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Wang Y, Guo Z, Yang Z, Deng Q, Huang Y, Chen Y. Long intergenic noncoding RNA for IGF2BP2 stability suppresses gastric cancer cell apoptosis by inhibiting the maturation of microRNA-34a. Open Med (Wars) 2024; 19:20240992. [PMID: 39381424 PMCID: PMC11459274 DOI: 10.1515/med-2024-0992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 05/05/2024] [Accepted: 06/09/2024] [Indexed: 10/10/2024] Open
Abstract
The oncogenic role of long intergenic noncoding RNA for IGF2BP2 stability (LINRIS) has been reported in colorectal cancer. This research aimed to study its potential involvement in gastric cancer (GC). In this study, paired GC and non-tumor tissues were obtained from 64 GC patients, and the levels of LINRIS, mature microRNA-34a (miR-34a), and miR-34a precursor in these tissues were measured with RT-qPCR. Linear regression was used to analyze their correlations. The role of LINRIS overexpression and siRNA silencing in regulating the maturation of miR-34a was analyzed by RT-qPCR. Cell apoptosis was studied with flow cytometry. It was observed that LINRIS was overexpressed in GC and showed a negative correlation with mature miR-34a, but not miR-34a precursor. In GC cells, LINRIS siRNA silencing upregulated mature miR-34a level, but not miR-34a precursor level. LINRIS overexpression downregulated miR-34a level. Cell apoptosis analysis showed that LINRIS siRNA silencing and miR-34a overexpression promoted GC cell apoptosis and suppressed cell migration and invasion, while LINRIS overexpression suppressed cell apoptosis and enhanced cell migration and invasion. In addition, the effect of LINRIS overexpression was reversed by miR-34a overexpression. Therefore, LINRIS siRNA silencing in GC may promote cell apoptosis by promoting miR-34a maturation.
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Affiliation(s)
- Yao Wang
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan, Guangdong, 528400, P.R. China
| | - Zhigang Guo
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan, Guangdong, 528400, P.R. China
| | - Zhifeng Yang
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan, Guangdong, 528400, P.R. China
| | - Qingyan Deng
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan, Guangdong, 528400, P.R. China
| | - Yueming Huang
- Department of Gastrointestinal Surgery, Zhongshan City People’s Hospital, Zhongshan, Guangdong, 528400, P.R. China
| | - Yanhong Chen
- Department of Hospital Infection Management, Zhongshan City People’s Hospital, No. 2 Sunwen East Road, Shiqi District, Zhongshan, Guangdong, 528400, P.R. China
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Jiang YK, Li W, Qiu YY, Yue M. Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer. World J Gastrointest Oncol 2024; 16:2318-2334. [PMID: 38994153 PMCID: PMC11236256 DOI: 10.4251/wjgo.v16.i6.2318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 04/04/2024] [Accepted: 04/18/2024] [Indexed: 06/13/2024] Open
Abstract
Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance. Human epidermal growth factor receptor 2 (HER2) is one of the most important targets in targeted therapy for gastric cancer. Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer. The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified. However, monoclonal antibodies, due to their large molecular weight, inability to penetrate the blood-brain barrier, and drug resistance, lead to decreased therapeutic efficacy, so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer. Small-molecule tyrosine kinase inhibitors, such as lapatinib and pyrrotinib, have the advantages of small molecular weight, penetrating the blood-brain barrier and high oral bioavailability, and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future. Antibo-drug conjugate, such as T-DM1 and T-DXd, can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing, and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab. Therefore, after more detailed stratification of gastric cancer patients, various gastric cancer drugs targeting HER2 are expected to play a more significant role.
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Affiliation(s)
- Ya-Kun Jiang
- Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Wei Li
- Health Management Center, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Ying-Yang Qiu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Meng Yue
- Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
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3
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Jiang L, Qu S, Yu Z, Wang J, Liu X. MOASL: Predicting drug mechanism of actions through similarity learning with transcriptomic signature. Comput Biol Med 2024; 169:107853. [PMID: 38104518 DOI: 10.1016/j.compbiomed.2023.107853] [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: 07/19/2023] [Revised: 11/02/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
Understanding the mechanisms of actions (MOAs) of compounds is crucial in drug discovery. A common step in drug MOAs annotation is to query the dysregulated gene signatures induced by drugs in a reference library of pre-defined signatures. However, traditional similarity-based computational strategies face challenges when dealing with high-dimensional and noisy transcriptional signature data. To address this issue, we introduce MOASL (MOAs prediction via Similarity Learning), a novel approach that contrastive to learn similarity embeddings among signatures with shared MOAs automatically. We evaluated the accuracy of signature matching on various transcriptional activity score (TAS) datasets and individual cell lines by using MOASL. The results show MOASL achieved higher performance over several statistical and machine learning methods. Furthermore, we provided the rationale of our model by visualizing the signature annotation procedure. Using MOASL, the MOAs label of query signature could be conveniently defined by calculating the similarity between the query embedding and the reference embeddings. Finally, we applied MOASL to repurpose thousands of compounds as glucocorticoid receptor (GR) agonists, accurately identifying 8 out of the top 10 compounds. MOASL is conveniently accessible on GitHub at https://github.com/jianglikun/MOASL, empowering researchers and practitioners in the field of drug discovery to predict the MOAs of drug.
