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Barati T, Mirzaei Z, Ebrahimi A, Shekari Khaniani M, Mansoori Derakhshan S. miR-449a: A Promising Biomarker and Therapeutic Target in Cancer and Other Diseases. Cell Biochem Biophys 2024; 82:1629-1650. [PMID: 38809350 DOI: 10.1007/s12013-024-01322-9] [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] [Accepted: 05/17/2024] [Indexed: 05/30/2024]
Abstract
In the regulation of gene expression, epigenetic factors like non-coding RNAs (ncRNAs) play an equal role in genetics. The role of microRNAs (miRNAs), which are members of the ncRNA family, in post-transcriptional gene regulation is well-documented and has important implications for both normal and abnormal biological processes, such as angiogenesis, proliferation, survival, and apoptosis. The purpose of this study was to synthesize previous research on miR-449a by analyzing published results from various databases, as there have been a number of investigations on miR-449's potential involvement in the development of human disorders. Based on our findings, miR-449 is strongly dysregulated in a wide range of diseases, from various cancers to cardiovascular diseases, cognitive impairments, and respiratory diseases, and it may play a pivotal role in the development of these problems. In addition, miR-449a functions as a crucial regulator of the expression of several well-known genes, including E2F-3, BCL2, NOTCH1, and SOX4. This, in turn, modulates various pathways and processes related to cancer, including Notch, PI3K, and TGF-β, and contributes to the improvement of cancer drug sensitivity. Curiously, abnormalities in the expression of this miRNA may serve as diagnostic or prognostic indicators for distinguishing between healthy people and patients or to evaluate the survival rates for specific disorders. This article provides a synopsis of the current understanding of miR-449a's role in human disease development through its regulation of gene expression and the biological processes related to these genes and their linked processes. In addition, we have covered the topic of miR-449a's potential as a clinical feature (diagnosis and prognosis) indicator for a range of disorders, both neoplastic and non-neoplastic. In general, our goal was to gain a thorough comprehension of the numerous functions of miR-449a in different disorders.
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Affiliation(s)
- Tahereh Barati
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Mirzaei
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Ebrahimi
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahmoud Shekari Khaniani
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Sima Mansoori Derakhshan
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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2
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Abdelmaksoud NM, Abulsoud AI, Doghish AS, Abdelghany TM. From resistance to resilience: Uncovering chemotherapeutic resistance mechanisms; insights from established models. Biochim Biophys Acta Rev Cancer 2023; 1878:188993. [PMID: 37813202 DOI: 10.1016/j.bbcan.2023.188993] [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: 07/24/2023] [Revised: 09/13/2023] [Accepted: 09/26/2023] [Indexed: 10/11/2023]
Abstract
Despite the tremendous advances in cancer treatment, resistance to chemotherapeutic agents impedes higher success rates and accounts for major relapses in cancer therapy. Moreover, the resistance of cancer cells to chemotherapy is linked to low efficacy and high recurrence of cancer. To stand up against chemotherapy resistance, different models of chemotherapy resistance have been established to study various molecular mechanisms of chemotherapy resistance. Consequently, this review is going to discuss different models of induction of chemotherapy resistance, highlighting the most common mechanisms of cancer resistance against different chemotherapeutic agents, including overexpression of efflux pumps, drug inactivation, epigenetic modulation, and epithelial-mesenchymal transition. This review aims to open a new avenue for researchers to lower the resistance to the existing chemotherapeutic agents, develop new therapeutic agents with low resistance potential, and establish possible prognostic markers for chemotherapy resistance.
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Affiliation(s)
- Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt.
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Tamer M Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt.
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Liu C, Li S, Tang Y. Mechanism of cisplatin resistance in gastric cancer and associated microRNAs. Cancer Chemother Pharmacol 2023; 92:329-340. [PMID: 37535106 DOI: 10.1007/s00280-023-04572-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 07/27/2023] [Indexed: 08/04/2023]
Abstract
Gastric cancer (GC) is a common malignant tumor with high morbidity and mortality rates that seriously affects human health worldwide. Although surgery is currently the preferred clinical treatment for GC, chemotherapy remains the first choice for perioperative treatment, adjuvant therapy, and palliative care for patients with advanced GC. Cisplatin (DDP) is an antineoplastic agent that has been used clinically for decades, and it is the first-line chemotherapy for many solid tumors. However, the therapeutic efficacy of DDP is often limited by resistance and the complexity of its resistance mechanisms, which involve multiple proteins and signaling pathways. It is well documented that a variety of microRNAs (miRNAs) differentially expressed in DDP-resistant GC cells play important roles in regulating or reversing DDP resistance via various pathways. In this review, we first provide an introduction to the cytotoxicity and major resistance mechanisms of DDP in GC and then discuss the role and mechanism of miRNAs in regulating the DDP resistance process in GC cells. This work demonstrates the potential of relevant miRNAs to become diagnostic and prognostic biomarkers for gastric cancer and targets of action to enhance chemosensitivity and provides directions for future research.
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Affiliation(s)
- Changqing Liu
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical School, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Shan Li
- Department of Pathology, People's Hospital of Shaoyang County, Hengyang, Hunan Province, People's Republic of China
| | - Yunlian Tang
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical School, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan Province, People's Republic of China.
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Fathi D, Elballal MS, Elesawy AE, Abulsoud AI, Elshafei A, Elsakka EG, Ismail A, El-Mahdy HA, Elrebehy MA, Doghish AS. An emphasis on the interaction of signaling pathways highlights the role of miRNAs in the etiology and treatment resistance of gastric cancer. Life Sci 2023; 322:121667. [PMID: 37023952 DOI: 10.1016/j.lfs.2023.121667] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/01/2023] [Accepted: 04/03/2023] [Indexed: 04/07/2023]
Abstract
Gastric cancer (GC) is 4th in incidence and mortality rates globally. Several genetic and epigenetic factors, including microRNAs (miRNAs), affect its initiation and progression. miRNAs are short chains of nucleic acids that can regulate several cellular processes by controlling their gene expression. So, dysregulation of miRNAs expressions is associated with GC initiation, progression, invasion capacity, apoptosis evasions, angiogenesis, promotion and EMT enhancement. Of important pathways in GC and controlled by miRNAs are Wnt/β-catenin signaling, HMGA2/mTOR/P-gp, PI3K/AKT/c-Myc, VEGFR and TGFb signaling. Hence, this review was conducted to review an updated view of the role of miRNAs in GC pathogenesis and their modulatory effects on responses to different GC treatment modalities.
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Ji X, Chu G, Chen Y, Jiao J, Lv T, Yao Q. Comprehensive analysis of novel prognosis-related proteomic signature effectively improve risk stratification and precision treatment for patients with cervical cancer. Arch Gynecol Obstet 2023; 307:903-917. [PMID: 35713693 DOI: 10.1007/s00404-022-06642-w] [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: 03/13/2021] [Accepted: 05/17/2022] [Indexed: 11/02/2022]
Abstract
OBJECTIVE Cervical cancer (CC) is one of the most common types of malignant female cancer, and its incidence and mortality are not optimistic. Protein panels can be a powerful prognostic factor for many types of cancer. The purpose of our study was to investigate a proteomic panel to predict the survival of patients with common CC. METHODS AND RESULTS The protein expression and clinicopathological data of CC were downloaded from The Cancer Proteome Atlas and The Cancer Genome Atlas database, respectively. We selected the prognosis-related proteins (PRPs) by univariate Cox regression analysis and found that the results of functional enrichment analysis were mainly related to apoptosis. We used Kaplan-Meier analysis and multivariable Cox regression analysis further to screen PRPs to establish a prognostic model, including BCL2, SMAD3, and 4EBP1-pT70. The signature was verified to be independent predictors of OS by Cox regression analysis and the area under curves. Nomogram and subgroup classification were established based on the signature to verify its clinical application. Furthermore, we looked for the co-expressed proteins of three-protein panel as potential prognostic proteins. CONCLUSION A proteomic signature independently predicted OS of CC patients, and the predictive ability was better than the clinicopathological characteristics. This signature can help improve prediction for clinical outcome and provides new targets for CC treatment.
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Affiliation(s)
- Xiaoyu Ji
- Department of Obstetrics and Gynecology, Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Qingdao, 266000, China
| | - Guangdi Chu
- Department of Urology, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266000, China
| | - Yulong Chen
- Department of Obstetrics and Gynecology, Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Qingdao, 266000, China
| | - Jinwen Jiao
- Department of Obstetrics and Gynecology, Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Qingdao, 266000, China
| | - Teng Lv
- Department of Obstetrics and Gynecology, Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Qingdao, 266000, China
| | - Qin Yao
- Department of Obstetrics and Gynecology, Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Qingdao, 266000, China.
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Qin Z, Zhou C. HOXA13 promotes gastric cancer progression partially via the FN1-mediated FAK/Src axis. Exp Hematol Oncol 2022; 11:7. [PMID: 35197128 PMCID: PMC8864865 DOI: 10.1186/s40164-022-00260-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 01/21/2022] [Indexed: 12/20/2022] Open
Abstract
Background Gastric cancer (GC) is one of the most common cancers causing a poor prognosis worldwide. HOXA13, as a member of the homeobox (HOX) family, is involved in the regulation of cancer progression and has attracted increasing attention, as a potential novel target for anticancer strategies. However, the significance of HOXA13 in GC remains unclear. This article aims to explore the potential mechanism of HOXA13 in GC progression. Methods Quantitative real-time PCR was carried out to detect the expression of HOXA13 and FN1 and the correlation between HOXA13 and FN1 in GC tissues. In vitro assays were conducted to investigate the role of HOXA13 and FN1 in the malignant phenotypes of GC cells and the function of HOXA13 in the activation of the FAK/Src axis in GC cells. Coimmunoprecipitation was performed to reveal the relationship between ITGA5, ITGB1 and FN1 in GC cells. A dual luciferase assay was performed to assess miR-449a-targeted regulation of HOXA13 expression. Results Quantitative real-time PCR verified that HOXA13 was elevated and positively correlated with FN1 in GC. In vitro and in vivo assays demonstrated that high expression of HOXA13 promoted GC progression, especially metastasis. Mechanistically, rescue experiments, chromatin immunoprecipitation and dual luciferase assays revealed that HOXA13 directly bound to the FN1 promoter region to enhance the activation of the FAK/Src axis, leading to GC cell proliferation and metastasis. Furthermore, the result of a dual luciferase assay suggested that HOXA13 was directly targeted by miR-449a. Conclusions Our results show that HOXA13 is a positive regulator of the FAK/Src axis mediated by FN1 in GC and promotes GC progression. Thus, targeting HOXA13, together with FN1, may provide a novel prospective anticancer strategy. Supplementary Information The online version contains supplementary material available at 10.1186/s40164-022-00260-7.
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Affiliation(s)
- Zhiwei Qin
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 85 Wujin Road, Shanghai, China
| | - Chongzhi Zhou
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 85 Wujin Road, Shanghai, China.
