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Byroju VV, Nadukkandy AS, Cordani M, Kumar LD. Retinoblastoma: present scenario and future challenges. Cell Commun Signal 2023; 21:226. [PMID: 37667345 PMCID: PMC10478474 DOI: 10.1186/s12964-023-01223-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/12/2023] [Indexed: 09/06/2023] Open
Abstract
With an average incidence of 1 in every 18,000 live births, retinoblastoma is a rare type of intraocular tumour found to affect patients during their early childhood. It is curable if diagnosed at earlier stages but can become life-threateningly malignant if not treated timely. With no racial or gender predisposition, or even environmental factors known to have been involved in the incidence of the disease, retinoblastoma is often considered a clinical success story in pediatric oncology. The survival rate in highly developed countries is higher than 95% and they have achieved this because of the advancement in the development of diagnostics and treatment techniques. This includes developing the already existing techniques like chemotherapy and embarking on new strategies like enucleation, thermotherapy, cryotherapy, etc. Early diagnosis, studies on the etiopathogenesis and genetics of the disease are the need of the hour for improving the survival rates. According to the Knudson hypothesis, also known as the two hit hypothesis, two hits on the retinoblastoma susceptibility (RB) gene is often considered as the initiating event in the development of the disease. Studies on the molecular basis of the disease have also led to deciphering the downstream events and thus in the discovery of biomarkers and related targeted therapies. Furthermore, improvements in molecular biology techniques enhanced the development of efficient methods for early diagnosis, genetic counseling, and prevention of the disease. In this review, we discuss the genetic and molecular features of retinoblastoma with a special emphasis on the mutation leading to the dysregulation of key signaling pathways involved in cell proliferation, DNA repair, and cellular plasticity. Also, we describe the classification, clinical and epidemiological relevance of the disease, with an emphasis on both the traditional and innovative treatments to tackle retinoblastoma. Video Abstract.
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Affiliation(s)
- Vishnu Vardhan Byroju
- Department of Biochemistry, American International Medical University, Gros Islet, St. Lucia, USA
| | | | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Complutense University of Madrid, and Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain.
| | - Lekha Dinesh Kumar
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, India.
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Eraky AM. Non-coding RNAs as Genetic Biomarkers for the Diagnosis, Prognosis, Radiosensitivity, and Histopathologic Grade of Meningioma. Cureus 2023; 15:e34593. [PMID: 36883085 PMCID: PMC9985895 DOI: 10.7759/cureus.34593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2023] [Indexed: 02/05/2023] Open
Abstract
Meningioma is considered the most common primary benign brain tumor. It originates from the arachnoid cells of the leptomeninges surrounding the brain. The mainstay treatment of meningiomas is microsurgical resection. Meningioma prognosis depends on tumor grade, location, and patient age. Recently, using non-coding RNA as a prognostic and diagnostic biomarker for many tumors became a trend. Herein, we demonstrate the importance of non-coding RNAs, including microRNAs and lncRNAs in meningioma and their potential role in meningioma's early diagnosis, prognosis, histological grade, and radiosensitivity. In this review, many microRNAs were found to be upregulated in radioresistant meningioma cells such as microRNA-221, microRNA-222, microRNA-4286, microRNA-4695-5p, microRNA-6732-5p, microRNA-6855-5p, microRNA-7977, microRNA-6765-3p, and microRNA-6787-5p. Moreover, there are many microRNAs downregulated in radioresistant meningioma cells such as microRNA-1275, microRNA-30c-1-3p, microRNA-4449, microRNA-4539, microRNA-4684-3p, microRNA-6129, and microRNA-6891-5p. Also, we highlight the possible use of non-coding RNAs as serum non-invasive biomarkers and their potential role as therapeutic targets to treat high-grade meningiomas. Recent studies show that microRNA-497, microRNA-195, microRNA-18a, microRNA-197, and microRNA-224 are downregulated in the serum of patients with meningiomas. Additionally, microRNA-106a-5p, microRNA-219-5p, microRNA-375, and microRNA-409-3p are found to be upregulated in the serum of patients with meningioma. We also found that there are many deregulated microRNAs in meningioma cells that can be used as potential biomarkers for meningioma diagnosis, prognosis, and histopathologic grade, such as microRNA-17-5p, microRNA-199a, microRNA-190a, microRNA-186-5p, microRNA155-5p, microRNA-22-3p, microRNA-24-3p, microRNA-26-5p, microRNA-27a-3p, microRNA-27b-3p, microRNA-96-5p, microRNA-146a-5p, microRNA-29c-3p, microRNA-219-5p, microRNA-335, microRNA-200a, microRNA-21, microRNA-107, microRNA-224, microRNA-195, microRNA-34a-3p, and microRNA-let-7d. Of interest, we found fewer studies discussing deregulated long non-coding RNAs (lncRNAs) in meningioma cells. LncRNAs work as competitive endogenous RNA (ceRNA) by binding to oncogenic or anti-oncogenic microRNAs. We found that lncRNA- NUP210, lncRNA-SPIRE2, lncRNA-SLC7A1, lncRNA-DMTN, lncRNA-LINC00702, and lncRNA-LINC00460 are upregulated in meningioma cells. In contrast, lncRNA-MALAT1 was found to be downregulated in meningioma cells.
