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Ebrahimnezhad M, Asl SH, Rezaie M, Molavand M, Yousefi B, Majidinia M. lncRNAs: New players of cancer drug resistance via targeting ABC transporters. IUBMB Life 2024; 76:883-921. [PMID: 39091106 DOI: 10.1002/iub.2888] [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: 04/11/2024] [Accepted: 05/30/2024] [Indexed: 08/04/2024]
Abstract
Cancer drug resistance poses a significant obstacle to successful chemotherapy, primarily driven by the activity of ATP-binding cassette (ABC) transporters, which actively efflux chemotherapeutic agents from cancer cells, reducing their intracellular concentrations and therapeutic efficacy. Recent studies have highlighted the pivotal role of long noncoding RNAs (lncRNAs) in regulating this resistance, positioning them as crucial modulators of ABC transporter function. lncRNAs, once considered transcriptional noise, are now recognized for their complex regulatory capabilities at various cellular levels, including chromatin modification, transcription, and post-transcriptional processing. This review synthesizes current research demonstrating how lncRNAs influence cancer drug resistance by modulating the expression and activity of ABC transporters. lncRNAs can act as molecular sponges, sequestering microRNAs that would otherwise downregulate ABC transporter genes. Additionally, they can alter the epigenetic landscape of these genes, affecting their transcriptional activity. Mechanistic insights reveal that lncRNAs contribute to the activity of ABC transporters, thereby altering the efflux of chemotherapeutic drugs and promoting drug resistance. Understanding these interactions provides a new perspective on the molecular basis of chemoresistance, emphasizing the regulatory network of lncRNAs and ABC transporters. This knowledge not only deepens our understanding of the biological mechanisms underlying drug resistance but also suggests novel therapeutic strategies. In conclusion, the intricate interplay between lncRNAs and ABC transporters is crucial for developing innovative solutions to combat cancer drug resistance, underscoring the importance of continued research in this field.
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Affiliation(s)
- Mohammad Ebrahimnezhad
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanaz Hassanzadeh Asl
- Student Research Committee, Faculty of Medicine, Tabriz Azad University of Medical Sciences, Tabriz, Iran
| | - Maede Rezaie
- Immunology research center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehran Molavand
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Molecular research center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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Meng X, Bai X, Ke A, Li K, Lei Y, Ding S, Dai D. Long Non-Coding RNAs in Drug Resistance of Gastric Cancer: Complex Mechanisms and Potential Clinical Applications. Biomolecules 2024; 14:608. [PMID: 38927012 PMCID: PMC11201466 DOI: 10.3390/biom14060608] [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: 03/10/2024] [Revised: 05/11/2024] [Accepted: 05/16/2024] [Indexed: 06/28/2024] Open
Abstract
Gastric cancer (GC) ranks as the third most prevalent malignancy and a leading cause of cancer-related mortality worldwide. However, the majority of patients with GC are diagnosed at an advanced stage, highlighting the urgent need for effective perioperative and postoperative chemotherapy to prevent relapse and metastasis. The current treatment strategies have limited overall efficacy because of intrinsic or acquired drug resistance. Recent evidence suggests that dysregulated long non-coding RNAs (lncRNAs) play a significant role in mediating drug resistance in GC. Therefore, there is an imperative to explore novel molecular mechanisms underlying drug resistance in order to overcome this challenging issue. With advancements in deep transcriptome sequencing technology, lncRNAs-once considered transcriptional noise-have garnered widespread attention as potential regulators of carcinogenesis, including tumor cell proliferation, metastasis, and sensitivity to chemo- or radiotherapy through multiple regulatory mechanisms. In light of these findings, we aim to review the mechanisms by which lncRNAs contribute to drug therapy resistance in GC with the goal of providing new insights and breakthroughs toward overcoming this formidable obstacle.
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Affiliation(s)
- Xiangyu Meng
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; (X.M.); (X.B.); (K.L.); (Y.L.); (S.D.)
- Department of Gastric Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang 110042, China
| | - Xiao Bai
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; (X.M.); (X.B.); (K.L.); (Y.L.); (S.D.)
| | - Angting Ke
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; (X.M.); (X.B.); (K.L.); (Y.L.); (S.D.)
| | - Kaiqiang Li
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; (X.M.); (X.B.); (K.L.); (Y.L.); (S.D.)
| | - Yun Lei
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; (X.M.); (X.B.); (K.L.); (Y.L.); (S.D.)
| | - Siqi Ding
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; (X.M.); (X.B.); (K.L.); (Y.L.); (S.D.)
| | - Dongqiu Dai
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; (X.M.); (X.B.); (K.L.); (Y.L.); (S.D.)
- Cancer Center, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
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Shi Y, Adu-Amankwaah J, Zhao Q, Li X, Yu Q, Bushi A, Yuan J, Tan R. Long non-coding RNAs in drug resistance across the top five cancers: Update on their roles and mechanisms. Heliyon 2024; 10:e27207. [PMID: 38463803 PMCID: PMC10923722 DOI: 10.1016/j.heliyon.2024.e27207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 02/21/2024] [Accepted: 02/26/2024] [Indexed: 03/12/2024] Open
Abstract
Cancer drug resistance stands as a formidable obstacle in the relentless fight against the top five prevalent cancers: breast, lung, colorectal, prostate, and gastric cancers. These malignancies collectively account for a significant portion of cancer-related deaths worldwide. In recent years, long non-coding RNAs (lncRNAs) have emerged as pivotal players in the intricate landscape of cancer biology, and their roles in driving drug resistance are steadily coming to light. This comprehensive review seeks to underscore the paramount significance of lncRNAs in orchestrating resistance across a spectrum of different cancer drugs, including platinum drugs (DDP), tamoxifen, trastuzumab, 5-fluorouracil (5-FU), paclitaxel (PTX), and Androgen Deprivation Therapy (ADT) across the most prevalent types of cancer. It delves into the multifaceted mechanisms through which lncRNAs exert their influence on drug resistance, shedding light on their regulatory roles in various facets of cancer biology. A comprehensive understanding of these lncRNA-mediated mechanisms may pave the way for more effective and personalized treatment strategies, ultimately improving patient outcomes in these challenging malignancies.
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Affiliation(s)
- Yue Shi
- Department of Physiology, Basic Medical School, Xuzhou Medical University, Xuzhou, China
| | - Joseph Adu-Amankwaah
- Department of Physiology, Basic Medical School, Xuzhou Medical University, Xuzhou, China
| | - Qizhong Zhao
- Department of Emergency, The First Hospital of China Medical University, Shenyang, China
| | - Xin Li
- Clinical Medical College, Jining Medical University, 272067, Jining, China
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, 272067, Jining, China
| | - Qianxue Yu
- Clinical Medical College, Jining Medical University, 272067, Jining, China
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, 272067, Jining, China
| | - Aisha Bushi
- School of International Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Jinxiang Yuan
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, 272067, Jining, China
- Lin He's Academician Workstation of New Medicine and Clinical Translation, Jining Medical University, 272067, Jining, China
| | - Rubin Tan
- Department of Physiology, Basic Medical School, Xuzhou Medical University, Xuzhou, China
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To KKW, Huang Z, Zhang H, Ashby CR, Fu L. Utilizing non-coding RNA-mediated regulation of ATP binding cassette (ABC) transporters to overcome multidrug resistance to cancer chemotherapy. Drug Resist Updat 2024; 73:101058. [PMID: 38277757 DOI: 10.1016/j.drup.2024.101058] [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: 11/06/2023] [Revised: 12/27/2023] [Accepted: 01/16/2024] [Indexed: 01/28/2024]
Abstract
Multidrug resistance (MDR) is one of the primary factors that produces treatment failure in patients receiving cancer chemotherapy. MDR is a complex multifactorial phenomenon, characterized by a decrease or abrogation of the efficacy of a wide spectrum of anticancer drugs that are structurally and mechanistically distinct. The overexpression of the ATP-binding cassette (ABC) transporters, notably ABCG2 and ABCB1, are one of the primary mediators of MDR in cancer cells, which promotes the efflux of certain chemotherapeutic drugs from cancer cells, thereby decreasing or abolishing their therapeutic efficacy. A number of studies have suggested that non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a pivotal role in mediating the upregulation of ABC transporters in certain MDR cancer cells. This review will provide updated information about the induction of ABC transporters due to the aberrant regulation of ncRNAs in cancer cells. We will also discuss the measurement and biological profile of circulating ncRNAs in various body fluids as potential biomarkers for predicting the response of cancer patients to chemotherapy. Sequence variations, such as alternative polyadenylation of mRNA and single nucleotide polymorphism (SNPs) at miRNA target sites, which may indicate the interaction of miRNA-mediated gene regulation with genetic variations to modulate the MDR phenotype, will be reviewed. Finally, we will highlight novel strategies that could be used to modulate ncRNAs and circumvent ABC transporter-mediated MDR.
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Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
| | - Zoufang Huang
- Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Hang Zhang
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, United States
| | - Liwu Fu
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
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Jin Y, Cao J, Cheng H, Hu X. LncRNA POU6F2-AS2 contributes to malignant phenotypes and paclitaxel resistance by promoting SKP2 expression in stomach adenocarcinoma. J Chemother 2023; 35:638-652. [PMID: 36797828 DOI: 10.1080/1120009x.2023.2177807] [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: 08/19/2022] [Revised: 12/12/2022] [Accepted: 02/01/2023] [Indexed: 02/18/2023]
Abstract
This study aimed to investigate the role and mechanism of POU6F2-AS2 in the development of gastric cancer. POU6F2-AS2 expression was considerably higher in clinical stomach adenocarcinoma (STAD) tissues and gastric cancer cell lines (MKN-28 and MGC-803) than in neighbouring normal tissues and gastric mucosa epithelial cells (GES-1). POU6F2-AS2 overexpression resulted in a low overall survival probability, progression-free survival probability and post progression survival probability, as well as increased cell viability, migration and invasion of gastric cancer cells, thereby inhibiting apoptosis. Based on RNA pull-down, cycloheximide and MG132 incubation experiments, POU6F2-AS2 promoted SKP2 by stabilizing NONO expression. In addition, in vivo silencing of POU6F2-AS2 in gastric cancer cells can inhibit tumour progression and produce a synergistic antitumour effect when combined with paclitaxel. POU6F2-AS2 is overexpressed in STAD, which is attributed to a bad prognosis. In vitro and in vivo experiments have confirmed that the POU6F2-AS2/NONO/SKP2 axis promotes STAD progression, and that the silencing of POU6F2-AS2 plays a synergistic antitumour effect when combined with paclitaxel. Therefore, POU6F2-AS2 may be potentially developed as a target to inhibit STAD and reduce chemoresistance.
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Affiliation(s)
- Yanzhao Jin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jiaqing Cao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Hua Cheng
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiaoyun Hu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Guan H, Lv P, Han P, Zhou L, Liu J, Wu W, Yan M, Xing Q, Cao W. Long non-coding RNA ESCCAL-1/miR-590/LRP6 signaling pathway participates in the progression of esophageal squamous cell carcinoma. Cancer Med 2023; 12:445-458. [PMID: 35655441 PMCID: PMC9844631 DOI: 10.1002/cam4.4915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/12/2022] [Accepted: 05/24/2022] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) have critical functions within esophageal squamous cell carcinoma (ESCC). However, the function and mechanism underlying ESCC-associated lncRNA-1 (ESCCAL-1) in ESCC tumorigenesis have not been well clarified. METHODS ESCCAL-1, miR-590 and LRP6 were quantified using qRT-PCR. Cell viability, migration and invasion abilities were measured using CCK-8 assay and transwell assays. The protein pression was determined with western blot assay. The xenograft model assays were used to examine the impact of ESCCAL-1 on tumorigenic effect in vivo. Direct relationships among ESCCAL-1, miR-590 and LRP6 were confirmed using dual-luciferase reporter assays. RESULTS The present work discovered the ESCCAL-1 up-regulation within ESCC. Furthermore, ESCCAL-1 was found to interact with miR-590 and consequently restrict its expression. Functionally, knocking down ESCCAL-1 or over-expressing miR-590 hindered ESCC cell growth, invasion, and migration in vitro. Moreover, inhibition of miR-590 could reverse the effect of knockdown of ESCCAL-1 on cells. Importantly, it was confirmed that LRP6 was miR-590's downstream target and LRP6 over-expression also partly abolished the role of miR-590 overexpression in ESCC cells. CONCLUSION We have uncovered a novel regulatory network comprising aberrant interaction of ESCCAL-1/miR-590/LRP6 participated in ESCC progression.