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Liu Y, Ao X, Ji G, Zhang Y, Yu W, Wang J. Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer. Front Oncol 2021; 11:768918. [PMID: 34912714 PMCID: PMC8667691 DOI: 10.3389/fonc.2021.768918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.,School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Guoqiang Ji
- Clinical Laboratory, Linqu People's Hospital, Linqu, China
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
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8
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Visser H, Thomas AD. MicroRNAs and the DNA damage response: How is cell fate determined? DNA Repair (Amst) 2021; 108:103245. [PMID: 34773895 DOI: 10.1016/j.dnarep.2021.103245] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/25/2021] [Accepted: 10/29/2021] [Indexed: 12/12/2022]
Abstract
It is becoming clear that the DNA damage response orchestrates an appropriate response to a given level of DNA damage, whether that is cell cycle arrest and repair, senescence or apoptosis. It is plausible that the alternative regulation of the DNA damage response (DDR) plays a role in deciding cell fate following damage. MicroRNAs (miRNAs) are associated with the transcriptional regulation of many cellular processes. They have diverse functions, affecting, presumably, all aspects of cell biology. Many have been shown to be DNA damage inducible and it is conceivable that miRNA species play a role in deciding cell fate following DNA damage by regulating the expression and activation of key DDR proteins. From a clinical perspective, miRNAs are attractive targets to improve cancer patient outcomes to DNA-damaging chemotherapy. However, cancer tissue is known to be, or to become, well adapted to DNA damage as a means of inducing chemoresistance. This frequently results from an altered DDR, possibly owing to miRNA dysregulation. Though many studies provide an overview of miRNAs that are dysregulated within cancerous tissues, a tangible, functional association is often lacking. While miRNAs are well-documented in 'ectopic biology', the physiological significance of endogenous miRNAs in the context of the DDR requires clarification. This review discusses miRNAs of biological relevance and their role in DNA damage response by potentially 'fine-tuning' the DDR towards a particular cell fate in response to DNA damage. MiRNAs are thus potential therapeutic targets/strategies to limit chemoresistance, or improve chemotherapeutic efficacy.
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Affiliation(s)
- Hartwig Visser
- Centre for Research in Biosciences, University of the West of England, Frenchay Campus, Bristol BS16 1QY, United Kingdom
| | - Adam D Thomas
- Centre for Research in Biosciences, University of the West of England, Frenchay Campus, Bristol BS16 1QY, United Kingdom.
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Zhou C, Chen L, Chen R, Xu F, Huang Z, Huang R, Wang W, Xu Q. miR-4486 enhances cisplatin sensitivity of gastric cancer cells by restraining the JAK3/STAT3 signalling pathway. J Chemother 2021; 34:35-44. [PMID: 34167436 DOI: 10.1080/1120009x.2021.1936957] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Along with the occurrence of cisplatin resistance, treatment on gastric cancer (GC) becomes difficult. Therefore, researches on new therapeutic methods to revert cisplatin resistance are becoming increasingly urgent. qRT-PCR was used to quantify the expression of miR-4486, JAK3 in SGC-7901 or SGC-7901/DDP cell lines. WB was utilized to analyze the expression of JAK3, STAT3 and p-STAT3 in SGC-7901/DDP cell lines. CCK-8 assay was used to determine the IC50 of cisplatin on both cell lines and cell viability of SGC-7901/DDP cell lines. The target relationship between miR-4486 and JAK3 was determined by luciferase assay. MiR-4486 expression on apoptosis of SGC-7901/DDP cell lines was determined by flow cytometry. qRT-PCR testified that miR-4486 decreased in SGC-7901/DDP cells, and the expression of miR-4486 mimic increased significantly compared with miR-4486 NC. By CCK-8 assay, the IC50 of cisplatin on both cell lines were 9 μg/mL and 81.3 μg/mL, and overexpression of miR-4486 decreased the viability of SGC-7901/DDP cells. Compared with DDP group, the expression of miR-4486 accelerated SGC-7901/DDP cells apoptosis. Dual-luciferase assay suggested that JAK3 was the target gene of miR-4486. qRT-PCR and WB proved that miR-4486/JAK3 axis inhibit the activation of JAK3/STAT3 pathway, and JAK3 overexpression can partly reverse this. As shown by CCK-8 and flow cytometry, miR-4486 overexpression decreased viability and stimulated apoptosis of SGC-7901/DDP cells. However, JAK3 overexpression can also partly revert this. miR-4486 overexpression could decrease viability and improve apoptosis of SGC-7901/DDP cells to revert its cisplatin-resistance, and the mechanism may be related to JAK3/STAT3 signalling pathway.
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Affiliation(s)
- Caijin Zhou
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Linxia Chen
- Department of Operating Room, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Rihong Chen
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Feipeng Xu
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Zhe Huang
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Renwei Huang
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Weiwei Wang
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Qingwen Xu
- Department of Gastrointestinal Surgery, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
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Zangouei AS, Moghbeli M. MicroRNAs as the critical regulators of cisplatin resistance in gastric tumor cells. Genes Environ 2021; 43:21. [PMID: 34099061 PMCID: PMC8182944 DOI: 10.1186/s41021-021-00192-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/24/2021] [Indexed: 12/13/2022] Open
Abstract
Combined chemotherapeutic treatment is the method of choice for advanced and metastatic gastric tumors. However, resistance to chemotherapeutic agents is one of the main challenges for the efficient gastric cancer (GC) treatment. Cisplatin (CDDP) is used as an important regimen of chemotherapy for GC which induces cytotoxicity by interfering with DNA replication in cancer cells and inducing their apoptosis. Majority of patients experience cisplatin-resistance which is correlated with tumor metastasis and relapse. Moreover, prolonged and high-dose cisplatin administrations cause serious side effects such as nephrotoxicity, ototoxicity, and anemia. Since, there is a high rate of recurrence after CDDP treatment in GC patients; it is required to clarify the molecular mechanisms associated with CDDP resistance to introduce novel therapeutic methods. There are various cell and molecular processes associated with multidrug resistance (MDR) including drug efflux, detoxification, DNA repair ability, apoptosis alteration, signaling pathways, and epithelial-mesenchymal transition (EMT). MicroRNAs are a class of endogenous non-coding RNAs involved in chemo resistance of GC cells through regulation of all of the MDR mechanisms. In present review we have summarized all of the miRNAs associated with cisplatin resistance based on their target genes and molecular mechanisms in gastric tumor cells. This review paves the way of introducing a miRNA-based panel of prognostic markers to improve the efficacy of chemotherapy and clinical outcomes in GC patients. It was observed that miRNAs are mainly involved in cisplatin response of gastric tumor cells via regulation of signaling pathways, autophagy, and apoptosis.
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Affiliation(s)
- Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Olmo IG, Olmo RP, Gonçalves ANA, Pires RGW, Marques JT, Ribeiro FM. High-Throughput Sequencing of BACHD Mice Reveals Upregulation of Neuroprotective miRNAs at the Pre-Symptomatic Stage of Huntington's Disease. ASN Neuro 2021; 13:17590914211009857. [PMID: 33906482 PMCID: PMC8718118 DOI: 10.1177/17590914211009857] [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] [Indexed: 12/26/2022] Open
Abstract
Huntington’s disease (HD) is a genetic disorder marked by transcriptional alterations that result in neuronal impairment and death. MicroRNAs (miRNAs) are non-coding RNAs involved in post-transcriptional regulation and fine-tuning of gene expression. Several studies identified altered miRNA expression in HD and other neurodegenerative diseases, however their roles in early stages of HD remain elusive. Here, we deep-sequenced miRNAs from the striatum of the HD mouse model, BACHD, at the age of 2 and 8 months, representing the pre-symptomatic and symptomatic stages of the disease. Our results show that 44 and 26 miRNAs were differentially expressed in 2- and 8-month-old BACHD mice, respectively, as compared to wild-type controls. Over-representation analysis suggested that miRNAs up-regulated in 2-month-old mice control the expression of genes crucial for PI3K-Akt and mTOR cell signaling pathways. Conversely, miRNAs regulating genes involved in neuronal disorders were down-regulated in 2-month-old BACHD mice. Interestingly, primary striatal neurons treated with anti-miRs targeting two up-regulated miRNAs, miR-449c-5p and miR-146b-5p, showed higher levels of cell death. Therefore, our results suggest that the miRNAs altered in 2-month-old BACHD mice regulate genes involved in the promotion of cell survival. Notably, over-representation suggested that targets of differentially expressed miRNAs at the age of 8 months were not significantly enriched for the same pathways. Together, our data shed light on the role of miRNAs in the initial stages of HD, suggesting a neuroprotective role as an attempt to maintain or reestablish cellular homeostasis.
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Affiliation(s)
- Isabella G Olmo
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, Brazil
| | - Roenick P Olmo
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, Brazil.,CNRS UPR9022, Inserm U1257, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France
| | - André N A Gonçalves
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, Universidade de São Paulo, São Paulo, Brazil
| | - Rita G W Pires
- Department of Physiological Sciences, Center for Health Sciences, Universidade Federal do Espirito Santo, Vitoria, Brazil
| | - João T Marques
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, Brazil.,CNRS UPR9022, Inserm U1257, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France
| | - Fabíola M Ribeiro
- Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, Brazil
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12
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Zhang W, Wang Z, Cai G, Huang P. Downregulation of Circ_0071589 Suppresses Cisplatin Resistance in Colorectal Cancer by Regulating the MiR-526b-3p/KLF12 Axis. Cancer Manag Res 2021; 13:2717-2731. [PMID: 33790646 PMCID: PMC8001125 DOI: 10.2147/cmar.s294880] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/28/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Chemoresistance is one key factor for the failure of cisplatin (CDDP)-based therapy in colorectal cancer (CRC). Although circular RNAs (circRNAs) are associated with chemoresistance development, the role and mechanism of hsa_circ_0071589 (circ_0071589) in the development of CDDP resistance in CRC remain unclear. METHODS CDDP-resistant and sensitive CRC samples were collected. CDDP-resistant HCT116/CDDP and LOVO/CDDP cells were established. The levels of circ_0071589, microRNA (miR)-526b-3p and Krüppel-like factor 12 (KLF12) were detected via quantitative reverse transcription polymerase chain reaction, Western blot or immunohistochemistry. Cell viability, proliferation, cycle process, apoptosis, migration and invasion were examined via Cell Counting Kit-8, flow cytometry, transwell assay and Western blot. The association between miR-526b-3p and circ_0071589 or KLF12 was predicted by starBase, and explored via dual-luciferase reporter assay and RNA immunoprecipitation. The effect of circ_0071589 on CDDP resistance in CRC in vivo was investigated using a xenograft model. RESULTS Circ_0071589 level was upregulated in CDDP-resistant CRC tissue samples and cell lines. Circ_0071589 knockdown inhibited CDDP resistance, proliferation, migration and invasion, and promoted apoptosis in CDDP-resistant CRC cells. Circ_0071589 was a sponge for miR-526b-3p. MiR-526b-3p knockdown reversed the role of circ_0071589 inhibition in CDDP resistance. MiR-526b-3p suppressed CDDP resistance by directly targeting KLF12. Circ_0071589 regulated KLF12 expression through modulating miR-526b-3p. Circ_0071589 knockdown aggravated CDDP-induced reduction of xenograft tumor growth by upregulating miR-526b-3p and decreasing KLF12. CONCLUSION Knockdown of circ_0071589 repressed CDDP resistance in CDDP-resistant CRC cells by regulating the miR-526b-3p/KLF12 axis.