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Affiliation(s)
- Akram M Eraky
- Neurological Surgery, Medical College of Wisconsin, Milwaukee, USA
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Zhu Q, Li K, Li H, Han F, Tang Z, Wang Z. Ketamine Induced Bladder Fibrosis Through MTDH/P38 MAPK/EMT Pathway. Front Pharmacol 2022; 12:743682. [PMID: 35153736 PMCID: PMC8837385 DOI: 10.3389/fphar.2021.743682] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 12/29/2021] [Indexed: 01/14/2023] Open
Abstract
Purpose: Ketamine is an anesthetic in clinical, but it has also been used as an abusing drug due to its low price and hallucinogenic effects. It is proved that ketamine abusing would cause multiple system damage including the urinary system, which is called ketamine-induced cystitis (KIC). Bladder fibrosis is late stage in KIC and threaten abusers’ life. This study aimed to investigate the molecular mechanism of ketamine-induced bladder fibrosis.Methods: Female Sprague Dawley (SD) rats were randomly divided into 3 groups. 2 groups were treated with tail vein injection of ketamine (25 mg/kg/day, 50 mg/kg/day ketamine hydrochloride solution, respectively) for 12 weeks, whereas the control group was treated with normal saline solution. In each group, rat bladders were extracted and samples were examined for pathological and morphological alterations via hematoxylin and eosin (HE) staining, Masson’s trichrome staining and immunohistochemistry (IHC). SV-HUC-1 cells were treated with different concentrations of ketamine solution (0, 0.1, 0.5, 1 mmol/L). Rat bladder and SV-HUC-1 cells were extracted protein and RNA for Western blot and RT-PCR detection. Metadherin (MTDH) siRNAs and overexpression plasmids were used to knock down and overexpress the relative genes. P38 mitogen-activated protein kinase (MAPK) inhibitor was utilized to inhibit the MAPK pathway.Results: Rats in the ketamine group exhibited fibrosis compared to rats of the control group and fibrosis were also markedly upregulated in SV-HUC-1 cells after treated with ketamine, which were ketamine concentration-dependent. After treating with ketamine in SV-HUC-1 cells, there was an increase expression of MTDH, epithelial-mesenchymal transition (EMT) markers, P38 MAPK. MTDH knockdown would suppresses P38 MAPK/EMT pathway to inhibit fibrosis, however, MTDH overexpression could promote the pathway in SV-HUC-1 cells.Conclusion: In rats and SV-HUC-1 cells ketamine-treated models, MTDH can regulate EMT through the P38 MAPK pathway to regulate the process of bladder fibrosis.
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Affiliation(s)
- Quan Zhu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Kaixuan Li
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Haozhen Li
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Feng Han
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhengyan Tang
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Provincial Laboratory for Diagnosis and Treatment of Genitourinary System Disease, Changsha, China
| | - Zhao Wang
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Zhao Wang,
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Chen Y, Huang S, Guo R, Chen D. Metadherin-mediated mechanisms in human malignancies. Biomark Med 2021; 15:1769-1783. [PMID: 34783585 DOI: 10.2217/bmm-2021-0298] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Metadherin (MTDH) has been recognized as a novel protein that is critical for the progression of multiple types of human malignancies. Studies have reported that MTDH enhances the metastatic potential of cancer cells by regulating multiple signaling pathways. miRNAs and various tumor-related proteins have been shown to interact with MTDH, making it a potential therapeutic target as well as a biomarker in human malignancies. MTDH plays a critical role in inflammation, angiogenesis, hypoxia, epithelial-mesenchymal transition and autophagy. In this review, we present the function and mechanisms of MTDH for cancer initiation and progression.
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Affiliation(s)
- Yuyuan Chen
- The Second Department of Breast Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, 650000, PR China
| | - Sheng Huang
- The Second Department of Breast Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, 650000, PR China
| | - Rong Guo
- The Second Department of Breast Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, 650000, PR China
| | - Dedian Chen
- The Second Department of Breast Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, 650000, PR China
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Manna D, Sarkar D. Multifunctional Role of Astrocyte Elevated Gene-1 (AEG-1) in Cancer: Focus on Drug Resistance. Cancers (Basel) 2021; 13:cancers13081792. [PMID: 33918653 PMCID: PMC8069505 DOI: 10.3390/cancers13081792] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/31/2021] [Accepted: 04/04/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Chemotherapy is a major mode of treatment for cancers. However, cancer cells adapt to survive in stressful conditions and in many cases, they are inherently resistant to chemotherapy. Additionally, after initial response to chemotherapy, the surviving cancer cells acquire new alterations making them chemoresistant. Genes that help adapt the cancer cells to cope with stress often contribute to chemoresistance and one such gene is Astrocyte elevated gene-1 (AEG-1). AEG-1 levels are increased in all cancers studied to date and AEG-1 contributes to the development of highly aggressive, metastatic cancers. In this review, we provide a comprehensive description of the mechanism by which AEG-1 augments tumor development with special focus on its ability to regulate chemoresistance. We also discuss potential ways to inhibit AEG-1 to overcome chemoresistance. Abstract Cancer development results from the acquisition of numerous genetic and epigenetic alterations in cancer cells themselves, as well as continuous changes in their microenvironment. The plasticity of cancer cells allows them to continuously adapt to selective pressures brought forth by exogenous environmental stresses, the internal milieu of the tumor and cancer treatment itself. Resistance to treatment, either inherent or acquired after the commencement of treatment, is a major obstacle an oncologist confronts in an endeavor to efficiently manage the disease. Resistance to chemotherapy, chemoresistance, is an important hallmark of aggressive cancers, and driver oncogene-induced signaling pathways and molecular abnormalities create the platform for chemoresistance. The oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) is overexpressed in a diverse array of cancers, and its overexpression promotes all the hallmarks of cancer, such as proliferation, invasion, metastasis, angiogenesis and chemoresistance. The present review provides a comprehensive description of the molecular mechanism by which AEG-1 promotes tumorigenesis, with a special emphasis on its ability to regulate chemoresistance.
