaiyo Takubo
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, 173-0015, Japan
| | - Junko Aida
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
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Mei LL, Qiu YT, Huang MB, Wang WJ, Bai J, Shi ZZ. MiR-99a suppresses proliferation, migration and invasion of esophageal squamous cell carcinoma cells through inhibiting the IGF1R signaling pathway. Cancer Biomark 2017; 20:527-537. [DOI: 10.3233/cbm-170345] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Mei LL, Qiu YT, Wang WJ, Bai J, Shi ZZ. Overexpression of microRNA-1470 promotes proliferation and migration, and inhibits senescence of esophageal squamous carcinoma cells. Oncol Lett 2017; 14:7753-7758. [PMID: 29344220 PMCID: PMC5755030 DOI: 10.3892/ol.2017.7190] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 08/11/2017] [Indexed: 01/20/2023] Open
Abstract
MicroRNA-1470 (miR-1470) is overexpressed in esophageal squamous cell carcinoma (ESCC); however, its role and underlying molecular mechanism remain unknown. The aim of the present study was to explore the tumorigenic role and mechanism of miR-1470 overexpression in ESCC. The expression of miR-1470 in ESCC tissues and cell lines was detected using human miRNA microarrays and the reverse transcription-quantitative polymerase chain reaction, respectively. The effects of miR-1470 on cell proliferation, migration and senescence were determined using a Cell Counting Kit-8 assay, Transwell migration assay and β-galactosidase staining kit. Western blotting was used to analyze the expression levels of genes in the apoptosis signaling pathway. An increased expression level of miR-1470 was observed in ESCC tissues compared with that in paracancerous tissues. Knockdown of miR-1470 significantly suppressed proliferation, and down-regulated the cell cycle regulatory gene cyclin E1. It was also revealed that knockdown of miR-1470 significantly inhibited migration, and decreased the expression levels of matrix metalloproteinase 2 (MMP2), MMP13 and MMP14. Western blotting analysis revealed that knockdown of miR-1470 induced apoptosis by increasing B-cell lymphoma 2 (Bcl-2) expression. The results of the present study suggest that overexpression of miR-1470 in ESCC promotes cancer cell proliferation by accelerating the cell cycle and inhibiting apoptosis, and also enhances cancer cell migration by upregulating MMPs.
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Affiliation(s)
- Li-Li Mei
- Medical School, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
| | - Yun-Tan Qiu
- Medical School, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
| | - Wen-Jun Wang
- Medical School, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
| | - Jie Bai
- Medical School, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
| | - Zhi-Zhou Shi
- Medical School, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.,State Key Laboratory of Molecular Oncology, Cancer Hospital, CAMS, Beijing 100021, P.R. China
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Mei LL, Wang WJ, Qiu YT, Xie XF, Bai J, Shi ZZ. miR-145-5p Suppresses Tumor Cell Migration, Invasion and Epithelial to Mesenchymal Transition by Regulating the Sp1/NF-κB Signaling Pathway in Esophageal Squamous Cell Carcinoma. Int J Mol Sci 2017; 18:ijms18091833. [PMID: 28832500 PMCID: PMC5618482 DOI: 10.3390/ijms18091833] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 06/30/2017] [Accepted: 08/14/2017] [Indexed: 01/19/2023] Open
Abstract
MicroRNAs (miRNAs) play important roles in the progression of human cancer. Although previous reports have shown that miR-145-5p is down-regulated in esophageal squamous cell carcinoma (ESCC), the roles and mechanisms of down-regulation of miR-145-5p in ESCC are still largely unknown. Using microRNA microarray and Gene Expression Omnibus (GEO) datasets, we confirmed that miR-145-5p was down-regulated in ESCC tissues. In vitro assays revealed that ectopic miR-145-5p expression repressed cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT). miR-145-5p also reduced the expressions of cell cycle genes including cyclin A2 (CCNA2), cyclin D1 (CCND1) and cyclin E1 (CCNE1), the EMT-associated transcription factor Slug, and matrix metalloproteinases (MMPs) including MMP2, MMP7 and MMP13. Furthermore, miR-145-5p mimics reduced candidate target gene specificity protein 1 (Sp1) and nuclear factor κ B (NF-κB) (p65) both in mRNA and protein levels. Knockdown of Sp1 phenocopied the effects of miR-145-5p overexpression on cell cycle regulators, EMT and the expression of NF-κB (p65). Importantly, inhibition of the NF-κB signaling pathway or knockdown of NF-κB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells. In conclusion, our results suggested that miR-145-5p plays tumor-suppressive roles by inhibiting esophageal cancer cell migration, invasion and EMT through regulating the Sp1/NF-κB signaling pathway.
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Affiliation(s)
- Li-Li Mei
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
| | - Wen-Jun Wang
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
| | - Yun-Tan Qiu
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
| | - Xiu-Feng Xie
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
| | - Jie Bai
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
| | - Zhi-Zhou Shi
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
- State Key Laboratory of Molecular Oncology, Cancer Hospital, CAMS, Beijing 100021, China.
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Yu Q, Dai J, Zhu Z, Shen H. Downregulation of RIKP by miR-200a promotes the invasive ability of esophageal cancer cells by upregulating the expression of LIN28 and MMP-14. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:8452-8460. [PMID: 31966697 PMCID: PMC6965412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 06/27/2017] [Indexed: 06/10/2023]
Abstract
Esophageal cancer (EC) is one of common digestive tract malignant tumors which morbidity and mortality were increased year by year. This study was aimed to investigate the role of microRNA (miR)-200a in EC. Human esophageal squamous cell carcinoma (ESCC) cells TE3 was transfected with miR-200a mimic or scramble control. Cell viability and invasion were assessed by MTT and Transwell assay, respectively. Binding effect of miR-200a on 3'UTR of RKIP was verified by luciferase activity assay. RKIP expression in miR-200a mimic transfected cells was measured. RKIP was overexpressed in miR-200a transfected cells and cell viability and invasion were measured. The expressions of Raf1, ERK, MMP-14, LIN28 and GRK-2 were also measured by qRT-PCR and Western blot analysis, respectively. Results showed that miR-200a mimic transfection increased cell viability and invasion of TE3 cells in vitro. miR-200a binding with 3'UTR of RKIP negatively regulated RKIP expression. RKIP overexpression inhibited effects of miR-200a on cell viability and invasion, as well as the increased phosphorylation levels of Raf1 and ERK. miR-200a increased expressions of MMP-14, LIN28 and GRK-2 in TE3 cells, and the up-regulations were inhibited by RKIP overexpression. In conclusion, the up-regulation of miR-200a in TE3 cells promoted cell viability and invasion via negatively regulating RKIP expression. RKIP was a direct target of miR-200a. miR-200a might be involved in activation of MAPK/ERK signaling pathway and expression of MMP-14, LIN28 and GRK-2 which were important factors of intracellular information transduction. Our findings demonstrated that miR-200a regulated ESCC cells via regulating RKIP expression.