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Affiliation(s)
- Hongya Guan
- Department of translational Medical CenterZhengzhou Central Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Pengju Lv
- Department of translational Medical CenterZhengzhou Central Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Pengli Han
- Department of translational Medical CenterZhengzhou Central Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Lijuan Zhou
- Department of translational Medical CenterZhengzhou Central Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Jia Liu
- Department of translational Medical CenterZhengzhou Central Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Wei Wu
- Department of MedicineUniversity of California, San FranciscoSan FranciscoCAUSA
| | - Ming Yan
- Basic Medical CollegeZhengzhou UniversityZhengzhouChina
| | - Qinghe Xing
- Institutes of Biomedical Sciences and Children's HospitalFudan UniversityShanghaiChina
| | - Wei Cao
- Department of translational Medical CenterZhengzhou Central Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
- Henan Diagnosis of Tumor Pathology Postdoctoral WorkstationZhengzhouChina
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Wei Y, Yang J, Feng X, Akhavan-Sigari R. Cellular and Molecular Mechanism of Cell Proliferation in Human Gastric Cancer Drug-Resistant Cells After Hyperthermia and Cisplatin: Role of mRNAs and Long-Non-coding RNAs. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2022; 33:377-386. [PMID: 35678795 PMCID: PMC11158417 DOI: 10.5152/tjg.2022.20845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 07/27/2021] [Indexed: 06/15/2023]
Abstract
BACKGROUND Since thermo-chemotherapy was suggested as an effective treatment for gastric cancer, we aimed to evaluate the effects of hyperthermia combined with cisplatin (DDP) on the inhibition of human gastric cancer drug-resistant cells in vitro and explore its possible mechanisms. METHODS SGC-7901/DDP cells were cultured and divided into control, cisplatin, hyperthermia, and hyperthermia combined with cispla- tin groups. Hyperthermia was done at 42°C, 44°C, 46°C, 48°C, and 50°C for 12 h, 24 h, 36 h; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- 2H-tetrazolium bromide (MTT) assay detected the proliferation of SGC-7901/DDP at different time and temperature, and the apoptotic rate of SGC-7901/DDP cells was evaluated by using Annexin staining assay. High-throughput Chromatin immunoprecipitation (ChIP)- seq was applied to test long non-coding RNA expression in SGC-7901/DDP cells. Then, real-time fluorescence quantitative polymerase chain reaction was used to verify the expression of long non-coding RNA in all groups. RESULTS Double staining showed that hyperthermia combined with cisplatin increased the rate of early apoptosis of SGC-7901/DDP cells. Long non-coding RNA high-throughput ChIP-seq showed a significantly larger amount of long non-coding RNAs and mRNAs in the cells treated with hyperthermia combined cisplatin group in comparison with the control group. We observed that the upregulated mRNAs and long non-coding RNAs were highly related to immune system response and CD95 signaling pathway in nucleus, and down- regulated mRNAs and long non-coding RNA were highly related to Mammalian target of rapamycin (mTOR) and Tumor necrosis factor (TNF) receptor signaling pathway in cytoplasm. CONCLUSION Hyperthermia combined with cisplatin reversed the expression of a large number of mRNAs and long non-coding RNAs in human gastric cancer drug-resistant cells. The molecular mechanism of inhibiting the proliferation of human gastric cancer drug- resistant cells may be related to the upregulation of long non-coding RNAs and mRNAs contributed in CD95, mTOR, and TNF receptor signaling pathway.
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Affiliation(s)
- Ying Wei
- Department of Internal Medicine, Mashhad University of Medical Sciences Faculty of Medicine, Mashhad, Iran
- Department of Gastroenterology, Shangrao People’s Hospital, Jiangxi Province, China
| | - Jing Yang
- Department of Pathology, Shangrao People’s Hospital, Jiangxi Province, China
- Department of Gastroenterology, Shangrao People’s Hospital, Jiangxi Province, China
| | - Xiaoke Feng
- Department of Gastroenterology, Shangrao People’s Hospital, Jiangxi Province, China
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing City, China
| | - Reza Akhavan-Sigari
- Department of Pathology, Shangrao People’s Hospital, Jiangxi Province, China
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Lei Y, Luo W, Gong Q, Luo L, Jing W. Long Non-Coding RNA Cancer Susceptibility Candidate 9 Regulates the Malignant Biological Behavior of Nasopharyngeal Carcinoma Cells by Targeting miR-497-5p/Wnt3a/β-catenin Signaling Pathway. Front Oncol 2022; 12:807052. [PMID: 35419295 PMCID: PMC8995468 DOI: 10.3389/fonc.2022.807052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 03/03/2022] [Indexed: 12/18/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a major kind of head and neck epithelial carcinoma. Increasing evidences reveal that long noncoding RNAs are considered as vital regulators in tumorigenesis and progression. Although previous studies have found that cancer susceptibility candidate 9 (CASC9) highly expresses in NPC, the underlying mechanisms need to be further studied. In this study, we found that CASC9 was overexpressed and associated with worse prognosis in NPC. CASC9 knockdown significantly inhibited the cell proliferation, migration and invasion in vitro and enhanced the sensitivity of tumor cells to cisplatin and paclitaxel. Mechanism research confirmed CASC9 regulated the malignant biological behavior of nasopharyngeal carcinoma cells by targeting miR-497-5p/Wnt3a/β-catenin signaling pathway. The present study might provide a novel mechanism for tumorigenesis and progression of NPC and contribute to the development of an effective molecular target therapy.
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Affiliation(s)
- Yue Lei
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenlong Luo
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiuyue Gong
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lan Luo
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wuyang Jing
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Ng JPL, Tiwari MK, Nasim AA, Zhang RL, Qu Y, Sharma R, Law BYK, Yadav DK, Chaudhary S, Coghi P, Wong VKW. Biological Evaluation in Resistant Cancer Cells and Study of Mechanism of Action of Arylvinyl-1,2,4-Trioxanes. Pharmaceuticals (Basel) 2022; 15:ph15030360. [PMID: 35337157 PMCID: PMC8955836 DOI: 10.3390/ph15030360] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/06/2022] [Accepted: 03/09/2022] [Indexed: 12/04/2022] Open
Abstract
1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, A2780, HCT8, MCF7, and SGC7901) and their corresponding drug-resistant cancer cell lines. Among all peroxides, only 7 and 8 showed a better P-glycoprotein (P-gp) inhibitory effect at a concentration of 100 nM. These in vitro results were further validated by in silico docking and molecular dynamic (MD) studies, where compounds 7 and 8 exhibited docking scores of −7.089 and −8.196 kcal/mol, respectively, and remained generally stable in 100 ns during MD simulation. Further experiments revealed that peroxides 7 and 8 showed no significant effect on ROS accumulations and caspase-3 activity in A549 cells. Peroxides 7 and 8 were also found to decrease cell membrane potential. In addition, peroxides 7 and 8 were demonstrated to oxidize a flavin cofactor, possibly elucidating its mechanism of action. In conclusion, apoptosis induced by 1,2,4-trioxane was shown to undergo via a ROS- and caspase-3-independent pathway with hyperpolarization of cell membrane potential.
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Affiliation(s)
- Jerome P. L. Ng
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (J.P.L.N.); (A.A.N.); (R.L.Z.); (Y.Q.); (B.Y.K.L.)
| | - Mohit K. Tiwari
- Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur 302017, India; (M.K.T.); (R.S.)
| | - Ali Adnan Nasim
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (J.P.L.N.); (A.A.N.); (R.L.Z.); (Y.Q.); (B.Y.K.L.)
| | - Rui Long Zhang
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (J.P.L.N.); (A.A.N.); (R.L.Z.); (Y.Q.); (B.Y.K.L.)
| | - Yuanqing Qu
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (J.P.L.N.); (A.A.N.); (R.L.Z.); (Y.Q.); (B.Y.K.L.)
| | - Richa Sharma
- Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur 302017, India; (M.K.T.); (R.S.)
| | - Betty Yuen Kwan Law
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (J.P.L.N.); (A.A.N.); (R.L.Z.); (Y.Q.); (B.Y.K.L.)
| | - Dharmendra K. Yadav
- College of Pharmacy, Gachon University of Medicine and Science, Incheon City 21924, Korea
- Correspondence: (D.K.Y.); (S.C.); (P.C.); (V.K.W.W.)
| | - Sandeep Chaudhary
- Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur 302017, India; (M.K.T.); (R.S.)
- Laboratory of Organic and Medicinal Chemistry (OMC Lab), National Institute of Pharmaceutical Education and Research (NIPER-R) Raebareli, Lucknow 226002, India
- Correspondence: (D.K.Y.); (S.C.); (P.C.); (V.K.W.W.)
| | - Paolo Coghi
- School of Pharmacy, Macau University of Science and Technology, Macau 999078, China
- Correspondence: (D.K.Y.); (S.C.); (P.C.); (V.K.W.W.)
| | - Vincent Kam Wai Wong
- Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (J.P.L.N.); (A.A.N.); (R.L.Z.); (Y.Q.); (B.Y.K.L.)
- Correspondence: (D.K.Y.); (S.C.); (P.C.); (V.K.W.W.)
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10
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Liu Y, Ao X, Wang Y, Li X, Wang J. Long Non-Coding RNA in Gastric Cancer: Mechanisms and Clinical Implications for Drug Resistance. Front Oncol 2022; 12:841411. [PMID: 35155266 PMCID: PMC8831387 DOI: 10.3389/fonc.2022.841411] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/10/2022] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, with high recurrence and mortality rate. Chemotherapy, including 5-fluorouracil (5-FU), adriamycin (ADR), vincristine (VCR), paclitaxel (PTX), and platinum drugs, remains one of the fundamental methods of GC treatment and has efficiently improved patients’ prognosis. However, most patients eventually develop resistance to chemotherapeutic agents, leading to the failure of clinical treatment and patients’ death. Recent studies suggest that long non-coding RNAs (lncRNAs) are involved in the drug resistance of GC by modulating the expression of drug resistance-related genes via sponging microRNAs (miRNAs). Moreover, lncRNAs also play crucial roles in GC drug resistance via a variety of mechanisms, such as the regulation of the oncogenic signaling pathways, inhibition of apoptosis, induction of autophagy, modulation of cancer stem cells (CSCs), and promotion of the epithelial-to-mesenchymal transition (EMT) process. Some of lncRNAs exhibit great potential as diagnostic and prognostic biomarkers, as well as therapeutic targets for GC patients. Therefore, understanding the role of lncRNAs and their mechanisms in GC drug resistance may provide us with novel insights for developing strategies for individual diagnosis and therapy. In this review, we summarize the recent findings on the mechanisms underlying GC drug resistance regulated by lncRNAs. We also discuss the potential clinical applications of lncRNAs as biomarkers and therapeutic targets in GC.
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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
- *Correspondence: Ying Liu,
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Yu Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiaoge Li
- 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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11
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Jiao Y, Liu Q, Zhao H, Hu X, Sun J, Liu X. Changes and Prognostic Value of lncRNA CASC9 in Patients with Advanced Colon Cancer after Chemotherapy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:1858974. [PMID: 34589129 PMCID: PMC8476242 DOI: 10.1155/2021/1858974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 08/29/2021] [Indexed: 11/18/2022]
Abstract
OBJECTIVE Colon cancer (CC) shows a gradual increasing incidence in recent years, and chemotherapy is a frequently adopted treatment for patients with middle or advanced colon cancer (ACC), but it lacks prognostic markers after CC. METHODS The changes of lncRNA CASC9 in 58 patients with CC were determined using a real-time quantitative PCR (qRT-PCR) assay before and after chemotherapy, and the correlation of serum lncRNA CASC9 with efficacy of FOLFOX4 regimen (oxaliplatin + calcium folinate + fluorouracil) was analyzed. The patients were followed up to understand the association of lncRNA CASC9 with overall survival (OS) and progression-free survival (PFS). RESULTS Patients with CC showed notably higher lncRNA CASC9 expression than controls, and lncRNA CASC9 presented an association with the clinical stage of the patients. In addition, lncRNA CASC9 demonstrated a clinical value in predicting efficacy on patients and acted as one independent prognostic factor for PFS in patients with ACC. CONCLUSIONS With increased expression of serum lncRNA CASC9, patients with ACC suffered an unfavorable chemotherapy effect. In addition, serum lncRNA CASC9 is a promising sensitive indicator for prediction of ACC and is related to the clinical efficacy and prognosis of patients.
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Affiliation(s)
- Yingwei Jiao
- Department of Proctology, Shaanxi Nuclear Industry 215 Hospital, Xianyang, Shaanxi 712000, China
| | - Qiang Liu
- Department of Proctology, Shaanxi Nuclear Industry 215 Hospital, Xianyang, Shaanxi 712000, China
| | - Hongbo Zhao
- Department of Proctology, Shaanxi Nuclear Industry 215 Hospital, Xianyang, Shaanxi 712000, China
| | - Xianzhen Hu
- Four Departments of General Surgery, Shaanxi Nuclear Industry 215 Hospital, Xianyang, Shaanxi 712000, China
| | - Jinlong Sun
- Department of Proctology, Shaanxi Nuclear Industry 215 Hospital, Xianyang, Shaanxi 712000, China
| | - Xiaohong Liu
- Department of Traditional Chinese Medicine, Baoji Maternal and Child Health Care Hospital, Baoji, Shaanxi 721000, China
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12
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Research updates on the clinical implication of long noncoding RNA in digestive system cancers and chemoresistance. 3 Biotech 2021; 11:423. [PMID: 34603923 DOI: 10.1007/s13205-021-02971-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 08/19/2021] [Indexed: 10/20/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are implicated in various biological processes, such as cell proliferation, differentiation, apoptosis, migration, and invasion. They are also key players in various biological pathways. LncRNA was considered as 'translational noise' before 1980s. It has been reported that lncRNAs are aberrantly expressed in different cancers, either as oncogene or tumor suppressor gene. Therefore, more and more lncRNAs are recognized as potential diagnostic biomarkers and/or therapeutic targets. As competitive endogenous RNA, lncRNAs can interact with microRNA to alter the expression of target genes, which may have extensive clinical implications in cancers, including diagnosis, treatment, prognosis, and chemoresistance. This review comprehensively summarizes the functions and clinical relevance of lncRNAs in digestive system cancers, especially as a potential tool to overcome chemoresistance.