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Fu L, Niu X, Jin R, Xu F, Ding J, Zhang L, Huang Z. Triptonide inhibits metastasis potential of thyroid cancer cells via astrocyte elevated gene-1. Transl Cancer Res 2020; 9:1195-1204. [PMID: 35117464 PMCID: PMC8799231 DOI: 10.21037/tcr.2019.12.94] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 11/29/2019] [Indexed: 11/25/2022]
Abstract
Background Triptonide (TN) was recently proved to have anti-tumor effects. The current study explored whether TN inhibited thyroid cancer and the possible underlying mechanism. Methods MDA-T68 and BCPAP cells were treated by TN. Cell viability, migration and invasion rate were detected by MTT and Transwell. Protein expressions were determined by Western blot and mRNA expressions were detected by Real-time Quantitative PCR (qPCR). Results TN at the concentration higher than 50 nmol/L inhibited cell viability, migration and invasion of MDA-T68 and BCPAP cells, and astrocyte elevated gene (AEG-1) expression, was decreased by TN at the concentration higher than 50 nmol/L. Furthermore, AEG-1 overexpression inhibited cell viability, migration and invasion capacity of MDA-T68 and BCPAP cells, while TN reduced AEG-1 expression, and weaken the effect of AEG-1 overexpression on cell viability, migration and invasion capacities. Moreover, TN depressed the increase of matrix metalloproteinase (MMP) 2, MMP9 and N-cadherin expressions caused by AEG-1 overexpression. Meanwhile, E-cadherin expression reduced by AEG-1 overexpression was increased by TN. Conclusions TN could inhibit the metastasis potential of thyroid cancer cells through inhibiting the expression of AEG-1. Our findings reveal the mechanism of TN in the treatment of thyroid cancer, which should be further explored in the study of thyroid cancer. Keywords Triptonide; metastasis; thyroid cancer; regulation; drug monomer
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Affiliation(s)
- Liangjie Fu
- Department of Scrofulosis, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing 210014, China
| | - Xiaohong Niu
- Department of Scrofulosis, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing 210014, China
| | - Ruhui Jin
- Department of Scrofulosis, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing 210014, China
| | - Feiyun Xu
- Department of Scrofulosis, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing 210014, China
| | - Jiguo Ding
- Department of Scrofulosis, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing 210014, China
| | - Li Zhang
- Department of Scrofulosis, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing 210014, China
| | - Zihui Huang
- Department of Scrofulosis, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing 210014, China
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He A, He S, Huang C, Chen Z, Wu Y, Gong Y, Li X, Zhou L. MTDH promotes metastasis of clear cell renal cell carcinoma by activating SND1-mediated ERK signaling and epithelial-mesenchymal transition. Aging (Albany NY) 2020; 12:1465-1487. [PMID: 31978894 PMCID: PMC7053596 DOI: 10.18632/aging.102694] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 12/25/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Metastasis is the principal cause of renal cell carcinoma-associated mortality. Metadherin (MTDH) was identified as a vital metastasis driver involved in the metastatic progression of various types of tumors, suggesting that MTDH is a prognostic metastatic biomarker and potential therapeutic target. The role and mechanism of MTDH in the metastatic progression of ccRCC have not yet been adequately explored. RESULTS MTDH was remarkably elevated in ccRCC tissues, especially in metastatic ccRCC tissues, compared with normal kidney tissues and correlated with advanced clinicopathological features and poor prognosis. MTDH activated ERK signaling and EMT, thus promoting the migration and invasion of ccRCC cells. The interaction between MTDH and SND1 at the protein level was confirmed using immunoprecipitation and immunofluorescence. Based on the analysis of datasets from GEO and TCGA, SND1 was remarkably increased in ccRCC, especially in metastatic ccRCC, and associated with advanced clinicopathological features and poor prognosis. Knockdown of SND1 mainly abolished the migration and invasion of ccRCC cells by blocking MTDH-mediated ERK and EMT signaling activation. CONCLUSION These results revealed that MTDH may be a prognostic metastatic biomarker of ccRCC that promotes ccRCC metastasis by activating SND1-mediated the ERK and EMT signaling pathways. MTDH may serve as an anti-tumor therapeutic target that can be applied for the clinical treatment of metastatic ccRCC. METHODS MTDH/SND1 mRNA expression in clear cell renal cell carcinoma (ccRCC) was comprehensively estimated by analysis of GEO-ccRCC and TCGA-KIRC datasets with R software and packages. MTDH protein expression was assessed in a total of 111 ccRCC patients from Peking University First Hospital by immunohistochemistry (IHC). In vitro migration and invasion assays were carried out, and an in vivo metastatic mouse model was developed to investigate the biological functions of MTDH in ccRCC cells. Correlation analysis, immunoprecipitation, western blotting and immunofluorescence were applied to explore the molecular mechanisms of MTDH in ccRCC.
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Affiliation(s)
- Anbang He
- Department of Urology, Peking University First Hospital, Beijing 100034, China
- Institute of Urology, Peking University, Beijing 100034, China
- National Urological Cancer Center, Beijing 100034, China
| | - Shiming He
- Department of Urology, Peking University First Hospital, Beijing 100034, China
- Institute of Urology, Peking University, Beijing 100034, China
- National Urological Cancer Center, Beijing 100034, China
| | - Cong Huang
- Department of Urology, Peking University First Hospital, Beijing 100034, China
- Institute of Urology, Peking University, Beijing 100034, China
- National Urological Cancer Center, Beijing 100034, China
| | - Zhicong Chen
- Department of Urology, Peking University First Hospital, Beijing 100034, China
- Institute of Urology, Peking University, Beijing 100034, China
- National Urological Cancer Center, Beijing 100034, China
| | - Yucai Wu
- Department of Urology, Peking University First Hospital, Beijing 100034, China
- Institute of Urology, Peking University, Beijing 100034, China
- National Urological Cancer Center, Beijing 100034, China
| | - Yanqing Gong
- Department of Urology, Peking University First Hospital, Beijing 100034, China
- Institute of Urology, Peking University, Beijing 100034, China
- National Urological Cancer Center, Beijing 100034, China
| | - Xuesong Li
- Department of Urology, Peking University First Hospital, Beijing 100034, China
- Institute of Urology, Peking University, Beijing 100034, China
- National Urological Cancer Center, Beijing 100034, China
| | - Liqun Zhou
- Department of Urology, Peking University First Hospital, Beijing 100034, China
- Institute of Urology, Peking University, Beijing 100034, China
- National Urological Cancer Center, Beijing 100034, China
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Gao RZ, Que Q, Lin P, Pang YY, Wu HY, Li XJ, Chen G, He Y, Yang H. Clinical roles of miR-136-5p and its target metadherin in thyroid carcinoma. Am J Transl Res 2019; 11:6754-6774. [PMID: 31814886 PMCID: PMC6895511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 10/29/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Thyroid carcinoma (TC) is a common malignancy of the endocrine system. This research aimed to examine the expression levels of miR-136-5p and metadherin (MTDH) in TC and unveil their potential targeting relationship. METHODS TC microRNA (miRNA) microarray and miRNA-sequencing data were collected to evaluated miR-136-5p expression. We assessed the comprehensive expression of miR-136-5p by calculating the standard mean difference (SMD) and summary receiver operating characteristic curves (sROC). Subsequently, the miR-136-5p mimic and inhibitor were transfected into the TC B-CPAP cell, Thiazolyl Blue Tetrazolium Bromide (MTT) assay and cell apoptosis assay by FACS with Annexin V-/7-AAD double staining were performed to explore the biological role of miR-136-5p in the B-CPAP cell line. Prediction of target genes and potential biological function analysis of miR-136-5p were made using miRWalk2.0 and DAVID, respectively. Through target gene prediction, MTDH may be the candidate target gene of miR-136-5p. Subsequently, gene microarrays and RNA-sequencing data were also leveraged for MTDH expression. The meta-analysis method was conducted to evaluate the comprehensive expression level of MTDH. In addition, MTDH protein expression was identified using immunohistochemistry. The MTDH protein levels post-miR-136-5p transfection were verified by western blot, and the dual luciferase reporter assay was adapted to confirm the direct targeting relation between miR-136-5p and MTDH. RESULTS The miR-136-5p level was remarkably downregulated in TC, the pooled SMD was -0.47 (95% CI: -0.70 to -0.23, I2=36.6%, P=0.192) and the area under the curve (AUC) of the sROC was 0.67 based on 543 cases of TC. MTT indicated that the overexpression of miR-136-5p dramatically inhibited the proliferation of B-CPAP cells. The cell apoptosis increased in the miR-136-5p mimic group compared to the negative control group. In addition, both MTDH mRNA and protein levels were markedly overexpressed, with the pooled SMD being 0.94 (95% CI: -0.35 to 2.24, I2=98.8%, P<0.001), and the AUC of the sROC being 0.85 with 1054 cases of TC. The MTDH protein level was significantly up-regulated in TC than in the non-carcinomic tissues by immunohistochemistry (8.292±1.717 vs. 2.618±2.570, P<0.001). Western blot indicated that MTDH protein expression was suppressed by miR-136-5p mimic in the B-CPAP cell line, which was further supported by the dual luciferase reporter assay. CONCLUSION The miR-136-5p/MTDH axis may play a vital role in modulating TC tumorigenesis, providing new insight into possible molecular mechanisms of TC oncogenesis.
