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Xing D, Bao J, He J, Gao H, Xue W, Chen J, Li J. miR-378d suppresses gastric cancer metastasis by targeting METTL4 to inhibit epithelial-mesenchymal transition. J Mol Histol 2025; 56:116. [PMID: 40119180 DOI: 10.1007/s10735-025-10392-9] [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: 01/03/2025] [Accepted: 03/06/2025] [Indexed: 03/24/2025]
Abstract
Metastasis is a major determinant of prognosis in gastric cancer (GC), and microRNAs (miRNAs) play crucial roles in driving the metastatic process. This study aimed to identify key miRNAs involved in GC metastasis and elucidate their underlying mechanisms. GC tissues from patients with and without metastasis were subjected to miRNA sequencing to identify differentially expressed miRNAs. Expression differences between GC and normal tissues, as well as their correlation with patient survival, were analyzed using data from The Cancer Genome Atlas and an internal cohort. miR-378d expression was measured by RT-qPCR in the internal cohort, and its association with clinicopathological features and prognosis was analyzed. Gene Set Enrichment Analysis (GSEA) was performed to investigate the potential mechanisms by which miR-378d influences GC metastasis. The findings were validated through in vitro wound healing, transwell assays, western blotting, and immunofluorescence, as well as in vivo models. MiRNA sequencing identified miR-378d as significantly downregulated in GC tissues and associated with poor prognosis. GSEA showed that miR-378d was negatively correlated with epithelial-mesenchymal transition (EMT). In vitro and in vivo experiments demonstrated that upregulation of miR-378d inhibited GC cell migration and invasion. Mechanistically, miR-378d suppressed EMT by downregulating METTL4 expression. miR-378d inhibits GC metastasis by suppressing EMT through the downregulation of METTL4, offering novel insights into the role of miRNAs in GC progression and highlighting potential therapeutic targets for intervention.
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Affiliation(s)
- Danjie Xing
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China
| | - Jiapeng Bao
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China
| | - Jiancheng He
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China
| | - Hanxu Gao
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China
| | - Wanjiang Xue
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China
| | - Junjie Chen
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China.
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China.
| | - Jia Li
- Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
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2
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Wang Q, Ling S, Lv J, Wu L. circ-ZEB1 Enhances NSCLC Metastasis and Proliferation by Modulating the miR-491-5p/EIF5A Axis. Anal Cell Pathol (Amst) 2025; 2025:5595692. [PMID: 39802932 PMCID: PMC11724732 DOI: 10.1155/ancp/5595692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 10/04/2024] [Accepted: 12/11/2024] [Indexed: 01/16/2025] Open
Abstract
Background: Circular RNAs (circRNAs), covalently closed single-stranded RNAs, have been implicated in cancer progression. A previous investigation revealed that circ-ZEB1 is expressed abnormally in liver cancer. However, the roles of circ-ZEB1 in non-small cell lung cancer (NSCLC) are unknown. Methods: In this study, we used fluorescence in situ hybridization (FISH) and RT-qPCR to study circ-ZEB1 expression in NSCLC cells and tissues. A luciferase reporter assay was performed to validate downstream targets of circ-ZEB1. Transwell migration, 5-ethynyl-20-deoxyuridine (EdU), and cell counting kit-8 (CCK8) assays were performed to assess proliferation and migration. In vivo metastasis and tumorigenesis assays were also performed to investigate circ-ZEB1 functions during NSCLC. Results: Our results showed that circ-ZEB1 expression was increased in NSCLC tissues and cells. circ-ZEB1 downregulation suppressed NSCLC cell proliferation as well as migration in vitro and in vivo. Luciferase data confirmed EIF5A and miR-491-5p as downstream targets of circ-ZEB1. EIF5A overexpression and miR-491-5p suppression reversed NSCLC cell migration post circ-ZEB1 silencing. Conclusion: Our collective findings advised that circ-ZEB1 takes part in the malignant progression through regulating the miR-491-5p/EIF5A axis, highlighting its potential as an effective NSCLC therapeutic target.
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Affiliation(s)
- Qi Wang
- Department of General Practice, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Shengying Ling
- Department of General Practice, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Jia Lv
- Department of Obstetrics and Gynecology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Lina Wu
- Department of General Practice, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
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3
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Chen JF, Ye SZ, Wang KJ, Meng XY, Yang BB, Wu KR, Ma Q. Long non-coding RNA OSTM1-AS1 promotes renal cell carcinoma progression by sponging miR-491-5p and upregulating MMP-9. Sci Rep 2025; 15:359. [PMID: 39747324 PMCID: PMC11696353 DOI: 10.1038/s41598-024-83154-4] [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: 03/31/2024] [Accepted: 12/11/2024] [Indexed: 01/04/2025] Open
Abstract
Long noncoding RNAs (lncRNAs) have been recognized as essential regulators in various human malignancies. Hundreds of lncRNAs were known to be abnormally expressed in renal cell carcinoma (RCC) through a lncRNA expression microarray, among which lncRNA OSTM1 antisense RNA 1(OSTM1-AS1) was revealed as one of the most abundant lncRNAs. However, the function of OSTM1-AS1 in RCC remains unknown. Here, we examined OSTM1-AS1 functional roles and mechanism in RCC development. OSTM1-AS1 expression was significantly highly expressed among RCC tissue specimens and cell lines. Functionally, OSTM1-AS1 knockdown significantly suppressed cell proliferation, migration along with metastasis of RCC cells. Mechanistically, miR-491-5p was targeted via OSTM1-AS1, and down-regulation of miR-491-5p reversed OSTM1-AS1 knockdown impact on RCC migration and invasion. MMP-9 was targeted via miR-491-5p, and MMP-9 overexpression reversed miR-491-5p or OSTM1-AS1 knockdown impact on cell migration and invasion. MMP-9 abundance was decreased by OSTM1-AS1 silence, that was reduced by miR-491-5p deficiency. Importantly, our investigation revealed that OSTM1-AS1 has the ability to interact with miR-491-5p, thereby increasing the MMP-9 expression. The in vivo trial demonstrated that OSTM1-AS1 suppression resulted in tumor growth inhibition among nude mice. In summary, our findings indicate, for the first time, at least to the best of our knowledge, that OSTM1-AS1 serves as an oncogene among RCC by promoting proliferation, invasion, and metastasis through its targeting of the miR-491-5p/MMP9 axis. Therefore, this axis could represent a promising alternative therapeutic target for RCC treatment.
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Affiliation(s)
- Jun-Feng Chen
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo Clinical Research Center for Urological Disease, Comprehensive Urogenital Cancer Center, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
| | - Sha-Zhou Ye
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo Clinical Research Center for Urological Disease, Comprehensive Urogenital Cancer Center, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
| | - Ke-Jie Wang
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo Clinical Research Center for Urological Disease, Comprehensive Urogenital Cancer Center, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
| | - Xiang-Yu Meng
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo Clinical Research Center for Urological Disease, Comprehensive Urogenital Cancer Center, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
| | - Bin-Bin Yang
- Department of Urology, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
| | - Ke Rong Wu
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo Clinical Research Center for Urological Disease, Comprehensive Urogenital Cancer Center, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China.
- Department of Urology, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China.
| | - Qi Ma
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo Clinical Research Center for Urological Disease, Comprehensive Urogenital Cancer Center, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China.
- Comprehensive Genitourinary Cancer Center, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China.
- Yi-Huan Genitourinary Cancer Group, Ningbo, 315010, Zhejiang, China.
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Yang X, Lin Y, Dong B, Li B, Liu R, Wang X, Li J, Cheng X, Li Z, Xiong W. Establishment and bioinformatics analysis of a four-miRNA prognostic signature for pleural mesothelioma. J Cancer 2024; 15:6505-6520. [PMID: 39668817 PMCID: PMC11632982 DOI: 10.7150/jca.101914] [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: 08/05/2024] [Accepted: 10/03/2024] [Indexed: 12/14/2024] Open
Abstract
Objective: Pleural mesothelioma (PM), an uncommon yet highly aggressive malignant neoplasm, has a very poor prognosis with a median survival of less than one year after diagnosis, morbidity and mortality due to PM are on the rise year by year worldwide. Our research aims to utilize molecular characteristics and microRNAs (miRNAs) as a breakthrough in predicting the survival of PM patients, hoping to find a molecular mechanism that can predict the survival of PM patients. Methods: The miRNA expression profiles and corresponding clinical information of patients with PM were obtained from The Cancer Genome Atlas (TCGA) database, a miRNA-based prognostic signature was developed using Cox regression analysis in the training cohort, which was validated in the testing cohort and complete cohort. The association between miRNA levels and survival outcomes was determined, the miRNAs in prognostic model were experimentally validated by quantitative real-time PCR (qRT-PCR) in cell lines. Target genes of prognostic miRNAs were identified using TargetScan, miRDB, and miRTarBase databases, biological function prediction of which was accomplished by GO and KEGG analysis. Gene Expression Omnibus (GEO) database was utilized for core targets recognition, immune infiltration and survival analysis were conducted to investigate the relationship between core targets and immune cells by bioinformatics analysis. Results: This miRNA-related prognostic risk model can effectively stratify patients into high-risk and low-risk groups, and have good sensitivity and specificity to assess the prognosis of patients with PM, which can also be used as an independent prognostic factor for overall survival (OS) prediction in patients with PM, the OS for patients in high-risk group was significantly poorer compared with patients in low-risk group. Moreover, all four miRNAs (hsa-miR-181a-2-3p, hsa-miR-491-5P, hsa-miR-503-5p, and hsa-miR-3934-5p) were found to be differentially expressed in PM cell lines as compared with normal cell line, GO and KEGG analysis revealed that target genes of miRNAs in prognostic model were involved in multiple tumor-associated signaling pathways and functions in PM, core miRNA targets also correlated with immune cell infiltration, indicating their potential role in PM initiation and progression. Conclusions: A robust four-miRNA prognostic signature with great performances in prediction of the OS for PM patients was developed in our study, providing new avenues for the prognostic predication of PM.
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Affiliation(s)
- Xi Yang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali 671000, Yunnan, China
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, Yunnan, China
| | - Yaru Lin
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali 671000, Yunnan, China
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, Yunnan, China
| | - Baoru Dong
- Department of General Surgery, The Second People's Hospital of Bao Shan, Bao Shan 678000, Yunnan, China
| | - Bin Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali 671000, Yunnan, China
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, Yunnan, China
| | - Ruai Liu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali 671000, Yunnan, China
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, Yunnan, China
| | - Xinmeng Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali 671000, Yunnan, China
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, Yunnan, China
| | - Jinsong Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali 671000, Yunnan, China
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, Yunnan, China
| | - Xue Cheng
- Department of Radiology, The First Affiliated Hospital of Dali University, Dali University, Dali 671000, Yunnan, China
| | - Zhengliang Li
- Department of Radiology, The First Affiliated Hospital of Dali University, Dali University, Dali 671000, Yunnan, China
| | - Wei Xiong
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali 671000, Yunnan, China
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, Yunnan, China
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5
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Zhang LX, Luo PQ, Wei ZJ, Xu AM, Guo T. Expression and significant roles of the long non-coding RNA CASC19/miR-491-5p/HMGA2 axis in the development of gastric cancer. World J Gastrointest Oncol 2024; 16:3559-3584. [PMID: 39171190 PMCID: PMC11334029 DOI: 10.4251/wjgo.v16.i8.3559] [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] [Received: 12/20/2023] [Revised: 04/25/2024] [Accepted: 06/12/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a common malignant tumor, long non-coding RNA and microRNA (miRNA) are important regulators that affect tumor proliferation, metastasis and chemotherapy resistance, and thus participate in tumor progression. CASC19 is a new bio-marker which can promote tumor invasion and metastasis. However, the mechanism by which CASC19 affects the progression of GC through miRNA is not clear. AIM To explore the role of the CASC19/miR-491-5p/HMGA2 regulatory axis in GC. METHODS To explore the expression and prognosis of CASC19 in GC through clinical samples, and investigate the effects of inhibiting CASC19 on the proliferation, migration, invasion and other functions of GC cells through cell counting Kit-8 (CCK-8), ethynyldeoxyuridine, Wound healing assay, Transwell, Western blot and flow cytometry experiments. The effect of miR-491-5p and HMGA2 in GC were also proved. The regulatory relationship between CASC19 and miR-491-5p, miR-491-5p and HMGA2 were validated through Dual-luciferase reporter gene assay and reverse transcription PCR. Then CCK-8, Transwell, Wound healing assay, flow cytometry and animal experiments verify the role of CASC19/miR-491-5p/HMGA2 regulatory axis. RESULTS The expression level of CASC19 is related to the T stage, N stage, and tumor size of patients. Knockdown of the expression of CASC19 can inhibit the ability of proliferation, migration, invasion and EMT conversion of GC cells, and knocking down the expression of CASC19 can promote the apoptosis of GC cells. Increasing the expression of miR-491-5p can inhibit the proliferation of GC cells, miR-491-5p mimics can inhibit EMT conversion, and promote the apoptosis of GC cells, while decreasing the expression of miR-491-5p can promote the proliferation and EMT conversion and inhibit the apoptosis of GC cells. The expression of HMGA2 in GC tissues is higher than that in adjacent tissues. At the same time, the expression level of HMGA2 is related to the N and T stages of the patients. Reducing the level of HMGA2 can promote cell apoptosis and inhibit the proliferation of GC cells. Cell experiments and animal experiments have proved that CASC19 can regulates the expression of HMGA2 through miR-491-5p, thereby affecting the biological functions of GC. CONCLUSION CASC19 regulates the expression of HMGA2 through miR-491-5p to affect the development of GC. This axis may serve as a potential biomarker and therapeutic target of GC.
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Affiliation(s)
- Li-Xiang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui Province, China
- Anhui Provincial Key Laboratory of Digestive Disease, Hefei 230031, Anhui Province, China
| | - Pan-Quan Luo
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui Province, China
| | - Zhi-Jian Wei
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui Province, China
| | - A-Man Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui Province, China
| | - Tao Guo
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui Province, China
- Anhui Public Health Clinical Center, Hefei 230000, Anhui Province, China
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6
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Lian Z, Yu SR, Cui YX, Li SF, Su L, Song JX, Lee CY, Chen QX, Chen H. Rosuvastatin Enhances Lymphangiogenesis after Myocardial Infarction by Regulating the miRNAs/Vascular Endothelial Growth Factor Receptor 3 (miRNAs/VEGFR3) Pathway. ACS Pharmacol Transl Sci 2024; 7:335-347. [PMID: 38357274 PMCID: PMC10863446 DOI: 10.1021/acsptsci.3c00151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 12/24/2023] [Accepted: 01/15/2024] [Indexed: 02/16/2024]
Abstract
BACKGROUND Several clinical studies have suggested that the early administration of statins could reduce the risk of in-hospital mortality in acute myocardial infarction (AMI) patients. Recently, some studies have identified that stimulating lymphangiogenesis after AMI could improve cardiac function by reducing myocardial edema and inflammation. This study aimed to identify the effect of rosuvastatin on postinfarct lymphangiogenesis and to identify the underlying mechanism of this effect. METHOD Myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in mice orally administered rosuvastatin for 7 days. The changes in cardiac function, pathology, and lymphangiogenesis following MI were measured by echocardiography and immunostaining. EdU, Matrigel tube formation, and scratch wound assays were used to evaluate the effect of rosuvastatin on the proliferation, tube formation, and migration of the lymphatic endothelial cell line SVEC4-10. The expression of miR-107-3p, miR-491-5p, and VEGFR3 was measured by polymerase chain reaction (PCR) and Western blotting. A gain-of-function study was performed using miR-107-3p and miR-491-5p mimics. RESULTS The rosuvastatin-treated mice had a significantly improved ejection fraction and increased lymphatic plexus density 7 days after MI. Rosuvastatin also reduced myocardial edema and inflammatory response after MI. We used a VEGFR3 inhibitor to partially reverse these effects. Rosuvastatin promoted the proliferation, migration, and tube formation of SVEC4-10 cells. PCR and Western blot analyses revealed that rosuvastatin intervention downregulated miR-107-3p and miR-491-5p and promoted VEGFR3 expression. The gain-of-function study showed that miR-107-3p and miR-491-5p could inhibit the proliferation, migration, and tube formation of SVEC4-10 cells. CONCLUSION Rosuvastatin could improve heart function by promoting lymphangiogenesis after MI by regulating the miRNAs/VEGFR3 pathway.