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Affiliation(s)
- Qiuyun Yu
- Department of Laboratory, Ningbo No. 2 HospitalNingbo, P. R. China
| | - Jinhua Dai
- Department of Laboratory, Ningbo No. 2 HospitalNingbo, P. R. China
| | - Zhankun Zhu
- Department of Laboratory, Ningbo No. 2 HospitalNingbo, P. R. China
| | - Haibo Shen
- Department of Thoracic Surgery, Ningbo No. 2 HospitalNingbo, P. R. China
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Karimi L, Mansoori B, shanebandi D, Mohammadi A, Aghapour M, Baradaran B. Function of microRNA-143 in different signal pathways in cancer: New insights into cancer therapy. Biomed Pharmacother 2017; 91:121-131. [DOI: 10.1016/j.biopha.2017.04.060] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 04/05/2017] [Accepted: 04/13/2017] [Indexed: 01/05/2023] Open
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Zhou P, Dong H, He S, Fang L, Jiang N, Sun Q. miR612 is associated with esophageal squamous cell carcinoma development and metastasis, mediated through TP53. Mol Med Rep 2017; 16:1855-1863. [PMID: 28656264 PMCID: PMC5562086 DOI: 10.3892/mmr.2017.6808] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 03/16/2017] [Indexed: 01/23/2023] Open
Abstract
MicroRNAs (miRNAs) serve an important role in the regulation of gene expression. In the present study, differential expressions of miRNAs were compared between esophageal squamous cell carcinoma (ESCC) tissues and normal esophageal tissues. In combination with miRNA target prediction databases, a significantly increased expression of miR-612 was discovered in ESCC. The relationship between miR-612 and TP53 gene expression and their roles in ESCC invasion and metastasis was further studied by reverse transcription-quantitative polymerase chain reaction and western blotting in EC109 cells and cancer tissues. The EC109 cell invasion and migration were significantly reduced after miR-612 expression was inhibited. The levels of wild type TP53 protein and mRNA were lower in ESCC tissues compared to the normal esophageal epithelium. In addition, the mRNA and protein expression levels were reported as downregulated further in tumors with metastasis than in tumors without. In conclusion, miR-612 is identified as associated with ESCC development and metastasis, likely through the regulation of TP53 expression, which could be a potential therapeutic target.
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Affiliation(s)
- Ping Zhou
- Department of Pathology, Qianfoshan Hospital Affiliated with Shandong University, Jinan, Shandong 250014, P.R. China
| | - He Dong
- Department of Pathology, Qianfoshan Hospital Affiliated with Shandong University, Jinan, Shandong 250014, P.R. China
| | - Shuqian He
- Department of Pathology, Qianfoshan Hospital Affiliated with Shandong University, Jinan, Shandong 250014, P.R. China
| | - Lei Fang
- Department of Pathology, Qianfoshan Hospital Affiliated with Shandong University, Jinan, Shandong 250014, P.R. China
| | - Nan Jiang
- Department of Pathology, Shandong University School of Medicine, Jinan, Shandong 250014, P.R. China
| | - Qing Sun
- Department of Pathology, Qianfoshan Hospital Affiliated with Shandong University, Jinan, Shandong 250014, P.R. China
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Gao W, Sun W, Yin J, Lv X, Bao J, Yu J, Wang L, Jin C, Hu L. Screening candidate microRNAs (miRNAs) in different lambskin hair follicles in Hu sheep. PLoS One 2017; 12:e0176532. [PMID: 28464030 PMCID: PMC5413071 DOI: 10.1371/journal.pone.0176532] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 04/12/2017] [Indexed: 12/31/2022] Open
Abstract
Hu sheep lambskin is a unique white lambskin from China that exhibits three types of flower patterns, including small waves, medium waves, and large waves, with small waves considered the best quality. However, our understanding of the molecular mechanism underlying flower pattern formation in Hu sheep lambskin is limited. The aim of the present study was to further explore the relevance between candidate microRNAs (miRNAs) and developmental characteristics of hair follicles and screen miRNAs for later functional validation. Herein, we employed Illumina Hiseq 2500 to identify differentially expressed miRNAs in hair follicles of different flower patterns with small, medium, and large waves to construct a comprehensive sequence database on the mechanism of hair follicle development. Paraffin sections of lambskin tissue were prepared to assess the structure of different hair follicles. Expression levels of candidate miRNAs in different flower patterns were analyzed by relative quantitation using real-time PCR, combined with histological observation and micro-observation technologies, and the correlation between expression levels of candidate miRNAs and histological properties of hair follicles was analyzed by using SPSS 17.0. A total of 522 differentially expressed miRNAs were identified, and RNA-seq analysis detected 7,266 target genes in different groups of flower patterns. Gene ontological analysis indicated these target genes were mainly involved in cell proliferation, differentiation, growth, apoptosis, and ion transport, and 14 miRNAs, including miR-143, miR-10a, and let-7 were screened as candidate miRNAs in Hu sheep hair follicle growth and development. In the same field of vision, variance analysis showed that the number of secondary follicles in small waves was significantly larger than that in large and medium waves (P<0.01); the diameter of the primary and secondary follicles in large waves was respectively larger than those in medium and small waves (P<0.01). Combined with correlation analysis between miRNA expression and histological properties of hair follicles, highly significant differences in miRNA-143 expression levels between large and small waves were observed (P<0.01), and significant differences in the miRNA-10a expression levels between large and small waves (P<0.05) and in let-7i expression levels between large and medium waves were observed (P<0.05). Significant differences in the expression of novel miRNAs of NW_004080184.1_6326 between medium and large waves were detected (P<0.05), and highly significant differences between medium and small waves were observed (P<0.01). Highly significant differences in the expression level of NW_004080165.1_8572 between medium and large and small waves (P<0.01), in that of NW_004080181.1_3961 between medium and small waves (P<0.01), and in that of NW_004080190.1_13733 between medium and large waves were observed, whereas no significant differences in the other miRNAs among large, medium, and small waves were detected. Overall, the present study showed that miRNA-143, miRNA-10a, let-7i, NW_004080184.1_6326, NW_004080165.1_8572, NW_004080181.1_3961, and NW_004080190.1_13733 could be considered as important candidate genes, indicating these seven miRNAs may play significant roles in hair follicle growth and development in Hu sheep lambskin.