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Affiliation(s)
- Rui-Zhi Gao
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Qiao Que
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Peng Lin
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yu-Yan Pang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hua-Yu Wu
- Department of Cell Biology and Genetics, School of Preclinical Medicine, Guangxi Medical UniversityNanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Jiao Li
- Department of Positron Emission Tomography-Computed Tomography, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yun He
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hong Yang
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi Zhuang Autonomous Region, China
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Chang Y, Li B, Xu X, Shen L, Bai H, Gao F, Zhang Z, Jonas JB. Correction: Lentivirus-Mediated Knockdown of Astrocyte Elevated Gene-1 Inhibits Growth and Induces Apoptosis through MAPK Pathways in Human Retinoblastoma Cells. PLoS One 2019; 14:e0223818. [PMID: 31609990 PMCID: PMC6791552 DOI: 10.1371/journal.pone.0223818] [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] [Indexed: 11/18/2022] Open
Abstract
[This corrects the article DOI: 10.1371/journal.pone.0148763.].
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Bai H, Chang Y, Li B, Mao Y, Jonas JB. Effects of lentivirus-mediated astrocyte elevated gene-1 overexpression on proliferation and apoptosis of human retinoblastoma cells. Acta Ophthalmol 2019; 97:e397-e402. [PMID: 30694025 DOI: 10.1111/aos.14034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 12/16/2018] [Indexed: 12/16/2022]
Abstract
PURPOSE To investigate the effect of astrocyte elevated gene-1 (AEG-1) overexpression on the biological behaviour of human retinoblastoma (RB) cells and its possible mechanism. METHODS Three human RB cell lines (SO-RB50, Y79 and WERI-RB1) were infected with AEG-1-GFP recombinant lentiviral vectors to induce AEG-1 overexpression, while the cells infected with negative lentiviral vectors and cells without any intervention formed control groups. RESULTS All three RB cell lines showed an overexpression of AEG-1 after lentivirus infection (p < 0.001 for all three cell lines). The survival rate of RB cells increased (all p < 0.001) in the AEG-1 overexpressed groups when compared with the control groups. There was a decrease in G0/G1 cell cycle phase arrest and an accumulation in G2/M cell cycle phase in all three RB cell lines (p < 0.001), with an induction in the S phase in WERI-RB1 cells. It was paralleled by a downregulation of p21 and p27 proteins and an upregulation of the Cdc2 protein. The apoptosis rate of RB cells declined (p < 0.001) when AEG-1 was overexpressed, in association with an upregulation of Bcl-2 protein and a downregulation of Bax protein and cleaved caspase-3 proteins. CONCLUSIONS A lentivirus-mediated AEG-1 overexpression in RB cells led in vitro to a growth promotion and an apoptosis inhibition of human RB cells, associated with an upregulation of the Bcl-2 protein, a downregulation of the Bax protein and of cleaved caspase-3 proteins, and with alterations of the cell cycle. AEG-1 may be involved in the development and progression of RB.
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Affiliation(s)
- Haixia Bai
- Beijing Institute of Ophthalmology; Beijing Tongren Eye Center; Beijing Ophthalmology & Visual Sciences Key Laboratory; Beijing Tongren Hospital; Capital Medical University; Beijing China
| | - Ying Chang
- Beijing Institute of Ophthalmology; Beijing Tongren Eye Center; Beijing Ophthalmology & Visual Sciences Key Laboratory; Beijing Tongren Hospital; Capital Medical University; Beijing China
- Department of Ophthalmology; Shanxi Eye Hospital; Taiyuan Shanxi China
| | - Bin Li
- Beijing Institute of Ophthalmology; Beijing Tongren Eye Center; Beijing Ophthalmology & Visual Sciences Key Laboratory; Beijing Tongren Hospital; Capital Medical University; Beijing China
| | - Ying Mao
- Beijing Institute of Ophthalmology; Beijing Tongren Eye Center; Beijing Ophthalmology & Visual Sciences Key Laboratory; Beijing Tongren Hospital; Capital Medical University; Beijing China
| | - Jost B. Jonas
- Department of Ophthalmology; Medical Faculty Mannheim; Heidelberg University; Mannheim Germany
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Wang L, Lyu X, Ma Y, Wu F, Wang L. MicroRNA‑504 targets AEG‑1 and inhibits cell proliferation and invasion in retinoblastoma. Mol Med Rep 2019; 19:2935-2942. [PMID: 30720088 DOI: 10.3892/mmr.2019.9923] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 12/14/2018] [Indexed: 11/06/2022] Open
Abstract
The dysregulation of microRNAs (miRNAs/miRs) has become increasingly recognized as a primary feature of retinoblastoma (RB). Furthermore, miRNAs have been demonstrated to be involved in the occurrence and development of RB. Therefore, it is crucial to investigate the expression profile and roles of miRNAs in RB in order to identify potential therapeutic targets to treat patients with RB. The expression profile and biological roles of miRNA‑504 (miR‑504) have been reported in numerous types of human cancer; however, the roles of miR‑504 in RB remain unknown. In the present study, it was demonstrated that miR‑504 expression was significantly decreased in RB tissues and cell lines. Functional analysis identified that resumption of miR‑504 expression suppressed cell proliferation and invasion in RB. Furthermore, astrocyte elevated gene‑1 (AEG‑1) was determined to be a direct target of miR‑504 in RB, and a negative correlation between miR‑504 and AEG‑1 mRNA expression levels was observed in RB tissues. Additionally, the tumor‑suppressing effects of miR‑504 overexpression in RB cells could be rescued by AEG‑1 upregulation. In conclusion, these results indicated a significant role of the miR‑504/AEG‑1 pathway in inhibiting the aggressiveness of RB, suggesting that this miRNA may be employed as a therapeutic target for the treatment of patients with this disease.