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de Mello RA, Amaral GA, Neves NM, Lippo EG, Parini F, Xu S, Tolia M, Charalampakis N, Tadokoro H, Castelo-Branco P, Zhu J. Current and potential biomarkers in gastric cancer: a critical review of the literature. Future Oncol 2021; 17:3383-3396. [PMID: 34291647 DOI: 10.2217/fon-2021-0084] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 06/09/2021] [Indexed: 12/30/2022] Open
Abstract
Gastric cancer is the fourth most common type of cancer worldwide and the second most lethal. Gastric cancer biomarkers can be used for diagnosis, prediction of sensitivity to treatment, and prognosis. The following search terms were applied to PubMed as of December 2020: 'gastric cancer classification', 'gastric cancer epidemiology', 'cancer metastasis' and 'gastric cancer biomarker'. Only experimental studies were reported in the 'biomarkers' section. Some biomarkers can serve as therapeutic targets for antitumoral drugs. The genes analyzed include E-cadherin, RPRM, XAF1, MINT25, TFF1, p16 and p53. The miRNAs analyzed include miR-18a, miR185-5p, miR-125b and miR-21. Some molecules were associated with metastasis of gastric cancer, specifically those involved with EMT process and tissue degradation.
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Affiliation(s)
- Ramon Andrade de Mello
- Algarve Biomedical Centre, Faculty of Medicine & Biomedical Sciences, University of Algarve (FMCB UALG), Faro 8005-139, Portugal
- Division of Medical Oncology, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo 04037-004, Brazil
- Precision Oncology & Health Economics Group (ONCOPRECH), Post-Graduation Program in Medicine, Nine of July University (UNINOVE), São Paulo 01525-000, Brazil
| | - Giovanna Araujo Amaral
- Division of Medical Oncology, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo 04037-004, Brazil
| | - Nathália Moisés Neves
- Division of Medical Oncology, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo 04037-004, Brazil
| | - Estela Gudin Lippo
- School of Biomedical Sciences, Santo Amaro University, São Paulo 01525-000, Brazil
| | - Fernanda Parini
- Precision Oncology & Health Economics Group (ONCOPRECH), Post-Graduation Program in Medicine, Nine of July University (UNINOVE), São Paulo 01525-000, Brazil
| | - Song Xu
- Tianjin Medical University General Hospital, Tianjin, China
| | - Maria Tolia
- Department of Radiotherapy, School of Medicine, University of Crete, Heraklion 715 00, Greece
| | | | - Hakaru Tadokoro
- Division of Medical Oncology, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo 04037-004, Brazil
| | - Pedro Castelo-Branco
- Algarve Biomedical Centre, Faculty of Medicine & Biomedical Sciences, University of Algarve (FMCB UALG), Faro 8005-139, Portugal
| | - Jinhui Zhu
- Department of General Surgery & Laparoscopic Center, The Second Affiliated Hospital Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou 310009, China
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14
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Li Y, Lu L, Wu X, Li Q, Zhao Y, Du F, Chen Y, Shen J, Xiao Z, Wu Z, Hu W, Cho CH, Li M. The Multifaceted Role of Long Non-Coding RNA in Gastric Cancer: Current Status and Future Perspectives. Int J Biol Sci 2021; 17:2737-2755. [PMID: 34345204 PMCID: PMC8326121 DOI: 10.7150/ijbs.61410] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/08/2021] [Indexed: 12/22/2022] Open
Abstract
Gastric cancer (GC) is one of the major public health concerns. Long non-coding RNAs (lncRNAs) have been increasingly demonstrated to possess a strong correlation with GC and play a critical role in GC occurrence, progression, metastasis and drug resistance. Many studies have shed light on the understanding of the underlying mechanisms of lncRNAs in GC. In this review, we summarized the updated research about lncRNAs in GC, focusing on their roles in Helicobacter pylori infection, GC metastasis, tumor microenvironment regulation, drug resistance and associated signaling pathways. LncRNAs may serve as novel biomarkers for diagnosis and prognosis of GC and potential therapeutic targets. The research gaps and future directions were also discussed.
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Affiliation(s)
- Yifan Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Lan Lu
- Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province,Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, Sichuan, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qianxiu Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Zhigui Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China.,Department of Pharmacy, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Wei Hu
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, Guangzhou, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
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15
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Zhang Y, Chen L, Ye X, Wu Z, Zhang Z, Sun B, Fu H, Fu C, Liang X, Jiang H. Expression and mechanism of exosome-mediated A FOXM1 related long noncoding RNA in gastric cancer. J Nanobiotechnology 2021; 19:133. [PMID: 33971889 PMCID: PMC8111998 DOI: 10.1186/s12951-021-00873-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/26/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Forkhead box protein M1 (FOXM1) is an oncogene regulating tumor growth and metastasis. Exosome was suggested to mediate cell communication by delivering active molecules in cancers. However, the existence of FOXM1 in circulating exosomes and the role of exosome FOXM1 in gastric cancer (GC) were not clear. This study aims to investigate the potential role of FOXM1 related long noncoding RNA (FRLnc1) in exosomes in GC. RESULTS The prepared CD63 immunomagnetic beads (CD63-IMB) had the characteristics of good dispersity and high magnetic response. The isolated exosomes were presented with elliptical membranous particles under a transmission electron microscope (TEM), with the particle size of 89.78 ± 4.8 nm. Western blot (WB) results showed that the exosomes were rich in CD9 and CD81. The Dil-labeled exosomes were distributed around cytoplasm and nucleus of cells by imaging flow cytometry (IFC) analysis. The results of quantitative real-time PCR (qRT-PCR) revealed that the FRLnc1 expressions were up-regulated in GC cells, tumor tissues, and serum of GC patients. An obviously up-regulated FRLnc1 expression was found in serum exosomes of GC patients. Up-regulation of FRLnc1 expression was closely correlated to lymph node metastasis (LNM) and TNM stage with the combination of relevant clinicopathological parameter analysis. The in vitro functional analyses demonstrated that FRLnc1 knockdown by RNA interference suppressed cell proliferation and migration in HGC-27 cells, whereas FRLnc1 overexpression promoted cell proliferation and migration in MKN45 cells. After exosome treatment, the FRLnc1 expression was significantly increased in MKN45 cells, and the MKN45 cells showed increased ability of proliferation and migration. CONCLUSION GC cells-derived exosomes played roles in promoting the growth and metastasis of GC by transporting FRLnc1, suggesting that FRLnc1 in the exosomes may be a potential biomarker for the diagnosis and treatment of GC. The delivery of FRLnc1 by the exosomes may provide a new way for the treatment of GC. Trial registration 2020-KYSB-094. Registered 23 March 2020-Retrospectively registered.
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Affiliation(s)
- Yan Zhang
- Department of Oncology, Tongji Hospital, Tongji University School of Medicine, No. 389, Putuoxincun Rd., Shanghai, 200065, China
| | - Lin Chen
- Department of Colorectal Surgery, Department of General Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China
| | - Xuanting Ye
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhixiong Wu
- Department of Oncology, Tongji Hospital, Tongji University School of Medicine, No. 389, Putuoxincun Rd., Shanghai, 200065, China
| | - Zeyu Zhang
- Department of Oncology, Tongji Hospital, Tongji University School of Medicine, No. 389, Putuoxincun Rd., Shanghai, 200065, China
| | - Biaofeng Sun
- Department of Oncology, Tongji Hospital, Tongji University School of Medicine, No. 389, Putuoxincun Rd., Shanghai, 200065, China
| | - Hong Fu
- Department of Oncology, Tongji Hospital, Tongji University School of Medicine, No. 389, Putuoxincun Rd., Shanghai, 200065, China
| | - Chuangang Fu
- Department of Colorectal Surgery, Department of General Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China.
| | - Xiaofei Liang
- Huzhou Lieyuan Medical Laboratory Company Ltd., No. 800, Rujiadian Rd., Huzhou, 313000, China.
| | - Hong Jiang
- Department of Oncology, Tongji Hospital, Tongji University School of Medicine, No. 389, Putuoxincun Rd., Shanghai, 200065, China.
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16
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Qi Y, Song C, Zhang J, Guo C, Yuan C. Oncogenic LncRNA CASC9 in Cancer Progression. Curr Pharm Des 2021; 27:575-582. [PMID: 32940174 DOI: 10.2174/1381612826666200917150130] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 08/07/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Long non-coding RNAs (LncRNAs), with the length of over 200 nucleotides, that originate from intergenic, antisense, or promoter-proximal regions, are a large family of RNAs that lack coding capacity. Emerging evidences illustrated that LncRNAs played significant roles in a variety of cellular functions and biological processes in profuse human diseases, especially in cancers. Cancer susceptibility candidate 9 (CASC9), as a member of the LncRNAs group, firstly found its oncogenic function in esophageal cancer. In the following recent studies, a growing amount of human malignancies are verified to be correlated with CASC9, most of which are derived from the squamous epithelium tissue. This present review attempts to highlight the latest insights into the expression, functional roles, and molecular mechanisms of CASC9 in different human malignancies. METHODS In this review, the latest findings related to the pathophysiological processes of CASC9 in human cancers were summarized and analyzed, and the associated studies collected in systematic retrieval of PubMed used lncRNA and CASA9 as keywords. RESULTS CASC9 expression is identified to be aberrantly elevated in a variety of malignancies. The over-expression of CASC9 has been suggested to accelerate cell proliferation, migration, cell growth and drug resistance of cancer cells, while depressing cell apoptosis, revealing its role as an oncogene. Moreover, the current review demonstrated CASC9 as closely related to the neoplastic transformation of squamous epithelial cells and squamous metaplasia in non-squamous epithelial tissues. Finally, we discuss the limitations and tremendous diagnostic/ therapeutic potential of CASC9 in various human cancers. CONCLUSION Long non-coding RNA CASC9 likely serve as useful disease biomarkers or therapeutic targets which be effectively applied in the treatment of different kinds of cancers.
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Affiliation(s)
- Yuying Qi
- China Three Gorges University, School of Medicine, Yichang, 443002, China
| | - Chaoying Song
- China Three Gorges University, School of Medicine, Yichang, 443002, China
| | - Jiali Zhang
- China Three Gorges University, School of Medicine, Yichang, 443002, China
| | - Chong Guo
- China Three Gorges University, School of Medicine, Yichang, 443002, China
| | - Chengfu Yuan
- China Three Gorges University, School of Medicine, Yichang, 443002, China
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17
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Li C, Zhang J, Zhou Y, Li B. Long non-coding RNA CASC9 promotes the progression and development of gastric cancer via regulating miR-370/EGFR axis. Dig Liver Dis 2021; 53:509-516. [PMID: 33478874 DOI: 10.1016/j.dld.2020.12.115] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 12/16/2020] [Accepted: 12/21/2020] [Indexed: 12/11/2022]
Abstract
lncRNA cancer susceptibility 9 (CASC9) is a pivotal modulator in various cancers, such as colorectal cancer, breast cancer and esophageal cancer. However, its exact role in gastric cancer (GC) has not been systematically studied. Here, using a combination of molecular and cell biology approaches, we found that CASC9 also acts as a factor promoting the progression of GC. First, mRNA and protein expression levels were quantified by real-time quantitative reverse transcription PCR (qRT-PCR) and western blot, respectively. Second, CCK-8 assay, colony formation assay and cell cycle analysis were performed to compare the cell growth abilities when CASC9 was knocked down. Third, the proliferative cells were determined by labeling Edu and the regulatory effect of CASC9 on miR-370 was detected by RNA-protein pull-down and luciferase reporter assays. Finally, in vivo mice model was established to verify the role of CASC9 in promoting GC progression. Our results showed that CASC9 was up-regulated significantly in both GC tissues and cell lines. Conversely, CASC9 knockdown inhibited GC growth in vitro. Further analysis indicated that CASC9 directly targeted miR-370 and negatively regulated miR-370 expression in GC. Besides, EGFR (epidermal growth factor receptor) was identified as a direct target gene of miR-370. Taken together our results support a model in which CASC9 promotes GC progression through miR-370/EGFR/ERK/AKT pathway. Finally, in vivo CASC9 knockdown resulted in impaired GC growth. In sum, this study firstly demonstrates that lncRNA CASC9 acts as an oncogene through altering EGFR expression level via negatively regulating miR-370 expression.
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Affiliation(s)
- Chunsheng Li
- Department of Gastrointestinal Colorectal and Anal surgery, China-Japan Union Hospital of Jilin University, NO.126 Xiantai Street, Changchun, Jilin 130033, China
| | - Jiayu Zhang
- Department of Gastrointestinal Colorectal and Anal surgery, China-Japan Union Hospital of Jilin University, NO.126 Xiantai Street, Changchun, Jilin 130033, China
| | - Yangyang Zhou
- Department of Neurology, The First Hospital of Jilin University, Jilin 130021, China
| | - Bo Li
- Department of Gastrointestinal Colorectal and Anal surgery, China-Japan Union Hospital of Jilin University, NO.126 Xiantai Street, Changchun, Jilin 130033, China.