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Affiliation(s)
- Weitong Zhang
- Department of Anorectal Surgery, Hainan General Hospital, Haikou, Hainan, 570311, People’s Republic of China
| | - Zhenfen Wang
- Department of Anorectal Surgery, Hainan General Hospital, Haikou, Hainan, 570311, People’s Republic of China
| | - Guohao Cai
- Department of Anorectal Surgery, Hainan General Hospital, Haikou, Hainan, 570311, People’s Republic of China
| | - Ping Huang
- Department of Anorectal Surgery, Hainan General Hospital, Haikou, Hainan, 570311, People’s Republic of China
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Abdi E, Latifi-Navid S, Abdi F, Taherian-Esfahani Z. Emerging circulating MiRNAs and LncRNAs in upper gastrointestinal cancers. Expert Rev Mol Diagn 2020; 20:1121-1138. [DOI: 10.1080/14737159.2020.1842199] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/22/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Esmat Abdi
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Saeid Latifi-Navid
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Fatemeh Abdi
- Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran
| | - Zahra Taherian-Esfahani
- Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
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14
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Xu C, Zhai J, Fu Y. Overexpression of Nuclear Enriched Autosomal Transcript 1 Facilitates Cell Proliferation, Migration Invasion, and Suppresses Apoptosis in Endometrial Cancer by Targeting MicroRNA-202-3p/T Cell Immunoglobulin and Mucin Domain 4 Axis. Cancer Biother Radiopharm 2020; 37:815-823. [PMID: 32882142 DOI: 10.1089/cbr.2020.3902] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background: Endometrial cancer (EC) is an intractable gynecological cancer with increasing incidence and mortality worldwide. Accumulating studies indicated that long noncoding RNA nuclear enriched autosomal transcript 1 (NEAT1) was a novel oncogene implicated in a variety of cancers. However, whether NEAT1 could accelerate cell growth in EC is unclear. Methods: NEAT1, microRNA (miR)-202-3p, and T cell immunoglobulin and mucin domain 4 (TIMD4) levels were detected by quantitative real-time polymerase chain reaction. Cell proliferation and apoptosis were examined by cell counting kit-8 and flow cytometry. Transwell assay was employed for the evaluation of cell migration and invasion. The relationship between miR-202-3p and NEAT1 or TIMD4 was determined by luciferase reporter system. TIMD4 protein expression was assessed by Western blot assay. Results: NEAT1 was upregulated, whereas miR-202-3p was downregulated in EC tumors and cells. Depletion of NEAT1 restrained EC cell proliferation, migration, invasion, and improved apoptosis. MiR-202-3p was targeted by NEAT1 and could bind to TIMD4. Subsequently, it is observed that miR-202-3p inhibitor neutralized NEAT1 silencing mediated suppression on EC cell progression. Meanwhile, TIMD4 rescued miR-202-3p induced inhibition on cell progression in EC. Furthermore, it was obvious that NEAT1 facilitated TIMD4 expression by absorbing miR-202-3p in EC. Conclusions: Upregulation of NEAT1 accelerated EC cell progression through sponging miR-202-3p to facilitate TIMD4 expression, providing potential novel treatment method for EC.
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Affiliation(s)
- Caiyan Xu
- Department of Gynecologic and Obstetric, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jianjun Zhai
- Department of Gynecologic and Obstetric, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yujing Fu
- Department of Gynecologic and Obstetric, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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15
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Wei L, Sun J, Zhang N, Zheng Y, Wang X, Lv L, Liu J, Xu Y, Shen Y, Yang M. Noncoding RNAs in gastric cancer: implications for drug resistance. Mol Cancer 2020; 19:62. [PMID: 32192494 PMCID: PMC7081551 DOI: 10.1186/s12943-020-01185-7] [Citation(s) in RCA: 331] [Impact Index Per Article: 66.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 03/12/2020] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer is the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Advanced gastric cancer patients can notably benefit from chemotherapy including adriamycin, platinum drugs, 5-fluorouracil, vincristine, and paclitaxel as well as targeted therapy drugs. Nevertheless, primary drug resistance or acquisition drug resistance eventually lead to treatment failure and poor outcomes of the gastric cancer patients. The detailed mechanisms involved in gastric cancer drug resistance have been revealed. Interestingly, different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are critically involved in gastric cancer development. Multiple lines of evidences demonstrated that ncRNAs play a vital role in gastric cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically summarized the emerging role and detailed molecular mechanisms of ncRNAs impact drug resistance of gastric cancer. Additionally, we propose the potential clinical implications of ncRNAs as novel therapeutic targets and prognostic biomarkers for gastric cancer.
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Affiliation(s)
- Ling Wei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Jujie Sun
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yan Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Xingwu Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Liyan Lv
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Jiandong Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yeyang Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yue Shen
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China.
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16
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Verma HK, Ratre YK, Mazzone P, Laurino S, Bhaskar LVKS. Micro RNA facilitated chemoresistance in gastric cancer: a novel biomarkers and potential therapeutics. ALEXANDRIA JOURNAL OF MEDICINE 2020; 56:81-92. [DOI: 10.1080/20905068.2020.1779992] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Affiliation(s)
- Henu Kumar Verma
- Developmental and Stem Cell Biology Laboratory, Institute of Experimental Endocrinology and Oncology CNR, Naples, Italy
- Section of Stem Cell and Development, Istituto di Ricerche Genetiche “Gaetano Salvatore” Biogem, Ariano Irpino, Italy
| | | | - Pellegrino Mazzone
- Section of Stem Cell and Development, Istituto di Ricerche Genetiche “Gaetano Salvatore” Biogem, Ariano Irpino, Italy
| | - Simona Laurino
- Laboratory of Preclinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata (CROB), Rionero in Vulture, Italy
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17
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Pang L, Cheng Y, Zou S, Song J. Long noncoding RNA SNHG7 contributes to cell proliferation, migration, invasion and epithelial to mesenchymal transition in non-small cell lung cancer by regulating miR-449a/TGIF2 axis. Thorac Cancer 2019; 11:264-276. [PMID: 31793741 PMCID: PMC6996990 DOI: 10.1111/1759-7714.13245] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 10/22/2019] [Accepted: 10/25/2019] [Indexed: 12/22/2022] Open
Abstract
Background Non‐small cell lung cancer (NSCLC) is an intractable malignant lung cancer with high rates of metastasis and mortality. Currently, long noncoding RNA nuclear RNA host gene 7 (SNHG7) is recognized as a biomarker of multiple cancers. However, the role of SNHG7 in NSCLC requires further understanding. Methods The expression of SNHG7, miR‐449a and TGIF2 in NSCLC tumors and cells was examined by quantitative real time polymerase chain reaction (qRT‐PCR). Cell viability was measured by MTT assay. Cell migration and invasion was conducted using transwell assay. Protein expression of TGIF2, vimentin, N‐cadherin and E‐cadherin was detected by western blot. The interaction between miR‐449a and SNHG7 or TGIF2 was determined by luciferase reporter system, RIP and RNA pull‐down assay, respectively. Xenograft mice models were established by subcutaneously injecting A549 cells transfected with sh‐SNHG7 and sh‐control. Results SNHG7 expression was upregulated in NSCLC tumors and cells compared with normal tissues and cells. SNHG7 silencing repressed cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT) in NSCLC. Consistently, SNHG7 knockdown hindered tumor growth in vivo. The subsequent luciferase reporter system, RIP and RNA pull‐down assay validated the interaction between miR‐449a and SNHG7 or TGIF2. The rescue experiments displayed that miR‐449a inhibitor counteracted SNHG7 silencing induced inhibition on proliferation, migration, invasion and EMT. Similarly, restoration of TGIF2 reversed miR‐449a mediated inhibition on cell progression. In addition, the results indicated that SNHG7 could regulate cell progression by targeting miR‐449a/TGIF2 axis. Conclusion SNHG7 contributed to cell proliferation, migration, invasion and EMT in NSCLC by upregulating TGIF2 via sponging miR‐449a, representing a novel targeted therapy method for NSCLC.
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Affiliation(s)
- Lingling Pang
- Department of Respiratory Medicine, Yantai Yuhuangding Hospital, Yantai, China
| | - Yun Cheng
- Department of Respiratory Medicine, Yantai Muping District Traditional Chinese Medical Hospital, Yantai, China
| | - Shenchun Zou
- Department of Respiratory Medicine, Yantai Yuhuangding Hospital, Yantai, China
| | - Jie Song
- Department of Respiratory Medicine, Yantai Yuhuangding Hospital, Yantai, China
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18
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Upadhyaya P, Di Serafino A, Sorino L, Ballerini P, Marchisio M, Pierdomenico L, Stuppia L, Antonucci I. Genetic and epigenetic modifications induced by chemotherapeutic drugs: human amniotic fluid stem cells as an in-vitro model. BMC Med Genomics 2019; 12:146. [PMID: 31660974 PMCID: PMC6816179 DOI: 10.1186/s12920-019-0595-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 09/26/2019] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Bleomycin, etoposide and cisplatin (BEP) are three chemotherapeutic agents widely used individually or in combination with each other or other chemotherapeutic agents in the treatment of various cancers. These chemotherapeutic agents are cytotoxic; hence, along with killing cancerous cells, they also damage stem cell pools in the body, which causes various negative effects on patients. The epigenetic changes due to the individual action of BEP on stem cells are largely unknown. METHODS Human amniotic fluid stem cells (hAFSCs) were treated with our in-vitro standardized dosages of BEP individually, for seven days. The cells were harvested after the treatment and extraction of DNA and RNA were performed. Real-time PCR and flow cytometry were conducted for cell markers analysis. The global DNA methylation was quantified using 5mC specific kit and promoter and CpG methylation % through bisulfite conversion and pyrosequencing. Micro- RNAs (miRNAs) were quantified with real-time qPCR. RESULTS The cytotoxic nature of BEP was observed even at low dosages throughout the experiment. We also investigated the change in the expression of various pluripotent and germline markers and found a significant change in the properties of the cells after the treatments. The methylation of DNA at global, promoter and individual CpG levels largely get fluctuated due to the BEP treatment. Several tested miRNAs showed differential expression. No positive correlation between mRNA and protein expression was observed for some markers. CONCLUSION Cytotoxic chemotherapeutic agents such as BEP were found to alter stem cell properties of hAFSCs. Different methylation profiles change dynamically, which may explain such changes in cellular properties. Data also suggests that the fate of hAFSCs after treatment may depend upon the interplay between the miRNAs. Finally, our results demonstrate that hAFSCs might prove to be a suitable in-vitro model of stem cells to predict genetic and epigenetic modification due to the action of various drugs.