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Affiliation(s)
- Lina Wang
- Department of Ophthalmology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Xueman Lyu
- Department of Ophthalmology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yunqing Ma
- Department of Intensive Care Unit, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Fei Wu
- Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Ling Wang
- Department of Ophthalmology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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12
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Xu ST, Ma YC, Wang CH, Xu Y, Gu GJ. Prognostic and clinicopathologic significance of AEG-1/MTDH and E-cadherin expression in human gallbladder carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:6025-6031. [PMID: 31949691 PMCID: PMC6963071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 10/25/2018] [Indexed: 06/10/2023]
Abstract
Astrocyte elevated gene-1 (AEG-1) and E-cadherin are associated with tumorigenesis and progression. The aim of this study is to investigate the expression of AEG-1 and E-cadherin in human gallbladder cancer (GBC) and explore their clinical and pathological significance. The expression of AEG-1 and E-cadherin protein were detected in 71 cases of human GBC and 22 cases of tumor-adjacent tissue by the immunohistochemical method. Our results demonstrate that the positive expression (high expression) rate of AEG-1 was 62.0% in human GBC which was higher than that in tumor-adjacent tissues (13.6%), P<0.001. The positive expression of AEG-1 protein was correlated with tumor TNM classification, histologic grade, and lymph node metastasis (P=0.037, P=0.033 and P=0.020, respectively). The positive expression rate of E-cadherin was 40.8% in GBC, which was lower than that in tumor-adjacent tissues (77.3%), P=0.003. Negative expression (Low expression) of E-Cadherin was significantly related with tumor TNM classification, histologic grade and lymphatic metastasis (P=0.028, P=0.003 and P=0.040, respectively). The expression of AEG-1 was negatively correlated with the expression of E-Cadherin (r=0.530, P<0.001). The log-rank test statistical analysis suggested that patients with positive expression of AEG-1 or negative expression of E-Cadherin protein had shorter overall survival time. Cox multivariate analysis showed that tumor TNM classification, histologic grade and lymphatic metastasis, AEG-1 and E-cadherin expression were independent factors for prognosis of GBC (P=0.013, P=0.019, P=0.001, P=0.011 and P=0.025 respectively). In conclusion, positive expression of AEG-1 and negative expression of E-Cadherin are markedly correlated with tumor TNM classification, histologic grade and lymphatic metastasis. The expression of AEG-1 was negatively correlated with the expression of E-Cadherin. Cox multivariate analysis showed that tumor TNM classification, histologic grade and lymphatic metastasis, positive expression of AEG-1 and negative expression of E-Cadherin were risk factors for prognosis of GBC. Detection of AEG-1 and E-Cadherin may be helpful to evaluate prognosis and infiltrative capability of gallbladder carcinoma.
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Affiliation(s)
- Song-Tao Xu
- Department of Clinical, Luohe Medical CollegeLuohe, Henan, PR China
- Innovative Science and Technological Team of Tumor Occurrence and Prevention in Henan ProvinceLuohe , Henan Province, PR China
| | - Yong-Chao Ma
- Department of Basic Medical Science, Luohe Medical CollegeLuohe, Henan, PR China
| | - Cai-Hong Wang
- Department of Medical Imaging, Taicang Affiliated Hospital of Soochow UniversityTaicang, Jiangsu, PR China
| | - Yue Xu
- Department of Neurosurgery, Taicang Affiliated Hospital of Soochow UniversityTaicang, Jiangsu, PR China
| | - Guo-Jian Gu
- Department of Pathology, Taicang Affiliated Hospital of Soochow UniversityTaicang, Jiangsu, PR China
- Department of Pathology, The First People’s Hospital of TaicangTaicang, Jiangsu, PR China
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13
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Chen J, Jia Y, Jia ZH, Zhu Y, Jin YM. Silencing the expression of MTDH increases the radiation sensitivity of SKOV3 ovarian cancer cells and reduces their proliferation and metastasis. Int J Oncol 2018; 53:2180-2190. [PMID: 30226587 DOI: 10.3892/ijo.2018.4541] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 06/12/2018] [Indexed: 11/06/2022] Open
Abstract
Ovarian cancer has a high mortality rate among women worldwide. Radiotherapy is considered an effective method of ovarian cancer treatment, however, radioresistance presents a challenge. It is necessary to develop techniques that can increase radiosensitivity in ovarian cancer, and gene therapy is a promising option. The aim of the present study was to investigate the effects of metadherin (MTDH) silencing on the radiosensitivity of ovarian cancer. Ovarian cancer tissues (n=273) and normal ovarian tissues (n=277) were used, as were SKOV3 ovarian cancer cells and the immortalized human ovarian epidermal HOSEpiC cell line. MTT, Transwell and wound-healing assays were performed to assess the proliferation, invasion and migration abilities of the SKOV3 cells. Colony-forming assays and flow cytometry were applied to detect the radiosensitivity and apoptosis of the SKOV3 cells. Nude mouse xenograft models were established to evaluate the effect of MTDH gene silencing on tumor growth and the efficacy of radiotherapy. Ovarian cancer, in tissues and cells, was demonstrated to have a high level of MTDH. Additionally, MTDH silencing was found to significantly inhibit proliferation, migration and invasion, and induce apoptosis in SKOV3 cells, and it was suggested that MTDH depletion significantly increased the sensitivity of the SKOV3 cells to X-ray radiation. MTDH silencing enhanced radiosensitivity and delayed tumor growth in the nude mouse xenograft model. Collectively, the results obtained in the present study suggest the potential role of MTDH silencing as a technique for ameliorating radioresistance in ovarian cancer. The present study provides a promising experimental basis for the improvement of ovarian cancer radiotherapy treatment.