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18
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Wang Y, Wang Y, Qin Z, Cai S, Yu L, Hu H, Zeng S. The role of non-coding RNAs in ABC transporters regulation and their clinical implications of multidrug resistance in cancer. Expert Opin Drug Metab Toxicol 2021; 17:291-306. [PMID: 33544643 DOI: 10.1080/17425255.2021.1887139] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Multi-drug resistance (MDR) is a hindrance toward the successful treatment of cancers. The primary mechanism that gives rise to acquired chemoresistance is the overexpression of adenosine triphosphate-binding cassette (ABC) transporters. The dysregulation of non-coding RNAs (ncRNAs) is a widely concerned reason contributing to this phenotype. AREAS COVERED In this review, we describe the role of intracellular and exosomal ncRNAs including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in ABC transporters-induced tumor MDR. Meanwhile, we will introduce the potential therapeutic strategies which reverse MDR in terms of reducing the expression of ABC transporters via targeting ncRNAs, like nucleic acid delivery with nanoparticles as well as miRNAs-targeted small molecular compounds. EXPERT OPINION The dysregulated ncRNAs-mediated overexpression of ABC transporters in chemo-resistant cancer is not negligible. Finding out the underlying mechanism may provide a theoretical basis for clinical therapy of cancer MDR, and the emergence of new approaches for gene therapy targeting ncRNAs to suppress ABC transporters makes reversing cancer MDR possible despite its clinical application requires further investigations. Also, the discovered ncRNAs regulating ABC transporters in chemo-resistant cancers are just a tip of the iceberg of the genetic transcripts, especially for circRNAs, which justify more concern.Abbreviations: MDR, multi-drug resistance; ABC, adenosine triphosphate-binding cassette; NcRNAs, non-coding RNAs; MiRNAs, microRNAs; LncRNAs, long non-coding RNAs; CircRNAs, circular RNAs; CeRNAs, competing endogenous RNAs; 3'UTR, 3'-untranslated regions; SLC, solute carrier; ABCB1/MDR1, ABC subfamily B member 1; ABCG2/BCRP, ABC subfamily G member 2; ABCCs/MRPs, ABC subfamily C 1 to 12; DLL1: Delta-like protein 1; DTX, docetaxel; DOX/ADM/ADR, doxorubicin/adriamycin; PTX, paclitaxel; VBL, vinblastine; VCR, vincristine; MTX, methotrexate; CDDP/DDP, cisplatin/cis-diaminedichloroplatinum; OXA/L-OHP, oxaliplatin; TMZ, temozolomide; 5-FU, 5-fluorouracil; MTA, pemetrexed; NSCLC, non-small cell lung carcinoma; HCC, hepatocellular carcinoma; CRC, colorectal carcinoma; RB, retinoblastoma; RCC, renal cell carcinoma; OS, osteosarcoma; PDAC, pancreatic ductal adenocarcinoma; TNBC, triple-negative breast cancer.
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Affiliation(s)
- Yu Wang
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yingying Wang
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Zhiyuan Qin
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Sheng Cai
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Lushan Yu
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Haihong Hu
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Su Zeng
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Khajehdehi M, Khalaj-Kondori M, Ghasemi T, Jahanghiri B, Damaghi M. Long Noncoding RNAs in Gastrointestinal Cancer: Tumor Suppression Versus Tumor Promotion. Dig Dis Sci 2021; 66:381-397. [PMID: 32185664 DOI: 10.1007/s10620-020-06200-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 03/07/2020] [Indexed: 01/17/2023]
Abstract
Approximately 80% of the human genome harbors biochemical marks of active transcription that its majority transcribes to noncoding RNAs, namely long noncoding RNAs (lncRNAs). LncRNAs are heterogeneous RNA transcripts that regulate critical biological processes such as cell survival and death. They involve in the progression of different cancers by affecting transcriptional and post-transcriptional modifications as well as epigenetic control of numerous tumor suppressors and oncogenes. Recent findings show that aberrant expression of lncRNAs is associated with tumor initiation, progression, invasion, and overall survival of patients with gastrointestinal (GI) cancers. Some lncRNAs play as tumor suppressors in all GI cancers, but others play as tumor promoters. However, some other lncRNAs might function as a tumor suppressor in one GI cancer, but as a tumor promoter in another GI cancer type. This fact highlights possible context dependency of the expression patterns and roles of at least some lncRNAs in GI cancer development and progression. Here, we review the functional relation of lncRNAs involved in the development and progression of GI cancer by focusing on their roles as tumor suppressor and tumor promoter genes.
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Affiliation(s)
- Mina Khajehdehi
- Department of Animal Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran.
| | - Tayyebeh Ghasemi
- Department of Animal Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - Babak Jahanghiri
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Mehdi Damaghi
- Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, 33612, FL, USA
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Li Z, Lü M, Zhou Y, Xu L, Jiang Y, Liu Y, Li X, Song M. Role of Long Non-Coding RNAs in the Chemoresistance of Gastric Cancer: A Systematic Review. Onco Targets Ther 2021; 14:503-518. [PMID: 33500626 PMCID: PMC7822221 DOI: 10.2147/ott.s294378] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 12/31/2020] [Indexed: 12/11/2022] Open
Abstract
PURPOSE Accumulating evidence demonstrates that long non-coding RNAs (lncRNAs) play a vital role in the chemoresistance of gastric cancer (GC). The present systematic review summarises the emerging role, potential targets or pathways and regulatory mechanisms of lncRNAs involved in chemoresistance and proposes a number of clinical implications of lncRNAs as novel therapeutic targets for GC. METHODS Studies on lncRNAs involved in the chemoresistance of GC published until July 2020 in the PubMed and Web of Science databases were systematically reviewed and the expression form, role in chemoresistance, targets or pathways, corresponding drugs and potential mechanisms of relevant lncRNAs were summarised in detail. RESULTS A total of 48 studies were included in this systematic review. Amongst these studies, 32 involved single drug resistance and 16 involved in multidrug resistance (MDR). The 48 studies collected described 38 lncRNAs in the drug-resistant cells of GC, including 33 upregulated and 5 downregulated lncRNAs. Cisplatin (DDP) was the most studied drug and lncRNA MALAT1 was the most studied lncRNA related to the chemoresistance of GC. The potential mechanisms of chemoresistance for lncRNAs in GC mainly included, amongst others, reduction of apoptosis, induction of autophagy, repair of DNA damage, promotion of epithelial-mesenchymal transition (EMT) and regulation of the related signalling pathways. CONCLUSION LncRNAs play a vital role in the chemoresistance of GC and are novel therapeutic targets for the disease. Detailed chemoresistance mechanisms, translational studies and clinical trials on lncRNAs in GC are urgently needed.
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Affiliation(s)
- Zonglin Li
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou646000, People’s Republic of China
| | - Muhan Lü
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou646000, People’s Republic of China
| | - Yejiang Zhou
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou646000, People’s Republic of China
| | - Linxia Xu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou646000, People’s Republic of China
| | - Yifan Jiang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou646000, People’s Republic of China
| | - Yi Liu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou646000, People’s Republic of China
| | - Xin Li
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou646000, People’s Republic of China
| | - Min Song
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou646000, People’s Republic of China
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21
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Sun W, Jiang C, Ji Y, Xiao C, Song H. Long Noncoding RNAs: New Regulators of Resistance to Systemic Therapies for Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8853269. [PMID: 33506041 PMCID: PMC7808844 DOI: 10.1155/2021/8853269] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/07/2020] [Accepted: 12/19/2020] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) is the second leading cause of cancer mortality and the fourth most commonly diagnosed malignant disease, with approximately 951,000 new cases diagnosed and approximately 723,000 cases of mortality each year. The highest mortality rate of GC is in East Asia, and the lowest is in North America. A large number of studies have demonstrated that GC patients are characterized by higher morbidity, metastasis rates, and mortality and lower early diagnosis rates, radical resection rates, and 5-year survival rates. All cases of GC can be divided into two important stages, namely, early- and advanced-stage GC, and the stage mainly determines the treatment strategy for and the therapeutic effect in GC patients. Patients with early-stage GC undergo radical surgery followed by chemotherapy, and the 5-year survival rate can be as high as 90%. However, patients with advanced-stage GC cannot undergo radical surgery because they are at risk for metastasis; therefore, they can choose only radiotherapy or chemotherapy and have a poor prognosis. Based on the lack of specific clinical manifestations and detection methods, most GC patients (>70%) are diagnosed in the advanced stage; therefore, continued efforts toward developing treatments have been focused on advanced-stage GC patients and include molecular targeted therapy, immunotherapy, and small molecular therapy. Nevertheless, in recent years, accumulating evidence has indicated that small molecules, especially long noncoding RNAs (lncRNAs), are involved in the occurrence, development, and progression of GC, and their abundantly dysregulated expression has been identified in GC tissues and cell lines. Therefore, lncRNAs are considered easily detectable molecules and ideal biomarkers or target-specific agents for the future diagnosis or treatment of GC. In this review, we primarily discuss the status of GC, the role of lncRNAs in GC, and the emerging systemic treatments for GC.
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Affiliation(s)
- Weihong Sun
- Department of Internal Medicine-Oncology Affiliated Qingdao Central Hospital, Qingdao University, 127 Siliu South Road, Qingdao 266042, China
- Department of Internal Medicine-Oncology Qingdao Tumor Hospital, 127 Siliu South Road, Qingdao 266042, China
| | - Changqing Jiang
- Department of Pathology Qingdao Municipal Hospital, Donghai Middle Road, Qingdao 266071, China
| | - Ying Ji
- Department of Internal Medicine-Oncology Affiliated Qingdao Central Hospital, Qingdao University, 127 Siliu South Road, Qingdao 266042, China
- Department of Internal Medicine-Oncology Qingdao Tumor Hospital, 127 Siliu South Road, Qingdao 266042, China
| | - Chao Xiao
- Department of Internal Medicine-Oncology Affiliated Qingdao Central Hospital, Qingdao University, 127 Siliu South Road, Qingdao 266042, China
- Department of Internal Medicine-Oncology Qingdao Tumor Hospital, 127 Siliu South Road, Qingdao 266042, China
| | - Haiping Song
- Department of Internal Medicine-Oncology Affiliated Qingdao Central Hospital, Qingdao University, 127 Siliu South Road, Qingdao 266042, China
- Department of Internal Medicine-Oncology Qingdao Tumor Hospital, 127 Siliu South Road, Qingdao 266042, China
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22
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Schwarzmueller L, Bril O, Vermeulen L, Léveillé N. Emerging Role and Therapeutic Potential of lncRNAs in Colorectal Cancer. Cancers (Basel) 2020; 12:E3843. [PMID: 33352769 PMCID: PMC7767007 DOI: 10.3390/cancers12123843] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
Maintenance of the intestinal epithelium is dependent on the control of stem cell (SC) proliferation and differentiation. The fine regulation of these cellular processes requires a complex dynamic interplay between several signaling pathways, including Wnt, Notch, Hippo, EGF, Ephrin, and BMP/TGF-β. During the initiation and progression of colorectal cancer (CRC), key events, such as oncogenic mutations, influence these signaling pathways, and tilt the homeostatic balance towards proliferation and dedifferentiation. Therapeutic strategies to specifically target these deregulated signaling pathways are of particular interest. However, systemic blocking or activation of these pathways poses major risks for normal stem cell function and tissue homeostasis. Interestingly, long non-coding RNAs (lncRNAs) have recently emerged as potent regulators of key cellular processes often deregulated in cancer. Because of their exceptional tissue and tumor specificity, these regulatory RNAs represent attractive targets for cancer therapy. Here, we discuss how lncRNAs participate in the maintenance of intestinal homeostasis and how they can contribute to the deregulation of each signaling pathway in CRC. Finally, we describe currently available molecular tools to develop lncRNA-targeted cancer therapies.
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Affiliation(s)
- Laura Schwarzmueller
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Oscar Bril
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Louis Vermeulen
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Nicolas Léveillé
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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23
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Non-coding RNAs underlying chemoresistance in gastric cancer. Cell Oncol (Dordr) 2020; 43:961-988. [PMID: 32495294 DOI: 10.1007/s13402-020-00528-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 04/17/2020] [Accepted: 04/24/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a major health issue in the Western world. Current clinical imperatives for this disease include the identification of more effective biomarkers to detect GC at early stages and enhance the prevention and treatment of metastatic and chemoresistant GC. The advent of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long-non coding RNAs (lncRNAs), has led to a better understanding of the mechanisms by which GC cells acquire features of therapy resistance. ncRNAs play critical roles in normal physiology, but their dysregulation has been detected in a variety of cancers, including GC. A subset of ncRNAs is GC-specific, implying their potential application as biomarkers and/or therapeutic targets. Hence, evaluating the specific functions of ncRNAs will help to expand novel treatment options for GC. CONCLUSIONS In this review, we summarize some of the well-known ncRNAs that play a role in the development and progression of GC. We also review the application of such ncRNAs in clinical diagnostics and trials as potential biomarkers. Obviously, a deeper understanding of the biology and function of ncRNAs underlying chemoresistance can broaden horizons toward the development of personalized therapy against GC.
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24
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Sharma U, Barwal TS, Acharya V, Tamang S, Vasquez KM, Jain A. Cancer Susceptibility Candidate 9 (CASC9): A Novel Targetable Long Noncoding RNA in Cancer Treatment. Transl Oncol 2020; 13:100774. [PMID: 32450549 PMCID: PMC7256364 DOI: 10.1016/j.tranon.2020.100774] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/26/2020] [Accepted: 04/01/2020] [Indexed: 12/19/2022] Open
Abstract
Based on epidemiological data provided by the World Health Organization (2018), cancer is the second most prevalent cause of death worldwide. Several factors are thought to contribute to the high mortality rate in cancer patients, including less-than-optimal diagnostic and therapeutic strategies. Thus, there is an urgent need to identify accurate biomarkers with diagnostic, prognostic, and potential therapeutic applications. In this regard, long noncoding RNAs (lncRNAs) hold immense potential due to their regulatory roles in cancer development and associated cancer hallmarks. Recently, CASC9 transcripts have attracted significant attention due to their altered expression during the pathogenesis of cancer and their apparent contributions to various cancer-associated phenotypes involving a broad spectrum of molecular mechanisms. Here, we have provided an in-depth review describing the known functions of the lncRNA CASC9 in cancer development and progression.