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Affiliation(s)
- Prabin Upadhyaya
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G.d'Annunzio" University, Chieti-Pescara, Via dei Vestini 31, 66013, Chieti, Italy
| | - Alessandra Di Serafino
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G.d'Annunzio" University, Chieti-Pescara, Via dei Vestini 31, 66013, Chieti, Italy
| | - Luca Sorino
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G.d'Annunzio" University, Chieti-Pescara, Via dei Vestini 31, 66013, Chieti, Italy
| | - Patrizia Ballerini
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G.d'Annunzio" University, Chieti-Pescara, Via dei Vestini 31, 66013, Chieti, Italy
- Centre of Aging Science and Translational Medicine (Ce.S.I.-Me.T.), G. d'Annunzio University, Chieti-Pescara, Italy
| | - Marco Marchisio
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G.d'Annunzio" University, Chieti-Pescara, Via dei Vestini 31, 66013, Chieti, Italy
- Centre of Aging Science and Translational Medicine (Ce.S.I.-Me.T.), G. d'Annunzio University, Chieti-Pescara, Italy
| | - Laura Pierdomenico
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G.d'Annunzio" University, Chieti-Pescara, Via dei Vestini 31, 66013, Chieti, Italy
- Centre of Aging Science and Translational Medicine (Ce.S.I.-Me.T.), G. d'Annunzio University, Chieti-Pescara, Italy
| | - Liborio Stuppia
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G.d'Annunzio" University, Chieti-Pescara, Via dei Vestini 31, 66013, Chieti, Italy
- Centre of Aging Science and Translational Medicine (Ce.S.I.-Me.T.), G. d'Annunzio University, Chieti-Pescara, Italy
| | - Ivana Antonucci
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G.d'Annunzio" University, Chieti-Pescara, Via dei Vestini 31, 66013, Chieti, Italy.
- Centre of Aging Science and Translational Medicine (Ce.S.I.-Me.T.), G. d'Annunzio University, Chieti-Pescara, Italy.
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19
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Tormo E, Ballester S, Adam-Artigues A, Burgués O, Alonso E, Bermejo B, Menéndez S, Zazo S, Madoz-Gúrpide J, Rovira A, Albanell J, Rojo F, Lluch A, Eroles P. The miRNA-449 family mediates doxorubicin resistance in triple-negative breast cancer by regulating cell cycle factors. Sci Rep 2019; 9:5316. [PMID: 30926829 PMCID: PMC6441107 DOI: 10.1038/s41598-019-41472-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 03/11/2019] [Indexed: 12/17/2022] Open
Abstract
The mechanisms of chemotherapy resistance in triple negative breast cancer remain unclear, and so, new molecules which might mediate this resistance could optimize treatment response. Here we analyzed the involvement of the miRNA-449 family in the response to doxorubicin. The cell viability, cell-cycle phases, and the expression of in silico target genes and proteins of sensitive/resistant triple negative breast cancer cell lines were evaluated in response to doxorubicin treatment and after gain/loss of miRNAs-449 function achieved by transient transfection. Triple negative breast cancer patients were selected for ex vivo experiments and to evaluate gene and miRNAs expression changes after treatment, as well as survival analysis by Kaplan-Meier. Doxorubicin treatment upregulated miRNAs-449 and DNA-damage responder factors E2F1 and E2F3 in triple negative breast cancer sensitive breast cancer cells, while expression remained unaltered in resistant ones. In vitro overexpression of miRNAs-449 sensitized cells to the treatment and significantly reduced the resistance to doxorubicin. These changes showed also a strong effect on cell cycle regulation. Finally, elevated levels of miRNA-449a associated significantly with better survival in chemotherapy-treated triple negative breast cancer patients. These results reveal for the first time the involvement of the miRNA-449 family in doxorubicin resistance and their predictive and prognostic value in triple negative breast cancer patients.
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Affiliation(s)
- Eduardo Tormo
- INCLIVA Biomedical Research Institute, Valencia, Spain.,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain
| | | | | | - Octavio Burgués
- INCLIVA Biomedical Research Institute, Valencia, Spain.,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain.,Pathology Department, Hospital Clínico Universitario, Valencia, Spain
| | - Elisa Alonso
- INCLIVA Biomedical Research Institute, Valencia, Spain.,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain.,Pathology Department, Hospital Clínico Universitario, Valencia, Spain
| | - Begoña Bermejo
- INCLIVA Biomedical Research Institute, Valencia, Spain.,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain
| | - Silvia Menéndez
- Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain
| | - Sandra Zazo
- Pathology Department, IIS- Fundación Jiménez Díaz- CIBERONC, Madrid, Spain
| | - Juan Madoz-Gúrpide
- Pathology Department, IIS- Fundación Jiménez Díaz- CIBERONC, Madrid, Spain
| | - Ana Rovira
- Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.,Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain
| | - Joan Albanell
- Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.,Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain.,Universitat Pompeu Fabra, Barcelona, Spain
| | - Federico Rojo
- Pathology Department, IIS- Fundación Jiménez Díaz- CIBERONC, Madrid, Spain
| | - Ana Lluch
- INCLIVA Biomedical Research Institute, Valencia, Spain.,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain.,Universidad de Valencia, Valencia, Spain
| | - Pilar Eroles
- INCLIVA Biomedical Research Institute, Valencia, Spain. .,Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain. .,COST action CA15204, Brussels, Belgium.
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Guo Q, Jing FJ, Qu HJ, Xu W, Han B, Xing XM, Ji HY, Jing FB. Ubenimex Reverses MDR in Gastric Cancer Cells by Activating Caspase-3-Mediated Apoptosis and Suppressing the Expression of Membrane Transport Proteins. BIOMED RESEARCH INTERNATIONAL 2019; 2019:4390839. [PMID: 30915355 PMCID: PMC6402206 DOI: 10.1155/2019/4390839] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 12/09/2018] [Accepted: 12/27/2018] [Indexed: 02/06/2023]
Abstract
Gastric cancer (GC) is one of the most malignant tumors, accounting for 10% of deaths caused by all cancers. Chemotherapy is often necessary for treatment of GC; the FOLFOX regimen is extensively applied. However, multidrug resistance (MDR) of GC cells prevents wider application of this treatment. Ubenimex, an inhibitor of CD13, is used as an immune adjuvant to treat hematological malignancies. Here, we demonstrate that CD13 expression positively correlates with MDR development in GC cells. Moreover, Ubenimex reverses the MDR of SGC7901/X and MKN45/X cells and enhances their sensitivity to FOLFOX, in part by decreasing CD13 expression, which is accompanied by downregulation of Bcl-xl, Bcl-2, and survivin expression; increased expression of Bax; and activation of the caspase-3-mediated apoptotic cascade. In addition, Ubenimex downregulates expression of membrane transport proteins, such as P-gp and MRP1, by inhibiting phosphorylation in the PI3K/AKT/mTOR pathway to increase intracellular accumulations of 5-fluorouracil and oxaliplatin, a process for which downregulation of CD13 expression is essential. Therefore, the present results reveal a previously uncharacterized function of CD13 in promoting MDR development in GC cells and suggest that Ubenimex is a candidate for reversing the MDR of GC cells.
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Affiliation(s)
- Qie Guo
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Fan-jing Jing
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Hai-jun Qu
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Wen Xu
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Bing Han
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Xiao-min Xing
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Hong-yan Ji
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Fan-Bo Jing
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
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21
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Li M, Huo X, Davuljigari CB, Dai Q, Xu X. MicroRNAs and their role in environmental chemical carcinogenesis. ENVIRONMENTAL GEOCHEMISTRY AND HEALTH 2019; 41:225-247. [PMID: 30171477 DOI: 10.1007/s10653-018-0179-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 08/23/2018] [Indexed: 02/05/2023]
Abstract
MicroRNAs (miRNAs) are a class of small, noncoding RNA species that play crucial roles across many biological processes and in the pathogenesis of major diseases, including cancer. Recent studies suggest that the expression of miRNA is altered by certain environmental chemicals, including metals, organic pollutants, cigarette smoke, pesticides and carcinogenic drugs. In addition, extensive studies have indicated the existence and importance of miRNA in different cancers, suggesting that cancer-related miRNAs could serve as potential markers for chemically induced cancers. The altered expression of miRNA was considered to be a vital pathogenic role in xenobiotic-induced cancer development. However, the significance of miRNA in the etiology of cancer and the exact mechanisms by which environmental factors alter miRNA expression remain relatively unexplored. Hence, understanding the interaction of miRNAs with environmental chemicals will provide important information on mechanisms underlying the pathogenesis of chemically induced cancers, and effectively diagnose and treat human cancers resulting from chronic or acute carcinogen exposure. This study presents the current evidence that the miRNA deregulation induced by various chemical carcinogens, different cancers caused by environmental carcinogens and the potentially related genes in the onset or progression of cancer. For each carcinogen, the specifically expressed miRNA may be considered as the early biomarkers of the cancer process. In this review, we also summarize various target genes of the altered miRNA, oncogenes or anti-oncogenes, and the existing evidence regarding the gene regulation mechanisms of cancer caused by environmentally induced miRNA alteration. The future perspective of miRNA may become attractive targets for the diagnosis and treatment of carcinogen-induced cancer.
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Affiliation(s)
- Minghui Li
- Laboratory of Environmental Medicine and Developmental Toxicology, and Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Xia Huo
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, Guangzhou, 511486, Guangdong, China
| | - Chand Basha Davuljigari
- Laboratory of Environmental Medicine and Developmental Toxicology, and Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Qingyuan Dai
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, Guangzhou, 511486, Guangdong, China
| | - Xijin Xu
- Laboratory of Environmental Medicine and Developmental Toxicology, and Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, 515041, Guangdong, China.
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, 515041, Guangdong, China.
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22
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Hsieh TH, Liu YR, Chang TY, Liang ML, Chen HH, Wang HW, Yen Y, Wong TT. Global DNA methylation analysis reveals miR-214-3p contributes to cisplatin resistance in pediatric intracranial nongerminomatous malignant germ cell tumors. Neuro Oncol 2019; 20:519-530. [PMID: 29036598 DOI: 10.1093/neuonc/nox186] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background Pediatric central nervous system germ cell tumors (CNSGCTs) are rare and heterogeneous neoplasms, which can be divided into germinomas and nongerminomatous germ cell tumors (NGGCTs). NGGCTs are further subdivided into mature teratomas and nongerminomatous malignant GCTs (NGMGCTs). Clinical outcomes suggest that NGMGCTs have poor prognosis and survival and that they require more extensive radiotherapy and adjuvant chemotherapy. However, the mechanisms underlying this difference are still unclear. DNA methylation alteration is generally acknowledged to cause therapeutic resistance in cancers. We hypothesized that the pediatric NGMGCTs exhibit a different genome-wide DNA methylation pattern, which is involved in the mechanism of its therapeutic resistance. Methods We performed methylation and hydroxymethylation DNA immunoprecipitation sequencing, mRNA expression microarray, and small RNA sequencing (smRNA-seq) to determine methylation-regulated genes, including microRNAs (miRNAs). Results The expression levels of 97 genes and 8 miRNAs were correlated with promoter DNA methylation and hydroxymethylation status, such as the miR-199/-214 cluster, and treatment with DNA demethylating agent 5-aza-2'-deoxycytidine elevated its expression level. Furthermore, smRNA-seq analysis showed 27 novel miRNA candidates with differential expression between germinomas and NGMGCTs. Overexpresssion of miR-214-3p in NCCIT cells leads to reduced expression of the pro-apoptotic protein BCL2-like 11 and induces cisplatin resistance. Conclusions We interrogated the differential DNA methylation patterns between germinomas and NGMGCTs and proposed a mechanism for chemoresistance in NGMGCTs. In addition, our sequencing data provide a roadmap for further pediatric CNSGCT research and potential targets for the development of new therapeutic strategies.