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Affiliation(s)
- Zheng Lian
- Cardiovascular
Center, Beijing Tongren Hospital, Capital
Medical University, Xihuan South Road No. 2, Economic-Technological
Development Area, Beijing 100176, China
- Department
of Cardiology, Peking University People’s
Hospital, Xizhimen South Road No. 11, Xicheng District, Beijing 100044, China
- Beijing
Key Laboratory of Early Prediction and Intervention of Acute Myocardial
Infarction, Peking University People’s
Hospital, Xizhimen South
Road No. 11, Xicheng District, Beijing 100044, China
- Center
for Cardiovascular Translational Research, Peking University People’s Hospital, Xizhimen South Road No. 11, Xicheng
District, Beijing 100044, China
| | - Shi-Ran Yu
- Department
of Cardiology, Peking University People’s
Hospital, Xizhimen South Road No. 11, Xicheng District, Beijing 100044, China
- Beijing
Key Laboratory of Early Prediction and Intervention of Acute Myocardial
Infarction, Peking University People’s
Hospital, Xizhimen South
Road No. 11, Xicheng District, Beijing 100044, China
- Center
for Cardiovascular Translational Research, Peking University People’s Hospital, Xizhimen South Road No. 11, Xicheng
District, Beijing 100044, China
| | - Yu-Xia Cui
- Department
of Cardiology, Peking University People’s
Hospital, Xizhimen South Road No. 11, Xicheng District, Beijing 100044, China
- Beijing
Key Laboratory of Early Prediction and Intervention of Acute Myocardial
Infarction, Peking University People’s
Hospital, Xizhimen South
Road No. 11, Xicheng District, Beijing 100044, China
- Center
for Cardiovascular Translational Research, Peking University People’s Hospital, Xizhimen South Road No. 11, Xicheng
District, Beijing 100044, China
| | - Su-Fang Li
- Department
of Cardiology, Peking University People’s
Hospital, Xizhimen South Road No. 11, Xicheng District, Beijing 100044, China
- Beijing
Key Laboratory of Early Prediction and Intervention of Acute Myocardial
Infarction, Peking University People’s
Hospital, Xizhimen South
Road No. 11, Xicheng District, Beijing 100044, China
- Center
for Cardiovascular Translational Research, Peking University People’s Hospital, Xizhimen South Road No. 11, Xicheng
District, Beijing 100044, China
| | - Li−Na Su
- Department
of Cardiology, Peking University People’s
Hospital, Xizhimen South Road No. 11, Xicheng District, Beijing 100044, China
- Beijing
Key Laboratory of Early Prediction and Intervention of Acute Myocardial
Infarction, Peking University People’s
Hospital, Xizhimen South
Road No. 11, Xicheng District, Beijing 100044, China
- Center
for Cardiovascular Translational Research, Peking University People’s Hospital, Xizhimen South Road No. 11, Xicheng
District, Beijing 100044, China
| | - Jun-Xian Song
- Department
of Cardiology, Peking University People’s
Hospital, Xizhimen South Road No. 11, Xicheng District, Beijing 100044, China
- Beijing
Key Laboratory of Early Prediction and Intervention of Acute Myocardial
Infarction, Peking University People’s
Hospital, Xizhimen South
Road No. 11, Xicheng District, Beijing 100044, China
- Center
for Cardiovascular Translational Research, Peking University People’s Hospital, Xizhimen South Road No. 11, Xicheng
District, Beijing 100044, China
| | - Chong-Yoo Lee
- Department
of Cardiology, Peking University People’s
Hospital, Xizhimen South Road No. 11, Xicheng District, Beijing 100044, China
- Beijing
Key Laboratory of Early Prediction and Intervention of Acute Myocardial
Infarction, Peking University People’s
Hospital, Xizhimen South
Road No. 11, Xicheng District, Beijing 100044, China
- Center
for Cardiovascular Translational Research, Peking University People’s Hospital, Xizhimen South Road No. 11, Xicheng
District, Beijing 100044, China
| | - Qi-Xin Chen
- Department
of Cardiology, Peking University People’s
Hospital, Xizhimen South Road No. 11, Xicheng District, Beijing 100044, China
- Beijing
Key Laboratory of Early Prediction and Intervention of Acute Myocardial
Infarction, Peking University People’s
Hospital, Xizhimen South
Road No. 11, Xicheng District, Beijing 100044, China
- Center
for Cardiovascular Translational Research, Peking University People’s Hospital, Xizhimen South Road No. 11, Xicheng
District, Beijing 100044, China
| | - Hong Chen
- Department
of Cardiology, Peking University People’s
Hospital, Xizhimen South Road No. 11, Xicheng District, Beijing 100044, China
- Beijing
Key Laboratory of Early Prediction and Intervention of Acute Myocardial
Infarction, Peking University People’s
Hospital, Xizhimen South
Road No. 11, Xicheng District, Beijing 100044, China
- Center
for Cardiovascular Translational Research, Peking University People’s Hospital, Xizhimen South Road No. 11, Xicheng
District, Beijing 100044, China
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7
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Sahib AS, Fawzi A, Zabibah RS, Koka NA, Khudair SA, Muhammad FA, Hamad DA. miRNA/epithelial-mesenchymal axis (EMT) axis as a key player in cancer progression and metastasis: A focus on gastric and bladder cancers. Cell Signal 2023; 112:110881. [PMID: 37666286 DOI: 10.1016/j.cellsig.2023.110881] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
The metastasis a major hallmark of tumors that its significant is not only related to the basic research, but clinical investigations have revealed that majority of cancer deaths are due to the metastasis. The metastasis of tumor cells is significantly increased due to EMT mechanism and therefore, inhibition of EMT can reduce biological behaviors of tumor cells and improve the survival rate of patients. One of the gaps related to cancer metastasis is lack of specific focus on the EMT regulation in certain types of tumor cells. The gastric and bladder cancers are considered as two main reasons of death among patients in clinical level. Herein, the role of EMT in regulation of their progression is evaluated with a focus on the function of miRNAs. The inhibition/induction of EMT in these cancers and their ability in modulation of EMT-related factors including ZEB1/2 proteins, TGF-β, Snail and cadherin proteins are discussed. Moreover, lncRNAs and circRNAs in crosstalk of miRNA/EMT regulation in these tumors are discussed and final impact on cancer metastasis and response of tumor cells to the chemotherapy is evaluated. Moreover, the impact of miRNAs transferred by exosomes in regulation of EMT in these cancers are discussed.
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Affiliation(s)
- Ameer S Sahib
- Department of Pharmacy, Al- Mustaqbal University College, 51001 Hilla, Iraq
| | - Amjid Fawzi
- Medical Technical College, Al-Farahidi University, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Nisar Ahmad Koka
- Department of English, Faculty of Languages and Translation, King Khalid University, Abha, Kingdom of Saudi Arabia.
| | | | | | - Doaa A Hamad
- Nursing Department, Hilla University College, Babylon, Iraq
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8
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Ebrahimi N, Hakimzadeh A, Bozorgmand F, Speed S, Manavi MS, Khorram R, Farahani K, Rezaei-Tazangi F, Mansouri A, Hamblin MR, Aref AR. Role of non-coding RNAs as new therapeutic targets in regulating the EMT and apoptosis in metastatic gastric and colorectal cancers. Cell Cycle 2023; 22:2302-2323. [PMID: 38009668 PMCID: PMC10730205 DOI: 10.1080/15384101.2023.2286804] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 05/11/2023] [Accepted: 08/01/2023] [Indexed: 11/29/2023] Open
Abstract
Colorectal cancer (CRC) and gastric cancer (GC), are the two most common cancers of the gastrointestinal tract, and are serious health concerns worldwide. The discovery of more effective biomarkers for early diagnosis, and improved patient prognosis is important. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), can regulate cellular processes such as apoptosis and the epithelial-mesenchymal transition (EMT) leading to progression and resistance of GC and CRC tumors. Moreover these pathways (apoptosis and EMT) may serve as therapeutic targets, to prevent metastasis, and to overcome drug resistance. A subgroup of ncRNAs is common to both GC and CRC tumors, suggesting that they might be used as biomarkers or therapeutic targets. In this review, we highlight some ncRNAs that can regulate EMT and apoptosis as two opposite mechanisms in cancer progression and metastasis in GC and CRC. A better understanding of the biological role of ncRNAs could open up new avenues for the development of personalized treatment plans for GC and CRC patients.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | - Ali Hakimzadeh
- Department of Medical Biotechnologies, University of Siena, Tuscany, Italy
| | - Farima Bozorgmand
- Department of Medical Nanotechnology, Faculty of Advanced Sciences and Technology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Sepehr Speed
- Medical Campus, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | | | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kobra Farahani
- Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Atena Mansouri
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Reza Aref
- Xsphera Biosciences, Translational Medicine group, Boston, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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Liu Q, Huang J, Yan W, Liu Z, Liu S, Fang W. FGFR families: biological functions and therapeutic interventions in tumors. MedComm (Beijing) 2023; 4:e367. [PMID: 37750089 PMCID: PMC10518040 DOI: 10.1002/mco2.367] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/28/2023] [Accepted: 08/11/2023] [Indexed: 09/27/2023] Open
Abstract
There are five fibroblast growth factor receptors (FGFRs), namely, FGFR1-FGFR5. When FGFR binds to its ligand, namely, fibroblast growth factor (FGF), it dimerizes and autophosphorylates, thereby activating several key downstream pathways that play an important role in normal physiology, such as the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase (PI3K)/AKT, phospholipase C gamma/diacylglycerol/protein kinase c, and signal transducer and activator of transcription pathways. Furthermore, as an oncogene, FGFR genetic alterations were found in 7.1% of tumors, and these alterations include gene amplification, gene mutations, gene fusions or rearrangements. Therefore, FGFR amplification, mutations, rearrangements, or fusions are considered as potential biomarkers of FGFR therapeutic response for tyrosine kinase inhibitors (TKIs). However, it is worth noting that with increased use, resistance to TKIs inevitably develops, such as the well-known gatekeeper mutations. Thus, overcoming the development of drug resistance becomes a serious problem. This review mainly outlines the FGFR family functions, related pathways, and therapeutic agents in tumors with the aim of obtaining better outcomes for cancer patients with FGFR changes. The information provided in this review may provide additional therapeutic ideas for tumor patients with FGFR abnormalities.
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Affiliation(s)
- Qing Liu
- Cancer CenterIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Jiyu Huang
- Cancer CenterIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Weiwei Yan
- Cancer CenterIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouGuangdongChina
| | - Zhen Liu
- Cancer CenterIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouGuangdongChina
- Key Laboratory of Protein Modification and DegradationBasic School of Guangzhou Medical UniversityGuangzhouGuangdongChina
| | - Shu Liu
- Department of Breast SurgeryThe Affiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
| | - Weiyi Fang
- Cancer CenterIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouGuangdongChina
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10
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Sun J, Li L, Chen X, Yang C, Wang L. The circRNA-0001361/miR-491/FGFR4 axis is associated with axillary response evaluated by ultrasound following NAC in subjects with breast cancer. Biochem Biophys Rep 2023; 34:101481. [PMID: 37250983 PMCID: PMC10209698 DOI: 10.1016/j.bbrep.2023.101481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/21/2023] [Accepted: 04/27/2023] [Indexed: 05/31/2023] Open
Abstract
Background miR-491-5p has been reported to regulate the expression of FGFR4 and promote gastric cancer metastasis. Hsa_circ_0001361 was demonstrated to play an oncogenic role in bladder cancer invasion and metastasis by sponging the expression of miR-491-5p. This work aimed to study the molecular mechanism of the effect of hsa_circ_0001361 on axillary response in the treatment of breast cancer. Methods Ultrasound examinations was performed to evaluate the response of breast cancer patients receiving NAC treatment. Quantitative real-time PCR, IHC assay, luciferase assay and Western blot were performed to analyze the molecular interaction between miR-491, circRNA_0001631 and FGFR4. Results Patients with low circRNA_0001631 expression had a better outcome after NAC treatment. The expression of miR-491 was remarkably higher in the tissue sample and serum collected from patients with lower circRNA_0001631 expression. On the contrary, the FGFR4 expression was notably suppressed in the tissue sample and serum collected from patients with lower circRNA_0001631 expression when compared with patients with high circRNA_0001631 expression. The luciferase activities of circRNA_0001631 and FGFR4 were effectively suppressed by miR-491 in MCF-7 and MDA-MB-231 cells. Moreover, inhibition of circRNA_0001631 expression using circRNA_0001361 shRNA effectively suppressed the expression of FGFR4 protein in MCF-7 and MDA-MB-231 cells. Up-regulation of circRNA_0001631 expression remarkably enhanced the expression of FGFR4 protein in MCF-7 and MDA-MB-231 cells. Conclusion Our study suggested that the up-regulation of hsa_circRNA-0001361 could up-regulate the expression of FGFR4 via sponging the expression of miR-491-5p, resulting in the alleviated axillary response after neoadjuvant chemotherapy (NAC) in breast cancer.
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Affiliation(s)
| | | | | | - Chunfeng Yang
- Department of Ultrasound, Yantai Yuhuangding Hospital, Yantai, 264099, China
| | - Li Wang
- Department of Ultrasound, Yantai Yuhuangding Hospital, Yantai, 264099, China
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11
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Jie XF, Li YP, Liu S, Fu Y, Xiong YY. miR-491-5p regulates the susceptibility of glioblastoma to ferroptosis through TP53. Biochem Biophys Res Commun 2023; 671:309-317. [PMID: 37327702 DOI: 10.1016/j.bbrc.2023.05.057] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 05/17/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Ferroptosis has excellent potential in glioblastoma (GBM) therapy. In this study, we attempted to explore the effect of miR 491-5p on ferroptosis in GBM. METHODS In this study, publicly available ferroptosis-related genome maps were used to screen genes upregulated in GBM and their target genes. The Spearman correlation coefficient was applied to analyze the correlation between the tumor protein p53 gene (TP53) and miR-491-5p. The expressions of miR-491-5p and TP53 were determined. The protein abundances of the TP53-encoded factors p53 and p21 were measured. Cell proliferation, migration and invasion were assessed. We pretreated U251MG cells and GBM mice with a ferroptosis inducer (erastin). The mitochondrial state was observed. The contents of reactive oxygen species (ROS), total Fe and Fe2+ were calculated. RESULTS The level of TP53 was significantly increased in GBM and negatively correlated with miR-491-5p. miR-491-5p overexpression promoted U251MG cell proliferation, migration and invasion and interfered with the p53/p21 pathway. TP53 supplement reversed the effects of miR-491-5p. U251MG cells and GBM mice exhibited significant accumulations of ROS and iron. Erastin promoted the expression of TP53. Inhibition of TP53 reversed erastin-induced physiological phenotypes. Moreover, miR-491-5p overexpression caused a decrease in the number of damaged mitochondria and the contents of ROS, total Fe and Fe2+. TP53 supplement disrupted miR-491-5p-repressed ferroptosis. Erastin could inhibit GBM growth, and miR-491-5p overexpression impeded the therapeutic effect of erastin. CONCLUSIONS Our findings reveal the functional diversity of miR-491-5p in GBM and suggest that miR-491-5p/TP53 signaling hinders the sensitivity of GBM to ferroptosis through the p53/p21 pathway.