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Affiliation(s)
- Wen Gao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Wei Sun
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
- * E-mail:
| | - Jinfeng Yin
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Xiaoyang Lv
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Jianjun Bao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Jiarui Yu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Lihong Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Chengyan Jin
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Liang Hu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
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Wang Y, Zhang J, Zhao W, Wang D, Ma W, Shang S, Feng C, Yu H. MicroRNA expression in esophageal squamous cell carcinoma: Novel diagnostic and prognostic biomarkers. Mol Med Rep 2017; 15:3833-3839. [PMID: 28440443 DOI: 10.3892/mmr.2017.6479] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 02/22/2017] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to identify more effective molecular diagnostic biomarkers for esophageal squamous cell carcinoma (ESCC). The non‑coding RNA profile GSE43732, generated from 238 paired frozen tissues from 119 patients, was analyzed. Raw data were preprocessed and the differentially expressed miRNAs were screened by limma package with log2 fold change >2. Prognosis‑associated miRNAs were identified using receiver operating characteristic (ROC) and Kaplan-Meier (KM) curve analysis. miRNAs with an area under the ROC curve of ≥0.7 were selected. miRNA target genes were identified from verification and predictive databases, and an miRNA regulatory network was constructed and visualized using Cytoscape software. Gene Ontology and pathway enrichment analyses of the target genes were performed using TargetMine. A total of 107 differentially expressed miRNAs, including 54 upregulated and 53 downregulated miRNAs, were obtained. The KM survival curves revealed that 44 miRNAs were significantly associated with prognosis. Furthermore, 9 upregulated and 3 downregulated miRNAs were obtained. Two upregulated miRNAs, hsa‑miR‑143‑3p and hsa‑miR‑145‑5p, and two downregulated miRNAs, hsa‑miR‑182‑5p and hsa‑miR‑455‑5p, were identified and demonstrated to be associated with prognosis in ESCC. In addition, 8 known and 245 predicted target genes of hsa‑miR‑455‑5p were screened and the regulatory networks were constructed. Furthermore, these genes were functionally associated with macromolecule metabolic process and melanoma. In conclusion, two novel tumor suppressive miRNAs including miR‑182‑5p and miR‑455‑5p were identified. miR‑455‑5p in particular may be involved in the regulation of ESCC. These miRNAs may be used to predict the prognosis of ESCC.
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Affiliation(s)
- Yan Wang
- Department of Thoracic Surgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Jinnan Zhang
- Department of Neurosurgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Wei Zhao
- Department of Thoracic Surgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Donglin Wang
- Department of General Surgery, Green Garden Changchun City Hospital, Changchun, Jilin 130062, P.R. China
| | - Wenduan Ma
- Department of Thoracic Surgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Shengtao Shang
- Department of Thoracic Surgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Chao Feng
- Department of Thoracic Surgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Haixin Yu
- Department of Thoracic Surgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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Deng X, Luo M. Expression of miR-944 in esophageal squamous cell carcinoma and its role in cell proliferation and invasion in human esophageal carcinoma cell line Eca109. Shijie Huaren Xiaohua Zazhi 2017; 25:684-690. [DOI: 10.11569/wcjd.v25.i8.684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To detect the expression of miRNA-944 in esophageal squamous cell carcinoma (ESCC), and to explore its role in cell proliferation and migration in human esophageal cancer cell line Eca109.
METHODS ESCC and matched tumor adjacent noncancerous tissue samples were obtained from 36 patients who underwent surgical treatment and were pathologically diagnosed with ESCC. Real-time quantitative PCR (qRT-PCR) was used to detect the expression levels of miRNA-944, and the relationship between miRNA-944 and clinical and pathological parameters were then analyzed. Eca109 cells were transfected with miR-944 mimic, inhibitor and negative control using LipofectamineTM2000, and then the expression level of miR-944 was detected by qRT-PCR. Cell proliferation and invasion were assessed by MTT assay and transwell assay, respectively.
RESULTS The expression level of miR-944 in ESCC tissues was significantly higher than that in tumor adjacent non-cancerous tissues (P < 0.01).The up-regulation of miR-944 expression in ESCC was correlated with advanced TNM stage (P < 0.01) and lymph node metastasis (P < 0.01). Compared to control cells, transfection of miR-944 mimic and inhibitor up- and down-regulated miR-944 expression in Eca109 cells, respectively (P < 0.01). Furthermore, transfection of miR-944 mimic enhanced cell proliferation and invasion, while transfection of miR-944 inhibitor inhibited cell proliferation and invasion (P < 0.01).
CONCLUSION The expression of miR-944 is up-regulated in ESCC and associated with TNM stage and lymph node metastasis, indicating that miR-944 may facilitate ESCC occurrence possibly by promoting the proliferation and invasion of ESCC cells.
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Yi J, Jin L, Chen J, Feng B, He Z, Chen L, Song H. MiR-375 suppresses invasion and metastasis by direct targeting of SHOX2 in esophageal squamous cell carcinoma. Acta Biochim Biophys Sin (Shanghai) 2017; 49:159-169. [PMID: 28069583 DOI: 10.1093/abbs/gmw131] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Indexed: 12/15/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the most common histological type in China. MicroRNAs are endogenously expressed in mammals and play a significant role in tumor invasion and metastasis by targeting potential downstream genes. In the present study, microarray analysis showed that miR-375 expression was distinctly downregulated in ESCC compared with that in normal esophageal epithelium tissues. Then, luciferase reporter assay showed that SHOX2 was the direct downstream target of miR-375 and this interaction was confirmed by the rescue experiments. Quantitative polymerase chain reaction results also showed that SHOX2 expression was upregulated in ESCC cells and tissues. Further analysis showed that SHOX2 induced proliferation, invasion, and metastasis of ESCC both in vivo and in vitro. Moreover, the interaction between miR-375 and SHOX2 affected the epithelial-to-mesenchymal transition. We conclude that miR-375 may suppress invasion and metastasis of ESCC by directly targeting SHOX2. The miR-375/SHOX2 axis may be a novel therapeutic target for ESCC.
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Affiliation(s)
- Jun Yi
- Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing 210002, China
| | - Li Jin
- Department of Medical Oncology, Jinling Hospital, Nanjing 210002, China
| | - Jing Chen
- Department of Medical Oncology, Jinling Hospital, Nanjing 210002, China
| | - Bing Feng
- Department of Medical Oncology, Jinling Hospital, Nanjing 210002, China
| | - Zhenyue He
- Department of Medical Oncology, Jinling Hospital, Nanjing 210002, China
| | - Longbang Chen
- Department of Medical Oncology, Jinling Hospital, Nanjing 210002, China
| | - Haizhu Song
- Department of Medical Oncology, Jinling Hospital, Nanjing 210002, China
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Fendereski M, Zia MF, Shafiee M, Safari F, Saneie MH, Tavassoli M. MicroRNA-196a as a Potential Diagnostic Biomarker for Esophageal Squamous Cell Carcinoma. Cancer Invest 2017; 35:78-84. [PMID: 28095062 DOI: 10.1080/07357907.2016.1254228] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
We observed significant up-regulation of miR-196a in esophageal squamous cell carcinoma (ESCC) as compared with their adjacent normal tissue (p = .002). Receiver operating characteristics curve analysis confirmed the suitability of miR-196a as a potential tumor marker for diagnosis of ESCC. Furthermore, analysis of miR-196a levels in saliva samples determined an average of 27-fold up-regulations in ESCC patients compared with healthy group. Our results suggest that salivary miR-196a may be a suitable noninvasive biomarker for diagnosis of ESCC. In addition, molecular pathway enrichment analysis of microRNA (miR)-196a determined focal adhesion, spliceosome and p53 signaling pathways as the most relevant pathways with miR-196a targetome.