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Affiliation(s)
- Jun Chen
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Yan Jia
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Zan-Hui Jia
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Yu Zhu
- Department of Ophthalmology, FAW General Hospital, The Fourth Hospital of Jilin University, Changchun, Jilin 130011, P.R. China
| | - Yue-Mei Jin
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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Zhang Y, Wang X, Zhao Y. MicroRNA‑874 prohibits the proliferation and invasion of retinoblastoma cells by directly targeting metadherin. Mol Med Rep 2018; 18:3099-3105. [PMID: 30015932 DOI: 10.3892/mmr.2018.9295] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 06/21/2018] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs (miRNAs/miRs) serve important roles in regulating gene expression by directly binding to the 3'‑untranslated regions of target genes. Multiple miRNAs are dysregulated in retinoblastoma (RB) and their dysregulation is closely related to RB malignancy. Therefore, exploring the detailed roles of miRNAs in RB is valuable to facilitate the development of effective therapeutic targets for patients with this disease. miRNA‑874‑3p (miR‑874) has been recently reported to be downregulated in several types of human cancer and serves an essential role in cancer progression. However, the expression pattern and detailed roles of miR‑874 in RB, as well as the underlying molecular mechanisms in RB, have not been clearly elucidated. Therefore, this study detected miR‑874 expression in RB tissues and cell lines. The biological roles of miR‑874 in RB were determined and the underlying mechanisms of its actions in RB cells were also examined. This study revealed that miR‑874 expression was aberrantly underexpressed in RB tissues and cell lines. However, returning miR‑874 expression restricted the proliferative and invasive abilities of RB cells. In terms of the underlying mechanism, metadherin (MTDH) was validated as a direct target gene of miR‑874 in RB cells. MTDH inhibition could imitate the inhibitory roles of miR‑874 overexpression in RB cells. Furthermore, forced MTDH expression partially reversed the suppressive effects of miR‑874 on RB cells. In conclusion, this study revealed that miR‑874 may inhibit RB progression by directly targeting MTDH. Restoration of miR‑874 expression may be a novel strategy for preventing the rapid growth and metastasis of RB cells.
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Affiliation(s)
- Yongfeng Zhang
- Department of Pediatrics, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
| | - Xueqin Wang
- Medical Imaging Center, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
| | - Yuehua Zhao
- Department of Pediatrics, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China
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15
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Yan J, Zhang J, Zhang X, Li X, Li L, Li Z, Chen R, Zhang L, Wu J, Wang X, Sun Z, Fu X, Chang Y, Nan F, Yu H, Wu X, Feng X, Li W, Zhang M. AEG-1 is involved in hypoxia-induced autophagy and decreases chemosensitivity in T-cell lymphoma. Mol Med 2018; 24:35. [PMID: 30134829 PMCID: PMC6038315 DOI: 10.1186/s10020-018-0033-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/05/2018] [Indexed: 02/07/2023] Open
Abstract
Background This study was to examine the link between astrocyte elevated gene-1 (AEG-1) and hypoxia induced-chemoresistance in T-cell non-Hodgkin’s lymphoma (T-NHL), as well as the underlying molecular mechanisms. Methods Expression of AEG-1, LC3-II, and Beclin-1 were initially examined in human T-NHL tissues (n = 30) and normal lymph node tissues (n = 16) using western blot, real-time PCR and immunohistochemistry. Western blot was also performed to analyze the expression of AEG-1, LC3-II, and Beclin-1 in T-NHL cells (Hut-78 and Jurkat cells) under normoxia and hypoxia. Additionally, the proliferation and apoptosis of Hut-78 cells exposed to different concentration of Adriamycin (ADM) in normoxia and hypoxia were evaluated by MTT and Annexin-V FITC/PI staining assay. Finally, the effects of AEG-1 on Hut-78 cells exposed to ADM in hypoxia were assessed by MTT and Annexin-V FITC/PI staining assay, and 3-MA (autophagy inhibitor) was further used to determine the underlying mechanism. Results AEG-1, LC3-II and Beclin-1 expression were significantly increased in T-NHL tissues compared with normal tissues. Incubation of Hut-78 and Jurkat cells in hypoxia obviously increased AEG-1, LC3-II and Beclin-1 expression. Hypoxia induced proliferation and reduced apoptosis of Hut-78 cells exposed to ADM. AEG-1 overexpression further increased proliferation and decreased apoptosis of Hut-78 cells exposed to ADM in hypoxia. Moreover, overexpression of AEG-1 significantly inversed 3-MA induced-changes in cell proliferation and apoptosis of Hut-78 cells exposed to ADM in hypoxia. Conclusions This study suggested that AEG-1 is associated with hypoxia-induced T-NHL chemoresistance via regulating autophagy, uncovering a novel target against hypoxia-induced T-NHL chemoresistance. Electronic supplementary material The online version of this article (10.1186/s10020-018-0033-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jiaqin Yan
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Junhui Zhang
- Department of Otorhinolaryngology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Xudong Zhang
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Xin Li
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Ling Li
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Zhaoming Li
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Renyin Chen
- Department of pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Lei Zhang
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Jingjing Wu
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Xinhua Wang
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Zhenchang Sun
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Xiaorui Fu
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Yu Chang
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Feifei Nan
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Hui Yu
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Xiaolong Wu
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Xiaoyan Feng
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China
| | - Wencai Li
- Department of pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan, 450052, People's Republic of China.
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16
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Xue HY, Liu Y, Liao JZ, Lin JS, Li B, Yuan WG, Lee RJ, Li L, Xu CR, He XX. Gold nanoparticles delivered miR-375 for treatment of hepatocellular carcinoma. Oncotarget 2018; 7:86675-86686. [PMID: 27880727 PMCID: PMC5349944 DOI: 10.18632/oncotarget.13431] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 11/02/2016] [Indexed: 12/12/2022] Open
Abstract
MiR-375 is a tumor suppressor miRNA that is downregulated in hepatocellular carcinoma (HCC). However, due to the lack of effective delivery strategies, miR-375 replacement as a therapy for HCC has not been investigated. In the present study, we have developed a straightforward strategy to deliver miR-375 into HCC cells by assembling miR-375 mimics on the surface of AuNPs and forming AuNP-miR-375 nanoparticles. AuNP-miR-375 exhibits high cellular uptake and preserves miR-375's activities to suppress cellular proliferation, migration/invasion, and colony formation, and to induce apoptosis in HCC cells. Furthermore, AuNP-delivered miR-375 efficiently downregulated its target genes through RNA interference. In primary and xenograft tumor mouse models, AuNP-miR-375 showed high tumor uptake, therapeutic efficacy, and no apparent toxicity to the host mice. In conclusion, our findings indicate that AuNPs is a reliable strategy to deliver miR-375 into HCC cells and tissue, and that AuNP-miR-375 has the potential in the clinic for treatment of unresectable HCC.