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Affiliation(s)
- Tsung-Han Hsieh
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.,Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yun-Ru Liu
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.,Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, Taipei, Taiwan
| | - Ting-Yu Chang
- Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, Taipei, Taiwan.,Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Muh-Lii Liang
- Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital (VGH-TPE), Taipei, Taiwan
| | - Hsin-Hung Chen
- Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital (VGH-TPE), Taipei, Taiwan
| | - Hsei-Wei Wang
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Yun Yen
- Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, Taipei, Taiwan.,Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Tai-Tong Wong
- Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, Taipei, Taiwan.,Institutes of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.,Neuroscience Research Center, Taipei Medical University Hospital, Taipei, Taiwan
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23
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Qian Y, Yang T, Zhao X, Yan Y, Li W, Fang C, Hou J, Tao L, Liu Y. Celastrus orbiculatus extracts induce apoptosis in mTOR-overexpressed human hepatocellular carcinoma HepG2 cells. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 18:328. [PMID: 30526568 PMCID: PMC6286504 DOI: 10.1186/s12906-018-2397-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 11/29/2018] [Indexed: 12/14/2022]
Abstract
Background Celastrus orbiculatus (Celastraceae) are used as traditional Chinese medicine to treat inflammation and cancer. This study aims to evaluate the effect of Celastrus orbiculatus extract (COE) on the apoptosis in human hepatic carcinoma HepG2 cells with mTOR overexpression. Methods The stable expression of mTOR in HepG2 cells (HepG2/mTOR+) were established by lipofectin transfection of GV238-mTOR recombinant plasmids and further antibiotic selection. Human hepatic carcinoma HepG2/mTOR+ cells were treated with different concentrations (20, 40, 80, 160, and 320 μg/mL) of COE for 24 h. The cell proliferation upon COE treatment was detected by MTT. Apoptosis was measured by Flow Cytometry. The activity of mTOR signaling pathway was detected by Western Blotting. Results COE significantly inhibited the proliferation of HepG2/mTOR+ cells. The expression levels of Bax and Caspase-3 protein were increased in the HepG2/mTOR+ cells in a dose-dependent manner. The proteins expression of Bcl2, Bcl-2 L12, mTOR, phospho-mTOR, 4EBP1, phospho-4EBP1, P70S6k, and phospho-P70S6k in HepG2/mTOR+ cells were reduced in dose-dependent manners. Furthermore, COE and mTOR inhibitor rapamycin (RAPA) synergistically induced apoptosis in HepG2/mTOR+ cells by regulating apoptosis-related proteins and inhibiting mTOR signaling pathways. Conclusion COE could inhibit the proliferation of HepG2/mTOR+ cells, and induce the cell apoptosis. The mechanisms may be related to the regulation of the expression of Bcl-2, Bcl-2 L12, and mTOR signaling pathways. These data suggest that COE may be a potential treatment for human hepatocellular carcinoma.
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24
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Wang BQ, Yang B, Yang HC, Wang JY, Hu S, Gao YS, Bu XY. MicroRNA-499a decelerates glioma cell proliferation while accelerating apoptosis through the suppression of Notch1 and the MAPK signaling pathway. Brain Res Bull 2018; 142:96-106. [DOI: 10.1016/j.brainresbull.2018.06.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 05/12/2018] [Accepted: 06/10/2018] [Indexed: 12/30/2022]
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25
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Li F, Liang J, Bai L. MicroRNA-449a functions as a tumor suppressor in pancreatic cancer by the epigenetic regulation of ATDC expression. Biomed Pharmacother 2018; 103:782-789. [DOI: 10.1016/j.biopha.2018.04.101] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/13/2018] [Accepted: 04/13/2018] [Indexed: 02/06/2023] Open
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26
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Jiang L, Yang W, Bian W, Yang H, Wu X, Li Y, Feng W, Liu X. MicroRNA-623 Targets Cyclin D1 to Inhibit Cell Proliferation and Enhance the Chemosensitivity of Cells to 5-Fluorouracil in Gastric Cancer. Oncol Res 2018; 27:19-27. [PMID: 29495973 PMCID: PMC7848397 DOI: 10.3727/096504018x15193469240508] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The dysregulation of microRNAs (miRNAs) plays an important function in the onset and progression of gastric cancer (GC). In addition, aberrantly expressed miRNAs affect the chemosensitivity of GC cells to chemotherapeutic drugs. Hence, miRNA-based targeted therapy might be applied to treat patients with GC exhibiting chemotherapeutic resistance. In this study, miRNA-623 (miR-623) expression was downregulated in GC tissues and cell lines. Functional analysis showed that the restored miR-623 expression could inhibit the proliferation of GC cells and enhance their chemosensitivity to 5-FU via the cell apoptosis pathway. Cyclin D1 (CCND1) was identified as a direct target gene of miR-623 in GC. The overexpressed CCND1 in GC tissues was negatively correlated with miR-623 level. The recovered CCND1 expression counteracted the effects of miR-623 on GC cell proliferation, chemosensitivity, and 5-FU-induced apoptosis. Thus, our results suggest that miR-623 might function as a tumor suppressor in GC and could be a promising therapeutic target for patients with GC, especially those with chemotherapeutic resistance.
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Affiliation(s)
- Lihua Jiang
- Department of Oncology, Linyi Third People's Hospital, Shandong, P.R. China
| | - Wenchuan Yang
- Department of Oncology, Linyi Third People's Hospital, Shandong, P.R. China
| | - Weishi Bian
- Department of Cardiology, Linyi Third People's Hospital, Shandong, P.R. China
| | - Hailin Yang
- Department of Oncology, Linyi Third People's Hospital, Shandong, P.R. China
| | - Xia Wu
- Department of Oncology, Linyi Third People's Hospital, Shandong, P.R. China
| | - Yuhua Li
- Department of Oncology, Linyi Third People's Hospital, Shandong, P.R. China
| | - Wen Feng
- Department of Oncology, Linyi Third People's Hospital, Shandong, P.R. China
| | - Xuejian Liu
- Department of Oncology, Linyi Third People's Hospital, Shandong, P.R. China
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27
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Abstract
MicroRNAs (miRNAs) have been reported to be associated with cancer progression and carcinogenesis. They are small, highly conserved, noncoding RNA molecules consisting of 19-25 nucleotides. By binding to complementary binding sites within the 3'-untranslated region of target mRNAs, miRNAs inhibit the translation of mRNAs or promote their degradation. miRNAs play critical roles in cancer initiation and development by functioning either as oncogenes or as tumor suppressors. Similarly, several studies have shown that miRNAs are involved in regulating various biological processes, including apoptosis, proliferation, cellular differentiation, signal transduction, and carcinogenesis. Among miRNAs, one that may be of particular interest in cancer biology is miR-449a, which has been reported to inhibit tumor growth, invasion, and metastasis, and to promote apoptosis and differentiation through the transforming growth factor-β activated kinase 1, NOTCH, nuclear factor-κB/P65/vascular endothelial growth factor, retinoblastoma-E2F, mitogen-activated protein kinase signaling pathways, WNT-β-catenin signaling, tumor protein P53, and androgen receptor signaling pathways. The miR-449 cluster is located in the second intron of CDC20B on chromosome 5q11.2, a region that has been identified as a susceptibility locus in cancer, and the abnormal expression of miR-449a may be related to the occurrence and development of tumors. As one example, miR-449a has been reported to be involved in the development of carcinoma and may be a potential prognostic indicator. On the basis of the putative pathogenetic relationships between cancer and miR-449a, we consider that miR-449a has the potential to serve as a therapeutic agent for the treatment of some types of cancer. In this review, the role of miR-449a in tumorigenesis and its mechanism of action are explored. Furthermore, its potential as a therapeutic agent in cancer treatment is considered.
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28
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Liu Y, Wang Y, Sun X, Mei C, Wang L, Li Z, Zha X. miR-449a promotes liver cancer cell apoptosis by downregulation of Calpain 6 and POU2F1. Oncotarget 2017; 7:13491-501. [PMID: 26375440 PMCID: PMC4924656 DOI: 10.18632/oncotarget.4821] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Accepted: 07/31/2015] [Indexed: 02/07/2023] Open
Abstract
Our previous study shows that Calpain 6 (CAPN6) expression is regulated by PI3K-Akt in liver cancer through POU2F1 and CAPN6 which promote cell proliferation and inhibit apoptosis of liver cancer cells. microRNAs (miRNAs) plays important roles in regulation of gene expression. However, whether miRNAs regulates CAPN6 expression and its cellular function is still unknown. This study aims to investigate how miRNAs regulate liver cancer apoptosis through POU2F1-CAPN6. It was verified that POU2F1 could promote cell proliferation and inhibit apoptosis through CAPN6. Using methods of bioinformatics, miR-449a was predicted as a potential regulator of both CAPN6 and POU2F1. It was verified that CAPN6 and POU2F1 were the target genes of miR-449a by luciferase assay. CAPN6 and POU2F1 protein and mRNA levels decreased in liver cancer cells with miR-449a overexpression using western blot and real time RT-PCR assays. miR-449a expression was lower in liver cancer tissues compared with their normal ones, so did the cells. Overexpression of miR-449a inhibited cell proliferation, induced G1 phase arrest and cell apoptosis in liver cancer. Further research demonstrated that miR-449a inhibited cancer cell proliferation and induced apoptosis via suppressing both POU2F1 and CAPN6. The study indicated that miR-449a functions as a tumor inhibitor in liver cancer by decreasing POU2F1 and CAPN6 expression in liver cancer.
