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Yang Q, Jin X, Zhang Y, Wu X, Lin H, Ji T, Li R. In vivo delivery of PBAE/ZIF-8 enhances the sensitivity of colorectal cancer to doxorubicin through sh-LncRNA ASB16-AS1. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2025; 36:495-512. [PMID: 39428651 DOI: 10.1080/09205063.2024.2410060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 09/22/2024] [Indexed: 10/22/2024]
Abstract
The aim of this study is to investigate the impact of sh-LncRNA ASB16-AS1 on doxorubicin (DOX) resistance in colorectal cancer (CRC). First, an in vitro study was conducted to investigate the effects of LncRNA ASB16-AS1, miR-185-5p, and TEAD1 on drug resistance in CRC cells. Subsequently, utilizing nanotechnology, poly(beta amino esters) (PBAE)/zeolitic imidazolate framework-8 (ZIF-8)@sh-LncRNA ASB16-AS1 nanoparticles (PZSNP) were synthesized and characterized, evaluating their cellular toxicity and hemolytic activity. Finally, a mouse subcutaneous tumor model was established by subcutaneous injection of SW480/DOX cell suspension to investigate the impact of PZSNP on the tumor. Under DOX treatment, downregulation of LncRNA ASB16-AS1, overexpression of miR-185-5p, or downregulation of TEAD1 suppressed the viability and proliferation of drug-resistant CRC cells while promoting apoptosis. Conversely, overexpression of LncRNA ASB16-AS1, inhibition of miR-185-5p, or overexpression of TEAD1 enhanced the viability and proliferation of drug-resistant CRC cells while inhibiting apoptosis. The synthesized PZSNP exhibited a spherical shape with an average particle size of 123.6 nm, possessed positive charge, displayed good stability. It effectively encapsulated shRNA and displayed low cellular toxicity and hemolytic activity. Under DOX treatment, significant tumor necrosis was observed in the PZSNP group, and tumor growth was suppressed without causing weight loss. LncRNA ASB16-AS1, miR-185-5p, and TEAD1 are involved in regulating cell viability, proliferation, and apoptosis, contributing to drug resistance in CRC cells. sh-LncRNA ASB16-AS1 enhances the sensitivity of CRC cells to DOX during treatment, and in vivo delivery of PZSNP may serve as an effective strategy to overcome chemotherapy resistance in CRC.
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Affiliation(s)
- Qing Yang
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Xiaosheng Jin
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Yuansen Zhang
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Xiaoqiu Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Haiying Lin
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Tingting Ji
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Rongzhou Li
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
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2
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Jia K, Shen J. Transcriptome-wide association studies associated with Crohn's disease: challenges and perspectives. Cell Biosci 2024; 14:29. [PMID: 38403629 PMCID: PMC10895848 DOI: 10.1186/s13578-024-01204-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 02/04/2024] [Indexed: 02/27/2024] Open
Abstract
Crohn's disease (CD) is regarded as a lifelong progressive disease affecting all segments of the intestinal tract and multiple organs. Based on genome-wide association studies (GWAS) and gene expression data, transcriptome-wide association studies (TWAS) can help identify susceptibility genes associated with pathogenesis and disease behavior. In this review, we overview seven reported TWASs of CD, summarize their study designs, and discuss the key methods and steps used in TWAS, which affect the prioritization of susceptibility genes. This article summarized the screening of tissue-specific susceptibility genes for CD, and discussed the reported potential pathological mechanisms of overlapping susceptibility genes related to CD in a certain tissue type. We observed that ileal lipid-related metabolism and colonic extracellular vesicles may be involved in the pathogenesis of CD by performing GO pathway enrichment analysis for susceptibility genes. We further pointed the low reproducibility of TWAS associated with CD and discussed the reasons for these issues, strategies for solving them. In the future, more TWAS are needed to be designed into large-scale, unified cohorts, unified analysis pipelines, and fully classified databases of expression trait loci.
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Affiliation(s)
- Keyu Jia
- Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Nephrology department, Shanghai Jiao Tong University, 1058 Huanzhen Northroad, Shanghai, 200444, China
| | - Jun Shen
- Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Nephrology department, Shanghai Jiao Tong University, 1058 Huanzhen Northroad, Shanghai, 200444, China.
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Research Center, Ren Ji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China.
- NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Division of Gastroenterology and Hepatology, Baoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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3
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Wang Z, Liu J, Xie J, Yuan X, Wang B, Shen W, Zhang Y. Regulation of autophagy by non-coding RNAs in gastric cancer. Front Oncol 2022; 12:947332. [PMID: 36353541 PMCID: PMC9637602 DOI: 10.3389/fonc.2022.947332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/18/2022] [Indexed: 11/22/2023] Open
Abstract
Autophagy is a conserved cellular self-digesting process that degrades obsoleting proteins and cellular components and plays a crucial role in the tumorigenesis, metastasis, and drug resistance of various tumors such as gastric cancer (GC). As a hotspot in molecular biology, non-coding RNAs (ncRNAs) are involved in the regulation of multiple biological processes, such as autophagy. Increasing evidence indicate that various ncRNAs exert double roles in the initiation and progression of GC, either serve as oncogenes or tumor suppressors. Recent studies have shown that some ncRNAs could modulate autophagy activity in GC cells, which would affect the malignant transformation and drug resistance. Whether the function of ncRNAs in GC is dependent on autophagy is undefined. Therefore, identifying the underlying moleculr targets of ncRNAs in autophagy pathways and the role of ncRNA-regulated autophagy in GC could develop new treatment interventions for this disease. This review summarizes the autophagy process and its role in GC, and the regulatory mechanisms of ncRNAs, as well as focuses on the dual role of ncRNAs-mediated autophagy in GC, for the development of potential therapeutic strategies in GC patients.
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Affiliation(s)
- Zijian Wang
- Graduate College, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jiarui Liu
- College of Life Science and Technology, Guangxi University, Nanning, China
| | - Jingri Xie
- Department of Gastroenterology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xingxing Yuan
- Graduate College, Heilongjiang University of Chinese Medicine, Harbin, China
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
| | - Bingyu Wang
- Graduate College, Heilongjiang University of Chinese Medicine, Harbin, China
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
| | - Wenjuan Shen
- Department of Gynaecology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
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4
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Lu L, Liang Q, Zhang X, Xu Y, Meng D, Liang Z. Autophagy Related Noncoding RNAs: Emerging Regulatory Factors of Gastric Cancer. Cancer Manag Res 2022; 14:2215-2224. [PMID: 35898946 PMCID: PMC9309173 DOI: 10.2147/cmar.s364761] [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: 03/02/2022] [Accepted: 07/12/2022] [Indexed: 11/29/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant cancers that seriously affect human health. Autophagy is a highly conserved self-defense mechanism found to plays an important role in the occurrence, progression, drug resistance, and prognosis of GC. Noncoding RNAs (ncRNAs) play a critical role in the occurrence and development of a variety of diseases including GC. In recent years, increasing attention has been given to research on autophagy-related ncRNAs, such as miRNA, lncRNA, and circRNA in GC. Herein, we briefly summarize the roles, functions, and the research progress of autophagy and autophagy-related ncRNAs in GC with a focus on the potential application in GC tumorigenesis, development, prognosis, and drug resistance. We also discussed prospects of clinical application, future research direction, and challenges in future research of autophagy-related ncRNAs.