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Affiliation(s)
- Likun Jiang
- Department of Computer Science, Xiamen University, Xiamen 361005, PR China; National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361005, PR China
| | - Susu Qu
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, PR China; Chinese Institute for Brain Research, Beijing 102206, PR China
| | - Zhengqiu Yu
- National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361005, PR China; School of Medicine, Xiamen University, Xiamen 361005, PR China
| | - Jianmin Wang
- The Interdisciplinary Graduate Program in Integrative Biotechnology and Translational Medicine, Yonsei University, Incheon 21983, South Korea
| | - Xiangrong Liu
- Department of Computer Science, Xiamen University, Xiamen 361005, PR China; National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361005, PR China.
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Chen R, Wang X, Deng X, Chen L, Liu Z, Li D. CPDR: An R Package of Recommending Personalized Drugs for Cancer Patients by Reversing the Individual’s Disease-Related Signature. Front Pharmacol 2022; 13:904909. [PMID: 35795573 PMCID: PMC9252520 DOI: 10.3389/fphar.2022.904909] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 04/29/2022] [Indexed: 11/13/2022] Open
Abstract
Due to cancer heterogeneity, only some patients can benefit from drug therapy. The personalized drug usage is important for improving the treatment response rate of cancer patients. The value of the transcriptome of patients has been recently demonstrated in guiding personalized drug use, and the Connectivity Map (CMAP) is a reliable computational approach for drug recommendation. However, there is still no personalized drug recommendation tool based on transcriptomic profiles of patients and CMAP. To fill this gap, here, we proposed such a feasible workflow and a user-friendly R package—Cancer-Personalized Drug Recommendation (CPDR). CPDR has three features. 1) It identifies the individual disease signature by using the patient subgroup with transcriptomic profiles similar to those of the input patient. 2) Transcriptomic profile purification is supported for the subgroup with high infiltration of non-cancerous cells. 3) It supports in silico drug efficacy assessment using drug sensitivity data on cancer cell lines. We demonstrated the workflow of CPDR with the aid of a colorectal cancer dataset from GEO and performed the in silico validation of drug efficacy. We further assessed the performance of CPDR by a pancreatic cancer dataset with clinical response to gemcitabine. The results showed that CPDR can recommend promising therapeutic agents for the individual patient. The CPDR R package is available at https://github.com/AllenSpike/CPDR.
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Affiliation(s)
| | | | | | | | | | - Dong Li
- *Correspondence: Zhongyang Liu, ; Dong Li,
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HAVCR1 Affects the MEK/ERK Pathway in Gastric Adenocarcinomas and Influences Tumor Progression and Patient Outcome. Gastroenterol Res Pract 2019; 2019:6746970. [PMID: 31885544 PMCID: PMC6914876 DOI: 10.1155/2019/6746970] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 08/16/2019] [Accepted: 10/03/2019] [Indexed: 01/09/2023] Open
Abstract
The hepatitis A virus cellular receptor 1 (HAVCR1) gene as a sensitive and specific biomarker has been reported in various diseases. Especially, HAVCR1 overexpression promotes the development and progression of several human cancers. Hence, we aimed to detect the effects of HAVCR1 on gastric adenocarcinoma (GAC). We first determined the expression of HAVCR1 in GAC tissues compared with normal gastric tissues based on the Cancer Genome Atlas (TCGA) database using bioinformatics analysis methods. Then, we assessed the biological function of HAVCR1 in GAC cells using quantitative real-time reverse transcription-PCR (qRT-PCR), western blot, cell counting kit-8- (CCK-) 8, colony formation assay, wound healing assay, and transwell assay. Our results showed that HAVCR1 expression was upregulated in GAC tissues and positively associated with poor survival. Loss-of-function analyses indicated that knockdown of HAVCR1 inhibited the proliferation, colony formation, migration, and invasion of GAC cells. Furthermore, reduction of HAVCR1 in GAC cells can decrease the expression of phosphorylated MEK/ERK. These findings suggested that HAVCR1 may represent a potential biomarker for GAC prognosis, as well as a novel therapeutic target for GAC treatment.