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Affiliation(s)
- Yonglei Liu
- Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Research Center of Linyi People Hospital, Linyi, Shandong, China
| | - Yutong Wang
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiangjun Sun
- Department of Hepatobiliary Surgery, Linyi People Hospital, Linyi, Shandong, China
| | - Chuanzhong Mei
- Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Liying Wang
- Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zengxia Li
- Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiliang Zha
- Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China
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29
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Yang J, Xiong LL, Wang YC, He X, Jiang L, Fu SJ, Han XF, Liu J, Wang TH. Oligodendrocyte precursor cell transplantation promotes functional recovery following contusive spinal cord injury in rats and is associated with altered microRNA expression. Mol Med Rep 2017; 17:771-782. [PMID: 29115639 PMCID: PMC5780154 DOI: 10.3892/mmr.2017.7957] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 08/08/2017] [Indexed: 02/05/2023] Open
Abstract
It has been reported that oligodendrocyte precursor cells (OPCs) may be used to treat contusive spinal cord injury (SCC), and may alter microRNA (miRNA/miR) expression following SCC in rats. However, the association between miRNA expression and the treatment of rats with SCC with OPC transplantation remain unclear. The present study transplanted OPCs into the spinal cord of rats with SCC and subsequently used the Basso, Beattie and Bresnahan (BBB) score to assess the functional recovery and pain scores. An miRNA assay was performed to detect differentially expressed miRNAs in the spinal cord of SCC rats transplanted with OPCs, compared with SCC rats transplanted with medium. Quantitative polymerase chain reaction was used to verify significantly altered miRNA expression levels. The results demonstrated that OPC transplantation was able to improve motor recovery and relieve mechanical allodynia in rats with SCC. In addition, through a miRNA assay, 45 differentially expressed miRNAs (40 upregulated miRNAs and 5 downregulated miRNAs) were detected in the spinal cord of rats in the OPC group compared with in the Medium group. Differentially expressed miRNAs were identified according to the following criteria: Fold change >2 and P<0.05. Furthermore, quantitative polymerase chain reaction was used to verify the most highly upregulated (miR‑375‑3p and miR‑1‑3p) and downregulated (miR‑363‑3p, miR‑449a‑5p and miR‑3074) spinal cord miRNAs that were identified in the miRNA assay. In addition, a bioinformatics analysis of these miRNAs indicated that miR‑375 and miR‑1 may act primarily to inhibit cell proliferation and apoptosis via transcriptional and translational regulation, whereas miR‑363, miR‑449a and miR‑3074 may act primarily to inhibit cell proliferation and neuronal differentiation through transcriptional regulation. These results suggested that OPC transplantation may promote functional recovery of rats with SCC, which may be associated with the expression of various miRNAs in the spinal cord, including miR‑375‑3p, miR‑1‑3p, miR‑363‑3p, miR‑449a‑5p and miR‑3074.
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Affiliation(s)
- Jin Yang
- Institute of Neuroscience, College of Basic Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Liu-Lin Xiong
- Department of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - You-Cui Wang
- Institute of Neurobiological Disease, State Key Laboratory of Biotherapy, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiang He
- Department of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ling Jiang
- Department of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Song-Jun Fu
- Institute of Neuroscience, College of Basic Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Xue-Fei Han
- Institute of Neuroscience, College of Basic Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Jia Liu
- Experimental Animal Center, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Ting-Hua Wang
- Institute of Neuroscience, College of Basic Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
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30
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Linarin suppresses glioma through inhibition of NF-κB/p65 and up-regulating p53 expression in vitro and in vivo. Biomed Pharmacother 2017; 95:363-374. [DOI: 10.1016/j.biopha.2017.08.023] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 07/24/2017] [Accepted: 08/04/2017] [Indexed: 01/16/2023] Open
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31
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Yang W, Ma J, Zhou W, Cao B, Zhou X, Yang Z, Zhang H, Zhao Q, Fan D, Hong L. Molecular mechanisms and theranostic potential of miRNAs in drug resistance of gastric cancer. Expert Opin Ther Targets 2017; 21:1063-1075. [PMID: 28994330 DOI: 10.1080/14728222.2017.1389900] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Systemic chemotherapy is a curative approach to inhibit gastric cancer cells proliferation. Despite the great progress in anti-cancer treatment achieved during the last decades, drug resistance and treatment refractoriness still extensively persists. Recently, accumulating studies have highlighted the role of miRNAs in drug resistance of gastric cancers by modulating some drug resistance-related proteins and genes expression. Pre-clinical reports indicate that miRNAs might serve as ideal biomarkers and potential targets, thus holding great promise for developing targeted therapy and personalized treatment for the patients with gastric cancer. Areas covered: This review provide a comprehensive overview of the current advances of miRNAs and molecular mechanisms underlying miRNA-mediated drug resistance in gastric cancer. We particularly focus on the potential values of drug resistance-related miRNAs as biomarkers and novel targets in gastric cancer therapy and envisage the future research developments of these miRNAs and challenges in translating the new findings into clinical applications. Expert opinion: Although the concrete mechanisms of miRNAs in drug resistance of gastric cancer have not been fully clarified, miRNA may be a promising theranostic approach. Further studies are still needed to facilitate the clinical applications of miRNAs in drug resistant gastric cancer.
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Affiliation(s)
- Wanli Yang
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Jiaojiao Ma
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Wei Zhou
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Bo Cao
- b The First Brigade of Student , Fourth Military Medical University , Xi'an , China
| | - Xin Zhou
- b The First Brigade of Student , Fourth Military Medical University , Xi'an , China
| | - Zhiping Yang
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Hongwei Zhang
- c Department of Digestive Surgery, Xijing Hospital , Fourth Military Medical University , Xi'an , China
| | - Qingchuan Zhao
- c Department of Digestive Surgery, Xijing Hospital , Fourth Military Medical University , Xi'an , China
| | | | - Liu Hong
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
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32
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An X, Liu X, Zhang L, Liu J, Zhao X, Chen K, Ma H, Li G, Cao B, Song Y. MiR-449a regulates caprine endometrial stromal cell apoptosis and endometrial receptivity. Sci Rep 2017; 7:12248. [PMID: 28947781 PMCID: PMC5612931 DOI: 10.1038/s41598-017-12451-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 09/08/2017] [Indexed: 11/09/2022] Open
Abstract
In this study, an RT-qPCR analysis showed that the expression levels of miR-449a in the pre-receptive endometrium were lower compared to the receptive endometrium, which is consistent with previous sequencing data (previous investigations). To detect the role of miR-449a in endometrial receptivity, we transfected caprine endometrial stromal cells (ESCs) cultured in vitro with miR-449a mimics. The results revealed that miR-449a decreased the mRNA and protein levels of LGR4 by targeting its 3′-untranslated region. The miR-449a mimics significantly reduced the G1 cell population from 52.56% (mimic NC) to 42.19% with a concordant increase in the G2 and S cell populations from 47.44% (mimic NC) to 57.81%, suggesting that miR-449a caused ESC cell cycle arrest. In addition, the number of apoptotic cells was significantly higher in ESCs transfected with miR-449a mimics (P < 0.05) than in ESCs transfected with mimic NC. In vivo, rich pinopodes were observed on the endometrial surface in the miR-449a agomir group compared with the miR-449a antagomir group. The results of hematoxylin-eosin staining showed that endometrial thickness was significantly increased in the miR-449a agomir group compared with the miR-449a antagomir group. These results suggest that miR-449a could enhance endometrial receptivity.
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Affiliation(s)
- Xiaopeng An
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Xiaorui Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Lei Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Junze Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Xinyan Zhao
- Northwest A&F University of Hospital, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Kaiwen Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Haidong Ma
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Guang Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Binyun Cao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China.
| | - Yuxuan Song
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China.
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Abstract
Human cancers are characterized by a number of hallmarks, including sustained proliferative signaling, evasion of growth suppressors, activated invasion and metastasis, replicative immortality, angiogenesis, resistance to cell death, and evasion of immune destruction. As microRNAs (miRNAs) are deregulated in virtually all human cancers, they show involvement in each of the cancer hallmarks as well. In this chapter, we describe the involvement of miRNAs in cancer from a cancer hallmarks and targeted therapeutics point of view. As no miRNA-based cancer therapeutics are available to date, and the only clinical trial on miRNA-based cancer therapeutics (MRX34) was terminated prematurely due to serious adverse events, we are focusing on protein-coding miRNA targets for which targeted therapeutics in oncology are already approved by the FDA. For each of the cancer hallmarks, we selected major protein-coding players and describe the miRNAs that target them.
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Affiliation(s)
| | - George A Calin
- The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
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34
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Zhou M, Zhang Q, Zhao J, Liao M, Wen S, Yang M. Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC. Oncol Rep 2017; 38:1742-1750. [PMID: 28731137 DOI: 10.3892/or.2017.5830] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 06/22/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor and can evolve rapidly to resistance to chemotherapies. Glycochenodeoxycholate (GCDA), which is toxic and hydrophobic, is the main ingredient in the bile and associated with carcinogenesis of gastrointenstinal tumors. Bcl-2 is the most important anti-apoptotic protein and overexpressed in various human tumors. In the present study, we found that GCDA can induce the chemoresistance of human liver cancer cells and specific depletion of Bcl-2 by RNA interference blocks GCDA-stimulated chemoresistance, which indicate the pivotal role of Bcl-2 in such process. Mechanistically, GCDA simultaneously stimulates phosphorylation of Bcl-2 at Ser70 site and activates extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of ERK1/2 by PD98059 (MAPK/ERK1/2 inhibitor) or siRNA (targeting ERK1/2) suppresses GCDA-stimulated phosphorylation of Bcl-2 and significantly attenuates the survival and chemoresistance induced by GCDA in liver cancer cells. Thus, GCDA-induced survival and chemoresistance of liver cancer cells may occur through activation of Bcl-2 by phosphorylation at Ser70 site through MAPK/ERK1/2 pathway, which may contribute to the development of human liver cancer and chemoresistance.
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Affiliation(s)
- Maojun Zhou
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Jinfeng Zhao
- Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Mingmei Liao
- Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Sailan Wen
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Manyi Yang
- Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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35
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Biersack B. Interactions between anticancer active platinum complexes and non-coding RNAs/microRNAs. Noncoding RNA Res 2017; 2:1-17. [PMID: 30159416 PMCID: PMC6096430 DOI: 10.1016/j.ncrna.2016.10.001] [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] [Received: 09/15/2016] [Revised: 10/07/2016] [Accepted: 10/07/2016] [Indexed: 12/13/2022] Open
Abstract
Platinum(II) complexes such as cisplatin, carboplatin and oxaliplatin are clinically approved for the therapy of various solid tumors. Challenging pathogenic properties of cancer cells and the response of cancers towards platinum-based drugs are strongly influenced by non-coding small RNA molecules, the microRNAs (miRNAs). Both increased platinum activity and formation of tumor resistance towards platinum drugs are controlled by miRNAs. This review gives an overview of the interactions between platinum-based drugs and miRNAs, and their influence on platinum activity in various cancer types is discussed.
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Key Words
- 5-FU, 5-fluorouracil
- Anticancer drugs
- CBDCA, cyclobutane-1,1-dicarboxylate
- Carboplatin
- Cisplatin
- DACH, 1,2-diaminocyclohexane
- DDP, cisplatin
- EGCG, (−)-epigallocatechin-3-gallate
- EOX, epirubicin/oxaliplatin/xeloda
- FOLFOX, folinate/5-FU/oxaliplatin
- GC, gemcitabine/cisplatin, gastric cancer
- LNA, locked nucleic acid
- MVAC, methotrexate/vinblastine/adriamycin/cisplatin
- MicroRNA
- Oxaliplatin
- Platinum complexes
- XELOX, xeloda/oxaliplatin
- dTTP, deoxythymidine triphosphate
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Miao X, Luo Q, Zhao H, Qin X. Genome-wide analysis of miRNAs in the ovaries of Jining Grey and Laiwu Black goats to explore the regulation of fecundity. Sci Rep 2016; 6:37983. [PMID: 27897262 PMCID: PMC5126701 DOI: 10.1038/srep37983] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 11/02/2016] [Indexed: 11/09/2022] Open
Abstract
Goat fecundity is important for agriculture and varies depending on the genetic background of the goat. Two excellent domestic breeds in China, the Jining Grey and Laiwu Black goats, have different fecundity and prolificacies. To explore the potential miRNAs that regulate the expression of the genes involved in these prolific differences and to potentially discover new miRNAs, we performed a genome-wide analysis of the miRNAs in the ovaries from these two goats using RNA-Seq technology. Thirty miRNAs were differentially expressed between the Jining Grey and Laiwu Black goats. Gene Ontology and KEGG pathway analyses revealed that the target genes of the differentially expressed miRNAs were significantly enriched in several biological processes and pathways. A protein-protein interaction analysis indicated that the miRNAs and their target genes were related to the reproduction complex regulation network. The differential miRNA expression profiles found in the ovaries between the two distinctive breeds of goats studied here provide a unique resource for addressing fecundity differences in goats.