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Affiliation(s)
- Mona Fendereski
- a Department of Biology, Faculty of Sciences , University of Isfahan , Isfahan , Iran
| | - Mohammad Farid Zia
- b Department of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences , Isfahan University of Medical Sciences , Gorgan , Iran
| | - Mohammad Shafiee
- c Department of Medical Genetics, School of Advanced Medical Technologies , Golestan University of Medical Sciences , Gorgan , Iran
| | - Forousan Safari
- a Department of Biology, Faculty of Sciences , University of Isfahan , Isfahan , Iran
| | | | - Manoochehr Tavassoli
- a Department of Biology, Faculty of Sciences , University of Isfahan , Isfahan , Iran
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Zhang JX, Chen ZH, Xu Y, Chen JW, Weng HW, Yun M, Zheng ZS, Chen C, Wu BL, Li EM, Fu JH, Ye S, Xie D. Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell-like Phenotype via Dysregulation of PITX2. Clin Cancer Res 2017; 23:298-310. [PMID: 27407092 DOI: 10.1158/1078-0432.ccr-16-0414] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 06/02/2016] [Accepted: 06/21/2016] [Indexed: 02/05/2023]
Abstract
PURPOSE We previously reported the oncogenic role of paired-like homeodomain 2 (PITX2) in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to identify the miRNA regulators of PITX2 and the mechanism underlying the pathogenesis of ESCC. EXPERIMENTAL DESIGN Using miRNA profiling and bioinformatics analyses, we identified miR-644a as a negative mediator of PITX2 in ESCC. A series of in vivo and in vitro assays were performed to confirm the effect of miR-644a on PITX2-mediated ESCC malignancy. RESULTS ESCC cells and tissues expressed less miR-644a than normal epithelial controls. In patient samples, lower expression of miR-644a in ESCC tissues was significantly correlated with tumor recurrence and/or metastasis, such that miR-644a, PITX2, and the combination of the two were independent prognostic indicators for ESCC patient's survival (P < 0.05). Gain- and loss-of-function studies demonstrated that miR-644a inhibited ESCC cell growth, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo In addition, miR-644a dramatically suppressed self-renewal and stem cell-like traits in ESCC cells. Furthermore, the effect of upregulation of miR-644a was similar to that of PITX2 knockdown in ESCC cells. Mechanistic studies revealed that miR-644a attenuates ESCC cells' malignancy and stem cell-associated phenotype, at least partially, by inactivation of the Akt/GSK-3β/β-catenin signaling pathway through PITX2. Furthermore, promoter hypermethylation caused downregulation of miR-644a in ESCC. CONCLUSIONS Downregulation of miR-644a plays an important role in promoting both aggressiveness and stem-like traits of ESCC cells, suggesting that miR-644a may be useful as a novel prognostic biomarker or therapeutic target for the disease. Clin Cancer Res; 23(1); 298-310. ©2016 AACR.
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Affiliation(s)
- Jia-Xing Zhang
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China
- Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
- Guangdong Esophageal Cancer Institute, Guangzhou, P.R. China
| | - Zhen-Hua Chen
- Department of Urology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Yi Xu
- Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Jie-Wei Chen
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China
- Guangdong Esophageal Cancer Institute, Guangzhou, P.R. China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China
| | - Hui-Wen Weng
- Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Miao Yun
- Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Zou-San Zheng
- Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Cui Chen
- Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Bing-Li Wu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - En-Min Li
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Jian-Hua Fu
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China
- Guangdong Esophageal Cancer Institute, Guangzhou, P.R. China
| | - Sheng Ye
- Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China.
| | - Dan Xie
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China.
- Guangdong Esophageal Cancer Institute, Guangzhou, P.R. China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China
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Chen JH, Yang R, Zhang W, Wang YP. Functions of microRNA-143 in the apoptosis, invasion and migration of nasopharyngeal carcinoma. Exp Ther Med 2016; 12:3749-3755. [PMID: 28101165 DOI: 10.3892/etm.2016.3847] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 09/13/2016] [Indexed: 01/02/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a common cancer characterized by poor prognosis in areas of Southern China where it is endemic. microRNAs (miRNAs) are a class of naturally occurring small noncoding RNAs, some of which contribute to the initiation and development of cancer. The current study was designed to examine the expression level of miR-143 in NPC tissues. The potential functional targets of miR-143 involved in tumor apoptosis, invasion and migration were also investigated. Reverse transcription-quantitative polymerase chain reaction was used to evaluate the expression levels of miR-143 in clinical NPC specimens. Western blotting was used to explore the expression levels of extracellular signal regulated kinase (ERK)-5, Kirsten rat sarcoma viral oncogene homolog (KRAS), caspase 3 and B-cell lymphoma 2 (Bcl-2) in CNE-2Z cells following transfection with miR-143. Significantly decreased expression levels of miR-143 were observed in NPC tissues in comparison with matched normal nasopharyngeal tissues. Moreover, negative associations of miR-143 with tumor invasion depth, as well as lymph node metastasis were found. The enforced expression of miR-143 induced NPC cell apoptosis in addition to the suppression of growth, migration and invasion. The functions of miR-143 in NPC are mediated, at least in part, by the inhibition of ERK-5 activity and promotion of caspase 3 and KRAS expression. These findings suggest that miR-143 may function as a tumor suppressor in the development and progression of NPC.