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Affiliation(s)
- Ling Lu
- Child Healthcare Department, the Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China
| | - Qiaoyan Liang
- Health Care Department, People’s Liberation Army Navy No. 971 Hospital, Qingdao, People’s Republic of China
| | - Xinyi Zhang
- School of Medicine, Jiangsu University, Zhenjiang, People’s Republic of China
| | - Yumeng Xu
- School of Medicine, Jiangsu University, Zhenjiang, People’s Republic of China
| | - Dehua Meng
- Department of Allergy, Dongtai People’s Hospital, Yancheng, People’s Republic of China
| | - Zhaofeng Liang
- School of Medicine, Jiangsu University, Zhenjiang, People’s Republic of China
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5
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Zhang Q, Zhong C, Yan Q, Zeng LH, Gao W, Duan S. miR-874: An Important Regulator in Human Diseases. Front Cell Dev Biol 2022; 10:784968. [PMID: 35465322 PMCID: PMC9019486 DOI: 10.3389/fcell.2022.784968] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 03/23/2022] [Indexed: 11/23/2022] Open
Abstract
miR-874 is located at 5q31.2, which is frequently deleted in cancer. miR-874 is downregulated in 22 types of cancers and aberrantly expressed in 18 types of non-cancer diseases. The dysfunction of miR-874 is not only closely related to the diagnosis and prognosis of tumor patients but also plays an important role in the efficacy of tumor chemotherapy drugs. miR-874 participates in the ceRNA network of long non-coding RNAs or circular RNAs, which is closely related to the occurrence and development of cancer and other non-cancer diseases. In addition, miR-874 is also involved in the regulation of multiple signaling pathways, including the Wnt/β-catenin signaling pathway, Hippo signaling pathway, PI3K/AKT signaling pathway, JAK/STAT signaling pathway, and Hedgehog signaling pathway. This review summarizes the molecular functions of miR-874 in the biological processes of tumor cell survival, apoptosis, differentiation, and tumorigenesis, and reveal the value of miR-874 as a cancer biomarker in tumor diagnosis and prognosis. Future work is necessary to explore the potential clinical application of miR-874 in chemotherapy resistance.
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Affiliation(s)
- Qiudan Zhang
- School of Medicine, Zhejiang University City College, Hangzhou, China
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Chenming Zhong
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Qianqian Yan
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Ling-hui Zeng
- School of Medicine, Zhejiang University City College, Hangzhou, China
| | - Wei Gao
- School of Medicine, Zhejiang University City College, Hangzhou, China
- *Correspondence: Wei Gao, ; Shiwei Duan,
| | - Shiwei Duan
- School of Medicine, Zhejiang University City College, Hangzhou, China
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
- *Correspondence: Wei Gao, ; Shiwei Duan,
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6
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Zhang X, Dai X, Zhao X, Wang J, Dou J, Zhuang H, Chen N, Zhao H. MiR-874-3p represses the migration and invasion yet promotes the apoptosis and cisplatin sensitivity via being sponged by long intergenic non-coding RNA 00922 (LINC00922) and targeting Glycerophosphodiester Phosphodiesterase Domain Containing 5 (GDPD5) in gastric cancer cells. Bioengineered 2022; 13:7082-7104. [PMID: 35282764 PMCID: PMC9208458 DOI: 10.1080/21655979.2022.2045831] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Our study mainly reports the specific mechanisms of microRNA (miR)-874-3p on drug resistance in gastric cancer (GC). Clinical specimen was collected. The upstream long non-coding RNA (lncRNA) and the downstream gene of miR-874-3p were predicted using bioinformatic analysis with the results being ascertained with dual-luciferase reporter assay. The viability, apoptosis, migration and invasion of transfected GC cells with or without cisplatin (DDP) treatment were evaluated by Cell Counting Kit-8 (CCK-8), flow cytometric, Scratch, and Transwell assays. An animal xenograft model was constructed. Expressions of long intergenic non-coding RNA 00922 (LINC00922), miR-874-3p and potential target genes were quantified by quantitative real-time polymerase-chain reaction (qRT-PCR) and Western blot. MiR-874-3p, which was lower-expressed in drug-resistant GC tissues and cells, was upregulated to repress the viability, migration and invasion but enhance the apoptosis and sensitivity in GC cells with or without DDP resistance. Downregulation of miR-874-3p eliminated the effects of silenced LINC00922, a upstream lncRNA of miR-874-3p, on cell viability, apoptosis, migration and invasion, as well as the expressions of Glycerophosphodiester Phosphodiesterase Domain Containing 5 (GDPD5) and the downstream gene of miR-874-3p in DDP-resistant GC cells. GDPD5 silencing diminished the effects of miR-874-3p downregulation on GDPD5 expression, viability, migration and invasion of DDP-resistant GC cells. Additionally, LINC00922 silencing enhanced the inhibitory effect of DDP on tumor growth, whereas reversing the effects of DDP on LINC00922, miR-874-3p and GDPD5 expressions in tumors. MiR-874-3p, an miRNA, which is sponged by LINC00922 and targets GDPD5, inhibits the GC progression yet enhances the DDP sensitivity in GC.