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Systems Biology Approaches to Investigate Genetic and Epigenetic Molecular Progression Mechanisms for Identifying Gene Expression Signatures in Papillary Thyroid Cancer. Int J Mol Sci 2019; 20:ijms20102536. [PMID: 31126066 PMCID: PMC6566633 DOI: 10.3390/ijms20102536] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 05/15/2019] [Accepted: 05/21/2019] [Indexed: 12/20/2022] Open
Abstract
Thyroid cancer is the most common endocrine cancer. Particularly, papillary thyroid cancer (PTC) accounts for the highest proportion of thyroid cancer. Up to now, there are few researches discussing the pathogenesis and progression mechanisms of PTC from the viewpoint of systems biology approaches. In this study, first we constructed the candidate genetic and epigenetic network (GEN) consisting of candidate protein–protein interaction network (PPIN) and candidate gene regulatory network (GRN) by big database mining. Secondly, system identification and system order detection methods were applied to prune candidate GEN via next-generation sequencing (NGS) and DNA methylation profiles to obtain the real GEN. After that, we extracted core GENs from real GENs by the principal network projection (PNP) method. To investigate the pathogenic and progression mechanisms in each stage of PTC, core GEN was denoted in respect of KEGG pathways. Finally, by comparing two successive core signaling pathways of PTC, we not only shed light on the causes of PTC progression, but also identified essential biomarkers with specific gene expression signature. Moreover, based on the identified gene expression signature, we suggested potential candidate drugs to prevent the progression of PTC with querying Connectivity Map (CMap).
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Assessment of Gastritis and Gastric Cancer Risk in the Chilean Population Using the OLGA System. Pathol Oncol Res 2018; 25:1135-1142. [PMID: 30467699 DOI: 10.1007/s12253-018-0532-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 10/31/2018] [Indexed: 02/06/2023]
Abstract
Gastric cancer (GC) is the first cancer-related cause of death in Chile; however, no plan for GC early detection has been implemented in this country. The OLGA system characterizes gastritis from stages 0 to IV according to the risk of developing GC based on H. pylori infection, atrophy, metaplasia and GC. In this study, the performance of the OLGA system was evaluated in 485 Chilean patients receiving routine endoscopy to improve the detection of early GC or preneoplastic lesions. The results showed that OLGA scores, atrophy, metaplasia and GC increased significantly with age (p < 0.001). Conversely, H. pylori infection was higher in younger groups (p < 0.05). All gastric lesions were more frequent in men than women. The majority of patients with atrophy also had metaplasia (99%, p < 0.0001). Patients with H. pylori infection had more gastric atrophy and metaplasia than those without infection (p < 0.05). Of the 485 patients, 21 (4.3%) had GC, being 2.3 times more frequent among men than women and about 2/3 (14) were in OLGA stage ≥2. In addition, 19 (90%) GC patients had atrophy and 18 (85%) had metaplasia (p < 0.001). In conclusion, the OLGA system facilitated the evaluation of GC precursor lesions particularly in patients with an OLGA score > 2 between 45 and 56 years old, because this group showed atrophy and intestinal metaplasia more frequently. Therefore, biennial endoscopic surveillance of patients with an OLGA >2 can be an important health policy in Chile for diagnosing GC in its early stages and reducing mortality over the next two decades.
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Musa A, Ghoraie LS, Zhang SD, Glazko G, Yli-Harja O, Dehmer M, Haibe-Kains B, Emmert-Streib F. A review of connectivity map and computational approaches in pharmacogenomics. Brief Bioinform 2018; 19:506-523. [PMID: 28069634 PMCID: PMC5952941 DOI: 10.1093/bib/bbw112] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Large-scale perturbation databases, such as Connectivity Map (CMap) or Library of Integrated Network-based Cellular Signatures (LINCS), provide enormous opportunities for computational pharmacogenomics and drug design. A reason for this is that in contrast to classical pharmacology focusing at one target at a time, the transcriptomics profiles provided by CMap and LINCS open the door for systems biology approaches on the pathway and network level. In this article, we provide a review of recent developments in computational pharmacogenomics with respect to CMap and LINCS and related applications.