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Affiliation(s)
- Jin-Hui Chen
- Department of Otorhinolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Rui Yang
- Department of Otorhinolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wei Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yong-Ping Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Han Q, Zhang HY, Zhong BL, Wang XJ, Zhang B, Chen H. MicroRNA-145 Inhibits Cell Migration and Invasion and Regulates Epithelial-Mesenchymal Transition (EMT) by Targeting Connective Tissue Growth Factor (CTGF) in Esophageal Squamous Cell Carcinoma. Med Sci Monit 2016; 22:3925-3934. [PMID: 27771733 PMCID: PMC5081241 DOI: 10.12659/msm.897663] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Background This study investigated the mechanism of miR-145 in targeting connective tissue growth factor (CTGF), which affects the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of ESCC cells. Material/Methods A total of 50 ESCC tissues and their corresponding normal adjacent esophageal tissue samples were collected. Then, miR-145 expression in both ESCC clinical specimens and cell lines was detected using quantitative real-time PCR. CTGF protein was detected using immunohistochemistry. Dual luciferase reporter gene assay was employed to assess the effect of miR-145 on the 3′UTR luciferase activity of CTGF. Eca109 cells were transfected with miR-145 mimics and CTGF siRNA, respectively, and changes in cellular proliferation, migration, and invasion were detected via MTT assay, wound-healing assay, and Transwell assay, respectively. Western blotting assay was used to detect the expression of marker genes related to EMT. Results MiR-145 was significantly down-regulated in ESCC tissues and cell lines compared with normal tissues and cell lines (P<0.05). We found significantly more positively expressed CTGF protein in ESCC tissues was than in normal adjacent esophageal tissues (P<0.01). Dual luciferase reporter gene assay showed that miR-145 can specifically bind with the 3′UTR of CTGF and significantly inhibit the luciferase activity by 55% (P<0.01). Up-regulation of miR-145 or down-regulation of CTGF can suppress the proliferation, migration, invasion, and EMT process of ESCC cells. Conclusions MiR-145 was significantly down-regulated in ESCC tissues and cell lines, while the protein expression of CTGF exhibited the opposite trend. MiR-145 inhibited the proliferation, migration, invasiveness, and the EMT process of ESCC cells through targeted regulation of CTGF expression.
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Affiliation(s)
- Qiang Han
- Department of Thoracic and Cardiovascular Surgery, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China (mainland)
| | - Hua-Yong Zhang
- Department of Thoracic and Cardiovascular Surgery, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China (mainland)
| | - Bei-Long Zhong
- Department of Thoracic and Cardiovascular Surgery, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China (mainland)
| | - Xiao-Jing Wang
- Department of Thoracic and Cardiovascular Surgery, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China (mainland)
| | - Bing Zhang
- Department of Thoracic and Cardiovascular Surgery, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China (mainland)
| | - Hua Chen
- Department of Thoracic and Cardiovascular Surgery, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China (mainland)
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Zhang HF, Alshareef A, Wu C, Jiao JW, Sorensen PH, Lai R, Xu LY, Li EM. miR-200b induces cell cycle arrest and represses cell growth in esophageal squamous cell carcinoma. Carcinogenesis 2016; 37:858-869. [PMID: 27496804 PMCID: PMC5008252 DOI: 10.1093/carcin/bgw079] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Revised: 07/12/2016] [Accepted: 07/30/2016] [Indexed: 02/05/2023] Open
Abstract
miR-200b is a pleiotropically acting microRNA in cancer progression, representing an attractive therapeutic target. We previously identified miR-200b as an invasiveness repressor in esophageal squamous cell carcinoma (ESCC), whereas further understanding is warranted to establish it as a therapeutic target. Here, we show that miR-200b mitigates ESCC cell growth by inducing G2-phase cell cycle arrest and apoptosis. The expression/activation of multiple key cell cycle regulators such as CDK1, CDK2, CDK4 and Cyclin B, and the Wnt/β-Catenin signaling are modulated by miR-200b. We identified CDK2 and PAF (PCNA-associated factor), two important tumor-promoting factors, as direct miR-200b targets in ESCC. Correlating with the frequent loss of miR-200b in ESCC, both CDK2 and PAF levels are significantly increased in ESCC tumors compared to case-matched normal tissues (n = 119, both P < 0.0001), and correlate with markedly reduced survival (P = 0.007 and P = 0.041, respectively). Furthermore, CDK2 and PAF are also associated with poor prognosis in certain subtypes of breast cancer (n = 1802) and gastric cancer (n = 233). Although CDK2 could not significantly mediate the biological function of miR-200b, PAF siRNA knockdown phenocopied while restored expression of PAF abrogated the biological effects of miR-200b on ESCC cells. Moreover, PAF was revealed to mediate the inhibitory effects of miR-200b on Wnt/β-Catenin signaling. Collectively, the pleiotropic effects of miR-200b in ESCC highlight its potential for therapeutic intervention in this aggressive disease.
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Affiliation(s)
- Hai-Feng Zhang
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong 515041, China
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
- Department of Molecular Oncology, British Columbia Cancer Research Centre and Department of Pathology, University of British Columbia, Vancouver, British Columbia V5Z 1L3, Canada and
| | - Abdulraheem Alshareef
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | - Chengsheng Wu
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | - Ji-Wei Jiao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong 515041, China
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Poul H. Sorensen
- Department of Molecular Oncology, British Columbia Cancer Research Centre and Department of Pathology, University of British Columbia, Vancouver, British Columbia V5Z 1L3, Canada and
| | - Raymond Lai
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | - Li-Yan Xu
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong 515041, China
- *To whom correspondence should be addressed. Tel: +86 754 88900464; Fax: +86 754 88900847;
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Jin YY, Chen QJ, Wei Y, Wang YL, Wang ZW, Xu K, He Y, Ma HB. Upregulation of microRNA-98 increases radiosensitivity in esophageal squamous cell carcinoma. JOURNAL OF RADIATION RESEARCH 2016; 57:468-476. [PMID: 27422937 PMCID: PMC5045086 DOI: 10.1093/jrr/rrw068] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 05/17/2016] [Indexed: 05/04/2023]
Abstract
Although radiation resistance is a common challenge in the clinical treatment of esophageal squamous cell carcinoma (ESCC), an effective treatment strategy has yet to be developed. Aberrant expression of microRNAs (miRNAs) is responsible for cancer sensitivity to radiation. In this study, we aimed to identify the miRNAs that are associated with radioresistance in ESCC. We used a miRNA microarray to perform a comparison of miRNA expression in both ESCC parental and acquired radioresistance cell lines. qRT-PCR was used to confirm the alterations. Cell radiosensitivity was determined with a survival fraction assay. Functional analyses of the identified miRNA in ESCC cells with regard to metastasis and apoptosis were performed by transwell assays and flow cytometry. The miRNA targets were identified with pathway analysis and confirmed with a luciferase assay. miR-98 was recognized as the most downregulated miRNA in established radioresistant cell line. AmiR-98 mimic enforced the expression of miRNA-98 and made ESCC cells sensitive to radiotherapy, while anti-miR-98 reversed this process. Optimal results were achieved by decreasing cellular proliferation, decreasing cell migration and inducing apoptosis. The luciferase target gene analysis results showed that the overexpression of miRNA-98 inhibited tumor growth and resistance tolerance by directly binding to the BCL-2 gene. Our study indicated that increasing miRNA-98 expression can be used as a potential radiosensitive therapeutic strategy for treating esophageal cancer cells.