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Affiliation(s)
- Xiaoyu Zhang
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, Jiangsu, China
| | - Xudong Dai
- Department of General Surgery, Lianshui People's Hospital Affiliated to Kangda College of Nanjing Medical University, Huaian, Jiangsu, China
| | - Xin Zhao
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, Jiangsu, China
| | - Jian Wang
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, Jiangsu, China
| | - Jin Dou
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, Jiangsu, China
| | - Haiwen Zhuang
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, Jiangsu, China
| | - Ning Chen
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, Jiangsu, China
| | - Haijian Zhao
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, Jiangsu, China
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7
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Lei Y, Chen L, Liu J, Zhong Y, Deng L. The MicroRNA-Based Strategies to Combat Cancer Chemoresistance via Regulating Autophagy. Front Oncol 2022; 12:841625. [PMID: 35211417 PMCID: PMC8861360 DOI: 10.3389/fonc.2022.841625] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/13/2022] [Indexed: 12/12/2022] Open
Abstract
Chemoresistance frequently occurs in cancer treatment, which results in chemotherapy failure and is one of the most leading causes of cancer-related death worldwide. Understanding the mechanism of chemoresistance and exploring strategies to overcome chemoresistance have become an urgent need. Autophagy is a highly conserved self-degraded process in cells. The dual roles of autophagy (pro-death or pro-survival) have been implicated in cancers and chemotherapy. MicroRNA (miRNA) is a class of small non-coding molecules that regulate autophagy at the post-transcriptional level in cancer cells. The association between miRNAs and autophagy in cancer chemoresistance has been emphasized. In this review, we focus on the dual roles of miRNA-mediated autophagy in facilitating or combating chemoresistance, aiming to shed lights on the potential role of miRNAs as targets to overcome chemoresistance.
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Affiliation(s)
- Yuhe Lei
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Lei Chen
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Junshan Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.,Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yinqin Zhong
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Lijuan Deng
- Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
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8
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Research Progress and Prospects of Autophagy in the Mechanism of Multidrug Resistance in Tumors. JOURNAL OF ONCOLOGY 2022; 2022:7032614. [PMID: 35136409 PMCID: PMC8818414 DOI: 10.1155/2022/7032614] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 12/19/2021] [Accepted: 12/23/2021] [Indexed: 12/11/2022]
Abstract
Although the treatment of cancer has made great strides in clinical practice, its high morbidity and fatality rates remain a major threat to human health. Multidrug resistance (MDR) often appears in the process of tumor treatment, leading to tumor refractory and aggravating the risk of tumor recurrence. Therefore, antitumor MDR plays a key role in tumor chemotherapy. Autophagy is an important process for the turnover of intracellular materials, which is commonly seen in the treatment of sensitive and multidrug-resistant tumors, and it can play different roles in various types of MDR tumor cells and tissues. Autophagy plays a dual regulatory role in MDR tumors. On the one hand, autophagy can promote the formation of MDR in tumor cells, weaken the killing effect of chemotherapy drugs on tumor cells, and play a protective role in tumor survival. On the other hand, autophagy production in the cellular environment can kill MDR tumor cells, reverse tumor resistance and enhance the efficiency of chemotherapy drugs. Therefore, the regulation of autophagy to overcome MDR has become increasingly significant in tumor chemotherapy. In this article, we discussed and summarized the research progress of autophagy in MDR tumors, mainly involving the different characteristics of autophagy in MDR cancer cells.
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9
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Yue Y, Lin X, Qiu X, Yang L, Wang R. The Molecular Roles and Clinical Implications of Non-Coding RNAs in Gastric Cancer. Front Cell Dev Biol 2021; 9:802745. [PMID: 34966746 PMCID: PMC8711095 DOI: 10.3389/fcell.2021.802745] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 11/29/2021] [Indexed: 01/19/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies in the world. It is also the fifth most common cancer in China. In recent years, a large number of studies have proved that non-coding RNAs (ncRNAs) can regulate cell proliferation, invasion, metastasis, apoptosis, and angiogenesis. NcRNAs also influence the therapeutic resistance of gastric cancer. NcRNAs mainly consist of miRNAs, lncRNAs and circRNAs. In this paper, we summarized ncRNAs as biomarkers and therapeutic targets for gastric cancer, and also reviewed their role in clinical trials and diagnosis. We sum up different ncRNAs and related moleculars and signaling pathway in gastric cancer, like Bcl-2, PTEN, Wnt signaling. In addition, the potential clinical application of ncRNAs in overcoming chemotherapy and radiotherapy resistance in GC in the future were also focused on.
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Affiliation(s)
- Yanping Yue
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Xinrong Lin
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xinyue Qiu
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Lei Yang
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Rui Wang
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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10
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Liu Y, Ao X, Ji G, Zhang Y, Yu W, Wang J. Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer. Front Oncol 2021; 11:768918. [PMID: 34912714 PMCID: PMC8667691 DOI: 10.3389/fonc.2021.768918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.,School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Guoqiang Ji
- Clinical Laboratory, Linqu People's Hospital, Linqu, China
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
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11
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Zhang H, Liu L, Chen L, Liu H, Ren S, Tao Y. Long noncoding RNA DANCR confers cytarabine resistance in acute myeloid leukemia by activating autophagy via the miR-874-3P/ATG16L1 axis. Mol Oncol 2021; 15:1203-1216. [PMID: 33638615 PMCID: PMC8024725 DOI: 10.1002/1878-0261.12661] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 05/01/2019] [Accepted: 03/04/2020] [Indexed: 12/12/2022] Open
Abstract
Autophagy is an important mechanism involved in the regulation of acute myeloid leukemia (AML) chemoresistance. The long noncoding RNA (lncRNA) differentiation antagonizing non‐protein coding RNA (DANCR) exhibits oncogenic activity in several types of human cancers, including AML, but it remains unclear whether it regulates autophagy and chemoresistance in AML. We report here that cytarabine (Ara‐C) treatment elevates DANCR expression in human AML cells. In addition, DANCR overexpression confers and its knockdown diminishes Ara‐C resistance in human AML cells, suggesting that DANCR positively regulates AML chemoresistance to Ara‐C. Moreover, DANCR promotes autophagy in Ara‐C‐treated human AML cells and acts as a sponge to decrease miR‐20a‐5p expression, thereby upregulating the expression of ATG16L1, a critical component of the autophagy machinery. Importantly, ATG16L1 silencing abrogates DANCR‐promoted autophagy and markedly restores DANCR‐conferred Ara‐C resistance, suggesting that DANCR promotes MIR‐874‐3P/ATG16L1 axis‐regulated autophagy to confer Ara‐C resistance in human AML cells. Together, this study identifies DANCR as a positive regulator of Ara‐C resistance in human AML cells, suggesting this lncRNA as a potential target for overcoming Ara‐C resistance in AML chemotherapy.