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Affiliation(s)
- Xiangyang Miao
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Qingmiao Luo
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Huijing Zhao
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Xiaoyu Qin
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
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Fan H, Liu G, Zhao C, Li X, Yang X. Transcription factor Oct4 promotes osteosarcoma by regulating lncRNA AK055347. Oncol Lett 2016; 13:396-402. [PMID: 28123573 DOI: 10.3892/ol.2016.5400] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 10/24/2016] [Indexed: 12/15/2022] Open
Abstract
Osteosarcoma is the most common primary bone tumor in children and adolescents, typically presenting with a poor prognosis. Octamer-binding transcription factor 4 (Oct4) protein, encoded by the POU class 5 homeobox 1 gene, is important in maintaining self-renewal of pluripotent stem cells, and is closely associated with cancer. However, its role in osteosarcoma remains to be elucidated. The present study observed Oct4 was markedly increased in osteosarcoma cell lines and in human osteosarcoma tissue samples. Following Oct4 downregulation by small interfering RNA (siRNA) in osteosarcoma F5M2 cells, the cells exhibited significant decreases in proliferation and invasion ability, and an increase in cell apoptosis. Notably, downregulation of Oct4 decreased the expression of AK055347, a newly identified long noncoding RNA (lncRNA) in human tissues. The downregulation of AK055347 by siRNA resulted in a significant suppressive effect on proliferative and invasive ability, and promotion of cell apoptosis in osteosarcoma cells. Thus, the current study suggests Oct4 exerts a promoting effect in osteosarcoma, and identifies a novel lncRNA in osteosarcoma progression.
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Affiliation(s)
- Hongwu Fan
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130001, P.R. China
| | - Guangyao Liu
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130001, P.R. China
| | - Changfu Zhao
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130001, P.R. China
| | - Xuefeng Li
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130001, P.R. China
| | - Xiaoyu Yang
- Department of Orthopedics, Orthopedics Hospital, The Second Hospital of Jilin University, Changchun, Jilin 130001, P.R. China
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38
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Shen B, Yu S, Zhang Y, Yuan Y, Li X, Zhong J, Feng J. miR-590-5p regulates gastric cancer cell growth and chemosensitivity through RECK and the AKT/ERK pathway. Onco Targets Ther 2016; 9:6009-6019. [PMID: 27757042 PMCID: PMC5055051 DOI: 10.2147/ott.s110923] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Background The aim of this study was to determine the role of miRNA-590-5p in gastric cancer (GC) progression. Methods Quantitative real-time polymerase chain reaction was performed to measure endogenous miR-590-5p levels in GC cells and tissues. Overexpression or knockdown of miR-590-5p in GC cells was performed by transfection with mimics or an inhibitor, respectively. MTT, matrigel transwell, and Western blot assays were used to assess the effects of miR-590-5p on cell proliferation, invasion, chemosensitivity of GC cells, and the AKT pathway, respectively. In silico prediction and luciferase reporter activity were used to identify potential targets of miR-590-5p. A xenograft model was also established to evaluate the function of miR-590-5p in vivo. Results The expression of miR-590-5p was significantly increased in GC cells and tissues, and upregulated miR-590-5p was associated with increased tumor size, lymph node metastasis, and poor survival. Overexpression of miR-590-5p promoted cell proliferation and invasion and reduced the sensitivity of GC cells to cisplatin and paclitaxel. In contrast, inhibition of miR-590-5p had the opposite effects on GC cells. RECK was identified as a direct target of miR-590-5p. Knockdown of RECK accelerated cell proliferation and motility and decreased the drug sensitivity. Furthermore, reintroduction of RECK inhibited the oncogenic effects of miR-590-5p by suppressing cell proliferation and invasion and increasing drug sensitivity. We found that the AKT/ERK and STAT3 signaling pathways were activated by miR-590-5p overexpression. The chemoresistance of miR-590-5p was also verified by in vivo analysis. Conclusion In summary, we suggest that the miR-590-5p/RECK/AKT axis contributes to GC and may serve as a promising therapeutic target for treatment.
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Affiliation(s)
- Bo Shen
- Department of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Shaorong Yu
- Department of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Yan Zhang
- Department of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Yuan Yuan
- Department of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Xiaoyou Li
- Department of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Jian Zhong
- Department of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Jifeng Feng
- Department of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
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Hu J, Shan Z, Hu K, Ren F, Zhang W, Han M, Li Y, Feng K, Lei L, Feng Y. miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1. Int J Oncol 2016; 49:325-35. [PMID: 27212195 DOI: 10.3892/ijo.2016.3533] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 04/25/2016] [Indexed: 11/05/2022] Open
Abstract
Sp1 plays critical roles in epithelial-mesenchymal transition (EMT) of certain cancer. However, few studies have indicated whether Sp1 is involved in the EMT of gastric cancer, and whether abnormal expression of Sp1 in gastric cancer EMT is regulated in a post-transcriptional manner, and the involvement of miRNAs in this regulation. In this study, we selected 20 cases of gastric cancers, their liver metastases and para-carcinoma tissues to examine the levels of Sp1 protein and mRNA by immunohistochemistry and fluorescent PCR, which showed that Sp1 was increased in gastric cancers and their metastases compared with adjacent tissues, but there was no difference in Sp1 mRNA between these three groups, suggesting changes in Sp1 may be attributed to inactivation of post-transcriptional regulation. We verified by a luciferase reporter system that miRNA-223 binds to 3'-UTR of Sp1 gene and inhibits its translation, in agreement with negative correlation between miRNA-223 and Sp1 protein levels in gastric cancer cells. By employing TGF-β1 to induce MGC-803, BGC-823 and SGC-7901, we successfully built cellular EMT model. Then, we overexpressed miRNA-223 in the model by using a lentiviral system, which diminished EMT indicators and suppressed proliferation and invasion ability, and induced apoptosis. Finally, we verified the specificity of the regulation pathway miRNA-223/Sp1/EMT. These findings suggest that low expression of miRNA-223 in gastric cancer cells is an important cause for EMT. miRNA-223 specifically regulates the EMT process of gastric cancer cells through its target gene Sp1. Overexpression of miRNA-223 in these cells inhibits EMT via the miRNA-223/Sp1/EMT pathway.
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Affiliation(s)
- Jing Hu
- School of Basic Medical Science, Harbin Medical University, Harbin, P.R. China
| | - Zhiyan Shan
- School of Basic Medical Science, Harbin Medical University, Harbin, P.R. China
| | - Kewei Hu
- Department of Anesthesiology, The Second Tumor Hospital of Heilongjiang Province, Harbin, P.R. China
| | - Fengyun Ren
- Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang, P.R. China
| | - Wei Zhang
- Department of Respiratory Medicine, Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, P.R. China
| | - Meiling Han
- Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang, P.R. China
| | - Yuezhen Li
- Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang, P.R. China
| | - Kejian Feng
- Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang, P.R. China
| | - Lei Lei
- School of Basic Medical Science, Harbin Medical University, Harbin, P.R. China
| | - Yukuan Feng
- School of Basic Medical Science, Harbin Medical University, Harbin, P.R. China
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Bucur O. microRNA regulators of apoptosis in cancer. Discoveries (Craiova) 2016; 4:e57. [PMID: 32309578 PMCID: PMC7159826 DOI: 10.15190/d.2016.4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 03/31/2016] [Accepted: 03/31/2016] [Indexed: 12/12/2022] Open
Abstract
This brief review summarizes our current knowledge on the microRNAs that regulate apoptosis machinery and are potentially involved in the dysregulation or deregulation of apoptosis, a well known hallmark of cancer. microRNAs are critical regulators of the most important cellular processes, including apoptosis. Expression of microRNAs is found to be dysregulated in many malignancies, leading to apoptosis inhibition in cancer, or resistance to current therapies. To date, there are over 80 microRNAs directly involved in apoptosis regulation or dysregulation that can impact cancer detection, initiation, progression, invasion, metastasis or resistance to anti-cancer therapy. Development of microRNA-based therapeutic strategies is now taking shape in the clinic. Thus, these microRNAs represent potential targets or tools for cancer therapy in the future.
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Affiliation(s)
- Octavian Bucur
- Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA
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41
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Emerging Role of miRNAs in the Drug Resistance of Gastric Cancer. Int J Mol Sci 2016; 17:424. [PMID: 27011182 PMCID: PMC4813275 DOI: 10.3390/ijms17030424] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 03/11/2016] [Accepted: 03/16/2016] [Indexed: 12/15/2022] Open
Abstract
Gastric cancer is the third leading cause of cancer mortality worldwide. Unfortunately, most gastric cancer cases are diagnosed in an advanced, non-curable stage and with a limited response to chemotherapy. Drug resistance is one of the most important causes of therapy failure in gastric cancer patients. Although the mechanisms of drug resistance have been broadly studied, the regulation of these mechanisms has not been completely understood. Accumulating evidence has recently highlighted the role of microRNAs in the development and maintenance of drug resistance due to their regulatory features in specific genes involved in the chemoresistant phenotype of malignancies, including gastric cancer. This review summarizes the current knowledge about the miRNAs’ characteristics, their regulation of the genes involved in chemoresistance and their potential as targeted therapies for personalized treatment in resistant gastric cancer.
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42
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Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating lncRNA AK022798 expression. Anticancer Drugs 2015; 26:632-40. [PMID: 25763542 DOI: 10.1097/cad.0000000000000227] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Gastric cancer is now the fourth most common malignancy and the second leading cause of death because of cancer. The resistance to anticancer drugs is the main cause of chemotherapy failure. In this study, we explored the role of Notch 1 and long noncoding RNA (lncRNA) in drug-resistant gastric cancer formation. First, we found that Notch 1 was highly expressed in the cisplatin-resistant gastric cancer cell lines SGC7901/DDP and BGC823/DDP cells. Then, we constructed a Notch 1 overexpression vector plasmid; after successful transfection, the SGC7901 and BGC823 cells highly expressed Notch 1. Moreover, the expression of multidrug resistance-associated protein 1 (MRP1), P-glycoprotein, increased significantly and the apoptosis of SGC7901 and BGC823 cells obviously reduced. We further screened out the lncRNA AK022798 involved in this process. Furthermore, we used siRNA to interfere with lncRNA AK022798 expression, and found that the expression of MRP1 and P-glycoprotein decreased significantly in SGC7901/DDP and BGC823/DDP cells, and their apoptosis as well as the expressions of caspase 3 and caspase 8 obviously increased. These results suggest that Notch 1 can promote the lncRNA AK022798 expression and result in the formation of SGC7901/DDP and BGC823/DDP cells. It may provide a new, useful method for gastric cancer chemotherapy.