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Affiliation(s)
- Aliyu Musa
- Predictive Medicine and Analytics Lab, Department of Signal Processing, Tampere University of Technology, Tampere, Finland
| | - Laleh Soltan Ghoraie
- Bioinformatics and Computational Genomics Laboratory, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Shu-Dong Zhang
- Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, University of Ulster, C-TRIC Building, Altnagelvin Area Hospital, Glenshane Road, Derry/Londonderry, Northern Ireland, UK
| | - Galina Glazko
- University of Rochester Department of Biostatistics and Computational Biology, Rochester, New York, USA
| | - Olli Yli-Harja
- Computational Systems Biology, Department of Signal Processing, Tampere University of Technology, Tampere, Finland
| | - Matthias Dehmer
- Institute for Bioinformatics and Translational Research, UMIT- The Health and Life Sciences University, Eduard Wallnoefer Zentrum 1, Hall in Tyrol, Austria
| | - Benjamin Haibe-Kains
- Bioinformatics and Computational Genomics Laboratory, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Department of Computer Science, University of Toronto, Toronto, ON, Canada
- Ontario Institute of Cancer Research, Toronto, ON, Canada
| | - Frank Emmert-Streib
- Predictive Medicine and Analytics Lab, Department of Signal Processing, Tampere University of Technology, Tampere, Finland
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Musa A, Ghoraie LS, Zhang SD, Glazko G, Yli-Harja O, Dehmer M, Haibe-Kains B, Emmert-Streib F. A review of connectivity map and computational approaches in pharmacogenomics. Brief Bioinform 2018. [PMID: 28069634 DOI: 10.1093/bib] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2023] Open
Abstract
Large-scale perturbation databases, such as Connectivity Map (CMap) or Library of Integrated Network-based Cellular Signatures (LINCS), provide enormous opportunities for computational pharmacogenomics and drug design. A reason for this is that in contrast to classical pharmacology focusing at one target at a time, the transcriptomics profiles provided by CMap and LINCS open the door for systems biology approaches on the pathway and network level. In this article, we provide a review of recent developments in computational pharmacogenomics with respect to CMap and LINCS and related applications.
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Affiliation(s)
- Aliyu Musa
- Predictive Medicine and Analytics Lab, Department of Signal Processing, Tampere University of Technology, Tampere, Finland
| | - Laleh Soltan Ghoraie
- Bioinformatics and Computational Genomics Laboratory, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Shu-Dong Zhang
- Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, University of Ulster, C-TRIC Building, Altnagelvin Area Hospital, Glenshane Road, Derry/Londonderry BT47 6SB, Northern Ireland, UK
| | - Galina Glazko
- University of Rochester Department of Biostatistics and Computational Biology, Rochester, New York 14642, USA
| | - Olli Yli-Harja
- Computational Systems Biology, Department of Signal Processing, Tampere University of Technology, Tampere, Finland
| | - Matthias Dehmer
- Institute for Bioinformatics and Translational Research, UMIT- The Health and Life Sciences University, Eduard Wallnoefer Zentrum 1, 6060 Hall in Tyrol, Austria
| | - Benjamin Haibe-Kains
- Bioinformatics and Computational Genomics Laboratory, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Department of Computer Science, University of Toronto, Toronto, ON, Canada
- Ontario Institute of Cancer Research, Toronto, ON, Canada
| | - Frank Emmert-Streib
- Predictive Medicine and Analytics Lab, Department of Signal Processing, Tampere University of Technology, Tampere, Finland
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Zhang F, Li J, Xiao H, Zou Y, Liu Y, Huang W. AFAP1-AS1: A novel oncogenic long non-coding RNA in human cancers. Cell Prolif 2018; 51:e12397. [PMID: 29057544 PMCID: PMC6528908 DOI: 10.1111/cpr.12397] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 09/24/2017] [Indexed: 02/05/2023] Open
Abstract
Long non-coding RNAs (lncRNAs), a group of non-protein-coding RNAs with more than 200 nucleotides in length, are involved in multiple biological processes, such as the proliferation, apoptosis, migration and invasion. Moreover, numerous studies have shown that lncRNAs play important roles as oncogenes or tumour suppressor genes in human cancers. In this paper, we concentrate on actin filament-associated protein 1-antisense RNA 1 (AFAP1-AS1), a well-known long non-coding RNA that is overexpressed in various tumour tissues and cell lines, including oesophageal cancer, pancreatic ductal adenocarcinoma, nasopharyngeal carcinoma, lung cancer, hepatocellular carcinoma, ovarian cancer, colorectal cancer, biliary tract cancer and gastric cancer. Moreover, high expression of AFAP1-AS1 was associated with the clinicopathological features and cancer progression. In this review, we sum up the current studies on the characteristics of AFAP1-AS1 in the biological function and mechanism of human cancers.