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Affiliation(s)
- Xin-Fang Jie
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yun-Peng Li
- Department of Neurosurgery, The People's Hospital of Ningdu County, Ningdu, 342800, Jiangxi, China
| | - Shuai Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yue Fu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yuan-Yuan Xiong
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
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12
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Sadri F, Hosseini SF, Aghayei A, Fereidouni M, Rezaei Z. The Tumor Suppressor Roles and Mechanisms of MiR-491 in Human Cancers. DNA Cell Biol 2022; 41:810-823. [PMID: 35914029 DOI: 10.1089/dna.2022.0274] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that bind to the 3' untranslated region (3'' UTR) of target mRNAs to control gene expression post-transcriptionally. Recent indications have highlighted their important roles in a variety of pathophysiological conditions as well as human malignancies. Dysregulated miRNAs act as tumor suppressor genes or oncogenes in a variety of cancers. MiR-491 has been shown to have a major effect on tumorigenesis in multiple malignancies through binding to specific genes and signaling cascades, thereby preventing cancer progression. This review provides an overview of miR-491 expression in regulatory mechanisms and biological procedures of tumor cells, as well as the prospective possible treatment effects of various types of human cancers.
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Affiliation(s)
- Farzad Sadri
- Student Research Committee, Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Seyede Fatemeh Hosseini
- Department of Nursing, Tabas School of Nursing, Birjand University of Medical Sciences, Birjand, Iran
| | - Atena Aghayei
- Department of Biology, Faculty of Science, Yazd University, Yazd, Iran
| | - Mohammad Fereidouni
- Department of Medical Immunology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran.,Cellular and Molecular Research Center, Department of Immunology, Birjand University of Medical Sciences, Birjand, Iran
| | - Zohreh Rezaei
- Cellular and Molecular Research Center, Department of Immunology, Birjand University of Medical Sciences, Birjand, Iran.,Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran
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13
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Song SJ, Liu X, Ji Q, Sun DZ, Xiu LJ, Xu JY, Yue XQ. Ziyin Huatan Recipe, a Chinese herbal compound, inhibits migration and invasion of gastric cancer by upregulating RUNX3 expression. JOURNAL OF INTEGRATIVE MEDICINE 2022; 20:355-364. [PMID: 35249836 DOI: 10.1016/j.joim.2022.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/30/2021] [Indexed: 06/14/2023]
Abstract
OBJECTIVES Ziyin Huatan Recipe (ZYHT), a traditional Chinese medicine comprised of Lilii Bulbus, Pinelliae Rhizoma, and Hedyotis Diffusa, has shown promise in treating gastric cancer (GC). However, its potential mechanism has not yet been clearly addressed. This study aimed to predict targets and molecular mechanisms of ZYHT in treating GC by network pharmacology analysis and to explore the role of ZYHT in GC both in vitro and in vivo. METHODS Targets and molecular mechanisms of ZYHT were predicted via network pharmacology analysis. The effects of ZYHT on the expression of metastasis-associated targets were further validated by Western blot and quantitative real-time polymerase chain reaction. To explore the specific molecular mechanisms of the effects of ZYHT on migration and invasion, the runt-related transcription factor 3 (RUNX3) gene was knocked out by clustered regularly interspaced short palindromic repeats/Cas9, and lentiviral vectors were transfected into SGC-7901 cells. Then lung metastasis model of GC in nude mice was established to explore the anti-metastasis effect of ZYHT. Western blot and immunohistochemistry were used to explore the impact of ZYHT on the expression of metastasis-related proteins with or without RUNX3 gene. RESULTS The network pharmacology analysis showed that ZYHT might inhibit focal adhesion, migration, invasion and metastasis of GC. ZYHT inhibited the proliferation, migration and invasion of GC cells in vitro via regulating the expression of metastasis-associated targets. Knocking out RUNX3 almost completely reversed the cell phenotypes (migration and invasion) and protein expression levels elicited by ZYHT. In vivo studies showed that ZYHT inhibited the metastasis of GC cells to the lung and prolonged the survival time of the nude mice. Knocking out RUNX3 partly reversed the metastasis of GC cells to the lung and the protein expression levels elicited by ZYHT. CONCLUSION ZYHT can effectively inhibit the invasion and migration of GC in vitro and in vivo, and its molecular mechanism may relate to the upregulation of RUNX3 expression.
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Affiliation(s)
- Shang-Jin Song
- Department of Traditional Chinese Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, China; Strategic Support Force Xingcheng Special Duty Sanatorium, Xingcheng 125100, Liaoning Province, China
| | - Xuan Liu
- Department of Traditional Chinese Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Qing Ji
- Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Da-Zhi Sun
- Department of Traditional Chinese Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Li-Juan Xiu
- Department of Traditional Chinese Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Jing-Yu Xu
- Department of Traditional Chinese Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Xiao-Qiang Yue
- Department of Traditional Chinese Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
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14
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Liu Y, Zhang Y, Li Q, Xu R, Huang N. MiR
‐200c‐3p and
miR
‐485‐5p overexpression elevates cisplatin sensitivity and suppresses the malignant phenotypes of non–small cell lung cancer cells through targeting
RRM2. Thorac Cancer 2022; 13:1974-1985. [PMID: 35599447 PMCID: PMC9250847 DOI: 10.1111/1759-7714.14475] [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: 03/18/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 12/03/2022] Open
Abstract
Background This study intended to investigate the potential mechanism of microRNA‐200c‐3p (miR‐200c‐3p) and miR‐485‐5p in mediating the cisplatin (DDP) resistance in non–small cell lung cancer (NSCLC). Methods Quantitative real‐time polymerase chain reaction (qRT‐PCR) was applied to measure the expression of miR‐200c‐3p, miR‐485‐5p, and ribonucleotide reductase regulatory subunit M2 (RRM2) messenger RNA (mRNA). 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay was used to analyze the DDP resistance and the proliferation of NSCLC cells. Colony formation assay was used to assess cell proliferation. Transwell assays were used to evaluate cell migration and invasion. The target relationship between RRM2 and miR‐200c‐3p or miR‐485‐5p was verified using dual‐luciferase reporter assay. The protein level of RRM2 was measured using Western blot assay. Animal experiments were conducted to analyze the roles of miR‐200c‐3p and miR‐485‐5p in the DDP resistance of xenograft tumors in vivo. Results MiR‐200c‐3p and miR‐485‐5p were both downregulated in DDP‐resistant NSCLC tissues and cell lines. Overexpressing miR‐200c‐3p or miR‐485‐5p suppressed the DDP resistance and malignant behaviors of NSCLC cells. MiR‐200c‐3p played a synergistic role with miR‐485‐5p in regulating the chemo‐resistance and biological behaviors NSCLC cells. RRM2 was confirmed as a target of miR‐200c‐3p and miR‐485‐5p. RRM2 silencing restrained the DDP resistance and progression of NSCLC. RRM2 overexpression partly reversed miR‐200c‐3p or miR‐485‐5p‐induced influences in NSCLC cells. The overexpression of miR‐200c‐3p or miR‐485‐5p aggravated DDP‐mediated suppressive effect on tumor growth in vivo. Conclusion MiR‐200c‐3p or miR‐485‐5p enhanced the DDP sensitivity and suppressed the malignant behaviors of NSCLC cells partly through targeting RRM2.
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Affiliation(s)
- Ying Liu
- Department of Oncology Jingmen No.1 People's Hospital Jingmen China
| | - Yong Zhang
- Department of Oncology Jingmen No.1 People's Hospital Jingmen China
| | - Qiubo Li
- Department of Oncology Jingmen No.1 People's Hospital Jingmen China
| | - Ruiqi Xu
- Department of Oncology Jingmen No.1 People's Hospital Jingmen China
| | - Nian Huang
- Department of Oncology Jingmen No.1 People's Hospital Jingmen China
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15
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Wang G, Lin X, Han H, Zhang H, Li X, Feng M, Jiang C. lncRNA H19 promotes glioblastoma multiforme development by activating autophagy by sponging miR-491-5p. Bioengineered 2022; 13:11440-11455. [PMID: 35506168 PMCID: PMC9275997 DOI: 10.1080/21655979.2022.2065947] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 12/20/2022] Open
Abstract
Glioblastoma multiforme (GBM) is a malignant cancer with severely poor survival, and the cells continue to thrive during hypoxia and toxic stress through autophagy. To validate the oncogenic role of long noncoding RNA H19 in GBM progression and examine whether autophagy and/or miR-491-5p participate in the process. The expression of H19 and autophagy-related genes in GBM and healthy control tissues was assessed via quantitative polymerase chain reaction. In addition, cell viability, proliferation, apoptosis and autophagy were respectively determined via cell counting kit-8 assay, clone formation assay, flow cytometry, western blotting and green fluorescent protein-microtubule-associated protein 1 light chain 3 alpha fluorescence analysis in vitro. Furthermore, a rescue assay was performed using rapamycin or miR-491-5p antagomir to examine the role of autophagy or miR-491-5p in H19-mediated regulation of proliferation and apoptosis. RNA pull-down and dual-luciferase reporter assays were employed to analyze the interaction between H19 and miR-491-5p. Additionally, tumor growth in a xenograft-bearing mouse model and autophagy in tumor mass were analyzed in vivo. The expression H19 was increased in GBM and was positively correlated with LC3 or Beclin-1. Silencing H19 inhibited growth and promoted apoptosis in GBM cells both in vitro and in vivo, and miR-491-5p was identified as one of the important mediators. H19 regulated the autophagy signaling pathway at least partly via miR-491-5p. Increased H19 expression in GBM exerts oncogenic effects by sponging miR-491-5p and enhancing autophagy. Therefore, H19 may be explored as a target for GBM therapy.
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Affiliation(s)
- Guo Wang
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Xiaoyan Lin
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Han Han
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Hongxu Zhang
- Department of Ophthalmology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Ophthalmology, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Xiaoli Li
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Mei Feng
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Chunming Jiang
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
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Functional Screen for microRNAs Suppressing Anchorage-Independent Growth in Human Cervical Cancer Cells. Int J Mol Sci 2022; 23:ijms23094791. [PMID: 35563182 PMCID: PMC9100801 DOI: 10.3390/ijms23094791] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 04/21/2022] [Indexed: 02/04/2023] Open
Abstract
The progression of anchorage-dependent epithelial cells to anchorage-independent growth represents a critical hallmark of malignant transformation. Using an in vitro model of human papillomavirus (HPV)-induced transformation, we previously showed that acquisition of anchorage-independent growth is associated with marked (epi)genetic changes, including altered expression of microRNAs. However, the laborious nature of the conventional growth method in soft agar to measure this phenotype hampers a high-throughput analysis. We developed alternative functional screening methods using 96- and 384-well ultra-low attachment plates to systematically investigate microRNAs regulating anchorage-independent growth. SiHa cervical cancer cells were transfected with a microRNA mimic library (n = 2019) and evaluated for cell viability. We identified 84 microRNAs that consistently suppressed growth in three independent experiments. Further validation in three cell lines and comparison of growth in adherent and ultra-low attachment plates yielded 40 microRNAs that specifically reduced anchorage-independent growth. In conclusion, ultra-low attachment plates are a promising alternative for soft-agar assays to study anchorage-independent growth and are suitable for high-throughput functional screening. Anchorage independence suppressing microRNAs identified through our screen were successfully validated in three cell lines. These microRNAs may provide specific biomarkers for detecting and treating HPV-induced precancerous lesions progressing to invasive cancer, the most critical stage during cervical cancer development.
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Analysis of Related Risk Factors and Prognostic Factors of Gastric Cancer with Bone Metastasis: A SEER-Based Study. J Immunol Res 2022; 2022:3251051. [PMID: 35211630 PMCID: PMC8863473 DOI: 10.1155/2022/3251051] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/06/2022] [Indexed: 12/17/2022] Open
Abstract
Background Gastric cancer is among the most common malignant tumors at home and abroad, because its early symptoms are mostly insidious, which leads to distant metastasis when gastric cancer is first diagnosed. The common metastatic sites of gastric cancer are mainly the liver, lung, and peritoneum, but bone metastasis is relatively rare, and the prognosis of gastric cancer bone metastasis is very poor. Therefore, this study is built on the SEER database to analyze the related risk factors of gastric cancer bone metastasis and related factors affecting the prognosis of gastric cancer patients, aiming at improving clinicians' understanding of clinical diagnosis and prognosis of bone metastasis of gastric cancer, thus reducing misdiagnosis and missed diagnosis. Methods The SEER database was collected to screen out patients with gastric cancer bone metastases and nonbone metastases matched with them from 2010 to 2016, and the Kaplan-Meier method was used to draw survival curves, and the comparison between survival curves was performed by Log-rank test to analyze the overall survival of the two groups of patient's time. Logistic regression analysis was used to analyze the related risk factors of gastric cancer bone metastasis, and the Cox regression proportional hazard model was used to analyze the relationship between gastric cancer bone metastasis and patient prognosis. Results Using Kaplan-Meier survival curve to analyze the 1, 3, and 5-year survival rates of gastric cancer patients with bone metastasis and non-metastasis groups were 14.2%, 1.8%, 0.6% and 71.4%, 44.3%, 36.4%, respectively; the average survival rate of the metastatic group was The time was 4.0 months (95%CI: 3.475~4.525), and the average survival time of the non-metastatic group was 30.0 months (95%CI: 26.778~33.222). The difference between the two groups was statistically significant (χ2 = 1076.866, P < 0.001). Multivariate logistic regression analysis showed that race (P = 0.007, OR = 1.296), grade (P < 0.001, OR = 0.575), marital status (P < 0.001, OR = 0.040), tumor size (P = 0.006, OR = 0.752), TNM stage (P < 0.001), T stage (P = 0.023, OR = 0.882), and M stage (P < 0.001, OR = 44.958) are independent risk factors for gastric cancer bone metastasis. The Cox univariate analysis suggests that gastric cancer bone metastasis is a risk factor for the prognosis of gastric cancer patients. The Cox multivariate analysis validates that gastric cancer bone metastasis (HR = 0.584, 95% CI: 0.497~0.688, P < 0.001) is independent of the overall survival rate of gastric cancer patients. Conclusions Race, grade, marital status, tumor size, TNM stage, T stage, and M stage are independent risk factors for gastric cancer bone metastasis; and gastric cancer bone metastasis is an independent risk factor that affects the prognosis of gastric cancer patients. Therefore, for such high-risk groups, large range screening of the above indicators can effectively improve the prognosis of gastric cancer patients to a certain extent.