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Affiliation(s)
- Ying-Ying Jin
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, Xiwu Lu, Xi'an 710004, Shaanxi Province, China
| | - Qing-Juan Chen
- Department of Oncology, Xianyang Center Hospital, Xianyang City, 610041, Shaanxi Province, China
| | - Yang Wei
- Scientific Research Center, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, Xiwu Lu, Xi'an 710004, Shaanxi Province, China
| | - Ya-Li Wang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, Xiwu Lu, Xi'an 710004, Shaanxi Province, China
| | - Zhong-Wei Wang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, Xiwu Lu, Xi'an 710004, Shaanxi Province, China
| | - Kun Xu
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, Xiwu Lu, Xi'an 710004, Shaanxi Province, China
| | - Yun He
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, Xiwu Lu, Xi'an 710004, Shaanxi Province, China
| | - Hong-Bing Ma
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, Xiwu Lu, Xi'an 710004, Shaanxi Province, China
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MicroRNAs in non-small cell lung cancer and idiopathic pulmonary fibrosis. J Hum Genet 2016; 62:57-65. [PMID: 27488441 DOI: 10.1038/jhg.2016.98] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 06/25/2016] [Accepted: 06/27/2016] [Indexed: 12/21/2022]
Abstract
In spite of advances in the diagnosis and current molecular target therapies of lung cancer, this disease remains the most common cause of cancer-related death worldwide. Approximately 80% of lung cancers is non-small cell lung cancer (NSCLC), and 5-year survival rate of the disease is ~20%. On the other hand, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. IPF is refractory to treatment and has a very low survival rate. Moreover, IPF is frequently associated with lung cancer. However, the common mechanisms shared by these two diseases remain poorly understood. In the post-genome sequence era, the discovery of noncoding RNAs, particularly microRNAs (miRNAs), has had a major impact on most biomedical fields, and these small molecules have been shown to contribute to the pathogenesis of NSCLC and IPF. Investigation of novel RNA networks mediated by miRNAs has improved our understanding of the molecular mechanisms of these diseases. This review summarizes our current knowledge on aberrantly expressed miRNAs regulating NSCLC and IPF based on miRNA expression signatures.
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Cui G, Liu D, Li W, Li Y, Liang Y, Shi W, Zhao S. Original Research: miR-194 inhibits proliferation and invasion and promotes apoptosis by targeting KDM5B in esophageal squamous cell carcinoma cells. Exp Biol Med (Maywood) 2016; 242:45-52. [PMID: 27480251 DOI: 10.1177/1535370216662712] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 07/13/2016] [Indexed: 01/08/2023] Open
Abstract
Increasing evidence suggests that miR-194 is down-regulated in esophageal squamous cell carcinoma tumor tissue. However, the role and underlying mechanism of miR-194 in esophageal squamous cell carcinoma have not been well defined. We used DIANA, TargetScan and miRanda to perform target prediction analysis and found KDM5B is a potential target of miR-194. Based on these findings, we speculated that miR-194 might play a role in esophageal squamous cell carcinoma development and progression by regulation the expression of KDM5B. We detected the expression of miR-194 and KDM5B by quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot assays, respectively, and found down-regulation of miR-194 and up-regulation of KDM5B existed in esophageal squamous cell carcinoma cell lines. By detecting proliferation, invasion and apoptosis of TE6 and TE14 cells transfected with miR-194 mimics or mimic control, miR-194 was found to inhibit proliferation and invasion and promote apoptosis of esophageal squamous cell carcinoma cells. miR-194 was further verified to regulate proliferation, apoptosis and invasion of esophageal squamous cell carcinoma cells by directly targeting KDM5B. Furthermore, animal studies were performed and showed that overexpression of miR-194 inhibited the growth of esophageal squamous cell carcinoma tumors in vivo. These results confirmed our speculation that miR-194 targets KDM5B to inhibit esophageal squamous cell carcinoma development and progression. These findings offer new clues for esophageal squamous cell carcinoma development and progression and novel potential therapeutic targets for esophageal squamous cell carcinoma.
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Affiliation(s)
- Guanghui Cui
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P.R. China
| | - Donglei Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P.R. China
| | - Weihao Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P.R. China
| | - Yuhang Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P.R. China
| | - Youguang Liang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P.R. China
| | - Wensong Shi
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P.R. China
| | - Song Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P.R. China
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Jiang S, Zhao C, Yang X, Li X, Pan Q, Huang H, Wen X, Shan H, Li Q, Du Y, Zhao Y. miR-1 suppresses the growth of esophageal squamous cell carcinoma in vivo and in vitro through the downregulation of MET, cyclin D1 and CDK4 expression. Int J Mol Med 2016; 38:113-22. [PMID: 27247259 PMCID: PMC4899011 DOI: 10.3892/ijmm.2016.2619] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 05/10/2016] [Indexed: 12/28/2022] Open
Abstract
Several aberrant microRNAs (miRNAs or miRs) have been implicated in esophageal cancer (EC), which is widely prevalent in China. However, their role in EC tumorigenesis has not yet been fully elucidated. In the present study, we determined that miR-1 was downregulated in esophageal squamous cell carcinoma (ESCC) tissues compared with adjacent non-neoplastic tissues using RT-qPCR, and confirmed this using an ESCC cell line. Using a nude mouse xenograft model, we confirmed that the re-expression of miR-1 significantly inhibited ESCC tumor growth. A tetrazolium assay and a trypan blue exclusion assay revealed that miR-1 suppressed ESCC cell proliferation and increased apoptosis, whereas the silencing of miR-1 promoted cell proliferation and decreased apoptosis, suggesting that miR-1 is a novel tumor suppressor. To elucidate the molecular mechanisms of action of miR-1 in ESCC, we investigated putative targets using bioinformatics tools. MET, cyclin D1 and cyclin-dependent kinase 4 (CDK4), which are involved in the hepatocyte growth factor (HGF)/MET signaling pathway, were found to be targets of miR-1. miR-1 expression inversely correlated with MET, cyclin D1 and CDK4 expression in ESCC cells. miR-1 directly targeted MET, cyclin D1 and CDK4, suppressing ESCC cell growth. The newly identified miR-1/MET/cyclin D1/CDK4 axis provides new insight into the molecular mechanisms of ESCC pathogenesis and indicates a novel strategy for the diagnosis and treatment of ESCC.