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Affiliation(s)
- Fuyou Zhang
- Key Laboratory of Medical Reprogramming TechnologyShenzhen Second People's HospitalFirst Affiliated Hospital of Shenzhen UniversityShenzhen518039Guangdong ProvinceChina
| | - Jianfa Li
- Key Laboratory of Medical Reprogramming TechnologyShenzhen Second People's HospitalFirst Affiliated Hospital of Shenzhen UniversityShenzhen518039Guangdong ProvinceChina
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and GeneticsInstitute of UrologyPeking University Shenzhen HospitalShenzhen PKU‐HKUST Medical CenterShenzhen518036China
| | - Huizhong Xiao
- Key Laboratory of Medical Reprogramming TechnologyShenzhen Second People's HospitalFirst Affiliated Hospital of Shenzhen UniversityShenzhen518039Guangdong ProvinceChina
- University of South ChinaHengyangHunan421001China
| | - Yifan Zou
- Key Laboratory of Medical Reprogramming TechnologyShenzhen Second People's HospitalFirst Affiliated Hospital of Shenzhen UniversityShenzhen518039Guangdong ProvinceChina
- Shantou University Medical CollegeShantou515041Guangdong ProvinceChina
| | - Yuchen Liu
- Key Laboratory of Medical Reprogramming TechnologyShenzhen Second People's HospitalFirst Affiliated Hospital of Shenzhen UniversityShenzhen518039Guangdong ProvinceChina
| | - Weiren Huang
- Key Laboratory of Medical Reprogramming TechnologyShenzhen Second People's HospitalFirst Affiliated Hospital of Shenzhen UniversityShenzhen518039Guangdong ProvinceChina
- University of South ChinaHengyangHunan421001China
- Shantou University Medical CollegeShantou515041Guangdong ProvinceChina
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Li J, Chen Y, Chen Z, He A, Xie H, Zhang Q, Cai Z, Liu Y, Huang W. SPRY4-IT1: A novel oncogenic long non-coding RNA in human cancers. Tumour Biol 2017; 39:1010428317711406. [PMID: 28651500 DOI: 10.1177/1010428317711406] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Long non-coding RNAs are classified as a kind of RNA, which are longer than 200 nucleotides in length and cannot be translated into proteins. Multiple studies have demonstrated that long non-coding RNAs are involved in various cellular processes, including proliferation, differentiation, cell death, and metastasis. Among numerous long non-coding RNAs, we focus on Sprouty4-Intron 1 (SPRY4-IT1), a well-known long non-coding RNA that is overexpressed in various kinds of tumor tissues and cell lines. Accumulating evidences show that SPRY4-IT1 was dysregulated in various cancers, including melanoma, breast cancer, esophageal squamous cell carcinoma, non-small cell lung cancer, gastric cancer, colon cancer, and hepatocellular carcinoma, and amplification of SPRY4-IT1 was associated with different clinicopathological features of cancer patients. Importantly, SPRY4-IT1 exerts important roles in tumor progression and metastasis. However, detailed molecular mechanisms of SPRY4-IT1 in cancer progression and metastasis were poorly understood. In this review, we have focused on the characteristics of SPRY4-IT1 and illustrated the biological function and mechanism of SPRY4-IT1 in cancer development.
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Affiliation(s)
- Jianfa Li
- 1 Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, People's Republic of China
- 2 Shantou University Medical College, Shantou, People's Republic of China
| | - Yincong Chen
- 2 Shantou University Medical College, Shantou, People's Republic of China
| | - Zhicong Chen
- 1 Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, People's Republic of China
- 2 Shantou University Medical College, Shantou, People's Republic of China
| | - Anbang He
- 2 Shantou University Medical College, Shantou, People's Republic of China
- 3 Anhui Medical University, Hefei, People's Republic of China
| | - Haibiao Xie
- 1 Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, People's Republic of China
- 2 Shantou University Medical College, Shantou, People's Republic of China
| | - Qiaoxiao Zhang
- 1 Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, People's Republic of China
| | - Zhiming Cai
- 1 Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, People's Republic of China
- 2 Shantou University Medical College, Shantou, People's Republic of China
- 3 Anhui Medical University, Hefei, People's Republic of China
| | - Yuchen Liu
- 1 Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, People's Republic of China
| | - Weiren Huang
- 1 Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, People's Republic of China
- 2 Shantou University Medical College, Shantou, People's Republic of China
- 3 Anhui Medical University, Hefei, People's Republic of China
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Xia J, Wang H, Li S, Wu Q, Sun L, Huang H, Zeng M. Ion channels or aquaporins as novel molecular targets in gastric cancer. Mol Cancer 2017; 16:54. [PMID: 28264681 PMCID: PMC5338097 DOI: 10.1186/s12943-017-0622-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Accepted: 02/22/2017] [Indexed: 12/21/2022] Open
Abstract
Gastric cancer (GC) is a common disease with few effective treatment choices and poor prognosis, and has the second-highest mortality rates among all cancers worldwide. Dysregulation and/or malfunction of ion channels or aquaporins (AQPs) are common in various human cancers. Furthermore, ion channels are involved in numerous important aspects of the tumor aggressive phonotype, such as proliferation, cell cycle, apoptosis, motility, migration, and invasion. Indeed, by localizing in the plasma membrane, ion channels or AQPs can sense and respond to extracellular environment changes; thus, they play a crucial role in cell signaling and cancer progression. These findings have expanded a new area of pharmaceutical exploration for various types of cancer, including GC. The involvement of multiple ion channels, such as voltage-gated potassium and sodium channels, intracellular chloride channels, ‘transient receptor potential’ channels, and AQPs, which have been shown to facilitate the pathogenesis of other tumors, also plays a role in GC. In this review, an overview of ion channel and aquaporin expression and function in carcinogenesis of GC is presented. Studies of ion channels or AQPs will advance our understanding of the molecular genesis of GC and may identify novel and effective targets for the clinical application of GC.