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The lncRNA-AK046375 Upregulates Metallothionein-2 by Sequestering miR-491-5p to Relieve the Brain Oxidative Stress Burden after Traumatic Brain Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8188404. [PMID: 35222805 PMCID: PMC8865981 DOI: 10.1155/2022/8188404] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 12/08/2021] [Accepted: 12/27/2021] [Indexed: 12/11/2022]
Abstract
We previously discovered that traumatic brain injury (TBI) induces significant perturbations in long noncoding RNA (lncRNA) levels in the mouse cerebral cortex, and lncRNA-AK046375 is one of the most significantly changed lncRNAs after TBI. lncRNA-AK046375 overexpression and knockdown models were successfully constructed both in vitro and in vivo. In cultured primary cortical neurons and astrocytes, lncRNA-AK046375 sequestered miR-491-5p, thereby enhancing the expression of metallothionein-2 (MT2), which ameliorated oxidative-induced cell injury. In addition, upregulated lncRNA-AK046375 promoted the recovery of motor, learning, and memory functions after TBI in C57BL/6 mice, and the underlying mechanism may be related to ameliorated apoptosis, inhibited oxidative stress, reduced brain edema, and relieved loss of tight junction proteins at the blood-brain barrier in the mouse brain. Therefore, we conclude that lncRNA-AK046375 enhances MT2 expression by sequestering miR-491-5p, ultimately strengthening antioxidant activity, which ameliorates neurological deficits post-TBI.
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Valacchi G, Pambianchi E, Coco S, Pulliero A, Izzotti A. MicroRNA Alterations Induced in Human Skin by Diesel Fumes, Ozone, and UV Radiation. J Pers Med 2022; 12:176. [PMID: 35207665 PMCID: PMC8880698 DOI: 10.3390/jpm12020176] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 11/17/2022] Open
Abstract
Epigenetic alterations are a driving force of the carcinogenesis process. MicroRNAs play a role in silencing mutated oncogenes, thus defending the cell against the adverse consequences of genotoxic damages induced by environmental pollutants. These processes have been well investigated in lungs; however, although skin is directly exposed to a great variety of environmental pollutants, more research is needed to better understand the effect on cutaneous tissue. Therefore, we investigated microRNA alteration in human skin biopsies exposed to diesel fumes, ozone, and UV light for over 24 h of exposure. UV and ozone-induced microRNA alteration right after exposure, while the peak of their deregulations induced by diesel fumes was reached only at the end of the 24 h. Diesel fumes mainly altered microRNAs involved in the carcinogenesis process, ozone in apoptosis, and UV in DNA repair. Accordingly, each tested pollutant induced a specific pattern of microRNA alteration in skin related to the intrinsic mechanisms activated by the specific pollutant. These alterations, over a short time basis, reflect adaptive events aimed at defending the tissue against damages. Conversely, whenever environmental exposure lasts for a long time, the irreversible alteration of the microRNA machinery results in epigenetic damage contributing to the pathogenesis of inflammation, dysplasia, and cancer induced by environmental pollutants.
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Affiliation(s)
- Giuseppe Valacchi
- Animal Science Department, Plants for Human Health Institute, North Carolina State University, Research Campus Kannapolis, Kannapolis, NC 28081, USA; (G.V.); (E.P.)
- Department of Environmental Sciences and Prevention, University of Ferrara, 44121 Ferrara, Italy
- Department of Food and Nutrition, Kyung Hee University, Seoul 130-701, Korea
| | - Erika Pambianchi
- Animal Science Department, Plants for Human Health Institute, North Carolina State University, Research Campus Kannapolis, Kannapolis, NC 28081, USA; (G.V.); (E.P.)
| | - Simona Coco
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
| | | | - Alberto Izzotti
- Department of Experimental Medicine, University of Genova, 16132 Genova, Italy
- UOC Mutagenesis and Cancer Prevention, IRCCS San Martino Hospital, 16132 Genova, Italy
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Tang W, Guo ZD, Chai WN, Du DL, Yang XM, Cao L, Chen H, Zhou C, Cheng CJ, Sun XC, Huang ZJ, Zhong JJ. Downregulation of miR-491-5p promotes neovascularization after traumatic brain injury. Neural Regen Res 2022; 17:577-586. [PMID: 34380897 PMCID: PMC8504397 DOI: 10.4103/1673-5374.314326] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
MicroRNA-491-5p (miR-491-5p) plays an important role in regulating cell proliferation and migration; however, the effect of miR-491-5p on neovascularization after traumatic brain injury remains poorly understood. In this study, a controlled cortical injury model in C57BL/6 mice and an oxygen-glucose deprivation model in microvascular endothelial cells derived from mouse brain were established to simulate traumatic brain injury in vivo and in vitro, respectively. In the in vivo model, quantitative real-time-polymerase chain reaction results showed that the expression of miR-491-5p increased or decreased following the intracerebroventricular injection of an miR-491-5p agomir or antagomir, respectively, and the expression of miR-491-5p decreased slightly after traumatic brain injury. To detect the neuroprotective effects of miR-491-p, neurological severity scores, Morris water maze test, laser speckle techniques, and immunofluorescence staining were assessed, and the results revealed that miR-491-5p downregulation alleviated neurological dysfunction, promoted the recovery of regional cerebral blood flow, increased the number of lectin-stained microvessels, and increased the survival of neurons after traumatic brain injury. During the in vitro experiments, the potential mechanism of miR-491-5p on neovascularization was explored through quantitative real-time-polymerase chain reaction, which showed that miR-491-5p expression increased or decreased in brain microvascular endothelial cells after transfection with an miR-491-5p mimic or inhibitor, respectively. Dual-luciferase reporter and western blot assays verified that metallothionein-2 was a target gene for miR-491-5p. Cell counting kit 8 (CCK-8) assay, flow cytometry, and 2?,7?-dichlorofluorescein diacetate (DCFH-DA) assay results confirmed that the downregulation of miR-491-5p increased brain microvascular endothelial cell viability, reduced cell apoptosis, and alleviated oxidative stress under oxygen-glucose deprivation conditions. Cell scratch assay, Transwell assay, tube formation assay, and western blot assay results demonstrated that miR-491-5p downregulation promoted the migration, proliferation, and tube formation of brain microvascular endothelial cells through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor pathway. These findings confirmed that miR-491-5p downregulation promotes neovascularization, restores cerebral blood flow, and improves the recovery of neurological function after traumatic brain injury. The mechanism may be mediated through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway and the alleviation of oxidative stress. All procedures were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China (approval No. 2020-304) on June 22, 2020.
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Affiliation(s)
- Wei Tang
- Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zong-Duo Guo
- Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei-Na Chai
- Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dong-Lin Du
- Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-Min Yang
- Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lang Cao
- Department of Ophthalmology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Chen
- Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chao Zhou
- Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chong-Jie Cheng
- Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-Chuan Sun
- Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Jian Huang
- Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jian-Jun Zhong
- Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Circular RNA circ-TNPO3 suppresses metastasis of GC by acting as a protein decoy for IGF2BP3 to regulate the expression of MYC and SNAIL. MOLECULAR THERAPY-NUCLEIC ACIDS 2021; 26:649-664. [PMID: 34703650 PMCID: PMC8516998 DOI: 10.1016/j.omtn.2021.08.029] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022]
Abstract
Gastric cancer (GC) continues to be the most common gastrointestinal malignancy in China, and tumor metastases are a major reason for poor prognosis. Circular RNAs (circRNAs) are an intriguing type of noncoding RNAs with important regulatory roles. However, the roles of circRNAs in GC metastasis have not been fully elucidated. Here, we reported that circ-transportin 3 (TNPO3) was significantly downregulated in 103 pairs of GC tissues compared with matched noncancerous tissues. The level of circ-TNPO3 expression correlated with differentiation of GC, and plasma circ-TNPO3 could serve as a potential diagnostic biomarker. Functionally, circ-TNPO3 inhibited proliferation and migration of GC in vitro and in vivo. We further verified that circ-TNPO3 competitively interacted with insulin-like growth factor 2 binding protein 3 (IGF2BP3) protein; thus, the role of IGF2BP3 in stabilizing MYC mRNA was weakened, which inhibited the expression of MYC and its target SNAIL. Taken together, circ-TNPO3 acts as a protein decoy for IGF2BP3 to regulate the MYC-SNAIL axis, thereby suppressing the proliferation and metastasis of GC. Therefore, circ-TNPO3 has the potential to serve as a therapeutic target for GC.
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Han GD, Sun Y, Hui HX, Tao MY, Liu YQ, Zhu J. MiR-1224 Acts as a Prognostic Biomarker and Inhibits the Progression of Gastric Cancer by Targeting SATB1. Front Oncol 2021; 11:748896. [PMID: 34604093 PMCID: PMC8484804 DOI: 10.3389/fonc.2021.748896] [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: 07/28/2021] [Accepted: 08/31/2021] [Indexed: 01/26/2023] Open
Abstract
Objective MiR-1224 has been reported to exhibit abnormal expression in several tumors. However, the expressing pattern and roles of miR-1224 in gastric cancer (GC) remain unclear. Our current research aimed to explore the potential involvement of miR-1224 in the GC progression. Materials and Methods The expression of miR-1224 was examined in tissue samples of 128 GC patients and cell lines by RT-PCR. Besides, the associations of miR-1224 expressions with clinicopathologic features and prognosis of GC patients were analyzed. Then, the possible influences of miR-1224 on cell proliferation and cell migration were determined. Afterward, the molecular target of miR-1224 was identified using bioinformatics assays and confirmed experimentally. Finally, RT-PCR and Western blot assays were performed to investigate the effect of the abnormal miR-1224 expression on the EMT and Wnt/β-catenin pathway. Results miR-1224 was lowly expressed in the GC specimens and cell lines due to T classification and TNM stage. Survival assays demonstrated that GC patients with low expressions of miR-1224 possessed poor overall survivals. Moreover, in vitro and in vivo assays revealed that the overexpression of miR-1224 inhibited cell proliferation, migration, and invasion in GC cells. SATB homeobox 1 (SATB1) was verified as a direct target of miR-1224 in GC. Furthermore, β-catenin and c-myc were significantly inhibited in miR-1224-overexpression cells. Conclusions Our findings highlight the potential of miR-1224 as a therapeutic target and novel biomarker for GC patients
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Affiliation(s)
- Guo-Dong Han
- Department of Orthopedics, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Yuan Sun
- Department of Medical Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Hong-Xia Hui
- Department of Medical Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Ming-Yue Tao
- Department of Medical Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Yang-Qing Liu
- Department of Medical Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Jing Zhu
- Department of Medical Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
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Huang WC, Chi HC, Tung SL, Chen PM, Shih YC, Huang YC, Chu PY. Identification of the Novel Tumor Suppressor Role of FOCAD/miR-491-5p to Inhibit Cancer Stemness, Drug Resistance and Metastasis via Regulating RABIF/MMP Signaling in Triple Negative Breast Cancer. Cells 2021; 10:2524. [PMID: 34685504 PMCID: PMC8534268 DOI: 10.3390/cells10102524] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/19/2021] [Accepted: 09/19/2021] [Indexed: 12/11/2022] Open
Abstract
Triple negative breast cancer (TNBC) possesses poor prognosis mainly due to development of chemoresistance and lack of effective endocrine or targeted therapies. MiR-491-5p has been found to play a tumor suppressor role in many cancers including breast cancer. However, the precise role of miR-491-5p in TNBC has never been elucidated. In this study, we reported the novel tumor suppressor function of FOCAD/miR-491-5p in TNBC. High expression of miR-491-5p was found to be associated with better overall survival in breast cancer patients. We found that miR-491-5p could be an intronic microRNA processed form FOCAD gene. We are the first to demonstrate that both miR-491-5p and FOCAD function as tumor suppressors to inhibit cancer stemness, epithelial-mesenchymal transition, drug resistance, cell migration/invasion, and pulmonary metastasis etc. in TNBC. MiR-491-5p was first reported to directly target Rab interacting factor (RABIF) to downregulate RABIF-mediated TNBC cancer stemness, drug resistance, cell invasion, and pulmonary metastasis via matrix metalloproteinase (MMP) signaling. High expression of RABIF was found to be correlated with poor clinical outcomes of breast cancer and TNBC patients. Our data indicated that miR-491-5p and RABIF are potential prognostic biomarkers and targeting the novel FOCAD/miR-491-5p/RABIF/MMP signaling pathway could serve as a promising strategy in TNBC treatment.
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Affiliation(s)
- Wei-Chieh Huang
- Graduate Institute of Integrated Medicine, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan; (W.-C.H.); (H.-C.C.); (P.-M.C.); (Y.-C.S.); (Y.-C.H.)
- Chinese Medicine Research Center, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan
| | - Hsiang-Cheng Chi
- Graduate Institute of Integrated Medicine, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan; (W.-C.H.); (H.-C.C.); (P.-M.C.); (Y.-C.S.); (Y.-C.H.)
- Chinese Medicine Research Center, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan
| | - Shiao-Lin Tung
- Department of Hematology and Oncology, Ton-Yen General Hospital, Hsinchu County 30210, Taiwan;
- Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan 33858, Taiwan
| | - Po-Ming Chen
- Graduate Institute of Integrated Medicine, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan; (W.-C.H.); (H.-C.C.); (P.-M.C.); (Y.-C.S.); (Y.-C.H.)
| | - Ya-Chi Shih
- Graduate Institute of Integrated Medicine, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan; (W.-C.H.); (H.-C.C.); (P.-M.C.); (Y.-C.S.); (Y.-C.H.)
| | - Yi-Ching Huang
- Graduate Institute of Integrated Medicine, China Medical University, NO91, Hsueh-Shih Road, Taichung 40402, Taiwan; (W.-C.H.); (H.-C.C.); (P.-M.C.); (Y.-C.S.); (Y.-C.H.)
| | - Pei-Yi Chu
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung 40402, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei 242, Taiwan
- Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
- Department of Health Food, Chung Chou University of Science and Technology, Changhua 510, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
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24
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Rood K, Begum K, Wang H, Wangworawat YC, Davis R, Yamauchi CR, Perez MC, Simental AA, Laxa RT, Wang C, Roy S, Khan S. Differential Expression of Non-Coding RNA Signatures in Thyroid Cancer between Two Ethnic Groups. ACTA ACUST UNITED AC 2021; 28:3610-3628. [PMID: 34590612 PMCID: PMC8482137 DOI: 10.3390/curroncol28050309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/27/2021] [Accepted: 09/16/2021] [Indexed: 11/16/2022]
Abstract
Filipino Americans show higher thyroid cancer recurrence rates compared to European Americans. Although they are likely to die of this malignancy, the molecular mechanism has not yet been determined. Recent studies demonstrated that small non-coding RNAs could be utilized to assess thyroid cancer prognosis in tumor models. The goal of this study is to determine whether microRNA (miRNA) signatures are differentially expressed in thyroid cancer in two different ethnic groups. We also determined whether these miRNA signatures are related to cancer staging. This is a retrospective study of archival samples from patients with thyroid cancer (both sexes) in the pathology division from the last ten years at Loma Linda University School of Medicine, California. Deidentified patient demographics were extracted from the patient chart. Discarded formalin-fixed paraffin-embedded tissues were collected post-surgeries. We determined the differential expressions of microRNA in archival samples from Filipino Americans compared to European Americans using the state-of-the-art technique, HiSeq4000. By ingenuity pathway analysis, we determined miRNA targets and the pathways that those targets are involved in. We validated their expressions by real-time quantitative PCR and correlated them with the clinicopathological status in a larger cohort of miRNA samples from both ethnicities. We identified the differentially upregulated/downregulated miRNA clusters in Filipino Americans compared to European Americans. Some of these miRNA clusters are known to target genes that are linked to cancer invasion and metastasis. In univariate analysis, ethnicity and tumor staging were significant factors predicting miR-4633-5p upregulation. When including these factors in a multivariate logistic regression model, ethnicity and tumor staging remained significant independent predictors of miRNA upregulation, whereas the interaction of ethnicity and tumor staging was not significant. In contrast, ethnicity remained an independent predictor of significantly downregulated miR-491-5p and let-7 family. We provide evidence that Filipino Americans showed differentially expressed tumor-tissue-derived microRNA clusters. The functional implications of these miRNAs are under investigation.