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Affiliation(s)
- Sen Jiang
- The 82nd Hospital of the People's Liberation Army, Huaian, Jiangsu 223001, P.R. China
| | - Chao Zhao
- The 82nd Hospital of the People's Liberation Army, Huaian, Jiangsu 223001, P.R. China
| | - Xiaodi Yang
- Department of Gastroenterology, Shanghai Sixth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200030, P.R. China
| | - Xiangyang Li
- The 82nd Hospital of the People's Liberation Army, Huaian, Jiangsu 223001, P.R. China
| | - Qing Pan
- Department of Laboratory Medicine, Huaiyin Hospital of Huaian city, Huaian, Jiangsu 233004, P.R. China
| | - Haijin Huang
- The 82nd Hospital of the People's Liberation Army, Huaian, Jiangsu 223001, P.R. China
| | - Xuyang Wen
- The 82nd Hospital of the People's Liberation Army, Huaian, Jiangsu 223001, P.R. China
| | - Husheng Shan
- The 82nd Hospital of the People's Liberation Army, Huaian, Jiangsu 223001, P.R. China
| | - Qianwen Li
- The 82nd Hospital of the People's Liberation Army, Huaian, Jiangsu 223001, P.R. China
| | - Yunxiang Du
- The 82nd Hospital of the People's Liberation Army, Huaian, Jiangsu 223001, P.R. China
| | - Yaping Zhao
- The 82nd Hospital of the People's Liberation Army, Huaian, Jiangsu 223001, P.R. China
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45
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A selective screening platform reveals unique global expression patterns of microRNAs in a cohort of human soft-tissue sarcomas. J Transl Med 2016; 96:481-91. [PMID: 26878133 DOI: 10.1038/labinvest.2015.168] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 12/18/2015] [Indexed: 01/29/2023] Open
Abstract
Sarcomas are malignant heterogenous tumors of mesenchymal derivation. Emerging data suggest that miRNA might have a causal role in sarcomagenesis. Herein, we used a selective miRNA screening platform to study the comparative global miRNA expression signatures in a cohort of human sarcomas with the caveat that comparisons between tumor and non-tumor cells were performed from the same patients using formalin-fixed paraffin-embedded tissue. Five histologic types were examined that included: myxoid liposarcoma, well-differentiated liposarcoma, dedifferentiated liposarcoma, pleomorphic rhabdomyosarcoma, and synovial sarcoma. In addition, soft-tissue lipomas and normal fat were included as a separate set of controls for the lipogenic tumors. Clustering analysis showed a distinct global difference in expression patterns between the normal and sarcoma tissues. Expression signatures in an unsupervised hierarchical clustering analysis revealed tight clustering in synovial and myxoid liposarcomas, and the least clustering was observed in the pleomorphic rhabdomyosarcoma subtype. MiR-145 showed underexpression in pleomorphic rhabdomyosarcoma, well-differentiated liposarcoma, and synovial sarcoma. Unexpectedly, we found that a set of muscle-specific microRNAs (miRNAs; myomiRs): miR-133, miR-1, and miR-206 was significantly underexpressed in well-differentiated liposarcoma and synovial sarcoma, suggesting that they may function as tumor suppressors as described in muscle-relevant rhabdomyosarcomas. In addition, a tight linear progression of miRNA expression was identified from normal fat to dedifferentiated liposarcoma. These results suggest that miRNA expression profiles could elucidate classes of miRNAs that may elicit tumor-relevant activities in specific sarcoma subtypes.
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Mao Y, Liu J, Zhang D, Li B. miR-143 inhibits tumor progression by targeting FAM83F in esophageal squamous cell carcinoma. Tumour Biol 2016; 37:9009-22. [PMID: 26758433 DOI: 10.1007/s13277-015-4760-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 12/29/2015] [Indexed: 11/25/2022] Open
Abstract
Family with sequence similarity 83 (FAM83) members play important roles in carcinogenesis and tumor progression in several tumor types. However, the mechanism by which cancer cells regulate FAM83F still remains unclear. In this study, we found that the FAM84F protein and messenger RNA (mRNA) levels were consistently upregulated in esophageal squamous cell carcinoma (ESCC) tissues, which suggests that a post-transcriptional mechanism may be involved in the regulation of FAM83F. Since microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we performed bioinformatic analyses to search for miRNAs that could potentially target FAM83F. We identified the specific targeting site of miR-143 in the 3'-untranslated region (3'-UTR) of FAM83F and confirmed the inverse correlation between the levels of miR-143 and FAM83F protein and mRNA in ESCC tissue samples. By overexpressing or silencing miR-143 in ESCC cells, we experimentally validated that miR-143 directly binds to the 3'-UTR of the FAM83F transcript and degrades the FAM83F mRNA to regulate FAM83F expression. Furthermore, the biological consequences that miR-143 mediated by targeting FAM83F were examined using in vitro cell proliferation, apoptosis, migration, and invasion assays. We demonstrate that miR-143 exerted a tumor-suppressing effect by inhibiting the proliferation, migration, and invasion and inducing G1/G0 phase arrest of ESCC cells via the negative regulation of FAM83F expression. Taken together, our findings provide important evidence which supports the role of miR-143 as a tumor suppressor in ESCC via the inhibition of FAM83F expression.
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Affiliation(s)
- Yu Mao
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
- Department of Radiation Oncology (Chest Section), Shandong's Key Laboratory of Radiation Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, 250117, Shandong Province, China
| | - Jia Liu
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
| | - Dakai Zhang
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
| | - Baosheng Li
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
- Department of Radiation Oncology (Chest Section), Shandong's Key Laboratory of Radiation Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, 250117, Shandong Province, China.
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Papadopoulos EI, Scorilas A. Cisplatin and Paclitaxel Alter the Expression Pattern of miR-143/145 and miR-183/96/182 Clusters in T24 Bladder Cancer Cells. Clin Transl Sci 2015; 8:668-75. [PMID: 26356996 PMCID: PMC5351132 DOI: 10.1111/cts.12323] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Although cisplatin-based chemotherapy is considered to be the treatment of choice for metastatic bladder cancer, its efficacy and tolerability has proven to be limited. MicroRNAs are small noncoding RNAs, whose genes are frequently organized in clusters. These molecules constitute posttranscriptional regulators of mRNA expression and are claimed to be deregulated in cancer. miR-143/145 and miR-183/96/182 clusters have been extensively studied in bladder cancer cells. Herein, we tried to add up to this knowledge by assessing the expression levels of the five mature microRNAs derived from the aforementioned clusters in T24 bladder cancer cells exposed to either cisplatin or paclitaxel. For both compounds, the viability of treated T24 cells was estimated via the MTT colorimetric assay and the Trypan Blue exclusion method, while a fraction of the cells was left to recover. The expression levels of all mature microRNAs were finally quantified both in treated and in recovered cells by performing real-time PCR. According to our data, cisplatin and paclitaxel strongly decreased T24 cells' viability, showing in parallel the ability to significantly down-regulate miR-143 levels, and up-regulate the expression levels of miR-145, miR-183, miR-96, and miR-182, which, in their total, demonstrated case-specific variations after recovery period.