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Affiliation(s)
- Uttam Sharma
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Tushar Singh Barwal
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Varnali Acharya
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Suraksha Tamang
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Karen M Vasquez
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA
| | - Aklank Jain
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India.
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25
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Huang J, Wen F, Huang W, Bai Y, Lu X, Shu P. Identification of hub genes and discovery of promising compounds in gastric cancer based on bioinformatics analysis. Biomark Med 2020; 14:1069-1084. [PMID: 32969243 DOI: 10.2217/bmm-2019-0608] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: To explore the mechanism of gastric carcinogenesis by mining potential hub genes and to search for promising small-molecular compounds for gastric cancer (GC). Materials & methods: The microarray datasets were downloaded from Gene Expression Omnibus database and the genes and compounds were analyzed by bioinformatics-related tools and software. Results: Six hub genes (MKI67, PLK1, COL1A1, TPX2, COL1A2 and SPP1) related to the prognosis of GC were confirmed to be upregulated in GC and their high expression was correlated with poor overall survival rate in GC patients. In addition, eight candidate compounds with potential anti-GC activity were identified, among which resveratrol was closely correlated with six hub genes. Conclusion: Six hub genes identified in the present study may contribute to a more comprehensive understanding of the mechanism of gastric carcinogenesis and the predicted potential of resveratrol may provide valuable clues for the future development of targeted anti-GC inhibitors.
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Affiliation(s)
- Jiani Huang
- Nanjing University of Chinese Medicine, Nanjing210029, Jiangsu Province, China
- College of Traditional ChineseMedicine, College of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Fang Wen
- Nanjing University of Chinese Medicine, Nanjing210029, Jiangsu Province, China
- Department of Oncology, Affiliated Hospital ofNanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
- Department of Oncology, Jiangsu Province Hospitalof Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Wenjie Huang
- Nanjing University of Chinese Medicine, Nanjing210029, Jiangsu Province, China
- Department of Oncology, Affiliated Hospital ofNanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
- Department of Oncology, Jiangsu Province Hospitalof Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Yingfeng Bai
- Nanjing University of Chinese Medicine, Nanjing210029, Jiangsu Province, China
- College of Traditional ChineseMedicine, College of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xiaona Lu
- Nanjing University of Chinese Medicine, Nanjing210029, Jiangsu Province, China
- Department of Oncology, Affiliated Hospital ofNanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
- Department of Oncology, Jiangsu Province Hospitalof Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Peng Shu
- Nanjing University of Chinese Medicine, Nanjing210029, Jiangsu Province, China
- Department of Oncology, Affiliated Hospital ofNanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
- Department of Oncology, Jiangsu Province Hospitalof Chinese Medicine, Nanjing 210029, Jiangsu Province, China
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26
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Yuan L, Xu ZY, Ruan SM, Mo S, Qin JJ, Cheng XD. Long non-coding RNAs towards precision medicine in gastric cancer: early diagnosis, treatment, and drug resistance. Mol Cancer 2020; 19:96. [PMID: 32460771 PMCID: PMC7251695 DOI: 10.1186/s12943-020-01219-0] [Citation(s) in RCA: 225] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer is a deadly disease and remains the third leading cause of cancer-related death worldwide. The 5-year overall survival rate of patients with early-stage localized gastric cancer is more than 60%, whereas that of patients with distant metastasis is less than 5%. Surgical resection is the best option for early-stage gastric cancer, while chemotherapy is mainly used in the middle and advanced stages of this disease, despite the frequently reported treatment failure due to chemotherapy resistance. Therefore, there is an unmet medical need for identifying new biomarkers for the early diagnosis and proper management of patients, to achieve the best response to treatment. Long non-coding RNAs (lncRNAs) in body fluids have attracted widespread attention as biomarkers for early screening, diagnosis, treatment, prognosis, and responses to drugs due to the high specificity and sensitivity. In the present review, we focus on the clinical potential of lncRNAs as biomarkers in liquid biopsies in the diagnosis and prognosis of gastric cancer. We also comprehensively discuss the roles of lncRNAs and their molecular mechanisms in gastric cancer chemoresistance as well as their potential as therapeutic targets for gastric cancer precision medicine.
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Affiliation(s)
- Li Yuan
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006 China
| | - Zhi-Yuan Xu
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Banshan Road 1#, Gongshu District, Hangzhou, 310022 China
| | - Shan-Ming Ruan
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006 China
| | - Shaowei Mo
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006 China
| | - Jiang-Jiang Qin
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Banshan Road 1#, Gongshu District, Hangzhou, 310022 China
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053 China
| | - Xiang-Dong Cheng
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Banshan Road 1#, Gongshu District, Hangzhou, 310022 China
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27
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Jiang W, Xia J, Xie S, Zou R, Pan S, Wang ZW, Assaraf YG, Zhu X. Long non-coding RNAs as a determinant of cancer drug resistance: Towards the overcoming of chemoresistance via modulation of lncRNAs. Drug Resist Updat 2020; 50:100683. [DOI: 10.1016/j.drup.2020.100683] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/18/2020] [Accepted: 02/21/2020] [Indexed: 12/11/2022]
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28
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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: 332] [Impact Index Per Article: 66.4] [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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29
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Chen Y, Li Y, Gao H. Long noncoding RNA CASC9 promotes the proliferation and metastasis of papillary thyroid cancer via sponging miR-488-3p. Cancer Med 2020; 9:1830-1841. [PMID: 31943867 PMCID: PMC7050070 DOI: 10.1002/cam4.2839] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 12/15/2019] [Accepted: 12/24/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer susceptibility candidate 9 (CASC9) is a recently identified lncRNA that acted as a tumor promotor in diversified cancer types. However, its role in papillary thyroid cancer (PTC) remains unknown. The expression of CASC9 was measured in 52 human PTC tissues and PTC cell lines as well as their controls. The proliferation, migration, and invasion of PTC cells were determined after knockdown or overexpression of CASC9 to evaluate the effect of CASC9 on PTC cells. Also, the role of PTC tumorigenesis was confirmed in mice xenograft models. Additionally, the underlying mechanisms of CASC9 were further researched. We found that CASC9 expression was augmented in human PTC tissues and cells. Higher CASC9 expression was associated with large tumor size, advanced stage, or lymph node metastasis. Downregulation of CASC9 significantly attenuated the proliferative, migrative, and invasive abilities of PTC cells, and suppressed tumorigenesis in vivo. While overexpression of CASC9 elevated the proliferation, migration, and invasion of PTC cells. miR-488-3p expression was decreased, and ADAM9 level was increased in PTC tissues and cells. CASC9 expression was negatively related to miR-488-3p, but positively associated with ADAM9 expression in PTC tissues. Molecular mechanism analysis revealed that CASC9 functioned via sponging miR-488-3p to regulate ADAM9 expression, followed by activation of EGFR-Akt signaling. In conclusion, lncRNA CASC9 promoted the malignant phenotypes of PTC via modulating miR-488-3p/ADAM9 pathway. This study may provide a novel therapeutic target for the treatment of PTC.
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Affiliation(s)
- Yonghui Chen
- Department of Nuclear MedicinePeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear MedicineBeijingChina
| | - Yaomei Li
- Department of Nuclear MedicineThe Mine Hospital of XuzhouXuzhouChina
| | - Hongbo Gao
- Department of Radionuclide Treatment CenterBeijing Nuclear Industry HospitalBeijingChina
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30
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Ghafouri-Fard S, Taheri M. Long non-coding RNA signature in gastric cancer. Exp Mol Pathol 2019; 113:104365. [PMID: 31899194 DOI: 10.1016/j.yexmp.2019.104365] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/18/2019] [Accepted: 12/28/2019] [Indexed: 02/07/2023]
Abstract
Gastric cancer as a common human malignancy has been associated with aberrant expressions of several coding and non-coding genes. Long non-coding RNAs (lncRNAs) as regulators of gene expressions at different genomic, transcriptomic and post-transcriptomic levels are among putative biomarkers and therapeutic targets in gastric cancer. In the present study, we have searched available literature and listed lncRNAs that are involved in the pathogenesis of gastric cancer. In addition, we discuss associations between expressions of these lncRNAs and tumoral features or risk factors for gastric cancer. Based on the established role of lncRNAs in regulation of genomic stability, cell cycle, apoptosis, angiogenesis and other aspects of cell physiology, the potential of these transcripts as therapeutic targets in gastric cancer should be evaluated in future studies.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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31
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Zeng YL, Guo ZY, Su HZ, Zhong FD, Jiang KQ, Yuan GD. Diagnostic and prognostic value of lncRNA cancer susceptibility candidate 9 in hepatocellular carcinoma. World J Gastroenterol 2019; 25:6902-6915. [PMID: 31908394 PMCID: PMC6938724 DOI: 10.3748/wjg.v25.i48.6902] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 11/27/2019] [Accepted: 12/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignant gastrointestinal tumor. There are currently few clinical diagnostic and prognostic markers for HCC. LncRNA cancer susceptibility candidate 9 (CASC9) is a long-chain non-coding RNA discovered in recent years, and previous studies have found that lncRNA CASC9 participates in the occurrence and development of HCC, but its clinical value remains unclear. AIM To determine the expression of lncRNA CASC9 in HCC and its diagnostic and prognostic value. METHODS Data on CASC9 expression in patients with HCC were collected from the Cancer Genome Atlas (TCGA) database to analyze the relationship between CASC9 and patient survival. A total of 80 HCC patients treated in The First Affiliated Hospital of Guangxi Medical University from May 2012 to January 2014 were enrolled in the patient group, and 50 healthy subjects were enrolled in the control group during the same period. CASC9 expression in the two groups was determined using quantitative real-time polymerase chain reaction, and its diagnostic and prognostic value was analyzed based on the CASC9 data and pathological data in these HCC patients. The relationship between CASC9 and patient survival was assessed during the 5-year follow-up period. RESULTS Analysis of data from TCGA database revealed that control samples showed significantly lower CASC9 expression than carcinoma tissue samples (P < 0.001); the low CASC9 expression group had a higher survival rate than the high CASC9 expression group (P = 0.011), and the patient group showed significantly increased expression of serum CASC9, with the area under the curve (AUC) of 0.933. CASC9 expression was related to tumor size, combined hepatitis, tumor, node, metastasis (TNM) staging, lymph node metastasis, differentiation and alpha fetoprotein, and the high CASC9 expression group showed lower 1-year, 3-year and 5-year survival rates than the low CASC9 expression group (all a P < 0.05). Multivariate Cox regression analysis revealed that TNM staging, lymph node metastasis, differentiation, alpha fetoprotein and CASC9 were independent factors affecting the prognosis of patients. Stage I+II patients with lymph node metastasis, low differentiation, and alpha fetoprotein > 200 ng/mL had a poor 5-year survival rate. CONCLUSION High CASC9 expression is beneficial in the prognosis of HCC patients. CASC9 is expected to be a potential diagnostic and prognostic indicator of HCC.
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Affiliation(s)
- Yong-Lian Zeng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Zhen-Ya Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Hui-Zhao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Fu-Di Zhong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Ke-Qing Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Guan-Dou Yuan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
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Luo YJ, Huang QM, Ren Y, Liu ZL, Xu CF, Wang H, Xiao JW. Non-coding RNA in drug resistance of gastric cancer. World J Gastrointest Oncol 2019; 11:957-970. [PMID: 31798777 PMCID: PMC6883183 DOI: 10.4251/wjgo.v11.i11.957] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 09/21/2019] [Accepted: 10/03/2019] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide. The poorly prognosis and survival of GC are due to diagnose in an advanced, non-curable stage and with a limited response to chemotherapy. The acquisition of drug resistance accounts for the majority of therapy failure of chemotherapy in GC patients. Although the mechanisms of anticancer drug resistance have been broadly studied, the regulation of these mechanisms has not been completely understood. Accumulating evidence has recently highlighted the role of non-coding RNAs (ncRNAs), including long non-coding RNAs and microRNAs, in the development and maintenance of drug resistance due to their regulatory features in specific genes involved in the chemoresistant phenotype of GC. We review the literature on ncRNAs in drug resistance of GC. This review summarizes the current knowledge about the ncRNAs’ characteristics, their regulation of the genes involved in chemoresistance and their potential as targeted therapies for personalized treatment in resistant GC.
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Affiliation(s)
- Ya-Jun Luo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Qing-Mei Huang
- Department of Oncology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Yan Ren
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Zi-Lin Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Cheng-Fei Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Hao Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Jiang-Wei Xiao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
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Li S, Teng Y, Yuan MJ, Ma TT, Ma J, Gao XJ. A seven long-noncoding RNA signature predicts prognosis of lung squamous cell carcinoma. Biomark Med 2019; 14:53-63. [PMID: 31729251 DOI: 10.2217/bmm-2019-0282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Aim: This study profiled differentially expressed long noncoding RNAs (lncRNAs) in lung squamous cell carcinoma (LSCC) to predict LSCC overall survival (OS) using The Cancer Genome Atlas data. Materials & methods: The RNA-seq and clinical dataset of 475 LSCC patients was retrieved from The Cancer Genome Atlas database and statistically analyzed. Results: There were 67 upregulated and 32 downregulated lncRNAs in LSCCs and 12 lncRNAs associated with OS. The seven-lncRNA signature was associated with poor OS and RP11-150O12.6 and CTA-384D8.35 were associated with better OS (p < 0.001). The seven lncRNAs-mRNA interaction network analysis showed their association with 187 protein-coding genes for cancer development, cell migration, adhesion, proliferation, apoptosis, angiogenesis and the MAPK signaling pathways. Conclusion: This seven-lncRNA signature is useful to predict LSCC OS.