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Affiliation(s)
- Kristiana Rood
- Division of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (K.R.); (H.W.); (R.D.); (C.R.Y.); (R.T.L.)
- Center for Health Disparities & Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Khodeza Begum
- Department of Biological Sciences, University of Texas El Paso, El Paso, TX 79968, USA;
- Border Biomedical Research Center, University of Texas El Paso, El Paso, TX 79968, USA
| | - Hanmin Wang
- Division of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (K.R.); (H.W.); (R.D.); (C.R.Y.); (R.T.L.)
| | - Yan C. Wangworawat
- Department of Pathology & Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (Y.C.W.); (M.C.P.)
| | - Ryan Davis
- Division of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (K.R.); (H.W.); (R.D.); (C.R.Y.); (R.T.L.)
- Division of Otolaryngology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;
| | - Celina R. Yamauchi
- Division of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (K.R.); (H.W.); (R.D.); (C.R.Y.); (R.T.L.)
- Division of Otolaryngology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;
| | - Mia C. Perez
- Department of Pathology & Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (Y.C.W.); (M.C.P.)
- Division of Otolaryngology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;
| | - Alfred A. Simental
- Division of Otolaryngology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;
| | - Ria T. Laxa
- Division of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (K.R.); (H.W.); (R.D.); (C.R.Y.); (R.T.L.)
- Division of Otolaryngology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;
| | - Charles Wang
- Center for Genomics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;
| | - Sourav Roy
- Department of Biological Sciences, University of Texas El Paso, El Paso, TX 79968, USA;
- Border Biomedical Research Center, University of Texas El Paso, El Paso, TX 79968, USA
- Correspondence: (S.R.); (S.K.)
| | - Salma Khan
- Division of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (K.R.); (H.W.); (R.D.); (C.R.Y.); (R.T.L.)
- Center for Health Disparities & Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
- Division of Otolaryngology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;
- Department of Internal Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA
- Correspondence: (S.R.); (S.K.)
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Wu J, Sun S, Liao W, Chen E, Wang X, Song Y, Duan F, Deng W, Li S. LINC00460 promotes pancreatic cancer progression by sponging miR-491-5p. J Gene Med 2021; 23:e3333. [PMID: 33789360 DOI: 10.1002/jgm.3333] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 03/21/2021] [Accepted: 03/21/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND A growing body of studies have suggested that LINC00460 is instrumental in tumorigenesis and tumour progression. Nonetheless, the biological function and mechanisms of LINC00460 in pancreatic ductal adenocarcinoma (PDAC) remain vague. METHODS Analysis based on public databases and a quantitative reverse transcription-polymerase chain reaction were performed to screen for differentially expressed lncRNAs in PDAC and to detect LINC00460 expression in PDAC cell lines and clinical samples. The survival of patients in the up-regulated and down-regulated LINC00460 expression groups was compared by using the Kaplan-Meier method. In addition, the potential biological functions of LINC00460 in PDAC were explored by cell counting kit-8, colony formation, flow cytometry and transwell assays. Furthermore, bioinformatics analysis, luciferase reporter assays and rescue experiments were applied to demonstrate the mechanism by which LINC00460 could directly bind to and inhibit miR-491-5p. RESULTS LINC00460 is up-regulated in PDAC and correlates with adverse survival outcomes. The results of functional tests verified that LINC00460 knockdown inhibited both cell proliferation and cell migration. Additionally, knockdown led to G0/G1 cell cycle blockage and enhanced cell apoptosis. Mechanistic investigations revealed that LINC00460 directly binds to and attenuates the tumour suppressor miR-491-5p, thus accelerating PDAC progression. CONCLUSIONS This research showed that LINC00460 is overexpressed in PDAC and correlates with adverse clinical outcomes. Additionally, LINC00460 promotes the aggressiveness of PDAC by targeting miR-491-5p. Thus, LINC00460 may serve as diagnostic biomarker of PDAC and a new target for PDAC therapy.
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Affiliation(s)
- Jiali Wu
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shuxin Sun
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wei Liao
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenhzen, China
| | - Enni Chen
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiaonan Wang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yunda Song
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Fangting Duan
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wuguo Deng
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shengping Li
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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Jia X, Wei L, Zhang Z. NEAT1 Overexpression Indicates a Poor Prognosis and Induces Chemotherapy Resistance via the miR-491-5p/ SOX3 Signaling Pathway in Ovarian Cancer. Front Genet 2021; 12:616220. [PMID: 33995475 PMCID: PMC8118527 DOI: 10.3389/fgene.2021.616220] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 01/27/2021] [Indexed: 12/15/2022] Open
Abstract
Background Accumulated studies have reported that dysregulated long non-coding RNAs (lncRNAs) are crucial in ovarian cancer (OC) initiation and development. However, detailed biological functions of lncRNA NEAT1 during the progression of OC remains to be uncovered. Purpose Our aim was to identify the role of NEAT1 in cisplatin resistance of ovarian cancer and the underlying mechanisms. Methods The expression patterns of NEAT1 in OC cell lines and tissue samples were identified by qRT-PCR. The cisplatin (DDP) sensitivity of OC cells was detected by MTT and CCK8 assay, while OC cell apoptosis and cell cycle were detected using flow cytometer assays. In addition, effects of NEAT1 on tumor growth were determined by xenograft tumor model. Luciferase reporter assay was conducted to prove the regulatory relation of miR-491-5p, NEAT1, and SOX3. Importantly, the expression of NEAT1 in exosomes from cisplatin-resistant patients was also determined by using qRT-PCR. Results In this study, upregulated NEAT1 was detected in OC cell lines and tissues. Meanwhile, NEAT1 was also increased in cisplatin-resistant OC cell lines and tissues. Upregulation of NEAT1 inhibited cisplatin-induced OC cell apoptosis and promoted cell proliferation, while knockdown of NEAT1 played the opposite role. These effects were also observed in vivo. Furthermore, direct interaction was observed between NEAT1 and miR-491-5p. NEAT1 led to the upregulation of miR-491-5p-targeted SOX3 mRNA. Importantly, this study also showed upregulated NEAT1 expression in serum exosomes derived from cisplatin-resistant patients. Conclusion NEAT1 is vital in the chemoresistance of ovarian cancer through regulating miR-491-5p/SOX3 pathway, showing that NEAT1 might be a potential target for OC resistance treatment.
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Affiliation(s)
- Xinzhuan Jia
- Department of Reproductive Medicine, The Fourth Hospital, Hebei Medical University, Shijiazhuang, China
| | - Lan Wei
- Department of Chest Surgery, Hebei Chest Hospital, Shijiazhuang, China
| | - Zhengmao Zhang
- Department of Gynecology, The Fourth Hospital, Hebei Medical University, Shijiazhuang, China
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Liu Y, Wang C, Li J, Zhu J, Zhao C, Xu H. Novel Regulatory Factors and Small-Molecule Inhibitors of FGFR4 in Cancer. Front Pharmacol 2021; 12:633453. [PMID: 33981224 PMCID: PMC8107720 DOI: 10.3389/fphar.2021.633453] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 03/05/2021] [Indexed: 01/02/2023] Open
Abstract
Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase receptor that is a member of the fibroblast growth factor receptor family and is stimulated by highly regulated ligand binding. Excessive expression of the receptor and its ligand, especially FGF19, occurs in many types of cancer. Abnormal FGFR4 production explains these cancer formations, and therefore, this receptor has emerged as a potential target for inhibiting cancer development. This review discusses the diverse mechanisms of oncogenic activation of FGFR4 and highlights some currently available inhibitors targeting FGFR4.
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Affiliation(s)
- Yanan Liu
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Canwei Wang
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jifa Li
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jiandong Zhu
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
| | - Chengguang Zhao
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Huanhai Xu
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
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LncRNA VPS9D1-AS1 promotes cell proliferation in acute lymphoblastic leukemia through modulating GPX1 expression by miR-491-5p and miR-214-3p evasion. Biosci Rep 2021; 40:226132. [PMID: 32808668 PMCID: PMC7536331 DOI: 10.1042/bsr20193461] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 08/13/2020] [Accepted: 08/17/2020] [Indexed: 12/16/2022] Open
Abstract
Alterations in messenger RNAs (mRNAs) of protein-coding genes can influence the malignant behaviors of acute lymphoblastic leukemia (ALL) cells. According to the prediction from The Cancer Genome Atlas (TCGA) database, we discovered that glutathione peroxidase 1 (GPX1) was up-regulated in acute myeloid leukemia (LAML) tissues, which pushed us to explore the feasible role and its related modulatory mechanism of GPX1 in ALL. In this research, we first proved the high expression of GPX1 in ALL cells compared with normal cells. Functional assays further revealed that the proliferation was obstructed and the apoptosis was facilitated in ALL cells with silenced GPX1. Then, both miR-491-5p and miR-214-3p that were down-regulated in ALL cells were affirmed to target GPX1. Subsequently, VPS9D1 antisense RNA 1 (VPS9D1-AS1) was recognized as the upstream regulator of miR-491-5p-miR-214-3p/GPX1 axis in a competing endogenous RNA (ceRNA) model. Importantly, we proved that VPS9D1-AS1 served as a tumor promoter in ALL through elevating GPX1. In conclusion, VPS9D1-AS1 contributed to ALL cell proliferation through miR-491-5p-miR-214-3p/GPX1 axis, hinting an optional choice for the treatment of ALL.
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Zhao YJ, Zhang J, Wang YC, Wang L, He XY. MiR-450a-5p Inhibits Gastric Cancer Cell Proliferation, Migration, and Invasion and Promotes Apoptosis via Targeting CREB1 and Inhibiting AKT/GSK-3β Signaling Pathway. Front Oncol 2021; 11:633366. [PMID: 33854971 PMCID: PMC8039465 DOI: 10.3389/fonc.2021.633366] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 01/08/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer seriously affects human health and research on gastric cancer is attracting more and more attentions. In recent years, molecular targets have become the research focus. Accumulating evidence indicates that miR-450a-5p plays a critical role in cancer progression. However, the biological role of miR-450a-5p in gastric carcinogenesis remains largely unknown. In this study, we explore the effects and mechanisms of miR-450a-5p on the development and progression of gastric cancer. We used gain-of-function approaches to investigate the role of miR-450a-5p on gastric cancer cell proliferation, migration, invasion, and apoptosis using biological and molecular techniques including real-time quantitative PCR (RT-qPCR), CCK-8, colony formation, flow cytometry, Western blot, wound healing, transwell chamber, dual luciferase reporter, and tumor xenograft mouse model. We found that gastric cancer cells have low expression of miR-450a-5p and overexpression of miR-450a-5p inhibited gastric cancer cell proliferation, migration and invasion, and induced apoptosis in vitro. Moreover, we demonstrated that ectopic expression of miR-450a-5p inhibited gastric cancer growth in vivo. At the molecular level, overexpression of miR-450a-5p significantly increased the expression of pro-apoptotic proteins, including caspase-3, caspase-9, and Bax, and inhibited the expression of anti-apoptotic protein Bcl-2. Luciferase reporter experiment suggested that camp response element binding protein 1 (CREB1) had a negative correlation with miR-450a-5p expression, and knockdown of CREB1 alleviated gastric cancer growth. Furthermore, we also found that miR-450a-5p inhibited the activation of AKT/GSK-3β signaling pathway to inhibit the progression of gastric cancer. Collectively, miR-450a-5p repressed gastric cancer cell proliferation, migration and invasion and induced apoptosis through targeting CREB1 by inhibiting AKT/GSK-3β signaling pathway. MiR-450a-5p could be a novel molecular target for the treatment of gastric cancer.
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Affiliation(s)
- Ya-Jun Zhao
- Department of Gastrointestinal Oncology Surgery, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jun Zhang
- Department of Gastrointestinal Oncology Surgery, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yong-Cang Wang
- Department of Gastrointestinal Oncology Surgery, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Liang Wang
- Center for Diagnostic Pathology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xin-Yang He
- Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Wu H, Tao Y, Zhang W, Wang G, Zhang Q. circ‑0000212 promotes cell proliferation of colorectal cancer by sponging miR‑491 and modulating FOXP4 expression. Mol Med Rep 2021; 23:300. [PMID: 33649850 PMCID: PMC7930931 DOI: 10.3892/mmr.2021.11939] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 02/01/2021] [Indexed: 12/30/2022] Open
Abstract
Colorectal cancer (CRC) is a lethal and common malignancy worldwide. Non-coding (nc)RNAs have been shown to modulate tumor progression in several types of cancer. The present study aimed to investigate the role of hsa_circ_0000212 in CRC, as a sponge of microRNA (miR)-491. The expression levels of miR-491 and forkhead box P4 (FOXP4) were analyzed using data from The Cancer Genome Atlas. The association between miR-491 and FOXP4 and the clinicopathological characteristics were also analyzed. A novel circular (circ)RNA, hsa_circ_0000212, was found to sponge miR-491 based on bioinformatics analysis. The potential binding site between miR-491 and FOXP4 or circ-0000212 was validated using luciferase and RNA immunoprecipitation assays. The expression levels and distribution of circ-0000212 was also determined. Cell Counting Kit-8 and colony formation assays were performed to determine the role of miR-491 or circ-0000212 on the proliferation of the CRC cells. Decreased miR-491 or increased FOXP4 expression levels were associated with the pathological stage in patients with CRC. In addition, miR-491 inhibited cell proliferation by targeting FOXP4. circ-0000212 was increased in CRC tissues and was predominantly localized in the cytoplasm. Furthermore, circ-0000212 augmented viability of the CRC cells by sponging miR-491 and modulating FOXP4. In conclusion, circ-0000212 may serve as a novel tumor-promoter and drug target in CRC.