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Affiliation(s)
- Hao Zhang
- Department of Hematology, Affiliated Hospital of Jining Medical University, China
| | - Ling Liu
- Department of Hematology, Affiliated Hospital of Jining Medical University, China
| | - Lulu Chen
- Graduate School, Jining Medical University, China
| | - Haihui Liu
- Department of Hematology, Affiliated Hospital of Jining Medical University, China
| | - Saisai Ren
- Department of Hematology, Affiliated Hospital of Jining Medical University, China
| | - Yanling Tao
- Department of Pediatric Hematology, Affiliated Hospital of Jining Medical University, China
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12
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Luo HL, Pi J, Zhang JA, Yang EZ, Xu H, Luo H, Shen L, Peng Y, Liu GB, Song CM, Li KY, Wu XJ, Zheng BY, Shen HB, Chen ZW, Xu JF. Circular RNA TRAPPC6B inhibits intracellular Mycobacterium tuberculosis growth while inducing autophagy in macrophages by targeting microRNA-874-3p. Clin Transl Immunology 2021; 10:e1254. [PMID: 33708385 PMCID: PMC7890665 DOI: 10.1002/cti2.1254] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 11/09/2020] [Accepted: 01/25/2021] [Indexed: 12/22/2022] Open
Abstract
Objectives Genetic and epigenetic mechanisms regulate antimicrobial immunity against Mycobacterium tuberculosis (Mtb) infection. Methods The present study assessed circular RNA TRAPPC6B (circTRAPPC6B) for antimicrobial immune functions and defined mechanisms wherein circTRAPPC6B regulates Mtb growth, autophagy and microRNA in macrophages. Results The Mtb infection of monocytes/macrophages resulted in a significantly decreased level of circTRAPPC6B that inhibited intracellular Mtb growth in macrophages. Conversely, circTRAPPC6B expression enhanced autophagy or autophagy-associated protein LC3-II production in Mtb-infected macrophages. circTRAPPC6B-enhanced autophagy aggregation or sequestration was also observed in fluorescence in situ hybridisation (FISH) analysis and confocal imaging. Mechanistically, circTRAPPC6B targets an inhibiting element miR-874-3p, as shown by bioinformatics, dual-luciferase reporter gene analysis and pull-down assay, respectively. Notably, miR-874-3p prohibited autophagy via suppressing autophagy protein ATG16L1 by binding to its 3'-untranslated region (UTR) in Mtb-infected macrophages and thus promoting intracellular Mtb growth. Concurrently, circTRAPPC6B enhanced autophagy in Mtb-infected macrophages by blocking the ability of miR-874-3p to inhibit ATG16L1. Thus, circTRAPPC6B antagonises the ability of miR-874-3p to suppress ATG16L1 expression and activate and enhance autophagy sequestration to restrict Mtb growth in macrophages. Conclusion The current findings suggested that both circTRAPPC6B and miR-874-3p mechanisms can be explored as potential therapeutics against Mtb infection.
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Affiliation(s)
- Hou-Long Luo
- Department of Clinical Immunology Institute of Laboratory Medicine Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China.,Department of Microbiology and Immunology Center for Primate Biomedical Research University of Illinois College of Medicine Chicago IL USA
| | - Jiang Pi
- Department of Clinical Immunology Institute of Laboratory Medicine Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China.,Department of Microbiology and Immunology Center for Primate Biomedical Research University of Illinois College of Medicine Chicago IL USA
| | - Jun-Ai Zhang
- Department of Clinical Immunology Institute of Laboratory Medicine Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China
| | - En-Zhuo Yang
- Department of Microbiology and Immunology Center for Primate Biomedical Research University of Illinois College of Medicine Chicago IL USA
| | - Huan Xu
- Department of Clinical Immunology Institute of Laboratory Medicine Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China
| | - Hong Luo
- Department of Clinical Immunology Institute of Laboratory Medicine Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China
| | - Ling Shen
- Department of Microbiology and Immunology Center for Primate Biomedical Research University of Illinois College of Medicine Chicago IL USA
| | - Ying Peng
- Department of Clinical Immunology Institute of Laboratory Medicine Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China
| | - Gan-Bin Liu
- Department of Respiration Dongguan 6th Hospital Dongguan China
| | - Cai-Mei Song
- Department of Clinical Immunology Institute of Laboratory Medicine Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China
| | - Ke-Yue Li
- Department of Clinical Immunology Institute of Laboratory Medicine Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China
| | - Xian-Jin Wu
- Department of Clinical Laboratory Huizhou Municipal Central Hospital Huizhou China
| | - Bi-Ying Zheng
- Department of Clinical Immunology Institute of Laboratory Medicine Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China
| | - Hong-Bo Shen
- Clinic and Research Center of Tuberculosis Shanghai Key Lab of Tuberculosis Shanghai Pulmonary Hospital Tongji University School of Medicine Shanghai China
| | - Zheng W Chen
- Department of Microbiology and Immunology Center for Primate Biomedical Research University of Illinois College of Medicine Chicago IL USA
| | - Jun-Fa Xu
- Department of Clinical Immunology Institute of Laboratory Medicine Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China
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13
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Spirina LV, Avgustinovich AV, Afanas'ev SG, Cheremisina OV, Volkov MY, Choynzonov EL, Gorbunov AK, Usynin EA. Molecular Mechanism of Resistance to Chemotherapy in Gastric Cancers, the Role of Autophagy. Curr Drug Targets 2021; 21:713-721. [PMID: 31775598 DOI: 10.2174/1389450120666191127113854] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 11/11/2019] [Accepted: 11/21/2019] [Indexed: 12/13/2022]
Abstract
Gastric cancer (GC) is biologically and genetically heterogeneous with complex carcinogenesis at the molecular level. Despite the application of multiple approaches in the GC treatment, its 5-year survival is poor. A major limitation of anti-cancer drugs application is intrinsic or acquired resistance, especially to chemotherapeutical agents. It is known that the effectiveness of chemotherapy remains debatable and varies according to the molecular type of GC. Chemotherapy has an established role in the management of GC. Perioperative chemotherapy or postoperative chemotherapy is applied for localized ones. Most of the advanced GC patients have a poor response to treatment and unfavorable outcomes with standard therapies. Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of MAPK, AKT/mTOR, and Wnt/β-catenin signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. We have summarized the mechanisms of resistance development to cisplatin, 5-fluorouracil, and multidrug resistance in the GC management. The complexity of molecular targets and components of signaling cascades altered in the resistance development results in the absence of significant benefits in GC treatment, and its efficacy remains low. The universal process responsible for the failure in the multimodal approach in GC treatment is autophagy. Its dual role in oncogenesis is the most unexplored issue. We have discussed the possible mechanism of autophagy regulation upon the action of endogenous factors and drugs. The experimental data obtained in the cultured GC cells need further verification. To overcome the cancer resistance and to prevent autophagy as the main reason of ineffective treatment, it is suggested the concept of the direct influence of autophagy molecular markers followed by the standard chemotherapy. Dozen of studies have focused on finding the rationale for the benefits of such complex therapy. The perspectives in the molecular-based management of GC are associated with the development of molecular markers predicting the protective autophagy initiation and search for novel targets of effective anticancer therapy.