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Affiliation(s)
- Shuai Li
- Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, PR China
| | - Yue Teng
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, PR China
| | - Min-Jie Yuan
- Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, PR China
| | - Ting-Ting Ma
- Department of Radiology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, The Key Laboratory of Cancer Prevention & Therapy, Tianjin 300060, PR China
| | - Jian Ma
- Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, PR China
| | - Xu-Jie Gao
- Department of Radiology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, The Key Laboratory of Cancer Prevention & Therapy, Tianjin 300060, PR China
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Liu L, Zhang Y, Wang J, Su H, Zhao Y. Long non-coding RNA CASC9 knockdown inhibits the progression of nasopharyngeal carcinoma by regulating miR-145. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2019; 12:4024-4033. [PMID: 31933798 PMCID: PMC6949778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 08/27/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) have been widely confirmed to modulate many tumorigeneses, including NPC. However, the exact roles of cancer susceptibility candidate 9 (CASC9) in nasopharyngeal carcinoma (NPC) and its underlying mechanisms have not been fully established. METHODS qRT-PCR was used to determine CASC9 and miR-145 expressions. Cell apoptosis, migration, and invasion were determined by flow cytometry and transwell assays, respectively. The protein expressions of BAX, Bcl-2, MMP 9, and MMP 2 were measured by western blot. The possible binding sites between miR-145 and CASC9 were predicted by the starBase v2.0 online database and verified by a luciferase report and an RNA immunoprecipitation (RIP) assay. A xenograft tumor model was established to confirm the effects of CASC9 in NPC progression in vivo. RESULTS The expression level of CASC9 was upregulated in NPC tissues and cells. The knockdown of CASC9 evidently suppressed migration and invasion but promoted apoptosis in NPC cells. In addition, the inhibition of CASC9 evidently increased the BAX protein level and inhibited the expression of the Bcl-2, MMP 9, and MPP2 proteins in NPC cells. Moreover, miR-145 was directly bound to CASC9, and its inhibition reversed the inhibitory effect of CASC9 knockdown on the progression of NPC. Furthermore, the expression of miR-145 was decreased and negatively associated with CASC9 in NPC tissues and cells. Also, the knockdown of CASC9 inhibited tumor growth in vivo. CONCLUSION CASC9 knockdown inhibited cell migration and invasion but increased cell apoptosis in NPC cells by regulating miR-145, providing a novel insight for the treatment of NPC.
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Affiliation(s)
- Lei Liu
- Department of Rhinology, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052, Henan Province, China
| | - Yuan Zhang
- Department of Rhinology, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052, Henan Province, China
| | - Jia Wang
- Department of Rhinology, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052, Henan Province, China
| | - Hongxia Su
- Department of Rhinology, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052, Henan Province, China
| | - Yulin Zhao
- Department of Rhinology, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052, Henan Province, China
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Sassenberg M, Droop J, Schulz WA, Dietrich D, Loick SM, Wiek C, Scheckenbach K, Gaisa NT, Hoffmann MJ. Upregulation of the long non-coding RNA CASC9 as a biomarker for squamous cell carcinoma. BMC Cancer 2019; 19:806. [PMID: 31412811 PMCID: PMC6694542 DOI: 10.1186/s12885-019-6021-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 08/06/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Few diagnostic and prognostic biomarkers are available for head-and-neck squamous cell carcinoma (HNSCC). Long non-coding RNAs (lncRNAs) have shown promise as biomarkers in other cancer types and in some cases functionally contribute to tumor development and progression. Here, we searched for lncRNAs useful as biomarkers in HNSCC. METHODS Public datasets were mined for lncRNA candidates. Two independent HNSCC tissue sets and a bladder cancer tissue set were analyzed by RT-qPCR. Effects of lncRNA overexpression or downregulation on cell proliferation, clonogenicity, migration and chemosensitivity were studied in HNSCC cell lines. RESULTS Data mining revealed prominently CASC9, a lncRNA significantly overexpressed in HNSCC tumor tissues according to the TCGA RNAseq data. Overexpression was confirmed by RT-qPCR analyses of patient tissues from two independent cohorts. CASC9 expression discriminated tumors from normal tissues with even higher specificity than HOTAIR, a lncRNA previously suggested as an HNSCC biomarker. Specificity of HNSCC detection by CASC9 was further improved by combination with HOTAIR. Analysis of TCGA pan-cancer data revealed significant overexpression of CASC9 across different other entities including bladder, liver, lung and stomach cancers and especially in squamous cell carcinoma (SCC) of the lung. By RT-qPCR analysis we furthermore detected stronger CASC9 overexpression in pure SCC of the urinary bladder and mixed urothelial carcinoma with squamous differentiation than in pure urothelial carcinomas. Thus, CASC9 might represent a general diagnostic biomarker and particularly for SCCs. Unexpectedly, up- or downregulation of CASC9 expression in HNSCC cell lines with low or high CASC9 expression, respectively, did not result in significant changes of cell viability, clonogenicity, migration or chemosensitivity. CONCLUSIONS CASC9 is a promising biomarker for HNSCC detection. While regularly overexpressed, however, this lncRNA does not seem to act as a major driver of development or progression in this tumor.
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Affiliation(s)
- Madeleine Sassenberg
- Department of Urology, Medical Faculty, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Johanna Droop
- Department of Urology, Medical Faculty, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Wolfgang A Schulz
- Department of Urology, Medical Faculty, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Dimo Dietrich
- Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany
| | - Sophia Marie Loick
- Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany
| | - Constanze Wiek
- Department of Otolaryngology, Medical Faculty, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Kathrin Scheckenbach
- Department of Otolaryngology, Medical Faculty, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Nadine T Gaisa
- Institute for Pathology, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Michèle J Hoffmann
- Department of Urology, Medical Faculty, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.
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Li X, Xiao X, Chang R, Zhang C. Comprehensive bioinformatics analysis identifies lncRNA HCG22 as a migration inhibitor in esophageal squamous cell carcinoma. J Cell Biochem 2019; 121:468-481. [PMID: 31236983 DOI: 10.1002/jcb.29218] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 06/04/2019] [Indexed: 12/18/2022]
Abstract
Esophageal cancer is one of the most lethal malignancies worldwide, and esophageal squamous cell carcinoma (ESCC) is the dominant histological type. However, the long noncoding RNA (lncRNA) alterations in ESCC have not been elucidated to date. In this study, reliable databases from Gene Expression Omnibus (GEO), which analyzed lncRNA expression in ESCC tumor tissues and adjacent normal tissues were searched, and common differentially expressed lncRNAs and genes were analyzed. Next, cis- trans analysis was performed to predict the underlying relationships between altered lncRNAs and mRNAs, and the lncRNA-mRNA regulatory network was established. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of altered lncRNA-related genes were performed. The promising lncRNA HCG22 was validated by quantitative polymerase chain reaction (qPCR), and clinicopathological data were collected to identify the relationship between lncRNA HCG22 expression level and clinical features. Finally, Transwell assays were performed to explore the biological functions of lncRNA HCG22 in ESCC cells. Two hundred forty-one lncRNAs and 835 mRNAs were observed to be remarkably altered between ESCC tumor tissues and adjacent normal tissues. The lncRNA-mRNA regulatory network showed the coexpression association between lncRNA HCG22 and SPINK7 and ADAMTS12. GO and KEGG analyses showed that HCG22 and ADAMTS12 had potential biological functions in the cell migration of ESCC. The downregulation of lncRNA HCG22 in ESCC tumor tissues was validated by qPCR, and the clinicopathological data showed a noticeable correlation between lncRNA HCG22 expression level and the ESCC differentiational degree and clinical TNM stage. Kaplan-Meier analysis showed that patients with ESCC having low lncRNA HCG22 expression in ESCC tissues had considerably shorter overall survival compared with patients with ESCC having high lncRNA HCG22 expression. Following Transwell assays confirmed the migratory role of lncRNA HCG22 in ESCC cells. In conclusion, lncRNA HCG22 was downregulated in ESCC tissues and can be a migration inhibitor of ESCC cells, and SPINK7 and ADAMTS12 are promising to be the regulatory targets of lncRNA HCG22.
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Affiliation(s)
- Xizhe Li
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaoxiong Xiao
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ruimin Chang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chunfang Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Luo K, Geng J, Zhang Q, Xu Y, Zhou X, Huang Z, Shi KQ, Pan C, Wu J. LncRNA CASC9 interacts with CPSF3 to regulate TGF-β signaling in colorectal cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:249. [PMID: 31186036 PMCID: PMC6560732 DOI: 10.1186/s13046-019-1263-3] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/03/2019] [Indexed: 12/19/2022]
Abstract
Background Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related death worldwide. Increasing evidence indicates that the deregulation of long noncoding RNAs (lncRNAs) contributes to tumor initiation and progression; however, little is known about the biological role of cancer susceptibility candidate 9 (CASC9) in CRC. Methods Novel lncRNAs potentially involved in CRC tumorigenesis were identified from datasets downloaded from The Cancer LncRNome Atlas and The Atlas of Noncoding RNAs in Cancer. The CRC cell lines HCT-116, HCT-116 p53−/−, SW620, SW480, HT-29, LoVo, LS-174T, and RKO were used. Colony-formation, MTS, cell-cycle, apoptosis, and in-vivo tumorigenesis assays were used to determine the role of CASC9 in CRC cell growth in vitro and in vivo. Potential interaction between CASC9 and cleavage and polyadenylation specificity factor subunit 3 (CPSF3) was evaluated using RNA immunoprecipitation and RNA-protein pull-down assays. RNA-sequencing was performed to analyze gene expression following CASC9 knockdown. RT-qPCR, western blotting, and mRNA decay assays were performed to study the mechanisms involved. Results CASC9 was frequently upregulated in CRC, which was correlated with advanced TNM stage, and higher CASC9 levels were associated with poor patient outcomes. Knockdown of CASC9 inhibited growth and promoted apoptosis in CRC cells, whereas ectopic CASC9 expression promoted cell growth in vitro and in vivo. We demonstrated that CPSF3 is a CASC9-interacting protein, and knockdown of CPSF3 mimicked the effects of CASC9 knockdown in CRC cells. Furthermore, we found that CASC9 exerts its oncogenic activity by modulating TGFβ2 mRNA stability and upregulating the levels of TGFβ2 and TERT, resulting in an increase in phosphorylated SMAD3 and activation of TGF-β signaling, and enhanced TERT complex function in CRC cells. Finally, CPSF3 was significantly upregulated in CRC tissues as compared with adjacent or non-adjacent normal colon tissues, and CASC9, CPSF3, and TGFβ2 levels in human CRC tissues were positively correlated. Conclusions CASC9 is a promising prognostic predictor for patients with CRC and the CASC9-CPSF3-TGFβ2 axis is a potential therapeutic target for CRC treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1263-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kaili Luo
- Institute of Genomic Medicine, Wenzhou Medical University, 268 Xueyuan Road, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Jingwen Geng
- Institute of Genomic Medicine, Wenzhou Medical University, 268 Xueyuan Road, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Qinkai Zhang
- Institute of Genomic Medicine, Wenzhou Medical University, 268 Xueyuan Road, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Yesha Xu
- Institute of Genomic Medicine, Wenzhou Medical University, 268 Xueyuan Road, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Xunzhu Zhou
- Institute of Genomic Medicine, Wenzhou Medical University, 268 Xueyuan Road, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Zheng Huang
- Institute of Genomic Medicine, Wenzhou Medical University, 268 Xueyuan Road, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Ke-Qing Shi
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of ZheJiang Province, Wenzhou, 325000, Zhejiang, People's Republic of China.,Center of Precision medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Chenwei Pan
- Department of Infectious Disease, The Second Affiliated Hospital and Yuying Children of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, People's Republic of China.,Pediatric Hepatitis & Liver disease Clinical Center, The Second Affiliated Hospital and Yuying Children of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, People's Republic of China
| | - Jianmin Wu
- Institute of Genomic Medicine, Wenzhou Medical University, 268 Xueyuan Road, Wenzhou, 325000, Zhejiang, People's Republic of China.