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Affiliation(s)
- Hui-Ying Xue
- Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yong Liu
- Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jia-Zhi Liao
- Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ju-Sheng Lin
- Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Bin Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wei-Gang Yuan
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Robert J Lee
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
| | - Lei Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chuan-Rui Xu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xing-Xing He
- Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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17
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Zhang L, Yang G, Chen H, Huang Y, Xue W, Bo J. Depletion of astrocyte elevated gene-1 suppresses tumorigenesis through inhibition of Akt activity in bladder cancer cells. Am J Transl Res 2017; 9:5422-5431. [PMID: 29312494 PMCID: PMC5752892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2017] [Accepted: 10/02/2017] [Indexed: 06/07/2023]
Abstract
Astrocyte elevated gene-1 (AEG-1) has been reported to promote tumorigenesis, however the molecular mechanisms by which AEG-1-induced bladder cancer progression has remained elusive. Here, we identified that depletion of AEG-1 in bladder cancer cells suppressed cell growth. Moreover, we observed that down-regulation of AEG-1 induced apoptosis and inhibited cell migration and invasion. Furthermore, depletion of AEG-1 inhibited Akt activity and suppressed Bcl-2 expression, but upregulated the levels of p21 and p27. Our findings reveal that AEG-1 carries out its oncogenic function via activation of the Akt pathway. Therefore, inhibition of AEG-1 could be a novel treatment approach for bladder cancer.
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Affiliation(s)
- Lianhua Zhang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai 200127, China
| | - Guoliang Yang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai 200127, China
| | - Haige Chen
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai 200127, China
| | - Yiran Huang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai 200127, China
| | - Wei Xue
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai 200127, China
| | - Juanjie Bo
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai 200127, China
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18
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Li H, Zhao J. let-7d suppresses proliferation and invasion and promotes apoptosis of meningioma by targeting AEG-1. Onco Targets Ther 2017; 10:4895-4904. [PMID: 29070952 PMCID: PMC5640403 DOI: 10.2147/ott.s141008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND let-7d has been indicated to act as a tumor suppressor in various cancers. However, the function and molecular mechanism of let-7d in meningioma progression have not been elucidated. MATERIALS AND METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression levels of let-7d and AEG-1 mRNA in meningioma tissues and cell lines. The protein level of AEG-1 was measured by Western blot analysis. MTT assay, Transwell invasion assay and flow cytometry analysis were carried out to determine the proliferation, invasion and apoptosis of IOMM-Lee and CH-157MN cells, respectively. Target gene of let-7d was verified by luciferase reporter analysis. RESULTS let-7d expression was downregulated, and AEG-1 expression was upregulated in meningioma tumor tissues. let-7d overexpression suppressed proliferation and invasion and induced apoptosis in IOMM-Lee and CH-157MN cells. Moreover, AEG-1 was a direct target of let-7d. Restoration of AEG-1 expression reversed let-7d-mediated suppression of the proliferation and invasion and let-7d-induced apoptosis in IOMM-Lee and CH-157MN cells. CONCLUSION let-7d repressed proliferation and invasion and promoted apoptosis of meningioma cells by targeting AEG-1. The present study provided a better understanding of the meningioma pathogenesis and a promising therapeutic target for meningioma patients.
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Affiliation(s)
- Hui Li
- Department of Neurology, Xinxiang Central Hospital, Xinxiang, China
| | - Jianmin Zhao
- Department of Neurology, Xinxiang Central Hospital, Xinxiang, China
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19
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Zhang Y, Peng G, Wang Y, Cui L, Wu W, Wang L, Liu C, Han X. Silencing of astrocyte elevated gene-1 inhibits proliferation and migration of melanoma cells and induces apoptosis. Clin Exp Pharmacol Physiol 2017; 44:815-826. [PMID: 28429540 DOI: 10.1111/1440-1681.12767] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 03/24/2017] [Accepted: 04/06/2017] [Indexed: 12/19/2022]
Abstract
Melanoma is an aggressive skin malignancy with a high mortality. Astrocyte elevated gene-1 (AEG-1), a downstream target of Ras and c-Myc, has been implicated in the development of multiple tumours, but its role in melanoma remains unclear. In the present study, the role of AEG-1 in melanoma was explored through AEG-1 silencing. Our results showed that silencing AEG-1 inhibited the proliferation of melanoma cells, induced cell cycle arrest, and reduced levels of cyclin A, cyclin B, cyclin D1, cyclin E, and cyclin-dependent kinase 2. AEG-1silencing also induced apoptosis in melanoma cells and altered the levels of cleaved caspase-3, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein. Moreover, silencing AEG-1 suppressed the migration and invasion of melanoma cells, reduced the expressions and activities of matrix metallopeptidase (MMP)-2 and MMP-9, and inhibited the activation of the Wnt/β-catenin signalling pathway in melanoma cells. Furthermore, in vivo experiments revealed that AEG-1 silencing inhibited the growth of melanoma xenografts in nude mice. In summary, our study demonstrates an oncogenic role of AEG-1 in melanoma and suggests that AEG-1 may serve as a potential therapeutic target in the treatment of melanoma.
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Affiliation(s)
- Yue Zhang
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ge Peng
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ying Wang
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lixia Cui
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wenqing Wu
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Luan Wang
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Chengyu Liu
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiuping Han
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, China
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20
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Xie Y, Zhong DW. AEG-1 is associated with hypoxia-induced hepatocellular carcinoma chemoresistance via regulating PI3K/AKT/HIF-1alpha/MDR-1 pathway. EXCLI JOURNAL 2016; 15:745-757. [PMID: 28337106 PMCID: PMC5318678 DOI: 10.17179/excli2016-694] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 11/03/2016] [Indexed: 01/08/2023]
Abstract
Hypoxia is a common characteristic of hepatocellular carcinoma (HCC) associated with reduced response to chemotherapy, thus increasing the probability of tumor recurrence. Astrocyte elevated gene-1 (AEG-1) has been involved in a wide array of cancer progression including proliferation, chemoresistance, angiogenesis and metastasis, but its effect on HCC chemoresistance induced by hypoxia is unclear. In this study, expression of AEG-1 and multiple drug resistance (MDR-1) were examined in HCC using immunohistochemical staining and RT-PCR. Furthermore, their expression levels were detected in HCC HepG2 cells in normoxia or hypoxia via RT-PCR and Western blot assays. Specific shRNAs were used to silence AEG-1 expression in HepG2 cells. Results showed AEG-1 and MDR-1 expression were higher in HCC tissues than in adjacent normal tissues. Incubation of HepG2 cells in hypoxia increased expression of AEG-1 and MDR-1, compared to incubation in normoxia. Exposure to hypoxia blunted sensitivity of HepG2 cells to Adriamycin, 5-fluorouracil and cis-platinum, as evidenced by modest alterations in cell viability and apoptosis rate, however the sensitivity was elevated with AEG-1 knockdown. PI3K/AKT/HIF-1/MDR-1 pathway was attenuated following AEG-1 knockdown in hypoxia. Based on these data, it was suggested that AEG-1 is associated with hypoxia-induced hepatocellular carcinoma chemoresistance via regulating PI3K/AKT/HIF-1/MDR-1 pathway. This study uncovered a novel potential target for development of an effective therapy against hypoxia-induced HCC chemoresistance.