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Affiliation(s)
- Hongyu Wu
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Yangbao Tao
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Weiyuan Zhang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Guiyu Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Qian Zhang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
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Li J, Zhang Y, Liu J, Shi Q, Liu W, Luo B. EBV-miR-BART12 inhibits cell migration and proliferation by targeting Snail expression in EBV-associated gastric cancer. Arch Virol 2021; 166:1313-1323. [PMID: 33646408 DOI: 10.1007/s00705-021-05001-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 12/29/2020] [Indexed: 02/06/2023]
Abstract
Epstein-Barr virus (EBV) was the first oncovirus found to encode microRNAs. In EBV-associated gastric cancer (EBVaGC), EBV-encoded BamHI-A rightward transcript microRNAs (BARTs) are highly expressed. However, the role of BARTs in EBVaGC remains obscure. In this study, we found that EBV-miR-BART12 (miR-BART12) inhibits cell proliferation and migration. Zinc finger protein SNAI1 (Snail) is an important epithelial-mesenchymal transition (EMT) inducer, and overexpression of Snail is closely associated with cancer metastasis. Here, we report that Snail expression in EBVaGC cells is lower than in EBV-negative gastric cancer (EBVnGC) cells. A dual luciferase reporter assay showed that miR-BART12 targets Snail directly by interacting with its 3'-UTR. A CHX chase assay revealed that miR-BART12 accelerates the degradation of Snail. Furthermore, we found that miR-BART12 can regulate the expression of EMT-related genes. Flow cytometry analysis showed that transfection with miR-BART12 induced G2/M phase arrest and promoted cell apoptosis. In summary, the results of our study have suggested a new mechanism by which BARTs can repress cell proliferation and migration in gastric cancer.
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Affiliation(s)
- Jun Li
- Department of Pathogenic Biology, Qingdao University Medical College, 2 Ningde Road, Qingdao, 266000, China
| | - Yan Zhang
- Department of Clinical Laboratory, Zibo Central Hospital, 54 Gongqingtuan Road, Zibo, 255036, China
| | - Juanjuan Liu
- Department of Pathogenic Biology, Qingdao University Medical College, 2 Ningde Road, Qingdao, 266000, China
| | - Qianzhu Shi
- Department of Pathogenic Biology, Qingdao University Medical College, 2 Ningde Road, Qingdao, 266000, China
| | - Wen Liu
- Department of Pathogenic Biology, Qingdao University Medical College, 2 Ningde Road, Qingdao, 266000, China
| | - Bing Luo
- Department of Pathogenic Biology, Qingdao University Medical College, 2 Ningde Road, Qingdao, 266000, China.
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Fan K, Ruan X, Wang L, Lu W, Shi Q, Xu Y. Circ_0004872 promotes platelet-derived growth factor-BB-induced proliferation, migration and dedifferentiation in HA-VSMCs via miR-513a-5p/TXNIP axis. Vascul Pharmacol 2021; 140:106842. [PMID: 33592319 DOI: 10.1016/j.vph.2021.106842] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/21/2021] [Accepted: 02/08/2021] [Indexed: 01/22/2023]
Abstract
The proliferation, migration and dedifferentiation of vascular smooth muscle cells (VSMCs) exert crucial roles in atherosclerosis (AS) progression. The aim of our study was to explore the influences of circular RNA 0004872 (circ_0004872) in platelet-derived growth factor-BB (PDGF-BB)-induced AS cell model and investigate the underlying mechanisms. Real-time quantitative polymerase chain reaction (RT-qPCR) was implemented for the expression detection of circ_0004872, mitogen-activated protein kinase 1 (MAPK1) messenger RNA (mRNA), microRNA-513a-5p (miR-513a-5p) and thioredoxin interacting protein (TXNIP). Cell proliferation was analyzed via Cell Counting Kit 8 (CCK8) assay. Cell migration was assessed via wound healing assay and transwell migration assay. Western blot assay was used to measure the expression of alpha smooth muscle actin (α-SMA), osteopontin (OPN), calponin and TXNIP. Dual-luciferase reporter assay and RNA-pull down assay were used for confirmation of interaction between miR-513a-5p and circ_0004872 or TXNIP. Circ_0004872 expression was elevated in PDGF-BB-induced human aortic vascular smooth muscle cells (HA-VSMCs) and carotid plaque tissues. Circ_0004872 silencing alleviated PDGF-BB-induced proliferation, migration and dedifferentiation in HA-VSMCs. MiR-513a-5p bound to circ_0004872, and circ_0004872 knockdown-induced effects in PDGF-BB-treated HA-VSMCs were largely attenuated by the silencing of miR-513a-5p. MiR-513a-5p bound to the 3' untranslated region (3'UTR) of TXNIP, and miR-513a-5p overexpression-mediated effects were counteracted by the transfection of pcDNA-TXNIP in PDGF-BB-induced HA-VSMCs. TXNIP was modulated by circ_0004872/miR-513a-5p signaling cascade in HA-VSMCs. Circ_0004872 accelerated PDGF-BB-induced proliferation, migration and dedifferentiation in HA-VSMCs through enhancing TXNIP level via sponging miR-513a-5p.
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Affiliation(s)
- Kaikai Fan
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Xinhua Ruan
- Department of Cardiovascular Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Leilei Wang
- Department of Neurosurgery, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Wanli Lu
- Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospitale, Tianjin, China
| | - Qiangwei Shi
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yawei Xu
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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FGFR4 c.1162G > A (p.Gly388Arg) Polymorphism Analysis in Turkish Patients with Retinoblastoma. JOURNAL OF ONCOLOGY 2021; 2020:9401038. [PMID: 33456465 PMCID: PMC7787726 DOI: 10.1155/2020/9401038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 12/16/2020] [Indexed: 12/31/2022]
Abstract
Purpose Various molecular variations are known to result in different gene variants in the FGFR4 gene, known for its oncogenic transformation activity. The goal of this study was to investigate the FGFR4 p.Gly388Arg variant that plays role in the progression of cancer and retinal growth and may be an effective candidate variant in the Turkish population in retinoblastoma patients with no RB1 gene mutation. Methods Using the Sanger sequencing methods, the FGFR4 p.Gly388Arg variant was bidirectionally sequenced in 49 patients with non-RB1 gene mutation in retinoblastoma patients and 13 healthy first-degree relatives and 146 individuals matched by sex and age in the control group. Results In Turkish population-specific study, the FGFR4 p.Gly388Arg variant was found in 27 (55.1 percent) of 49 patients; mutation was found in 7 (53.8 percent) of these patients' 13 healthy relatives screened. When FGFR4 p.Gly388Arg mutation status is evaluated in terms of 146 healthy controls, in 70 (47.9 percent) individuals, mutation was observed. Our analysis showed that the FGFR4 p.Gly388Arg allele frequency, which according to different databases is seen as 30 percent in the general population, is 50 percent common in the Turkish population. Conclusions In patients with advanced retinoblastoma who were diagnosed with retinoblastoma prior to 24 months, the FGFR4 p.Gly388Arg allele was found to be significantly higher. As a result, these results indicate that the polymorphism of FGFR4 p.Gly388Arg may play a role in both the development of tumors and the progression of aggressive tumors.
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Kipkeeva F, Muzaffarova T, Korotaeva A, Nikulin M, Grishina K, Mansorunov D, Apanovich P, Karpukhin A. MicroRNA in Gastric Cancer Development: Mechanisms and Biomarkers. Diagnostics (Basel) 2020; 10:E891. [PMID: 33142817 PMCID: PMC7692123 DOI: 10.3390/diagnostics10110891] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/20/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is one of the most common and difficult diseases to treat. The study of signaling pathway regulation by microRNA provides information on the mechanisms of GC development and is the basis for biomarker creation. In this study, a circuit of microRNA interactions with signaling pathways was constructed. The microRNAs, associated with metastasis and chemoresistance, are described. In most cases, microRNAs in GC regulate the Wnt/β-catenin, PI3K/AKT/mTOR, RAS/RAF/ERK/MAPK, NF-kB, TGF-β, and JAK/STAT pathways. Part of the microRNA acts on several target genes that function in different pathways. This often leads to an intensification of the induced processes. MicroRNAs have also been described that have the opposite effect on different pathways, causing different functional consequences. By acting on several target genes, or genes associated with several pathways, microRNAs can function in a signaling network. MicroRNAs associated with metastasis most often interact with the Wnt/β-catenin pathway. MicroRNAs affecting chemoresistance, in most cases, affect the regulators of apoptosis and are associated with the PI3K/AKT/mTOR pathway. The characteristics of microRNAs proposed as candidates for GC biomarkers were analyzed. The currently developed diagnostic and prognostic panels of microRNAs are also considered.
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Affiliation(s)
- Fatimat Kipkeeva
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Tatyana Muzaffarova
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Alexandra Korotaeva
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Maxim Nikulin
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 24 Kashirskoe Shosse, Moscow 115478, Russia;
| | - Kristina Grishina
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Danzan Mansorunov
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Pavel Apanovich
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Alexander Karpukhin
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
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Li H, He L, Tuo Y, Huang Y, Qian B. Circular RNA hsa_circ_0000282 contributes to osteosarcoma cell proliferation by regulating miR-192/XIAP axis. BMC Cancer 2020; 20:1026. [PMID: 33097010 PMCID: PMC7583201 DOI: 10.1186/s12885-020-07515-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 10/09/2020] [Indexed: 01/20/2023] Open
Abstract
Background Circular RNAs (circRNAs) have emerged as a novel category of non-coding RNA, which exhibit a pivotal effect on regulating gene expression and biological functions, yet how circRNAs function in osteosarcoma (OSA) still demands further investigation. This study aimed at probing into the function of hsa_circ_0000282 in OSA. Methods The expressions of circ_0000282 and miR-192 in OSA tissues and cell lines were examined by quantitative real-time polymerase chain reaction (qRT-PCR), and the correlation between the expression level of circ_0000282 and clinicopathological features of OSA patients was analyzed. The expressions of X-linked inhibitor of apoptosis protein (XIAP), B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) in OSA cells were assayed by Western blot. The proliferation and apoptosis of OSA cells were examined by CCK-8, BrdU and flow cytometry, respectively. Bioinformatics analysis, dual-luciferase reporter gene assay and RIP experiments were employed to predict and validate the targeting relationships between circ_0000282 and miR-192, and between miR-192 and XIAP, respectively. Results Circ_0000282 was highly expressed in OSA tissues and cell lines, which represented positive correlation with Enneking stage of OSA patients and negative correlation with tumor differentiation degree. In vitro experiments confirmed that overexpression of circ_0000282 markedly facilitated OSA cell proliferation and repressed cancer cell apoptosis in comparison to control group. Besides, knockdown of circ_0000282 repressed OSA cell proliferation and promoted apoptosis. Additionally, the binding relationships between circ_0000282 and miR-192, and between miR-192 and XIAP were validated. Circ_0000282 indirectly up-regulated XIAP expression by adsorbing miR-192, thereby playing a role in promoting cancer in OSA. Conclusion Circ_0000282 was a novel oncogenic circRNA in OSA. Circ_0000282/miR-192/XIAP axis regulated OSA cell proliferation apoptosis with competitive endogenous RNA mechanism.
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Affiliation(s)
- Houkun Li
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, No. 76 Nanguo Road, Xi'an, 710054, Shaanxi, China.
| | - Limin He
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, No. 76 Nanguo Road, Xi'an, 710054, Shaanxi, China
| | - Yuan Tuo
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, No. 76 Nanguo Road, Xi'an, 710054, Shaanxi, China
| | - Yansheng Huang
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, No. 76 Nanguo Road, Xi'an, 710054, Shaanxi, China
| | - Bing Qian
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, No. 76 Nanguo Road, Xi'an, 710054, Shaanxi, China
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Liu E, Zhou Y, Li J, Zhang D. MicroRNA‑491‑5p inhibits trophoblast cell migration and invasion through targeting matrix metalloproteinase‑9 in preeclampsia. Mol Med Rep 2020; 22:5033-5040. [PMID: 33174053 PMCID: PMC7646938 DOI: 10.3892/mmr.2020.11604] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 02/04/2020] [Indexed: 01/03/2023] Open
Abstract
Insufficient invasion of trophoblasts is correlated with the development of preeclampsia (PE). MicroRNA (miR)-491-5p has been reported to be implicated in human cancer cell invasion; however, whether miR-491-5p is involved in the development of PE remains largely unclear. The aim of the present study was to investigate the role of miR-491-5p in trophoblastic invasion in vitro and to determine its underlying mechanism of action. The expression levels of miR-491-5p were validated using reverse transcription-quantitative PCR. The effects of miR-491-5p on trophoblast cell invasion were evaluated in vitro. Then, the association between miR-491-5p and its downstream target was investigated in both cell lines and clinical specimens. miR-491-5p expression levels were observed to be significantly increased in the placental tissues from patients with PE. The invasive capacity of HTR-8/SVneo trophoblast cells was suppressed following the upregulation of miR-491-5p and increased following the inhibition of miR-491-5p. Matrix metalloproteinase-9 (MMP-9), a well-known regulator of trophoblast cell invasion, was discovered to be a direct target of miR-491-5p in HTR-8/SVneo trophoblast cells. Moreover, miR-491-5p expression levels were found to be inversely correlated with MMP-9 expression levels in placental tissues from patients with PE. The overexpression of MMP-9 partly attenuated the inhibitory effects of miR-491-5p on HTR-8/SVneo trophoblast cells invasion. Collectively, these findings suggested that the aberrant expression of miR-491-5p may contribute to PE through suppressing trophoblast invasion, thus highlighting the novel roles of miR-491-5p in the molecular pathogenesis of PE. The present study also showed that the miR-491-5p/MMP-9 axis may be an effective biomarker or a viable drug target for therapeutic intervention in PE.
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Affiliation(s)
- Enling Liu
- Department of Obstetrics and Gynecology, Tangshan Gongren Hospital, Hebei Medical University, Tangshan, Hebei 063000, P.R. China
| | - Yuxiu Zhou
- Department of Immunity, Tangshan Gongren Hospital, Hebei Medical University, Tangshan, Hebei 063000, P.R. China
| | - Jun Li
- Department of Obstetrics and Gynecology, Tangshan Gongren Hospital, Hebei Medical University, Tangshan, Hebei 063000, P.R. China
| | - Donghong Zhang
- Department of Obstetrics and Gynecology, Tangshan Gongren Hospital, Hebei Medical University, Tangshan, Hebei 063000, P.R. China
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Chen L, Chi K, Xiang H, Yang Y. Circ_0032821 Facilitates Gastric Cancer Cell Proliferation, Migration, Invasion and Glycolysis by Regulating MiR-1236-3p/HMGB1 Axis. Cancer Manag Res 2020; 12:9965-9976. [PMID: 33116853 PMCID: PMC7567569 DOI: 10.2147/cmar.s270164] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/10/2020] [Indexed: 01/03/2023] Open
Abstract
Background Circular RNAs (circRNAs) play an essential role in the pathogenesis of malignant tumors, including gastric cancer (GC). However, the effect of circ_0032821 on GC remains largely unknown. Methods QRT-PCR assay was employed to examine the levels of circ_0032821, CEP128 mRNA and miR-1236-3p. RNase R digestion assay was utilized to verify the feature of circ_0032821. Cell Counting Kit-8 (CCK-8) assay and transwell assay were adopted to evaluate cell proliferation and metastasis. The level of glycolysis was evaluated through detecting ECAR, OCR, lactate production, glucose uptake and ATP synthesis. Dual-luciferase reporter assay and RIP assay were conducted to analyze the relationship between miR-1236-3p and circ_0032821 or HMGB1. Western blot assay was adopted for high mobility group box 1 (HMGB1) level. Murine xenograft model assay was utilized for the effect of circ_0032821 in vivo. Results High level of circ_0032821 was observed in GC tissues and cells. Silencing of circ_0032821 markedly repressed cell proliferation, metastasis and glycolysis in GC cells in vitro and blocked tumorigenesis of GC in vivo. For mechanism analysis, circ_0032821 was identified as the sponge of miR-1236-3p and HMGB1 was the target gene of miR-1236-3p. Moreover, miR-1236-3p suppression restored the influences of circ_0032821 deficiency on GC cell proliferation, metastasis and glycolysis. Overexpression of miR-1236-3p relieved the malignant behaviors of GC cells by targeting HMGB1. Conclusion Circ_0032821 accelerated GC development through elevating HMGB1 expression via sponging miR-1236-3p.