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Affiliation(s)
- Liudmila V Spirina
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation.,Siberian State Medical University, 2, Moskovsky trakt, Tomsk, 634050, Russian Federation
| | - Alexandra V Avgustinovich
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation
| | - Sergey G Afanas'ev
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation
| | - Olga V Cheremisina
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation
| | - Maxim Yu Volkov
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation
| | - Evgeny L Choynzonov
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation.,Siberian State Medical University, 2, Moskovsky trakt, Tomsk, 634050, Russian Federation
| | - Alexey K Gorbunov
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation
| | - Evgeny A Usynin
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation.,Siberian State Medical University, 2, Moskovsky trakt, Tomsk, 634050, Russian Federation
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14
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Chen E, Li E, Liu H, Zhou Y, Wen L, Wang J, Wang Y, Ye L, Liang T. miR-26b enhances the sensitivity of hepatocellular carcinoma to Doxorubicin via USP9X-dependent degradation of p53 and regulation of autophagy. Int J Biol Sci 2021; 17:781-795. [PMID: 33767588 PMCID: PMC7975695 DOI: 10.7150/ijbs.52517] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 01/16/2021] [Indexed: 12/30/2022] Open
Abstract
Multi-drug resistance is a major challenge to hepatocellular carcinoma (HCC) treatment, and the over-expression or deletion of microRNA (miRNA) expression is closely related to the drug-resistant properties of various cell lines. However, the underlying molecular mechanisms remain unclear. CCK-8, EdU, flow cytometry, and transmission electron microscopy were performed to determine cell viability, proliferation, apoptosis, autophagic flow, and nanoparticle characterization, respectively. In this study, the results showed that the expression of miR-26b was downregulated following doxorubicin treatment in human HCC tissues. An miR-26b mimic enhanced HCC cell doxorubicin sensitivity, except in the absence of p53 in Hep3B cells. Delivery of the proteasome inhibitor, MG132, reversed the inhibitory effect of miR-26b on the level of p53 following doxorubicin treatment. Tenovin-1 (an MDM2 inhibitor) protected p53 from ubiquitination-mediated degradation only in HepG2 cells with wild type p53. Tenovin-1 pretreatment enhanced HCC cell resistance to doxorubicin when transfected with an miR-26b mimic. Moreover, the miR-26b mimic inhibited doxorubicin-induced autophagy and the autophagy inducer, rapamycin, eliminated the differences in the drug sensitivity effect of miR-26b. In vivo, treatment with sp94dr/miR-26b mimic nanoparticles plus doxorubicin inhibited tumor growth. Our current data indicate that miR-26b enhances HCC cell sensitivity to doxorubicin through diminishing USP9X-mediated p53 de-ubiquitination caused by DNA damaging drugs and autophagy regulation. This miRNA-mediated pathway that modulates HCC will help develop novel therapeutic strategies.
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Affiliation(s)
- Enjiang Chen
- The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Enliang Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hao Liu
- Department of Medical Oncology, Tongde hospital of Zhejiang Province, Hangzhou, Zhejiang, 310012, China
| | - Yue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liang Wen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yi Wang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
- Department of Medical Oncology, Tongde hospital of Zhejiang Province, Hangzhou, Zhejiang, 310012, China
| | - Longyun Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Tingbo Liang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Disease, Hangzhou, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
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15
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Zeng X, Wang HY, Bai SY, Pu K, Wang YP, Zhou YN. The Roles of microRNAs in Multidrug-Resistance Mechanisms in Gastric Cancer. Curr Mol Med 2021; 20:667-674. [PMID: 32209033 DOI: 10.2174/1566524020666200226124336] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 02/10/2020] [Accepted: 02/14/2020] [Indexed: 12/24/2022]
Abstract
Multidrug resistance (MDR) is one of the most significant reasons for the
chemotherapeutics failure in gastric cancer. Although accumulating investigations and
researches have been made to elucidate the mechanisms of multidrug resistance, the
detail is far from completely understood. The importance of microRNAs in cancer
chemotherapeutic resistance has been demonstrated recently, which provides a new
strategy to overcome multidrug resistance. The different mechanisms are related to the
phenomena of MDR itself and the roles of miRNAs in these multi-mechanisms by which
MDR is acquired. In turn, the aim of this review was to summarize recent publications of
microRNAs in regulating MDR in gastric cancer, thereby potentially developing as
targeted therapies. Further unraveling the roles of microRNAs in MDR mechanisms
including the ATP-binding cassette (ABC) transporter family, autophagy induction,
cancer stem cell regulation, hypoxia induction, DNA damage and repair, epigenetic
regulation, and exosomes in gastric cancer will be helpful for us to win the battle against
it.
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Affiliation(s)
- Xi Zeng
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Hao-Ying Wang
- Department of Gastroenterology, The first Hospital of Lanzhou University, Lanzhou, China
| | - Su-Yang Bai
- Department of Gastroenterology, The first Hospital of Lanzhou University, Lanzhou, China
| | - Ke Pu
- Department of Gastroenterology, The first Hospital of Lanzhou University, Lanzhou, China
| | - Yu-Ping Wang
- Department of Gastroenterology, The first Hospital of Lanzhou University, Lanzhou, China
| | - Yong-Ning Zhou
- Department of Gastroenterology, The first Hospital of Lanzhou University, Lanzhou, China
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16
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Shan C, Chen X, Cai H, Hao X, Li J, Zhang Y, Gao J, Zhou Z, Li X, Liu C, Li P, Wang K. The Emerging Roles of Autophagy-Related MicroRNAs in Cancer. Int J Biol Sci 2021; 17:134-150. [PMID: 33390839 PMCID: PMC7757044 DOI: 10.7150/ijbs.50773] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
Autophagy is a conserved catabolic process involving the degradation and recycling of damaged biomacromolecules or organelles through lysosomal-dependent pathways and plays a crucial role in maintaining cell homeostasis. Consequently, abnormal autophagy is associated with multiple diseases, such as infectious diseases, neurodegenerative diseases and cancer. Currently, autophagy is considered to be a dual regulator in cancer, functioning as a suppressor in the early stage while supporting the growth and metastasis of cancer cells in the later stage and may also produce therapeutic resistance. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level by silencing targeted mRNA. MiRNAs have great regulatory potential for several fundamental biological processes, including autophagy. In recent years, an increasing number of studies have linked miRNA dysfunction to the growth, metabolism, migration, metastasis, and responses of cancer cells to therapy. Therefore, the study of autophagy-related miRNAs in cancer will provide insights into cancer biology and lead to the development of novel anti-cancer strategies. In the present review, we summarise the current knowledge of miRNA dysregulation during autophagy in cancer, focusing on the relationship between autophagy and miRNAs, and discuss their involvement in cancer biology and cancer treatment.