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Gao L, Guo YN, Zeng JH, Ma FC, Luo J, Zhu HW, Xia S, Wei KL, Chen G. The expression, significance and function of cancer susceptibility candidate 9 in lung squamous cell carcinoma: A bioinformatics and in vitro investigation. Int J Oncol 2019; 54:1651-1664. [PMID: 30896821 PMCID: PMC6439977 DOI: 10.3892/ijo.2019.4758] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 02/14/2019] [Indexed: 12/13/2022] Open
Abstract
The cancer susceptibility candidate 9 (CASC9) gene has been reported to exert an oncogenic effect in several types of cancer. However, its role in lung squamous cell carcinoma (LUSC) is unknown. Therefore, the present study examined the expression of CASC9 in LUSC and non-cancer tissues by reverse transcription-quantitative polymerase chain reaction assays and by data mining of high-throughput public databases, including The Cancer Genome Atlas, the Gene Expression Omnibus, ArrayExpress and the Cancer Cell Line Encyclopedia. In vitro experiments were conducted to investigate the effects of CASC9 on the viability and the proliferation of LUSC cells. Furthermore, consulting the alteration status of CASC9 in LUSC from cBioPortal, functional enrichment analysis of co-expressed genes, prediction of potential transcription factors, and inspection of adjacent protein-coding genes were conducted to explore the potential molecular mechanism of CASC9 in LUSC. The results revealed that CASC9 was overexpressed in LUSC tissue, and significantly associated with the malignant progression of LUSC. In vitro experiments demonstrated that CASC9 knockdown by RNA interference attenuated the viability and proliferation of LUSC cells. Multiple copies of CASC9 gene were detected in 4 of 179 available sequenced LUSC cases. A functional enrichment analysis of 200 co-expressed genes indicated that these genes were significantly associated with terms, including 'cell-cell junction organization', 'desmosome organization', 'epidermis development', 'Hippo signaling pathway', 'pathogenic Escherichia coli infection' and 'PID HIF1 TF pathway'. Three genes, Fos-related antigen 2 (FOSL2), SWI/SNF complex subunit SMARCC2, and transcription factor COE1 (EBF1), were predicted by lncRNAMap to be associated with CASC9. Among these, the expression of FOSL2 and EBF1 was positively and negatively correlated with the expression of CASC9, respectively. Two adjacent protein-coding genes, cysteine-rich secretory protein LCCL domain-containing 1 and hepatocyte nuclear factor 4-γ, were also positively correlated with CASC9 expression. In conclusion, the present data suggest that CASC9 serves as an oncogene in LUSC and may be a promising target for alternative therapeutic options for patients with this condition.
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Affiliation(s)
- Li Gao
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yi-Nan Guo
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jiang-Hui Zeng
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Fu-Chao Ma
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jie Luo
- Department of Medical Oncology, Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Hua-Wei Zhu
- Department of Medical Oncology, Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Shuang Xia
- Department of Human Anatomy, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Kang-Lai Wei
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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Chen C, Tang X, Liu Y, Zhu J, Liu J. Induction/reversal of drug resistance in gastric cancer by non-coding RNAs (Review). Int J Oncol 2019; 54:1511-1524. [PMID: 30896792 PMCID: PMC6438417 DOI: 10.3892/ijo.2019.4751] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/21/2019] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is one of the most prevalent and malignant types of cancer worldwide. In China, it is the second most common type of cancer and the malignancy with the highest incidence and mortality rate. Chemotherapy for GC is not always effective due to the development of drug resistance. Drug resistance, which is frequently observed in GC, undermines the success rate of chemotherapy and the survival of patients with GC. The dysregulation of non‑coding RNAs (ncRNAs), primarily microRNAs (miRNAs or miRs) and long non‑coding RNAs (lncRNAs), is involved in the development of GC drug resistance via numerous mechanisms. These mechanisms contribute to the involvement of a large and complex network of ncRNAs in drug resistance. In this review, we focus on and summarize the latest research on the specific mechanisms of action of miRNAs and lncRNAs that modulate drug resistance in GC. In addition, we discuss future prospects and clinical applications of ncRNAs as potential targeted therapies against the chemoresistance of GC.
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Affiliation(s)
- Chao Chen
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Xiaohuan Tang
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Yuanda Liu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Jiaming Zhu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Jingjing Liu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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Shao G, Wang M, Fan X, Zhong L, Wang Z, Zhang P, Ji S. lncRNA CASC9 positively regulates CHK1 to promote breast cancer cell proliferation and survival through sponging the miR‑195/497 cluster. Int J Oncol 2019; 54:1665-1675. [PMID: 30816435 PMCID: PMC6438439 DOI: 10.3892/ijo.2019.4734] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 08/07/2018] [Indexed: 12/16/2022] Open
Abstract
Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) play important roles in the pathogenesis and development of diverse types of human disorders. Cancer susceptibility candidate 9 (CASC9), a gene encoding a lncRNA, has frequently been reported to be dysregulated and has been implicated in multiple types of human malignancies. However, the biological role of lncRNA CASC9 in breast cancer (BC) remains largely unknown. The present study aimed to investigate the role of lncRNA CASC9 in BC and to elucidate the potential molecular mechanisms involved. In the present study, lncRNA CASC9 was found to be significantly upregulated in both BC tissues and cell lines. Furthermore, functional analyses revealed that lncRNA CASC9 accelerated BC cell proliferation, promoted cell cycle progression and suppressed cell apoptosis. Moreover, mechanical experiments demonstrated that lncRNA CASC9 positively regulated checkpoint kinase 1 (CHK1) by competitively binding to the miR-195/497 cluster in BC cells. Additionally, the knockdown of lncRNA CASC9 was observed to suppress breast tumor growth in vivo. Taken together, the results of this study indicate that lncRNA CASC9 plays an oncogenic role in BC through sponging the miR-195/497 cluster, and that lncRNA CASC9 may be used as a novel therapeutic target and as a potential diagnostic marker for BC.
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Affiliation(s)
- Guoli Shao
- Specialized Medical Service Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Mengchuan Wang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Xulong Fan
- Maternity and Children's Healthcare Hospital of Foshan, Foshan, Guangdong 52800, P.R. China
| | - Lin Zhong
- Specialized Medical Service Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Zixiang Wang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Pusheng Zhang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Shufeng Ji
- Specialized Medical Service Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
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Yang Y, Chen D, Liu H, Yang K. Increased expression of lncRNA CASC9 promotes tumor progression by suppressing autophagy-mediated cell apoptosis via the AKT/mTOR pathway in oral squamous cell carcinoma. Cell Death Dis 2019; 10:41. [PMID: 30674868 PMCID: PMC6381212 DOI: 10.1038/s41419-018-1280-8] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 12/12/2018] [Accepted: 12/13/2018] [Indexed: 12/11/2022]
Abstract
Recent studies showed that lncRNA CASC9 was upregulated and acted as an oncogene in a variety of tumors. However, the expression and biological functions of CASC9 in oral squamous cell carcinoma (OSCC) remain unknown. In this study, we found for the first time that CASC9 was remarkably upregulated in OSCC tissues and cell lines compared with paired noncancerous tissues and normal oral epithelial cells. Highly expressed CASC9 is strongly associated with tumor size, clinical stage, regional lymph node metastasis and overall survival time in OSCC patients. In vitro, CASC9 knockdown in OSCC cells SCC15 and CAL27 significantly promotes autophagy and apoptosis, while inhibiting proliferation. Moreover, the expression levels of p-AKT, p-mTOR, P62 and BCL-2 were significantly decreased, while the expression levels of BAX and the LC3BII/LC3BI ratio were increased in CASC9-knockdown SCC15 and CAL27 cells. After the addition of the AKT activator SC79 in CASC9-knockdown SCC15 and CAL27 cells, we found that the increased autophagy and apoptosis were remarkably rescued. Furthermore, the increased apoptosis was remarkably rescued in CASC9-knockdown OSCC cells treated with the autophagy inhibitor Autophinib. In addition, CASC9 depletion suppressed tumor growth in vivo. In conclusion, our findings demonstrate that lncRNA CASC9 promotes OSCC progression through enhancing cell proliferation and suppressing autophagy-mediated cell apoptosis via the AKT/mTOR pathway. CASC9 could potentially be used as a valuable biomarker for OSCC diagnosis and prognosis.
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Affiliation(s)
- Yixin Yang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Dan Chen
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Huan Liu
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Kai Yang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Hu X, Li Y, Kong D, Hu L, Liu D, Wu J. Long noncoding RNA CASC9 promotes LIN7A expression via miR-758-3p to facilitate the malignancy of ovarian cancer. J Cell Physiol 2018; 234:10800-10808. [PMID: 30537154 DOI: 10.1002/jcp.27903] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 10/23/2018] [Indexed: 01/06/2023]
Abstract
The long noncoding RNA cancer susceptibility 9 (CASC9) has been reported to be a pivot modulator in growth and metastasis of breast cancer, liver cancer, esophageal squamous cell carcinoma, lung adenocarcinoma, gastric cancer, and nasopharyngeal cancer. However, its potential roles in ovarian cancer remain unclear. In this study, we aimed at its functions and molecular mechanism in ovarian cancer progression. We showed that CASC9 was highly expressed in ovarian cancer tissues and cell lines. An elevated level of CASC9 predicts an unfavorable prognosis in patients with ovarian cancer. Loss-of-function and gain-of-function assays illustrated that CASC9 promotes ovarian cancer cell proliferation, migration, and invasion in vitro, and accelerates tumor growth in vivo. We showed that CASC9 works as a competing endogenous RNA (ceRNA) for miR-758-3p which targets LIN7A. CASC9 inhibits the level of miR-758-3p, and in turn stimulates LIN7A expression in ovarian cancer. Overexpression of LIN7A reverses the suppressive roles of CASC9 depletion on ovarian cancer. In sum, our findings reveal a novel undefined regulatory signaling pathway, namely CASC9/miR-758-3p/LIN7A axis, involved in ovarian cancer progression.
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Affiliation(s)
- Xiaowei Hu
- Department of Head and Neck and Genito-Urinary Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yang Li
- Department of Breast Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Dan Kong
- Department of Gynecological Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Longhu Hu
- Department of Geriatrics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Donghui Liu
- Department of Hematology and Oncology, The Second Hospital of Harbin, Harbin, China
| | - Jin Wu
- Department of Head and Neck and Genito-Urinary Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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Klingenberg M, Groß M, Goyal A, Polycarpou-Schwarz M, Miersch T, Ernst AS, Leupold J, Patil N, Warnken U, Allgayer H, Longerich T, Schirmacher P, Boutros M, Diederichs S. The Long Noncoding RNA Cancer Susceptibility 9 and RNA Binding Protein Heterogeneous Nuclear Ribonucleoprotein L Form a Complex and Coregulate Genes Linked to AKT Signaling. Hepatology 2018; 68:1817-1832. [PMID: 29790588 DOI: 10.1002/hep.30102] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 05/08/2018] [Accepted: 05/12/2018] [Indexed: 12/31/2022]
Abstract
The identification of viability-associated long noncoding RNAs (lncRNAs) might be a promising rationale for new therapeutic approaches in liver cancer. Here, we applied an RNA interference screening approach in hepatocellular carcinoma (HCC) cell lines to find viability-associated lncRNAs. Among the multiple identified lncRNAs with a significant impact on HCC cell viability, we selected cancer susceptibility 9 (CASC9) due to the strength of its phenotype, expression, and up-regulation in HCC versus normal liver. CASC9 regulated viability across multiple HCC cell lines as shown by clustered regularly interspaced short palindromic repeats interference and single small interfering RNA (siRNA)-mediated and siRNA pool-mediated depletion of CASC9. Further, CASC9 depletion caused an increase in apoptosis and a decrease of proliferation. We identified the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL) as a CASC9 interacting protein by RNA affinity purification and validated it by native RNA immunoprecipitation. Knockdown of HNRNPL mimicked the loss-of-viability phenotype observed upon CASC9 depletion. Analysis of the proteome (stable isotope labeling with amino acids in cell culture) of CASC9-depleted and HNRNPL-depleted cells revealed a set of coregulated genes which implied a role of the CASC9:HNRNPL complex in AKT signaling and DNA damage sensing. CASC9 expression levels were elevated in patient-derived tumor samples compared to normal control tissue and had a significant association with overall survival of HCC patients. In a xenograft chicken chorioallantoic membrane model, we measured decreased tumor size after knockdown of CASC9. Conclusion: Taken together, we provide a comprehensive list of viability-associated lncRNAs in HCC; we identified the CASC9:HNRNPL complex as a clinically relevant viability-associated lncRNA/protein complex which affects AKT signaling and DNA damage sensing in HCC.