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Affiliation(s)
- Lei Chen
- Department of Emergency Medicine, Xiang'an Hospital of Xiamen University, Xiamen, 361101, People's Republic of China
| | - Kun Chi
- Department of Nursing, Qingdao Municipal Hospital (Group), Qingdao 266071, People's Republic of China
| | - Huaguo Xiang
- Medical Laboratory, Shenzhen Baoan District Fuyong People's Hospital, Shenzhen 518103, People's Republic of China
| | - Yan Yang
- Department of Gastroenterology, Central People's Hospital of Tengzhou, Tengzhou 277500, People's Republic of China
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Wang Y, Wu Z, Li Y, Zheng Z, Yan J, Tian S, Han L. Long Non-Coding RNA H19 Promotes Proliferation, Migration and Invasion and Inhibits Apoptosis of Breast Cancer Cells by Targeting miR-491-5p/ZNF703 Axis. Cancer Manag Res 2020; 12:9247-9258. [PMID: 33061615 PMCID: PMC7532042 DOI: 10.2147/cmar.s246009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 08/25/2020] [Indexed: 12/24/2022] Open
Abstract
Background Breast cancer is one of the most common cancers worldwide. Long non-coding RNAs and microRNAs act as important regulators in human cancers. This study aims to explore the molecular mechanism among H19, miR-491-5p and zinc finger 703 (ZNF703) in breast cancer. Materials and Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the expression of H19, miR-491-5p and ZNF703. Cell Counting Kit 8 (CCK-8) assay was performed to evaluate cell proliferation. Cell apoptosis was assessed by flow cytometry assay. The number of migrated and invaded cells was counted by transwell assay. Dual luciferase reporter assay was carried out to test luciferase activity. Protein level of ZNF703 was measured by Western blot assay. Results H19 was highly expressed in breast tissues and cells. H19 knockdown inhibited proliferation, induced apoptosis and blocked migration and invasion. Moreover, H19 bound to miR-491-5p and negatively regulated miR-491-5p expression. MiR-491-5p inhibition abrogated the activities of proliferation, apoptosis, migration and invasion affected by H19 knockdown. Furthermore, miR-491-5p directly targeted ZNF703 and inversely modulated ZNF703 expression. ZNF703 up-regulation rescued the effects of miR-491-5p overexpression on proliferation, apoptosis, migration and invasion. In addition, H19 knockdown reduced ZNF703 expression by targeting miR-491-5p/ZNF703 axis. Conclusion H19 promoted proliferation, migration and invasion and retarded apoptosis of breast cancer cells via sponging miR-491-5p to down-regulate ZNF703 expression.
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Affiliation(s)
- Yongkun Wang
- Department of Thyroid Surgery, Liaocheng People's Hospital (Clinical Hospital of Shandong First Medical University) Liaocheng, Shandong, People's Republic of China
| | - Zhen Wu
- Department of Thyroid Surgery, Liaocheng People's Hospital (Clinical Hospital of Shandong First Medical University) Liaocheng, Shandong, People's Republic of China
| | - Yingxue Li
- Department of Pathology, Liaocheng People's Hospital (Clinical Hospital of Shandong First Medical University) Liaocheng, Shandong, People's Republic of China
| | - Zheng Zheng
- Department of Pathology, Liaocheng People's Hospital (Clinical Hospital of Shandong First Medical University) Liaocheng, Shandong, People's Republic of China
| | - Jinqiang Yan
- Department of Pathology, Liaocheng People's Hospital (Clinical Hospital of Shandong First Medical University) Liaocheng, Shandong, People's Republic of China
| | - Shuyan Tian
- Department of Pathology, Liaocheng People's Hospital (Clinical Hospital of Shandong First Medical University) Liaocheng, Shandong, People's Republic of China
| | - Lin Han
- Department of Pathology, Liaocheng People's Hospital (Clinical Hospital of Shandong First Medical University) Liaocheng, Shandong, People's Republic of China
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Landeros N, Santoro PM, Carrasco-Avino G, Corvalan AH. Competing Endogenous RNA Networks in the Epithelial to Mesenchymal Transition in Diffuse-Type of Gastric Cancer. Cancers (Basel) 2020; 12:cancers12102741. [PMID: 32987716 PMCID: PMC7598708 DOI: 10.3390/cancers12102741] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/15/2020] [Accepted: 09/16/2020] [Indexed: 12/13/2022] Open
Abstract
Simple Summary The diffuse-type of gastric cancer is associated with epithelial to mesenchymal transition. Loss of E-cadherin expression is the hallmark of this process and is largely due to the upregulation of the transcription factors ZEB1/2, Snail, Slug, and Twist1/2. However, miRNA and lncRNAs can also participate through these transcription factors which directly target E-cadherin. The competing endogenous RNA (ceRNA) network hypothesis state that lncRNA can sponge the miRNA pool that targets these transcripts. Based on the lack of said networks in the epithelial to mesenchymal transition, we performed a prediction analysis that resulted in novel ceRNA networks which will expand our knowledge of the molecular basis of the diffuse-type of gastric cancer. Abstract The diffuse-type of gastric cancer (DGC), molecularly associated with epithelial to mesenchymal transition (EMT), is increasing in incidence. Loss of E-cadherin expression is the hallmark of the EMT process and is largely due to the upregulation of the EMT-inducing transcription factors ZEB1/2, Snail, Slug, and Twist1/2. However, ncRNA, such as miRNA and lncRNAs, can also participate in the EMT process through the direct targeting of E-cadherin and other EMT-inducing transcription factors. Additionally, lncRNA can sponge the miRNA pool that targets these transcripts through competing endogenous RNA (ceRNA) networks. In this review, we focus on the role of ncRNA in the direct deregulation of E-cadherin, as well as EMT-inducing transcription factors. Based on the relevance of the ceRNA network hypothesis, and the lack of said networks in EMT, we performed a prediction analysis for all miRNAs and lncRNAs that target E-cadherin, as well as EMT-inducing transcription factors. This analysis resulted in novel predicted ceRNA networks for E-cadherin and EMT-inducing transcription factors (EMT-TFs), as well as the expansion of the molecular basis of the DGC.
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Affiliation(s)
- Natalia Landeros
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago 8330034, Chile; (N.L.); (P.M.S.)
- Advanced Center for Chronic Diseases, Universidad de Chile, Santiago 8380000, Chile
| | - Pablo M. Santoro
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago 8330034, Chile; (N.L.); (P.M.S.)
- Advanced Center for Chronic Diseases, Universidad de Chile, Santiago 8380000, Chile
| | - Gonzalo Carrasco-Avino
- Department of Pathology, Hospital Clinico Universidad de Chile and Clinica Las Condes, Santiago 7550000, Chile;
| | - Alejandro H. Corvalan
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago 8330034, Chile; (N.L.); (P.M.S.)
- Advanced Center for Chronic Diseases, Universidad de Chile, Santiago 8380000, Chile
- Correspondence: ; Tel.: +56-2235-48289
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You W, Liu X, Yu Y, Chen C, Xiong Y, Liu Y, Sun Y, Tan C, Zhang H, Wang Y, Li R. miR-502-5p affects gastric cancer progression by targeting PD-L1. Cancer Cell Int 2020; 20:395. [PMID: 32821248 PMCID: PMC7429713 DOI: 10.1186/s12935-020-01479-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 08/03/2020] [Indexed: 02/07/2023] Open
Abstract
Background Studies have shown that miR-502-5p functions as a tumor suppressor and is associated with tumor growth and metastasis. This study intends to uncover the potential mechanism of miR-502-5p functioning as a tumor suppressor in gastric cancer. Methods Expression levels of miR-502-5p and PD-L1 were measured by using qRT-PCR. Cell proliferation abilities were examined by EDU incorporation assay. Cell migration, invasion and cell cycle analysis of cells were determined by transwell assay, transwell-matrigel assay and flow cytometry, respectively. The relationship between miR-502-5p expression and the overall survival of xenograft tumor mice was statistically analyzed. Bioinformatics analysis and luciferase reporter assays were applied to analyze the relationship between miR-502-5p and CD40, STAT3 or PD-L1. Expressions of CD40, STAT3 and PD-L1 at protein level were detected by western blot. Results The results showed that miR-502-5p was significantly downregulated in gastric cancer tumor tissues compared with adjacent normal tissues. Overexpression of miR-502-5p significantly attenuated the proliferation, migration/invasion and induced the G1 phase arrest of gastric cancer cells. Consistently, miR-502-5p suppressed tumor growth and metastasis in vivo. Mechanically, we demonstrated that miR-502-5p had inhibited the malignant behaviour of gastric cancer by down-regulating PD-L1 expression at transcriptional level and post-transcriptional levels. Conclusions These findings suggest that miR-502-5p acts as a tumor suppressor in gastric cancer (GC). MiR-502-5p/PD-L1 may be a novel therapeutic target in GC treatment.
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Affiliation(s)
- Wendao You
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Xiaoyu Liu
- Yulin No.2 Hospital, Yulin, 719000 China
| | - Yang Yu
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Chen Chen
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Yujia Xiong
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Yiting Liu
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Yibin Sun
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Chenhuan Tan
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | | | | | - Rui Li
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, 215006 China
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Hong CS, Sun EG, Choi JN, Kim DH, Kim JH, Ryu KH, Shim HJ, Hwang JE, Bae WK, Kim HR, Kim KK, Jung C, Chung IJ, Cho SH. Fibroblast growth factor receptor 4 increases epidermal growth factor receptor (EGFR) signaling by inducing amphiregulin expression and attenuates response to EGFR inhibitors in colon cancer. Cancer Sci 2020; 111:3268-3278. [PMID: 32533590 PMCID: PMC7469799 DOI: 10.1111/cas.14526] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 06/03/2020] [Accepted: 06/06/2020] [Indexed: 02/06/2023] Open
Abstract
Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross‐talk between FGFR4 and EGFR, and the effect of anti‐EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab‐induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti‐EGFR therapy in colon cancer.
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Affiliation(s)
- Chang-Soo Hong
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
| | - Eun-Gene Sun
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
| | - Ji-Na Choi
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
| | - Dae-Hwan Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
| | - Jo-Heon Kim
- Department of Pathology, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Kyung-Hyun Ryu
- Department of Biological Science, Sookmyung Women's University, Seoul, Korea
| | - Hyun-Jeong Shim
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
| | - Jun-Eul Hwang
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
| | - Woo-Kyun Bae
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea.,Combinatorial Tumor Immunotherapy MRC, Chonnam National University Medical School, Hwasun, Korea
| | - Hyeong-Rok Kim
- Department of Surgery, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Kyung Keun Kim
- Department of Pharmacology, Chonnam National University Medical School, Hwasun, Korea
| | - Chaeyong Jung
- Department of Anatomy, Chonnam National University Medical School, Hwasun, Korea
| | - Ik-Joo Chung
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea.,Combinatorial Tumor Immunotherapy MRC, Chonnam National University Medical School, Hwasun, Korea
| | - Sang-Hee Cho
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea.,Combinatorial Tumor Immunotherapy MRC, Chonnam National University Medical School, Hwasun, Korea
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Qi G, Li L. LncRNA TTN-AS1 Promotes Progression of Non-Small Cell Lung Cancer via Regulating miR-491-5p/ZNF503 Axis. Onco Targets Ther 2020; 13:6361-6371. [PMID: 32669856 PMCID: PMC7335898 DOI: 10.2147/ott.s238890] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 03/19/2020] [Indexed: 12/13/2022] Open
Abstract
Background Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with high mortality worldwide. Long non-coding RNA (lncRNA) TTN antisense RNA1 (TTN-AS1) has been demonstrated to play a crucial role in a variety of cancers. This study was designed to investigate the function and molecular mechanism of lncRNA TTN-AS1 in NSCLC. Methods The expression levels of TTN-AS1, miR-491-5p and zinc finger protein 503 (ZNF503) were examined by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot assay, respectively. Cell viability was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Cell migration and invasion were assessed by transwell assay. Epithelial-to-mesenchymal transition (EMT)-related proteins were measured using Western blot assay. The relationship between TTN-AS1, miR-491-5p and ZNF503 was predicted by starBase2.0 and confirmed by dual-luciferase reporter assay. Xenograft tumor experiment was conducted to analyze the tumor growth in vivo. Results The levels of TTN-AS1 and ZNF503 were up-regulated, while miR-491-5p expression was reduced in NSCLC tissues and cells. Knockdown of TTN-AS1 or ZNF503 suppressed cell proliferation, migration, invasion and EMT in NSCLC cells. Overexpression of ZNF503 reversed the effect of TTN-AS1 silencing on NSCLC progression. TTN-AS1 could modulate the expression of ZNF503 via sponging miR-491-5p. Furthermore, TTN-AS1 induced tumor growth in vivo. Conclusion Inhibition of TTN-AS1 hindered cell proliferation, migration, invasion and EMT in NSCLC cells by modulating miR-491-5p/ZNF503 axis, providing a promising biomarker for NSCLC treatment.
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Affiliation(s)
- Guanbin Qi
- Department of Respiratory and Critical Care Medicine, Huaihe Hospital, Henan University, Kaifeng, Henan 475000, People's Republic of China
| | - Lei Li
- Department of Respiratory and Critical Care Medicine, Huaihe Hospital, Henan University, Kaifeng, Henan 475000, People's Republic of China
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Liu L, Wang Q, Qiu Z, Kang Y, Liu J, Ning S, Yin Y, Pang D, Xu S. Noncoding RNAs: the shot callers in tumor immune escape. Signal Transduct Target Ther 2020; 5:102. [PMID: 32561709 PMCID: PMC7305134 DOI: 10.1038/s41392-020-0194-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 05/05/2020] [Accepted: 05/06/2020] [Indexed: 01/17/2023] Open
Abstract
Immunotherapy, designed to exploit the functions of the host immune system against tumors, has shown considerable potential against several malignancies. However, the utility of immunotherapy is heavily limited due to the low response rate and various side effects in the clinical setting. Immune escape of tumor cells may be a critical reason for such low response rates. Noncoding RNAs (ncRNAs) have been identified as key regulatory factors in tumors and the immune system. Consequently, ncRNAs show promise as targets to improve the efficacy of immunotherapy in tumors. However, the relationship between ncRNAs and tumor immune escape (TIE) has not yet been comprehensively summarized. In this review, we provide a detailed account of the current knowledge on ncRNAs associated with TIE and their potential roles in tumor growth and survival mechanisms. This review bridges the gap between ncRNAs and TIE and broadens our understanding of their relationship, providing new insights and strategies to improve immunotherapy response rates by specifically targeting the ncRNAs involved in TIE.