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Affiliation(s)
- Chan Shan
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xinzhe Chen
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Hongjing Cai
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xiaodan Hao
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jing Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yinfeng Zhang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jinning Gao
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Zhixia Zhou
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xinmin Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Cuiyun Liu
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Peifeng Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Kun Wang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
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17
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Wu M, Chen B, Pan X, Su J. Prognostic Value of Autophagy-related Proteins in Human Gastric Cancer. Cancer Manag Res 2020; 12:13527-13540. [PMID: 33414645 PMCID: PMC7783202 DOI: 10.2147/cmar.s278354] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/19/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose Autophagy-related proteins (ATG) play a crucial role in autophagy. Recently, the functions of autophagy in cancer have been gathering attention. However, the prognostic value of ATGs in gastric cancer (GC) has not been explored. Methods The Kaplan–Meier plotter (KM plotter) online database was used to examine the value of ATGs gene expression levels in overall survival (OS) prediction in GC patients with different clinical stage, differentiation, gender, HER2 status, and therapeutic strategy. In vitro experiments applied VE-822, an effective GC treatment, to assess cell migration and proliferation in gastric mucosa epithelial cells, and real-time PCR was used to measure alterations of autophagy-related gene expression. Results High ATG3, ATG4C, ATG5, and ATG10 mRNA levels were associated with good OS, while increased ATG4B, ATG7, ATG12, ATG16L1, and TECPR1 mRNA levels related to unfavorable OS in patients with GC. ATG12 overexpression had different effects on OS due to high levels of heterogeneity. High ATG12 expression was correlated with good OS in female patients with GC and with bad OS for male patients. Additionally, the increased ATG12 expression was more likely to get a satisfactory OS in patients who underwent surgery alone but was associated with poor OS for patients treated with 5-FU adjuvant. In addition, elevated TECPR1 expression was related to favorable OS for patients with poorly differentiated type, while for patients with moderate differentiation, it was relevant to poor OS. The in vitro experiments showed that berzosertib could significantly inhibit the migration and proliferation of human gastric mucosa epithelial cells, and further real-time PCR assessment of ATG expressions partially coincided with the bioinformation analysis above. Conclusion These results indicate that individual ATGs have unique prognostic significance interpreted using Kaplan–Meier plotter analysis and in vitro experiments, and this may help guide clinical therapeutic strategy and promote OS by individualizing therapy for GC patients.
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Affiliation(s)
- Minmin Wu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, People's Republic of China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, People's Republic of China
| | - Xiaodong Pan
- Department of Transplantation Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, People's Republic of China
| | - Jiadong Su
- Department of Traumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, People's Republic of China
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18
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Xu JL, Yuan L, Tang YC, Xu ZY, Xu HD, Cheng XD, Qin JJ. The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe? Front Cell Dev Biol 2020; 8:621428. [PMID: 33344463 PMCID: PMC7744622 DOI: 10.3389/fcell.2020.621428] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 11/12/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is the third most common cause of cancer-related death worldwide. Drug resistance is the main inevitable and vital factor leading to a low 5-year survival rate for patients with gastric cancer. Autophagy, as a highly conserved homeostatic pathway, is mainly regulated by different proteins and non-coding RNAs (ncRNAs) and plays dual roles in drug resistance of gastric cancer. Thus, targeting key regulatory nodes in the process of autophagy by small molecule inhibitors or activators has become one of the most promising strategies for the treatment of gastric cancer in recent years. In this review, we provide a systematic summary focusing on the relationship between autophagy and chemotherapy resistance in gastric cancer. We comprehensively discuss the roles and molecular mechanisms of multiple proteins and the emerging ncRNAs including miRNAs and lncRNAs in the regulation of autophagy pathways and gastric cancer chemoresistance. We also summarize the regulatory effects of autophagy inhibitor and activators on gastric cancer chemoresistance. Understanding the vital roles of autophagy in gastric cancer chemoresistance will provide novel opportunities to develop promising therapeutic strategies for gastric cancer.
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Affiliation(s)
- Jing-Li Xu
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, China.,Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.,The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Li Yuan
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, China.,Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.,The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yan-Cheng Tang
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tsai, Hong Kong, China
| | - Zhi-Yuan Xu
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, China.,Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Han-Dong Xu
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, China.,Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.,The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiang-Dong Cheng
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, China.,Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jiang-Jiang Qin
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, China.,Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
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19
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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: 31] [Impact Index Per Article: 6.2] [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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20
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Xie Y, Liu X, Hu T, Wang W. miR-302e Suppresses Glioma Progression by Targeting VEGFA. Cancer Manag Res 2020; 12:10965-10974. [PMID: 33154675 PMCID: PMC7608593 DOI: 10.2147/cmar.s268222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/09/2020] [Indexed: 12/15/2022] Open
Abstract
Background MiRNA can be involved in regulating tumor genesis and development by regulating the expression of specific genes and regulating corresponding signaling pathways. In this study, we explored the function and mechanisms of miR-302e in glioma progression. Methods Experimental methods include the following: real-time quantitative PCR, Western Blot Analysis, CCK8 assay and detection of apoptosis. Results MiR-302e was down-regulated in cancer tissues and cell lines, and the expression of miR-302e was negatively correlated with the tumor grade, which indicated poor prognosis in glioma patients. Followed functional analysis showed overexpression of miR-302e inhibited proliferation, migration and invasion but promoted apoptosis of glioma cells, while silencing miR-302e showed the opposite effects. Mechanistic studies have shown that VEGFA was a directed target of miR-302e. Forced expression of VEGFA removed the inhibiting impact of miR-302e on glioma development. In vivo tumorigenesis experiments showed that miR-302e suppressed glioma development by targeting VEGFA. Conclusion Present study emphasized miR-302e suppressed glioma development by targeting VEGFA, which might be a valuable target for glioma treatment.