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Affiliation(s)
- Marcel Klingenberg
- Division of RNA Biology & Cancer, German Cancer Research Center.,Faculty of Biosciences, Heidelberg University.,Institute of Pathology, University Hospital Heidelberg.,Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology, University of Heidelberg
| | - Matthias Groß
- Division of RNA Biology & Cancer, German Cancer Research Center.,Institute of Pathology, University Hospital Heidelberg
| | - Ashish Goyal
- Division of RNA Biology & Cancer, German Cancer Research Center
| | | | - Thilo Miersch
- Division of Signaling and Functional Genomics, German Cancer Research Center
| | - Anne-Sophie Ernst
- Faculty of Biosciences, Heidelberg University.,Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology, University of Heidelberg.,Institute of Physiology and Pathophysiology, University of Heidelberg
| | - Jörg Leupold
- Department of Experimental Surgery-Cancer Metastasis, Medical Faculty Mannheim, and Centre for Biomedicine and Medical Technology Mannheim, University of Heidelberg
| | - Nitin Patil
- Department of Experimental Surgery-Cancer Metastasis, Medical Faculty Mannheim, and Centre for Biomedicine and Medical Technology Mannheim, University of Heidelberg
| | - Uwe Warnken
- Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany
| | - Heike Allgayer
- Department of Experimental Surgery-Cancer Metastasis, Medical Faculty Mannheim, and Centre for Biomedicine and Medical Technology Mannheim, University of Heidelberg
| | | | | | - Michael Boutros
- Division of Signaling and Functional Genomics, German Cancer Research Center
| | - Sven Diederichs
- Division of RNA Biology & Cancer, German Cancer Research Center.,Division of Cancer Research, Department of Thoracic Surgery, Medical Center, University of Freiburg.,Faculty of Medicine, University of Freiburg.,German Cancer Consortium, Freiburg, Germany
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Chen C, Maimaiti A, Zhang X, Qu H, Sun Q, He Q, Yu W. Knockdown of RAI14 suppresses the progression of gastric cancer. Onco Targets Ther 2018; 11:6693-6703. [PMID: 30349303 PMCID: PMC6186306 DOI: 10.2147/ott.s175502] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background Retinoic acid induced 14 (RAI14), also known as NORPEG, is reported as being deregulated in non-small-cell lung cancer, together with having involvement in its cell proliferation as a super enhancer related gene. Purpose The objective of this study was to investigate the role of RAI14 in the progression and metastasis of gastric cancer and explore the associated mechanism. Materials and methods GEPIA database was used to analyze the expression of RAI14 in gastric cancer. MNK45 and AGS cells were transfected with siRNA-RAI14 to block the expression of RAI14. Cell Counting Kit 8 and colony formation assays were performed to measure cell proliferation. Cell migration and invasion capacities was examined by transwell assay. Apoptosis rate was detected using flow cytometry, and the protein levels of apoptosis-related proteins was determined using Western blot assay. Reverse-transcription PCR assay was used to detect the expressions of RAB31. Results Gene expression profiling interactive analysis revealed that RAI14 was substantially upregu-lated in gastric cancer and higher expression of RAI14 was associated with worse prognosis. We also observed that the knockdown of RAI14 by siRNA-RAI14 transfection suppressed growth capacity of MKN45 and AGS cells. Also, RAI14 knockdown inhibited migration and invasion of MKN45 and AGS cells in vitro. Moreover, RAI14 knockdown was observed to accelerate cell apoptosis via down-regulation of Bcl-2 and upregulation of Bax in MKN45 and AGS cells. Furthermore, downregulation of RAI14 inhibited the activation of Akt pathway, and activation of Akt by IGF-1 could restore the reduced proliferation induced by RAI14 knockdown. In addition, we found that RAI14 had a positive correlation with the RAB31 in gastric cancer by GEPIA reverse-transcription PCR and Western blot assays, and the reduced proliferation caused by RAI14 knockdown was restored by RAB31. Conclusion RAI14 knockdown inhibited proliferation, migration and invasion and promoted apoptosis by downregulating the Akt pathway in gastric cancer cells, and RAB31 might be a downstream target gene of RAI14, providing a novel sight into the molecular mechanism of RAI14 and a potential target for gastric cancer treatment.
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Affiliation(s)
- Cheng Chen
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, People's Republic of China,
| | - Aihemaiti Maimaiti
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, People's Republic of China,
| | - Xin Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, People's Republic of China,
| | - Hui Qu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, People's Republic of China,
| | - Qilong Sun
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, People's Republic of China,
| | - Qingsi He
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, People's Republic of China,
| | - Wenbin Yu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, People's Republic of China,
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Jiang B, Li Y, Qu X, Zhu H, Tan Y, Fan Q, Jiang Y, Liao M, Wu X. Long noncoding RNA cancer susceptibility candidate 9 promotes doxorubicin‑resistant breast cancer by binding to enhancer of zeste homolog 2. Int J Mol Med 2018; 42:2801-2810. [PMID: 30106089 DOI: 10.3892/ijmm.2018.3812] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 07/24/2018] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the effect of the long noncoding RNA cancer susceptibility candidate 9 (CASC9) on doxorubicin (DOX)‑resistant breast cancer and to reveal the potential underlying mechanisms. The expression of CASC9 in breast cancer tissues and cell lines, in addition to drug‑resistant breast cancer cells (MCF‑7/DOX), was detected by reverse transcription‑quantitative polymerase chain reaction. Subsequently, MCF‑7/DOX cells were transfected with the silencing vector pS‑CASC9, containing enhancer of zeste homolog 2 (EZH2), multidrug resistance protein 1 (MDR1) or control small interfering (si)RNAs. The viability, apoptosis, migration and invasion of the transfected cells were assessed via an MTT assay, flow cytometry and a Transwell assay, respectively. The expression levels of apoptosis‑associated proteins (apoptosis regulator Bcl‑2, apoptosis regulator BAX, caspase‑3 and caspase‑9) were determined by western blotting. An RNA pull‑down assay was performed to identify CASC9‑binding candidates. In addition, the expression levels of the MDR1 gene and its encoded protein, P‑glycoprotein, were detected. CASC9 expression was upregulated in breast cancer tissues and cell lines, and drug‑resistant breast cancer cells. CASC9 knockdown significantly inhibited the growth and metastasis of drug‑resistant breast cancer cells, and decreased the half‑maximal inhibitory concentration DOX in MCF‑7/DOX cells. The RNA pull‑down assay revealed that CASC9 engaged EZH2; EZH2 siRNA significantly inhibited the cell growth, metastasis and chemoresistance of MCF‑7/DOX cells. Additionally, EZH2 may regulate the MDR1 gene. The present study demonstrated the oncogenic role of CASC9 in drug‑resistant breast cancer by binding to EZH2 and regulating the MDR1 gene. Modulation of CASC9 expression may be a promising target in the therapy of breast cancer and drug‑resistant breast cancer.
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Affiliation(s)
- Baohong Jiang
- Department of Pharmacy, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yuehua Li
- Department of Medical Oncology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaofei Qu
- Department of Medical Oncology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Hongbo Zhu
- Department of Medical Oncology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yeru Tan
- Department of Medical Oncology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Qun Fan
- Department of Medical Oncology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yiling Jiang
- Department of Medical Oncology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Mingchu Liao
- Department of Medical Oncology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaoping Wu
- Department of Medical Oncology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
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Pucci P, Rescigno P, Sumanasuriya S, de Bono J, Crea F. Hypoxia and Noncoding RNAs in Taxane Resistance. Trends Pharmacol Sci 2018; 39:695-709. [PMID: 29891252 DOI: 10.1016/j.tips.2018.05.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 05/15/2018] [Accepted: 05/17/2018] [Indexed: 12/15/2022]
Abstract
Taxanes are chemotherapeutic drugs employed in the clinic to treat a variety of malignancies. Despite their overall efficacy, cancer cells often display resistance to taxanes. Therefore, new strategies to increase the effectiveness of taxane-based chemotherapeutics are urgently needed. Multiple molecular players are linked to taxane resistance; these include efflux pumps, DNA repair mechanisms, and hypoxia-related pathways. In addition, emerging evidence indicates that both non-coding RNAs and epigenetic effectors might also be implicated in taxane resistance. Here we focus on the causes of taxane resistance, with the aim to envisage an integrated model of the 'taxane resistance phenome'. This model could help the development of novel therapeutic strategies to treat taxane-resistant neoplasms.
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Affiliation(s)
- Perla Pucci
- School of Life Health and Chemical Sciences, The Open University, Milton Keynes, UK
| | - Pasquale Rescigno
- Prostate Cancer Targeted Therapy Group, The Institute of Cancer Research, Sutton, UK; Department of Clinical Medicine, University of Naples 'Federico II', Naples, Italy
| | - Semini Sumanasuriya
- Prostate Cancer Targeted Therapy Group, The Institute of Cancer Research, Sutton, UK
| | - Johann de Bono
- Prostate Cancer Targeted Therapy Group, The Institute of Cancer Research, Sutton, UK
| | - Francesco Crea
- School of Life Health and Chemical Sciences, The Open University, Milton Keynes, UK.
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LncRNA CASC9 promotes esophageal squamous cell carcinoma metastasis through upregulating LAMC2 expression by interacting with the CREB-binding protein. Cell Death Differ 2018; 25:1980-1995. [PMID: 29511340 PMCID: PMC6219493 DOI: 10.1038/s41418-018-0084-9] [Citation(s) in RCA: 205] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 01/31/2018] [Accepted: 02/08/2018] [Indexed: 02/07/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal cancer. Long noncoding RNAs (lncRNAs) are thought to play a critical role in cancer development. Recently, lncRNA CASC9 was shown to be dysregulated in many cancer types, but the mechanisms whereby this occurs remain largely unknown. In this study, we found that CASC9 was significantly upregulated in ESCC tissues, with further analysis revealing that elevated CASC9 expression was associated with ESCC prognosis and metastasis. Furthermore, we found that CASC9 knockdown significantly repressed ESCC migration and invasion in vitro and metastasis in nude mice in vivo. A microarray analysis and mechanical experiments indicated that CASC9 preferentially affected gene expression linked to ECM–integrin interactions, including LAMC2, an upstream inducer of the integrin pathway. We demonstrated that LAMC2 was consistently upregulated in ESCC and promoted ESCC metastasis. LAMC2 overexpression partially compromised the decrease of cell migration and invasion capacity in CASC9 knockdowns. In addition, we found that both CASC9 and LAMC2 depletion reduced the phosphorylation of FAK, PI3K, and Akt, which are downstream effectors of the integrin pathway. Moreover, the reduction in phosphorylation caused by CASC9 depletion was rescued by LAMC2 overexpression, further confirming that CASC9 exerts a pro-metastatic role through LAMC2. Mechanistically, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assay indicated that CASC9 could bind with the transcriptional coactivator CREB-binding protein (CBP) in the nucleus. Chromatin immunoprecipitation (ChIP) assay additionally illustrated that CASC9 increased the enrichment of CBP and H3K27 acetylation in the LAMC2 promoter, thereby upregulating LAMC2 expression. In conclusion, we demonstrate that CASC9 upregulates LAMC2 expression by binding with CBP and modifying histone acetylation. Our research reveals the prognostic and pro-metastatic roles for CASC9 in ESCC, suggesting that CASC9 could serve as a biomarker for prognosis and a target for metastasis treatment.
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MiR-192 and miR-662 enhance chemoresistance and invasiveness of squamous cell lung carcinoma. Lung Cancer 2018; 118:111-118. [PMID: 29571988 DOI: 10.1016/j.lungcan.2018.02.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 01/30/2018] [Accepted: 02/02/2018] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Overexpression of miR-192, miR-192* and miR-662 was previously found to correlate with poor prognosis of early-stage squamous cell lung cancer (SCC) patients. In this study, we investigated the relevance of these miRNAs to cancer cell biology and chemoresistance. MATERIALS AND METHODS MiRNA expression profile was analysed in 10 non-small cell lung cancer (NSCLC) cell lines using RT-qPCR. H520 and H1703 cells were transfected with miRNA inhibitors (anti-miR-192, -192* and -662) for functional studies. Chemoresistance to cisplatin and etoposide was evaluated using MTT colorimetric assay. H520 cells were subjected to 3D soft-agar colony formation assay and H1703 cells to wound healing assay. Whole transcriptome analysis was used to assess the effect of miR-192 and miR-662 inhibition on gene expression. RESULTS SCC cell lines, H520 and H1703, differed in miRNA expression and phenotypic features. MiR-192 and miR-662 inhibition decreased clonogenicity and motility of SCC cells. MiR-192 and miR-662 inhibition sensitized SCC cells to etoposide but not to cisplatin. Whole transcriptome analysis revealed genes regulated by miR-192 and miR-662 in SCC, relevant to maintaining chemoresistance, invasiveness, epithelial-mesenchymal transition (EMT) and immune evasion. CONCLUSIONS We showed for the first time that miR-192 and miR-662 have functional role in SCC cells. Our findings suggest that targeting these miRNAs may impact both chemoresistance and invasiveness of SCC, and add to the evidence linking these aspects of tumour biology. Overexpression of miR-192 and miR-662 might be useful as a marker of resistance to etoposide.
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Shang C, Tang W, Pan C, Hu X, Hong Y. Long non-coding RNA TUSC7 inhibits temozolomide resistance by targeting miR-10a in glioblastoma. Cancer Chemother Pharmacol 2018; 81:671-678. [DOI: 10.1007/s00280-018-3522-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 01/12/2018] [Indexed: 12/15/2022]
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50
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He W, Zhong G, Jiang N, Wang B, Fan X, Chen C, Chen X, Huang J, Lin T. Long noncoding RNA BLACAT2 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. J Clin Invest 2018; 128:861-875. [PMID: 29355840 PMCID: PMC5785244 DOI: 10.1172/jci96218] [Citation(s) in RCA: 151] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 12/07/2017] [Indexed: 12/11/2022] Open
Abstract
The prognosis for bladder cancer patients with lymph node (LN) metastasis is dismal and only minimally improved by current treatment modalities. Elucidation of the molecular mechanisms that underlie LN metastasis may provide clinical therapeutic strategies for LN-metastatic bladder cancer. Here, we report that a long noncoding RNA LINC00958, which we have termed bladder cancer-associated transcript 2 (BLACAT2), was markedly upregulated in LN-metastatic bladder cancer and correlated with LN metastasis. Overexpression of BLACAT2 promoted bladder cancer-associated lymphangiogenesis and lymphatic metastasis in both cultured bladder cancer cell lines and mouse models. Furthermore, we demonstrate that BLACAT2 epigenetically upregulated VEGF-C expression by directly associating with WDR5, a core subunit of human H3K4 methyltransferase complexes. Importantly, administration of an anti-VEGF-C antibody inhibited LN metastasis in BLACAT2-overexpressing bladder cancer. Taken together, these findings uncover a molecular mechanism in the lymphatic metastasis of bladder cancer and indicate that BLACAT2 may represent a target for clinical intervention in LN-metastatic bladder cancer.
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