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Affiliation(s)
- Lei Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Qin Wang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Zhilin Qiu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yujuan Kang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Jiena Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Shipeng Ning
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yanling Yin
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Da Pang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China. .,Heilongjiang Academy of Medical Sciences, Harbin, 150086, China.
| | - Shouping Xu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
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Xu G, Zhang Y, Li N, Wu Y, Zhang J, Xu R, Ming H. LBX2-AS1 up-regulated by NFIC boosts cell proliferation, migration and invasion in gastric cancer through targeting miR-491-5p/ZNF703. Cancer Cell Int 2020; 20:136. [PMID: 32351330 PMCID: PMC7183605 DOI: 10.1186/s12935-020-01207-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 04/06/2020] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND The crucial role of long non-coding RNAs (lncRNAs) has been certified in human cancers. The lncRNAs with abnormal expressions could act as tumor inhibitors or oncogenes in the advancement of tumors. LBX2-AS1 was once reported to accelerate esophageal squamous cell carcinoma. Nonetheless, its function in gastric cancer (GC) remained a riddle. METHODS RT-qPCR was used to examine the expression of NFIC/LBX2-AS1/miR-491-5p/ZNF703 in GC cell lines. The functions of LBX2-AS1 in GC were appraised by colony formation, EdU, flow cytometry analysis, transwell and wound healing assays. Luciferase reporter, ChIP and RNA pull down assays were utilized to evaluate the interactions among genes. RESULTS LBX2-AS1 was up-regulated in GC cell lines. Knockdown of LBX2-AS1 repressed the proliferative, migratory, and invasive abilities of GC cells. Moreover, LBX2-AS1 was transcriptionally activated by NFIC. And LBX2-AS1 could bind with miR-491-5p. Besides, miR-491-5p depletion or ZNF703 upregulation could counteract the repressing effects of LBX2-AS1 silence on GC progression. CONCLUSION In a word, LBX2-AS1 up-regulated by NFIC promoted GC progression via targeting miR-491-5p/ZNF703, implying LBX2-AS1 was an underlying treatment target for GC patients.
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Affiliation(s)
- Gang Xu
- Oncology Department, The 960th Hospital of the PLA, No. 20 Zhanbei Road, Zibo, 255300 Shandong China
| | - Yan Zhang
- Oncology Department, The 960th Hospital of the PLA, No. 20 Zhanbei Road, Zibo, 255300 Shandong China
| | - Na Li
- Oncology Department, The 960th Hospital of the PLA, No. 20 Zhanbei Road, Zibo, 255300 Shandong China
| | - Yanling Wu
- Oncology Department, The 960th Hospital of the PLA, No. 20 Zhanbei Road, Zibo, 255300 Shandong China
| | - Jinbiao Zhang
- Oncology Department, The 960th Hospital of the PLA, No. 20 Zhanbei Road, Zibo, 255300 Shandong China
| | - Rui Xu
- Oncology Department, The 960th Hospital of the PLA, No. 20 Zhanbei Road, Zibo, 255300 Shandong China
| | - Hui Ming
- Oncology Department, The 960th Hospital of the PLA, No. 20 Zhanbei Road, Zibo, 255300 Shandong China
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Zhu Z, Wen Y, Xuan C, Chen Q, Xiang Q, Wang J, Liu Y, Luo L, Zhao S, Deng Y, Zhao Z. Identifying the key genes and microRNAs in prostate cancer bone metastasis by bioinformatics analysis. FEBS Open Bio 2020; 10:674-688. [PMID: 32027093 PMCID: PMC7137804 DOI: 10.1002/2211-5463.12805] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 01/18/2020] [Accepted: 02/04/2020] [Indexed: 12/14/2022] Open
Abstract
Prostate adenocarcinoma (PCa) is the most common cause of death due to malignancy among men, and bone metastasis is the leading cause of mortality in patients with PCa. Therefore, identifying the causes and molecular mechanism of bone metastasis is important for early detection, diagnosis and personalized therapy. In this study, we systematically analyzed molecular correlates of bone metastasis by bioinformatics analysis. A total of 12 differentially expressed microRNAs (miRNAs) and 102 differentially expressed genes were identified. Five miRNAs had prognostic significance in biochemical recurrence‐free survival (miR‐636, miR‐491‐5p, miR‐199b‐5p, miR‐199b‐3p, miR‐28‐3p). The differentially expressed genes were significantly enriched in extracellular matrix, cell‐substrate adhesion, collagen and integrin. Seven hub genes (VCAN, COL3A1, COL1A1, APOE, COL1A2, SDC1, THY1) with worse biochemical recurrence‐free survival and one hub gene (MMP9) with worse overall survival were detected. miR‐636, a novel oncogene, was found to be up‐regulated in bone metastatic PCa tissues and also predominately up‐regulated in human PCa cell lines. miR‐636 promoted cellular invasion and migration, and may promote bone metastasis via targeting MBNL2, TNS1 and STAB1. In conclusion, we have successfully defined molecular signatures of bone metastasis in PCa.
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Affiliation(s)
- Zhiguo Zhu
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yaoan Wen
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Chunxiang Xuan
- Department of Nursing, Taian City Centre Hospital Branch, Taian, China
| | - Qingping Chen
- School of Information Management, Sun Yat-Sen University, Guangzhou, China
| | - Qian Xiang
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiamin Wang
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yangzhou Liu
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lianmin Luo
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shankun Zhao
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yihan Deng
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhigang Zhao
- Department of Urology & Andrology, Minimally Invasive Surgery Center, Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Skrzypek K, Majka M. Interplay among SNAIL Transcription Factor, MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Regulation of Tumor Growth and Metastasis. Cancers (Basel) 2020; 12:E209. [PMID: 31947678 PMCID: PMC7017348 DOI: 10.3390/cancers12010209] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/20/2019] [Accepted: 01/09/2020] [Indexed: 02/06/2023] Open
Abstract
SNAIL (SNAI1) is a zinc finger transcription factor that binds to E-box sequences and regulates the expression of genes. It usually acts as a gene repressor, but it may also activate the expression of genes. SNAIL plays a key role in the regulation of epithelial to mesenchymal transition, which is the main mechanism responsible for the progression and metastasis of epithelial tumors. Nevertheless, it also regulates different processes that are responsible for tumor growth, such as the activity of cancer stem cells, the control of cell metabolism, and the regulation of differentiation. Different proteins and microRNAs may regulate the SNAIL level, and SNAIL may be an important regulator of microRNA expression as well. The interplay among SNAIL, microRNAs, long non-coding RNAs, and circular RNAs is a key event in the regulation of tumor growth and metastasis. This review for the first time discusses different types of regulation between SNAIL and non-coding RNAs with a focus on feedback loops and the role of competitive RNA. Understanding these mechanisms may help develop novel therapeutic strategies against cancer based on microRNAs.
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Affiliation(s)
- Klaudia Skrzypek
- Jagiellonian University Medical College, Faculty of Medicine, Institute of Pediatrics, Department of Transplantation, Wielicka 265, 30-663 Cracow, Poland
| | - Marcin Majka
- Jagiellonian University Medical College, Faculty of Medicine, Institute of Pediatrics, Department of Transplantation, Wielicka 265, 30-663 Cracow, Poland
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Liu YP, Wu X, Meng JH, Yao J, Wang BJ. Functional Analysis of the 3' Untranslated Region of the Human GRIN1 Gene in Regulating Gene Expression in vitro. Neuropsychiatr Dis Treat 2020; 16:2361-2370. [PMID: 33116535 PMCID: PMC7567549 DOI: 10.2147/ndt.s268753] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 09/12/2020] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Abnormal expression of the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor may potentially increase the susceptibility to neuropsychiatric diseases. The purpose of this study was to investigate the functional sequence of the 3'UTR of the human GRIN1 gene, which encodes the GluN1 receptor to determine the effect on the expression of GluN1 receptor. METHODS We transferred seven recombinant pmirGLO recombinant vectors containing the 3'UTR truncated fragment of the GRIN1 gene into HEK-293, SK-N-SH, and U87 cell lines and compared the relative fluorescence intensity of adjacent length fragments. The TargetScan database was used to predict miRNAs. Then, miRNA mimics/inhibitors were co-transfected into the three cell lines with the 3'UTR of GRIN1 (pmirGLO - GRIN1), to investigate their influence on GRIN1 gene expression. RESULTS Compared with the pmirGLo-Basic vector, the relative fluorescence intensity of the complete GRIN1 gene 3'UTR recombinant sequence -27 bp - +1284 bp (the next base of the stop codon is +1) was significantly decreased in all three cell lines. The relative fluorescence intensities were significantly different between -27 bp - +294 bp and -27 bp - +497 bp regions, and between -27 bp - +708 bp and -27 bp - +907 bp regions. According to the prediction of the TargetScan database and analysis, miR-212-5p, miR-324-3p and miR-326 may bind to +295 bp - +497 bp, while miR-491-5p may bind to +798 bp - +907 bp. After co-transfection of miRNA mimic/inhibitor or mimic/inhibitor NC with a recombinant vector in the 3'UTR region of GRIN1 gene, we found that has-miR-491-5p inhibited GRIN1 expression significantly in all three cell lines, while has-miR-326 inhibitor upregulated GRIN1 expression in HEK-293 and U87 cells. CONCLUSION miR-491-5p may bind to the 3'UTR of the GRIN1 gene (+799 bp - +805 bp, the next base of the stop codon is +1) and down-regulate gene expression in HEK-293, SK-N-SH, and U87 cell lines, which implicates a potential role of miR-491-5p in central nervous system diseases.
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Affiliation(s)
- Yong-Ping Liu
- School of Forensic Medicine, China Medical University, Shenyang 110122, People's Republic of China
| | - Xue Wu
- School of Forensic Medicine, China Medical University, Shenyang 110122, People's Republic of China
| | - Jing-Hua Meng
- School of Forensic Medicine, China Medical University, Shenyang 110122, People's Republic of China
| | - Jun Yao
- School of Forensic Medicine, China Medical University, Shenyang 110122, People's Republic of China
| | - Bao-Jie Wang
- School of Forensic Medicine, China Medical University, Shenyang 110122, People's Republic of China
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The Role of MicroRNAs upon Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease. Cells 2019; 8:cells8111461. [PMID: 31752264 PMCID: PMC6912477 DOI: 10.3390/cells8111461] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 11/03/2019] [Accepted: 11/18/2019] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence suggest the significance of inflammation in the progression of cancer, for example the development of colorectal cancer in Inflammatory Bowel Disease (IBD) patients. Long-lasting inflammation in the gastrointestinal tract causes serious systemic complications and breaks the homeostasis of the intestine, where the altered expression of regulatory genes and miRNAs trigger malignant transformations. Several steps lead from acute inflammation to malignancies: epithelial-to-mesenchymal transition (EMT) and inhibitory microRNAs (miRNAs) are known factors during multistage carcinogenesis and IBD pathogenesis. In this review, we outline the interactions between EMT components and miRNAs that may affect cancer development during IBD.
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Liu Z, Lü Y, Jiang Q, Yang Y, Dang C, Sun R. miR-491 inhibits BGC-823 cell migration via targeting HMGA2. Int J Biol Markers 2019; 34:364-372. [PMID: 31668113 DOI: 10.1177/1724600819874488] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE miR-491 functions as a tumor suppressor in several types of cancer. However, its function and mechanism in gastric cancer proliferation and metastasis have not been well defined. The aim of this study was to explore the role and regulatory mechanism of miR-491 in cell proliferation and migration in gastric cancer. METHODS Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to detect the expression pattern of miR-491 in gastric cancer tissues. miR-491 overexpression vector, miR-491 inhibitor, and siHMGA2 were used; and MTT, wound healing, and transwell assays were employed to examine proliferation and migration for BGC-823 cells. A dual-luciferase reporter gene was used to measure the target relationship between miR-491 and HMGA2. RESULTS Most gastric cancer patients exhibit decreased miR-491 expression. miR-491 overexpression inhibited cell proliferation and migration, whereas miR-491 inhibitor treatment produced the opposite effect. Mechanistically, HMGA2 was identified as a direct target of miR-491. Moreover, HMGA2 knockdown inhibited cell proliferation and migration, which was similar to the effect of miR-491 overexpression. HMGA2 was decreased after transfection of the miR-491 vector and increased after transfection of the miR-491 inhibitor. CONCLUSION Our results suggest that miR-491 suppressed cell proliferation and cell motility in gastric cancer by targeting HMGA2. Silencing HMGA2 produced a similar effect to miR-491 overexpression on cell proliferation and migration. miR-491/HMGA2 signaling may be a potential therapeutic target for gastric cancer patients with decreased miR-491 expression.
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Affiliation(s)
- Zhigang Liu
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China.,Department of Thoracic Surgery, Shaanxi Provincial Tumor Hospital, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Yun Lü
- Pharmacy Intravenous Admixture Services, Shaanxi Provincial Tumor Hospital, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Qiuyu Jiang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Yang Yang
- School of Public Health, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Chengxue Dang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Ruifang Sun
- Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
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Lin J, Cai D, Li W, Yu T, Mao H, Jiang S, Xiao B. Plasma circular RNA panel acts as a novel diagnostic biomarker for colorectal cancer. Clin Biochem 2019; 74:60-68. [PMID: 31669510 DOI: 10.1016/j.clinbiochem.2019.10.012] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 10/16/2019] [Accepted: 10/17/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common cancers worldwide, and emerging lines of evidence have implicated circular RNAs (circRNAs), a novel class of endogenous noncoding RNAs, in CRC development. However, whether plasma circRNAs might be novel diagnostic biomarkers for CRC remains unclear. METHODS We investigated the plasma levels of selected circRNAs by quantitative real-time PCR (qRT-PCR). The presence of the candidate circRNAs was confirmed through RNase R assays, qRT-PCR and DNA sequencing, and their diagnostic value was evaluated using a receiver operating characteristic (ROC) curve. RESULTS The plasma levels of three circRNAs (circ-CCDC66, circ-ABCC1 and circ-STIL) were significantly decreased in CRC patients (n = 45) compared with healthy controls (n = 61). The ROC curve analysis showed that the area under the ROC curve (AUC) of the three-circRNA panel was 0.780, which is higher than that of traditional protein biomarkers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). Combining the circRNA panel with CEA and CA19-9 might improve the ability to diagnose CRC (AUC = 0.855). In addition, the plasma circ-ABCC1 level was related to tumor growth and progression, and the plasma circ-CCDC66 and circ-ABCC1 levels were decreased in precursor lesions of CRC, including colon adenomas and adenomatous polyps. More importantly, circ-CCDC66 and circ-STIL were found to be useful for diagnosing early-stage CRC, and the three-circRNA panel improved the ability to diagnose CEA-negative and CA19-9-negative CRC. CONCLUSION Our study provides the first identification of a panel of three plasma circRNAs that could serve as a novel and independent diagnostic biomarker for CRC.
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Affiliation(s)
- Jie Lin
- Department of Clinical Laboratory, The 904th Hospital of The People's Liberation Army, Wuxi 214044, PR China.
| | - Dongping Cai
- Department of Clinical Laboratory, The 904th Hospital of The People's Liberation Army, Wuxi 214044, PR China
| | - Wei Li
- Department of Pharmacy, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China
| | - Ting Yu
- Department of Clinical Laboratory, The 89th Hospital of The People's Liberation Army, Weifang 261000, PR China
| | - Hui Mao
- Department of Clinical Laboratory, The 904th Hospital of The People's Liberation Army, Wuxi 214044, PR China
| | - Shan Jiang
- Institute for Advanced Study, Shenzhen University, Shenzhen 518060, PR China.
| | - Bin Xiao
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China.
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