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Affiliation(s)
- Yunpeng Xie
- Department of Neurosurgery, Chengde Medical College Affiliated Hospital, Chengde, Hebei Province, People's Republic of China
| | - Xin Liu
- Department of Oncology, Chengde Medical College Affiliated Hospital, Chengde, Hebei Province, People's Republic of China
| | - Tiemin Hu
- Department of Neurosurgery, Chengde Medical College Affiliated Hospital, Chengde, Hebei Province, People's Republic of China
| | - Weixing Wang
- Department of Neurosurgery, Chengde Medical College Affiliated Hospital, Chengde, Hebei Province, People's Republic of China
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21
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Zhang M, Chen Y, Cheng X, Cai Z, Qiu S. GATA1/SP1 and miR-874 mediate enterovirus-71-induced apoptosis in a granzyme-B-dependent manner in Jurkat cells. Arch Virol 2020; 165:2531-2540. [PMID: 32851429 DOI: 10.1007/s00705-020-04783-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/21/2020] [Indexed: 01/20/2023]
Abstract
Enterovirus 71 (EV71)-induced T lymphocyte apoptosis plays an important role in hand, foot, and mouth disease (HFMD), and granzyme B (GZMB) has been shown to be critical for this process. However, the mechanisms underlying GZMB-mediated apoptosis of T lymphocytes remain unknown. In this study, we investigated whether transcription factors and microRNAs (miRNAs) are involved in GZMB-mediated apoptosis of T lymphocytes in response to EV71 infection. Our findings indicated that EV71 infection significantly induced apoptosis in Jurkat cells, a human T lymphocytes cell line, as revealed in flow cytometric analysis. Furthermore, EV71 increased the expression of pro-apoptosis Bcl-2-associated X (Bax) and cleaved caspase 3 but decreased the expression of anti-apoptosis B-cell lymphoma protein 2 (Bcl2). GZMB knockdown decreased cell apoptosis and prevented EV71-induced changes in the expression of Bax, cleaved caspase 3, and Bcl2 in Jurkat cells, highlighting the role of GZMB as a key factor in EV71-induced apoptosis. Our study also indicated that overexpression of the transcription factors GATA binding factor 1 (GATA1) and specificity protein 1 (SP1) significantly increased luciferase activity when this gene was inserted in the GZMB 3' untranslated region (3'UTR). GATA1/SP1 overexpression induced cell apoptosis, increased the expression of Bax and cleaved caspase 3, and decreased the expression of Bcl2. Finally, our results suggested that miR-874 plays an essential role in GZMB-mediated cell apoptosis, since an miR-874 mimic decreases the expression of GZMB by targeting its 3'UTR. Collectively, these data indicated that GATA1/SP1 and miR-874 mediate EV71-induced apoptosis in a granzyme B-dependent manner. This signaling pathway may provide a new pharmacological target for the prevention and treatment of HFMD.
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Affiliation(s)
- Meijuan Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Ying Chen
- Department of Laboratory Medicine, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Xiangjun Cheng
- Department of Laboratory Medicine, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Zhenzhen Cai
- Department of Laboratory Medicine, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Shengfeng Qiu
- Department of Laboratory Medicine, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
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22
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Wang J, Yu Z, Wang J, Shen Y, Qiu J, Zhuang Z. LncRNA NUTM2A-AS1 positively modulates TET1 and HIF-1A to enhance gastric cancer tumorigenesis and drug resistance by sponging miR-376a. Cancer Med 2020; 9:9499-9510. [PMID: 33089970 PMCID: PMC7774746 DOI: 10.1002/cam4.3544] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/19/2020] [Accepted: 09/29/2020] [Indexed: 12/19/2022] Open
Abstract
Long noncoding RNA NUTM2A‐AS1 has been shown to be dysregulated in non‐small cell lung carcinoma. To date, it is unclear whether NUTM2A‐AS1 plays a role in gastric cancer progression. The purpose of this study is to elucidate the molecular mechanism of the role of NUTM2A‐AS1 in gastric cancer. mRNA and protein levels were measured by RT‐qPCR and western blot methods. Invasion ability was examined by transwell assay. Cell viability was determined by MTT assay. Dual‐luciferase assay, RNA pull down, and RNA immunoprecipitation were used to confirm direct binding of between miR‐376a and NUTM2A‐AS1 or TET1. Xenografting tumor assay and TCGA analysis showed the contributory role of NUTM2A‐AS1 in vivo and human clinical setting. Our results suggested that NUTM2A‐AS1 promoted cell viability, invasion, and drug resistance of gastric cancer cells, which was largely rescued by miR‐376a. More interestingly, TET1 and HIF‐1A were negatively regulated by miR‐376a. TET1 could interact with HIF‐1A to modulate PD‐L1. Finally, we revealed that PD‐L1 was key to NUTM2A‐AS1‐ and miR‐376a‐mediated tumorigenesis and drug resistance. In summary, our conclusions facilitate us understand the underlying mechanism and develop novel treatment strategy for gastric cancer.
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Affiliation(s)
- Ji Wang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Ziyang Yu
- Department of gynaecology and obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jun Wang
- Department of General Surgery, The Fifth People's Hospital of Wujiang, Suzhou, China
| | - Yidan Shen
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Junlan Qiu
- Department of Oncology and Hematology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China
| | - Zhixiang Zhuang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Participation of MicroRNAs in the Treatment of Cancer with Phytochemicals. Molecules 2020; 25:molecules25204701. [PMID: 33066509 PMCID: PMC7587345 DOI: 10.3390/molecules25204701] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/08/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer is a global health concern and one of the main causes of disease-related death. Even with considerable progress in investigations on cancer therapy, effective anti-cancer agents and regimens have thus far been insufficient. There has been compelling evidence that natural phytochemicals and their derivatives have potent anti-cancer activities. Plant-based anti-cancer agents, such as etoposide, irinotecan, paclitaxel, and vincristine, are currently being applied in medical treatments for patients with cancer. Further, the efficacy of plenty of phytochemicals has been evaluated to discover a promising candidate for cancer therapy. For developing more effective cancer therapy, it is required to apprehend the molecular mechanism deployed by natural compounds. MicroRNAs (miRNAs) have been realized to play a pivotal role in regulating cellular signaling pathways, affecting the efficacy of therapeutic agents in cancer. This review presents a feature of phytochemicals with anti-cancer activity, focusing mainly on the relationship between phytochemicals and miRNAs, with insights into the role of miRNAs as the mediators and the regulators of anti-cancer effects of phytochemicals.