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Affiliation(s)
- Jianling Xia
- Cancer Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Hospital of the University of Electronic Science and Technology of China, The Western First Round Road, Section 2#32, Chengdu, 610072, China.,Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Hongqiang Wang
- Department of Oncology, Zhoushan Hospital, Zhoushan, 316000, China.,Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Shi Li
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China
| | - Qinghui Wu
- Department of Urology, Hainan Provincial People's Hospital, Haikou, 570311, China
| | - Li Sun
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Hongxiang Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ming Zeng
- Cancer Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Hospital of the University of Electronic Science and Technology of China, The Western First Round Road, Section 2#32, Chengdu, 610072, China.
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Lei X, Wang F, Ke Y, Wei D, Gu H, Zhang Z, Jiang L, Lv L, Lin J, Wang L. The role of antiangiogenic agents in the treatment of gastric cancer: A systematic review and meta-analysis. Medicine (Baltimore) 2017; 96:e6301. [PMID: 28272258 PMCID: PMC5348206 DOI: 10.1097/md.0000000000006301] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 02/09/2017] [Accepted: 02/10/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The survival of advanced gastric cancer (GC) is dismal, and effects of antiangiogenic agents remain inconclusive. The purpose of this study is to assess combination of chemotherapy with antiangiogenic therapy versus traditional chemotherapy. METHODS To achieve the goal of scientific rigor, statistics from both referenced works and experiments were analyzed. We carefully searched for the referenced works by retrieving, as well as analyzing, literature databases for information on antiangiogenic therapy compared to other therapeutic approaches used to treat GC patients. Two groups were defined in the experiment: experimental and control groups. The experimental group was treated with antiangiogenic drug, and the control group was treated with standard chemotherapy or placebo. RESULTS The study included a total of 3240 participants. Overall, there was significant improvement in overall survival (hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.67-0.91, P = 0.002), progression-free survival (HR 0.65, 95% CI: 0.52-0.81, P = 0.0002), objective response rate (risk ratio [RR] = 1.58, 95% CI: 1.33-1.88, P < 0.00001), and disease control rate (RR 2.44, 95% CI: 1.57-3.78, P < 0.0001) in the group with antiangiogenic drug versus the group with standard chemotherapy or placebo. Moreover, this new treatment approach showed tolerable toxicity. CONCLUSION This study confirms the superior efficacy of combination therapy with antiangiogenic agents in comparison to traditional chemotherapy regimens for patients with GC. Moreover, this new treatment approach showed tolerable toxicity. This meta-analysis provides important information for clinicians who are interested in using antiangiogenic therapies to treat GC patients.
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Affiliation(s)
| | - Feng Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, PR China
| | - Yang Ke
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan
| | - Dong Wei
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan
| | - Hou Gu
- Department of Medical Oncology
| | | | | | - Li Lv
- Department of Medical Oncology
| | - Jie Lin
- Department of Medical Oncology
| | - Lin Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan
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Cai H, Xu J, Han Y, Lu Z, Han T, Ding Y, Ma L. Integrated miRNA-risk gene-pathway pair network analysis provides prognostic biomarkers for gastric cancer. Onco Targets Ther 2016; 9:2975-86. [PMID: 27284247 PMCID: PMC4881735 DOI: 10.2147/ott.s95129] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose This study aimed to identify molecular prognostic biomarkers for gastric cancer. Methods mRNA and miRNA expression profiles of eligible gastric cancer and control samples were downloaded from Gene Expression Omnibus to screen the differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs), using MetaDE and limma packages, respectively. Target genes of the DEmiRs were also collected from both predictive and experimentally validated target databases of miRNAs. The overlapping genes between selected targets and DEGs were identified as risk genes, followed by functional enrichment analysis. Human pathways and their corresponding genes were downloaded from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database for the expression analysis of each pathway in gastric cancer samples. Next, co-pathway pairs were selected according to the Pearson correlation coefficients. Finally, the co-pathway pairs, miRNA–target pairs, and risk gene–pathway pairs were merged into a complex interaction network, the most important nodes (miRNAs/target genes/co-pathway pairs) of which were selected by calculating their degrees. Results Totally, 1,260 DEGs and 144 DEmiRs were identified. There were 336 risk genes found in the 9,572 miRNA–target pairs. Judging from the pathway expression files, 45 co-pathway pairs were screened out. There were 1,389 interactive pairs and 480 nodes in the integrated network. Among all nodes in the network, focal adhesion/extracellular matrix–receptor interaction pathways, CALM2, miR-19b, and miR-181b were the hub nodes with higher degrees. Conclusion CALM2, hsa-miR-19b, and hsa-miR-181b might be used as potential prognostic targets for gastric cancer.