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Affiliation(s)
- Yong Xie
- Department of Hepatobiliary Surgery, the 2nd XiangYa Hospital of Centre South University, 139#, Renmin Road, Changsha, Hunan, P.R. China
| | - De-Wu Zhong
- Department of Hepatobiliary Surgery, the 2nd XiangYa Hospital of Centre South University, 139#, Renmin Road, Changsha, Hunan, P.R. China
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Metadherin facilitates podocyte apoptosis in diabetic nephropathy. Cell Death Dis 2016; 7:e2477. [PMID: 27882943 PMCID: PMC5260885 DOI: 10.1038/cddis.2016.335] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 09/23/2016] [Accepted: 09/23/2016] [Indexed: 02/01/2023]
Abstract
Apoptosis, one of the major causes of podocyte loss, has been reported to have a vital role in diabetic nephropathy (DN) pathogenesis, and understanding the mechanisms underlying the regulation of podocyte apoptosis is crucial. Metadherin (MTDH) is an important oncogene, which is overexpressed in most cancers and responsible for apoptosis, metastasis, and poor patient survival. Here we show that the expression levels of Mtdh and phosphorylated p38 mitogen-activated protein kinase (MAPK) are significantly increased, whereas those of the microRNA-30 family members (miR-30s) are considerably reduced in the glomeruli of DN rat model and in high glucose (HG)-induced conditionally immortalized mouse podocytes (MPC5). These levels are positively correlated with podocyte apoptosis rate. The inhibition of Mtdh expression, using small interfering RNA, but not Mtdh overexpression, was shown to inhibit HG-induced MPC5 apoptosis and p38 MAPK pathway, and Bax and cleaved caspase 3 expression. This was shown to be similar to the effects of p38 MAPK inhibitor (SB203580). Furthermore, luciferase assay results demonstrated that Mtdh represents the target of miR-30s. Transient transfection experiments, using miR-30 microRNA (miRNA) inhibitors, led to the increase in Mtdh expression and induced the apoptosis of MPC5, whereas the treatment with miR-30 miRNA mimics led to the reduction in Mtdh expression and apoptosis of HG-induced MPC5 cells in comparison with their respective controls. Our results demonstrate that Mtdh is a potent modulator of podocyte apoptosis, and that it represents the target of miR-30 miRNAs, facilitating podocyte apoptosis through the activation of HG-induced p38 MAPK-dependent pathway.
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Wu YH, Chang JYF, Tseng CH, Chiang CP, Wang YP. Expression of astrocyte elevated gene-1 protein in ameloblastomas, keratocystic odontogenic tumors, and dentigerous cysts. J Oral Pathol Med 2016; 46:121-126. [DOI: 10.1111/jop.12472] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2016] [Indexed: 01/22/2023]
Affiliation(s)
- Yu-Hsueh Wu
- Graduate Institute of Clinical Dentistry and Graduate Institute of Oral Biology; School of Dentistry; National Taiwan University; Taipei Taiwan
| | - Julia Yu-Fong Chang
- Graduate Institute of Clinical Dentistry and Graduate Institute of Oral Biology; School of Dentistry; National Taiwan University; Taipei Taiwan
- Department of Dentistry; College of Medicine; National Taiwan University Hospital; National Taiwan University; Taipei Taiwan
- Faculty of Dentistry; School of Dentistry; National Taiwan University; Taipei Taiwan
| | - Chih-Huang Tseng
- Graduate Institute of Clinical Dentistry and Graduate Institute of Oral Biology; School of Dentistry; National Taiwan University; Taipei Taiwan
| | - Chun-Pin Chiang
- Graduate Institute of Clinical Dentistry and Graduate Institute of Oral Biology; School of Dentistry; National Taiwan University; Taipei Taiwan
- Department of Dentistry; College of Medicine; National Taiwan University Hospital; National Taiwan University; Taipei Taiwan
- Faculty of Dentistry; School of Dentistry; National Taiwan University; Taipei Taiwan
| | - Yi-Ping Wang
- Graduate Institute of Clinical Dentistry and Graduate Institute of Oral Biology; School of Dentistry; National Taiwan University; Taipei Taiwan
- Department of Dentistry; College of Medicine; National Taiwan University Hospital; National Taiwan University; Taipei Taiwan
- Faculty of Dentistry; School of Dentistry; National Taiwan University; Taipei Taiwan
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Hong S, Sun N, Liu M, Wang J, Pei R. Building a chimera of aptamer–antisense oligonucleotide for silencing galectin-1 gene. RSC Adv 2016. [DOI: 10.1039/c6ra21250f] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Galectin-1 is closely related with immune systems, and its overexpression may cause tumor metastasis.
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Affiliation(s)
- Shanni Hong
- School of Nano Technology and Nano Bionics
- University of Science and Technology of China
- Hefei 230026
- China
- Suzhou Institute of Nano-Tech and Nano-Bionics
| | - Na Sun
- Suzhou Institute of Nano-Tech and Nano-Bionics
- Chinese Academy of Sciences
- Suzhou 215123
- China
| | - Min Liu
- Suzhou Institute of Nano-Tech and Nano-Bionics
- Chinese Academy of Sciences
- Suzhou 215123
- China
| | - Jine Wang
- Suzhou Institute of Nano-Tech and Nano-Bionics
- Chinese Academy of Sciences
- Suzhou 215123
- China
| | - Renjun Pei
- Suzhou Institute of Nano-Tech and Nano-Bionics
- Chinese Academy of Sciences
- Suzhou 215123
- China
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