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Affiliation(s)
- Emmanuel I. Papadopoulos
- Department of Biochemistry and Molecular BiologyFaculty of BiologyUniversity of AthensPanepistimiopolisAthensGreece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular BiologyFaculty of BiologyUniversity of AthensPanepistimiopolisAthensGreece
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Gao QY, Fang JY. Early esophageal cancer screening in China. Best Pract Res Clin Gastroenterol 2015; 29:885-93. [PMID: 26651250 DOI: 10.1016/j.bpg.2015.09.018] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 09/02/2015] [Indexed: 01/31/2023]
Abstract
In China, the incidence of esophageal cancer (EC) and its related mortality are high. Screening strategies aiming at early diagnosis can improve the prognosis. Researches on detection of early EC, especially in China are reviewed. Compared to esophageal balloon cytology or routine endoscopy, chromoendoscopy with Lugol's staining and biopsy appears to be the gold standard for early EC diagnosis in China today. Narrow-band imaging endoscopy, Confocal Laser endomicroscopy and other novel diagnostic approaches are more and more widely used in developed urban areas, but cost and lack of essential training to the endoscopists have made their use limited in rural areas. No specific biomarkers or serum markers were strongly commended to be used in screening strategies currently, which need to be evaluated in future. Trials on organized screening have been proposed in some regions of china with high disease prevalence. Screening in these areas has been shown to be cost effective.
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Affiliation(s)
- Qin-Yan Gao
- Division of Gastroenterology and Hepatology, Ren-Ji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes, 145 Middle Shandong Rd, Shanghai 200001, China
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Ren-Ji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes, 145 Middle Shandong Rd, Shanghai 200001, China.
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49
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Zhang HF, Alshareef A, Wu C, Li S, Jiao JW, Cao HH, Lai R, Xu LY, Li EM. Loss of miR-200b promotes invasion via activating the Kindlin-2/integrin β1/AKT pathway in esophageal squamous cell carcinoma: An E-cadherin-independent mechanism. Oncotarget 2015; 6:28949-60. [PMID: 26334393 PMCID: PMC4745703 DOI: 10.18632/oncotarget.5027] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 08/07/2015] [Indexed: 02/05/2023] Open
Abstract
Our previous studies have shown that loss of miR-200b enhances the invasiveness of esophageal squamous cell carcinoma (ESCC) cells. However, whether the miR-200-ZEB1/2-E-cadherin regulatory cascade, a master regulator of epithelial-to-mesenchymal transition (EMT), is involved in the regulation of ESCC invasion remains elusive. Here, we show that miR-200b represses ESCC cell invasion in vivo without altering the expression of E-cadherin and vimentin, two surrogate markers of EMT. However, an inverse correlation was observed between the expression levels of miR-200b and ZEB1/2 in both ESCC cell lines (n = 7, P < 0.05) and ESCC tumor samples (n = 88, P < 0.05). Methylation of E-cadherin gene was found to block the regulation of E-cadherin by the miR-200b-ZEB1/2 axis, indicating that an E-cadherin-independent mechanism can mediate the biological function of miR-200b in ESCC. We revealed that miR-200b suppresses the integrin β1-AKT pathway via targeting Kindlin-2 to mitigate ESCC cell invasiveness. In two independent cohorts of ESCC samples (n = 20 and n = 53, respectively), Kindlin-2 expression positively correlated with the activation status of both the integrin signaling pathway and the PI3K-AKT signaling pathway (both P < 0.01). These data highlight that suppression of the Kindlin-2-integrin β1-AKT regulatory axis is an alternative mechanism underlying the tumor suppressor function of miR-200b in ESCC.
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MESH Headings
- Animals
- Antigens, CD
- Cadherins/genetics
- Cadherins/metabolism
- Carcinoma, Squamous Cell/enzymology
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/therapy
- Cell Line, Tumor
- Cell Movement
- DNA Methylation
- Down-Regulation
- Esophageal Neoplasms/enzymology
- Esophageal Neoplasms/genetics
- Esophageal Neoplasms/mortality
- Esophageal Neoplasms/pathology
- Esophageal Neoplasms/therapy
- Esophageal Squamous Cell Carcinoma
- Gene Expression Regulation, Neoplastic
- Homeodomain Proteins/metabolism
- Humans
- Integrin beta1/metabolism
- Kaplan-Meier Estimate
- Male
- Membrane Proteins/metabolism
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Neoplasm Invasiveness
- Neoplasm Proteins/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- RNA Interference
- Repressor Proteins/metabolism
- Signal Transduction
- Time Factors
- Transcription Factors/metabolism
- Transfection
- Zinc Finger E-box Binding Homeobox 2
- Zinc Finger E-box-Binding Homeobox 1
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Affiliation(s)
- Hai-Feng Zhang
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Abdulraheem Alshareef
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Chengsheng Wu
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Shang Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Ji-Wei Jiao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
| | - Hui-Hui Cao
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, China
| | - Raymond Lai
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Li-Yan Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, China
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
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50
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Ansari MH, Irani S, Edalat H, Amin R, Mohammadi Roushandeh A. Deregulation of miR-93 and miR-143 in human esophageal cancer. Tumour Biol 2015; 37:3097-103. [PMID: 26427659 DOI: 10.1007/s13277-015-3987-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 08/25/2015] [Indexed: 12/31/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the second and third most common malignancy in Iranian males and females, respectively. Treatment of ESCC is largely ineffective due to lack of detection at early stages of the disease. In recent years, miRNA, a small RNA molecule, has drawn much attention to researchers as a potential biomarker for esophageal cancer. miR-93 and miR-143 are two miRNA molecules reported to be frequently deregulated in various cancers, including prostate, stomach, cervix, and etc. The purpose of this study was to investigate the expression levels of these miRNAs and evaluate their diagnostic and therapeutic potential in esophageal squamous cell carcinoma. In this study, total RNA was extracted from 30 tumor tissues and 30 nontumor tissues of esophageal tumor margins, using RNX-plus solution. After validating the quality and quantity of total RNA, cDNAs of interest were synthesized using microRNA-specific cDNA Synthesis Kit. The expression level of miR-93 and miR-143 was evaluated using quantitative real-time PCR with miRNA-specific primers. Finally, the obtained data was analyzed by SPSS ver.20 software and paired t test was performed to observe the significance of difference between groups. The expression level of miR-93 was significantly increased and of miR-143 was significantly decreased in most of the examined tumor tissues, compared to nontumor tissues. Also, our findings did not detect correlation between mir-93 and mir-143 expressions in regard to stage and grade of the samples. These findings suggest that the deregulation of these miRNAs may play an important role in esophageal squamous cell carcinoma. Both miR-93 and miR-143 might be used as potential biomarkers in esophageal squamous cell carcinoma. However, more studies with large population of samples are necessary.
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Affiliation(s)
- Mohammad Hossein Ansari
- Research Center for Molecular Medicine, Medicine Faculty, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Shiva Irani
- Department of Biology, School of Basic Sciences, Sciences and Research Branch, Islamic Azad University, Tehran, Iran
| | - Houri Edalat
- Research Center for Molecular Medicine, Medicine Faculty, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ruhul Amin
- Department of Project Program, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan
| | - Amaneh Mohammadi Roushandeh
- Research Center for Molecular Medicine, Medicine Faculty, Hamadan University of Medical Sciences, Hamadan, Iran. .,Department of Anatomical Sciences, Medicine Faculty, Hamadan University of Medical Sciences, Hamadan, Iran.
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