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Affiliation(s)
- Hui Cai
- Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Jiping Xu
- Department of Medical Administration, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Yifang Han
- Department of Epidemiology, Research Institute for Medicine of Nanjing Command, Nanjing, People's Republic of China
| | - Zhengmao Lu
- Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Ting Han
- Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Yibo Ding
- Department of Epidemiology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Liye Ma
- Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
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DCT015, a new sorafenib derivate, inhibits tumor growth and angiogenesis in gastric cancer models. Tumour Biol 2016; 37:9221-32. [PMID: 26768619 DOI: 10.1007/s13277-016-4826-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 01/08/2016] [Indexed: 12/13/2022] Open
Abstract
The objective of this study is to investigate antiproliferative activities against gastric cancer and anti-angiogenesis of DCT015, a novel sorafenib derivate, and potential mechanisms. The effects of DCT015 on proliferation and apoptosis in gastric cancer cells were evaluated by cytotoxicity assays, apoptosis analysis, flow cytometry analysis, and Western blotting assays. The in vivo antitumor effects were carried out in nude mice bearing gastric cancer. On the other hand, the anti-angiogenesis effects of DCT015 were measured by human umbilical vein endothelial cell (HUVEC) proliferation, migration, tube formation, and Western blotting analysis. The results showed that DCT015 inhibited the proliferation, induced the morphological changes of apoptosis, and increased the apoptosis percentage, as well as increased the "sub-G1" population in gastric cancer cells. DCT015 also significantly decreased the tumor volumes and tumor weights in vivo by oral administration. Immunohistochemistry assay demonstrated that DCT015 inhibited tumor growth and neovascularization. In vitro studies found that DCT015 inhibited both MEK/ERK and PI3K/Akt signaling pathways by Western blotting assays. Moreover, DCT015 significantly inhibited VEGF-induced migration and tube formation in HUVECs. Western blotting analysis showed that DCT015 downregulated VEGF-induced VEGFR2 phosphorylation with the decreased phosphorylation of the downstream key proteins. Taken together, our findings highlight that DCT015 is a promising orally anticancer drug for treating gastric cancer.
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16
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The use of high-throughput screening in identifying chemotherapeutic agents for gastric cancer. Future Med Chem 2015; 6:2103-12. [PMID: 25531971 DOI: 10.4155/fmc.14.131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer claims many lives around the world, particularly in Asia. Although diagnosis and treatment has improved, long-term survival of patients is still poor and there is an urgent need to develop more effective treatments for this disease. This review outlines some of the more innovative high-throughput screening-based approaches and strategies that may be used to identify compounds that have new or novel mechanisms of action and could be developed further as possible gastric cancer treatments in the future.
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17
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Zhu C, Xu J, Li M, Zhao G, Cao H. Heterogeneity of c-Met expression in Chinese gastric cancer patients. Hum Pathol 2015; 46:1901-7. [PMID: 26472163 DOI: 10.1016/j.humpath.2015.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 05/28/2015] [Accepted: 06/03/2015] [Indexed: 01/29/2023]
Abstract
c-Met is an attractive target for gastric cancer (GC) therapy, and detection of c-Met expression is critical for diagnosis. The aims of this study were to quantify the heterogeneous expression of c-Met in GC and to explore its impact on diagnosis. The expression of c-Met in 199 tumor fragments derived from 47 GC patients was evaluated by immunohistochemistry. In parallel, copy numbers of MET were determined by fluorescence in situ hybridization. Expression of c-Met was observed in 22 patients, and 18 (81.8%) of 22 were heterogeneous; but the incidence rate of heterogeneity was not significantly different among patient subgroups with various degrees of c-Met expression. MET copies were increased in 4 patients. Two represented polysomy, and 2 were caused by amplification. Expression of c-Met in MET-amplified tumors was homogeneous. In conclusion, heterogeneity of c-Met expression was widely observed in GC but was not associated with the extent of expression.
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Affiliation(s)
- Chunchao Zhu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Jia Xu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Maoran Li
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Gang Zhao
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China.
| | - Hui Cao
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China.