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43
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miR-449a enhances radiosensitivity through modulating pRb/E2F1 in prostate cancer cells. Tumour Biol 2015; 37:4831-40. [DOI: 10.1007/s13277-015-4336-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 10/26/2015] [Indexed: 11/27/2022] Open
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Yang Q, Zhang RW, Sui PC, He HT, Ding L. Dysregulation of non-coding RNAs in gastric cancer. World J Gastroenterol 2015; 21:10956-10981. [PMID: 26494954 PMCID: PMC4607897 DOI: 10.3748/wjg.v21.i39.10956] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/28/2015] [Accepted: 09/15/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the standard of care treatment, including surgery, chemotherapy and radiotherapy, remains poor. Developing novel treatment strategies, identifying new molecules for targeted therapy, and devising screening techniques to detect this cancer in its early stages are needed for GC patients. The discovery of non-coding RNAs (ncRNAs), primarily microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), helped to elucidate the mechanisms of tumorigenesis, diagnosis and treatment of GC. Recently, significant research has been conducted on non-coding RNAs and how the regulatory dysfunction of these RNAs impacts the tumorigenesis of GC. In this study, we review papers published in the last five years concerning the dysregulation of non-coding RNAs, especially miRNAs and lncRNAs, in GC. We summarize instances of aberrant expression of the ncRNAs in GC and their effect on survival-related events, including cell cycle regulation, AKT signaling, apoptosis and drug resistance. Additionally, we evaluate how ncRNA dysregulation affects the metastatic process, including the epithelial-mesenchymal transition, stem cells, transcription factor activity, and oncogene and tumor suppressor expression. Lastly, we determine how ncRNAs affect angiogenesis in the microenvironment of GC. We further discuss the use of ncRNAs as potential biomarkers for use in clinical screening, early diagnosis and prognosis of GC. At present, no ideal ncRNAs have been identified as targets for the treatment of GC.
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45
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Chen SP, Liu BX, Xu J, Pei XF, Liao YJ, Yuan F, Zheng F. MiR-449a suppresses the epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by multiple targets. BMC Cancer 2015; 15:706. [PMID: 26471185 PMCID: PMC4608176 DOI: 10.1186/s12885-015-1738-3] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 10/08/2015] [Indexed: 12/15/2022] Open
Abstract
Background Increasing evidence indicates that Epithelial–mesenchymal transition (EMT) can be regulated by microRNAs (miRNAs). MiR-449a is a liver abundant miRNA. However, the role of miR-449a in the metastasis of hepatocellular carcinoma (HCC) remains largely unknown. Methods The expression levels of miR-449a were first examined in HCC cell lines and tumour tissues by real-time PCR. The in vitro and in vivo functional effect and underlying molecular mechanisms of miR-449a were examined further. Results In the present study, we found that miR-449a was significantly decreased in HCC cells and tissues, especially in those with the portal vein tumor thrombus. In HCC cell lines, stable overexpression of miR-449a was sufficient to inhibit cell motility in vitro, and pulmonary metastasis in vivo. In addition, ectopic overexpression of miR-449a in HCC cells promoted the expression of epithelial markers and reduced the levels of mesenchymal markers. Further studies revealed that the reintroduction of miR-449a attenuated the downstream signaling of Met, and consequently reduced the accumulation of Snail in cell nucleus by targeting the 3’-untranslated regions (3’-UTR) of FOS and Met. Conclusions Our data highlight an important role of miR-449a in the molecular etiology of HCC, and implicate the potential application of miR-449a in cancer therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1738-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shu-Peng Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107, Yanjiang West Road, Guangzhou, 510120, China. .,The State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, No. 651, Dongfeng Road East, Guangzhou, China.
| | - Bao-Xin Liu
- Department of orthopedics, Guangzhou hospital of traditional Chinese medicine, No. 16, Zhuji Road, Guangzhou, China.
| | - Jie Xu
- Department of Pathology, Guangdong Provincial People's Hospital, No.107, Zhongshan Er Road, Guangzhou, China.
| | - Xiao-Feng Pei
- Department of Radiation Oncology, the Fifth Affiliated Hospital, Sun Yat-sen University, No. 57, Meihua East Road, Zhuhai, China.
| | - Yi-Ji Liao
- The State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, No. 651, Dongfeng Road East, Guangzhou, China.
| | - Feng Yuan
- Department of Breast Surgery, Hubei Provincial Cancer Hospital, No. 116, Zhuodaoquan South Road, Wuhan, China.
| | - Fang Zheng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107, Yanjiang West Road, Guangzhou, 510120, China.
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WANG YUE, XIN HUA, HAN ZHIFENG, SUN HONGBING, GAO NAN, YU HAIXIANG. MicroRNA-374a promotes esophageal cancer cell proliferation via Axin2 suppression. Oncol Rep 2015; 34:1988-94. [DOI: 10.3892/or.2015.4182] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 05/18/2015] [Indexed: 11/06/2022] Open
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Zhao M, Sun L, Chen S, Li D, Zhang L, He P, Liu X, Zhang L, Zhang H, Yang D, Huang R, Xie P. Borna disease virus infection impacts microRNAs associated with nervous system development, cell differentiation, proliferation and apoptosis in the hippocampi of neonatal rats. Mol Med Rep 2015; 12:3697-3703. [PMID: 26004383 DOI: 10.3892/mmr.2015.3828] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 04/22/2015] [Indexed: 11/05/2022] Open
Abstract
MicroRNAs (miRNAs) regulate gene expression by inhibiting transcription or translation and are involved in diverse biological processes, including development, cellular differentiation and tumor generation. miRNA microarray technology is a high‑throughput global analysis tool for miRNA expression profiling. Here, the hippocampi of four borna disease virus (BDV)‑infected and four non‑infected control neonatal rats were selected for miRNA microarray and bioinformatic analysis. Reverse transcription quantitative polymerase chain reaction (RT‑qPCR) analysis was subsequently performed to validate the dysregulated miRNAs. Seven miRNAs (miR‑145*, miR‑146a*, miR‑192*, miR‑200b, miR‑223*, miR‑449a and miR‑505), showed increased expression, whereas two miRNAs (miR‑126 and miR‑374) showed decreased expression in the BDV‑infected group. By RT‑qPCR validation, five miRNAs (miR‑126, miR‑200b, miR‑374, miR‑449a and miR‑505) showed significantly decreased expression (P<0.05) in response to BDV infection. Biocarta pathway analysis predicted target genes associated with 'RNA', 'IGF1mTOR', 'EIF2', 'VEGF', 'EIF', 'NTHI', 'extrinsic', 'RB', 'IL1R' and 'IGF1' pathways. Gene Ontology analysis predicted target genes associated with 'peripheral nervous system development', 'regulation of small GTPase-mediated signal transduction', 'regulation of Ras protein signal transduction', 'aerobic respiration', 'membrane fusion', 'positive regulation of cell cycle', 'cellular respiration', 'heterocycle metabolic process', 'protein tetramerization' and 'regulation of Rho protein signal transduction' processes. Among the five dysregulated miRNAs identified by RT‑qPCR, miR‑126, miR‑200b and miR‑449a showed a strong association with nervous system development, cell differentiation, proliferation and apoptosis.
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Affiliation(s)
- Mingjun Zhao
- Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402460, P.R. China
| | - Lin Sun
- Institute of Neuroscience and the Collaborative Innovation Centre for Brain Science, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Shigang Chen
- Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402460, P.R. China
| | - Dan Li
- Institute of Neuroscience and the Collaborative Innovation Centre for Brain Science, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Liang Zhang
- Institute of Neuroscience and the Collaborative Innovation Centre for Brain Science, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Peng He
- Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402460, P.R. China
| | - Xia Liu
- Institute of Neuroscience and the Collaborative Innovation Centre for Brain Science, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Lujun Zhang
- Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402460, P.R. China
| | - Hong Zhang
- Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402460, P.R. China
| | - Deyu Yang
- Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402460, P.R. China
| | - Rongzhong Huang
- Institute of Neuroscience and the Collaborative Innovation Centre for Brain Science, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Peng Xie
- Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402460, P.R. China
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miRNA-449a is downregulated in osteosarcoma and promotes cell apoptosis by targeting BCL2. Tumour Biol 2015; 36:8221-9. [DOI: 10.1007/s13277-015-3568-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 05/13/2015] [Indexed: 10/23/2022] Open
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Song Y, An X, Zhang L, Fu M, Peng J, Han P, Hou J, Zhou Z, Cao B. Identification and profiling of microRNAs in goat endometrium during embryo implantation. PLoS One 2015; 10:e0122202. [PMID: 25886011 PMCID: PMC4401794 DOI: 10.1371/journal.pone.0122202] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Accepted: 02/08/2015] [Indexed: 01/09/2023] Open
Abstract
Background MicroRNAs (miRNAs) are short, highly conserved small noncoding RNAs that had fundamental roles in post-transcriptional gene expression, and they are crucial for proper control of biological processes and known to participate in embryo implantation. However, miRNA expression profiles in the pre-receptive and receptive phases of the goat endometrium during embryo implantation are unknown. Results A total of 1,069 and 847 miRNAs were expressed in receptive (R) and pre-receptive (P) goat endometrium, and 632 miRNAs were co-expressed in both phases. We identified 545 (50.98%) known miRNAs in the R library and 522 (61.63%) in the P library. There were 110 up-expressed miRNAs and 33 down-expressed miRNAs in receptive endometrium compared with the pre-receptive endometrium meeting the criteria of P-values< 0.05. Moreover, GO and KEGG analysis of the target genes of the differentially expressed miRNAs revealed some candidate miRNAs, genes and pathways that may involve in the formation of the receptive endometrium. Based on stem-loop RT-qPCR, 15 miRNAs were detected and the results suggested that the majority of the miRNA expression data measured by Solexa deep sequencing could represent actual miRNA expression levels. Conclusions Our data revealed the first miRNA profile related to the biology of the goat receptive endometrium during embryo implantation, and the results suggested that a subset of miRNAs might play important roles in the formation of endometrial receptivity. Thus, elucidating the physiological roles of endometrial miRNAs will help us better understand the genetic control of embryo implantation in goats.
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Affiliation(s)
- Yuxuan Song
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Xiaopeng An
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Lei Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Mingzhe Fu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Jiayin Peng
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Peng Han
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Jingxing Hou
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Zhanqin Zhou
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
| | - Bingyun Cao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China
- * E-mail:
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Zhang C, Peng G. Non-coding RNAs: An emerging player in DNA damage response. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2015; 763:202-11. [DOI: 10.1016/j.mrrev.2014.11.003] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Revised: 11/03/2014] [Accepted: 11/04/2014] [Indexed: 01/02/2023]
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