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Zhu XS, Gao P, Dai YC, Xie JP, Zeng W, Lian QN. Attenuation of enoyl coenzyme A hydratase short chain 1 expression in gastric cancer cells inhibits cell proliferation and migration in vitro. Cell Mol Biol Lett 2014; 19:576-89. [PMID: 25338767 PMCID: PMC6275702 DOI: 10.2478/s11658-014-0213-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Accepted: 10/10/2014] [Indexed: 01/13/2023] Open
Abstract
Enoyl coenzyme A hydratase short chain 1 (ECHS1) is an important part of the mitochondrial fatty acid β-oxidation pathway. Altered ECHS1 expression has been implicated in cancer cell proliferation. This study assessed ECHS1 expression in human gastric cancer cell lines and investigated the effects of ECHS1 knockdown on gastric cancer cell proliferation and migration. The human gastric cancer cell lines SGC-7901, BGC-823 and MKN-28, and the immortalized human gastric epithelial mucosa GES-1 cell line were analyzed for ECHS1 protein levels using western blot. The effectiveness of ECHS1-RNA interference was also determined using western blot. Proliferation and migration of the siECHS1 cells were respectively measured with the CCK-8 and transwell assays. Phosphorylation of PKB and GSK3β was assessed using western blot. ECHS1 protein levels were significantly higher in poorly differentiated cells than in well-differentiated cells and immortalized gastric epithelial mucosa cells. Stable expression of ECHS1 shRNA was associated with an over 41% reduction in the ECHS1 protein levels of siECHS1 cells. Constitutive knockdown of the ECHS1 gene in siECHS1 cells was associated with significantly inhibited cell proliferation and migration. We also observed decreased levels of PKB and GSK3β phosphorylation in siECHS1 cells. ECHS1 expression is increased in human gastric cancer cells. Increased ECHS1 expression activates PKB and GSK3β by inducing the phosphorylation of the two kinases. ECHS1 may play important roles in gastric cancer cell proliferation and migration through PKB- and GSK3β-related signaling pathways.
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Affiliation(s)
- Xiao-San Zhu
- Department of Gastroenterology, Chenggong Hospital Affiliated to Xiamen University, Xiamen, Fujian, 361003 China
| | - Peng Gao
- Department of Gastroenterology, Chenggong Hospital Affiliated to Xiamen University, Xiamen, Fujian, 361003 China
| | - Yi-Chen Dai
- Department of Gastroenterology, Chenggong Hospital Affiliated to Xiamen University, Xiamen, Fujian, 361003 China
| | - Jun-Pei Xie
- Department of Gastroenterology, Chenggong Hospital Affiliated to Xiamen University, Xiamen, Fujian, 361003 China
| | - Wei Zeng
- Department of Gastroenterology, Chenggong Hospital Affiliated to Xiamen University, Xiamen, Fujian, 361003 China
| | - Qing-Na Lian
- Department of Gastroenterology, Chenggong Hospital Affiliated to Xiamen University, Xiamen, Fujian, 361003 China
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Shao Y, Chen H, Jiang X, Chen S, Li P, Ye M, Li Q, Sun W, Guo J. Low expression of lncRNA-HMlincRNA717 in human gastric cancer and its clinical significances. Tumour Biol 2014; 35:9591-5. [PMID: 24961350 DOI: 10.1007/s13277-014-2243-z] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 06/16/2014] [Indexed: 12/13/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) have been gradually confirmed to be tumor-associated biological molecules in recent years. However, the clinical significances of most lncRNAs in the screening of gastric cancer are largely unknown. Based on our lncRNA array results, in this study, we explored the potential relationship between HMlincRNA717 expression levels and clinicopathologic factors of gastric cancer. A total of 313 samples were collected from two cancer centers, and then HMlincRNA717 level in human gastric cancer tissues and gastric cell lines was measured by real-time reverse transcription-polymerase chain reaction. Then, HMlincRNA717 levels at multiple stages of gastric tumorigenesis were investigated and the potential association between it levels, and clinicopathological features were analyzed. The expression levels of HMlincRNA717 in five gastric cancer cell lines, AGS, BGC-823, HGC-27, MGC-803, and SGC-7901, were significantly downregulated than those in normal gastric mucosal epithelial cell line GES-1. It was not only downregulated in 62.6 % (67/107) gastric cancer tissues compared with the paired adjacent normal tissues but also in gastric precancerous lesions. More importantly, our results indicated that HMlincRNA717 expression levels were correlated with cancer distal metastasis (P = 0.034), venous invasion (P = 0.029), and nervous invasion (P = 0.024). Our data suggested that lncRNA-HMlincRNA717 may play crucial roles during cancer occurrence and progression and may be a new potential biomarker of early gastric cancer.
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Affiliation(s)
- Yongfu Shao
- Department of Biochemistry and Molecular Biology and Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211, China
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