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Zhang H, Yu Y, Cai W, Lu H, He R, Zhang R, Pei F, Wang X, Fang Y, Wei F. [Chloroquine enhances cisplatin-induced apoptosis of nasopharyngeal carcinoma cells by inhibiting autophagy via upregulating miR129]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:361-369. [PMID: 32376584 DOI: 10.12122/j.issn.1673-4254.2020.03.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To investigate the role of miR129 in mediating the effect of chloroquine to enhance cisplatin- induced apoptosis in nasopharyngeal carcinoma cells (HNE1). METHODS MTT assay was used to detect the viability of HNE1 cells treated with different concentrations of cisplatin. Colony formation of HNE1 cells treated with cisplatin and chloroquine, alone or in combination, was observed using crystal violet staining. BALB/C unde mice were inoculated with HNE1 cells and randomly divided into 4 groups with 6 mice in each group. The mice received intraperitoneal injections of cisplatin and chloroquine, alone or in combination once every 3 days for 4 consecutive weeks, and the tumor growth was observed in each group. The expression of miR129 in HNE1 cells treated with chloroquine, cisplatin, or both was detected with qPCR. The effects of miR129 suppression with a miR129 inhibitor on the expressions of autophagy related proteins p62, LC3B, Beclin1 and the drug-resistant related protein P-glycoprotein (P-gp) were examined using Western blotting in HNE1 cells treated with chloroquine, cisplatin, or both; the changes in cell apoptosis were detected Annexin V/PI double staining. RESULTS Chloroquine combined with cisplatin significantly inhibited HNE1 cell proliferation in vitro and the growth of HNE1 cell-derived tumor in nude mice as compared with cisplatin alone (P < 0.01). In cultured HNE1 cells, inhibition of the expression of miR129 significantly promoted autophagy and up-regulated P-gp expression (P < 0.01); Chloroquine obviously inhibited cisplatin-induced autophagy and up-regulated the expression of miR129 in HNE1 cells (P < 0.01). Transfection of the cells with the miR129 inhibitor abolished the inhibitory effect of chloroquine on cisplatin-induced autophagy, and significantly increased the cell survival rate (P < 0.05) and lower the cell apoptotic rate (P < 0.01) after combined treatment with chloroquine and cisplatin. CONCLUSIONS Chloroquine enhances the pro-apoptotic effect of cisplatin by up-regulating miR129 to inhibit autophagy and drug resistance in HNE1 cells.
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Affiliation(s)
- Haoxuan Zhang
- Department of Basic Medical Sciences, Bengbu Medical College, Bengbu 233030, China
| | - Yun Yu
- School of Pharmacy, Bengbu Medical College, Bengbu 233030, China
| | - Weiwei Cai
- School of Pharmacy, Bengbu Medical College, Bengbu 233030, China
| | - Huaqiu Lu
- School of Pharmacy, Bengbu Medical College, Bengbu 233030, China
| | - Rui He
- School of Pharmacy, Bengbu Medical College, Bengbu 233030, China
| | - Renhao Zhang
- School of Pharmacy, Bengbu Medical College, Bengbu 233030, China
| | - Feilong Pei
- School of Pharmacy, Bengbu Medical College, Bengbu 233030, China
| | - Xiaodie Wang
- School of Pharmacy, Bengbu Medical College, Bengbu 233030, China
| | - Yini Fang
- College of Clinical Medicine, Bengbu Medical College, Bengbu 233030, China
| | - Fang Wei
- School of Pharmacy, Bengbu Medical College, Bengbu 233030, China
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25
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Zhou J, Kang Y, Chen L, Wang H, Liu J, Zeng S, Yu L. The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents. Front Pharmacol 2020; 11:343. [PMID: 32265714 PMCID: PMC7100275 DOI: 10.3389/fphar.2020.00343] [Citation(s) in RCA: 273] [Impact Index Per Article: 54.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 03/09/2020] [Indexed: 01/17/2023] Open
Abstract
Platinum-based anticancer drugs, including cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin, are heavily applied in chemotherapy regimens. However, the intrinsic or acquired resistance severely limit the clinical application of platinum-based treatment. The underlying mechanisms are incredibly complicated. Multiple transporters participate in the active transport of platinum-based antitumor agents, and the altered expression level, localization, or activity may severely decrease the cellular platinum accumulation. Detoxification components, which are commonly increasing in resistant tumor cells, can efficiently bind to platinum agents and prevent the formation of platinum–DNA adducts, but the adducts production is the determinant step for the cytotoxicity of platinum-based antitumor agents. Even if adequate adducts have formed, tumor cells still manage to survive through increased DNA repair processes or elevated apoptosis threshold. In addition, autophagy has a profound influence on platinum resistance. This review summarizes the critical participators of platinum resistance mechanisms mentioned above and highlights the most potential therapeutic targets or predicted markers. With a deeper understanding of the underlying resistance mechanisms, new solutions would be produced to extend the clinical application of platinum-based antitumor agents largely.
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Affiliation(s)
- Jiabei Zhou
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yu Kang
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Lu Chen
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hua Wang
- Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China
| | - Junqing Liu
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Su Zeng
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Lushan Yu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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26
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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: 324] [Impact Index Per Article: 64.8] [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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27
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Zhao X, Hu GF, Shi YF, Xu W. Research Progress in microRNA-Based Therapy for Gastric Cancer. Onco Targets Ther 2019; 12:11393-11411. [PMID: 31920330 PMCID: PMC6935305 DOI: 10.2147/ott.s221354] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 12/10/2019] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is one of the leading causes of tumor-related mortality. In addition to surgery and endoscopic resection, systemic therapy remains the main treatment option for GC, especially for advanced-stage disease and for cases not suitable for surgical therapy. Hence, improving the efficacy of systemic therapy is still an urgent problem to overcome. In the past decade, the essential roles of microRNAs (miRNAs) in tumor treatment have been increasingly recognized. In particular, miRNAs were recently shown to reverse the resistance to chemotherapy drugs such as 5-fluorouracil, cisplatin, and doxorubicin. Synthesized nanoparticles loaded with mimics or inhibitors of miRNAs can directly target tumor cells to suppress their growth. Moreover, exosomes may serve as promising safe carriers for mimics or inhibitors of miRNAs to treat GC. Some miRNAs have also been shown to play roles in the mechanism of action of other anti-tumor drugs. Therefore, in this review, we highlight the research progress on microRNA-based therapy in GC and discuss the challenges and prospects associated with this strategy. We believe that microRNA-based therapy has the potential to offer a clinical benefit to GC patients, and this review would contribute to and motivate further research to promote this field toward this ultimate goal.
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Affiliation(s)
- Xu Zhao
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Gao-Feng Hu
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.,Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Yan-Fen Shi
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, People's Republic of China
| | - Wei Xu
- Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
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28
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Seo HA, Moeng S, Sim S, Kuh HJ, Choi SY, Park JK. MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies. Cells 2019; 9:cells9010029. [PMID: 31861937 PMCID: PMC7016872 DOI: 10.3390/cells9010029] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 12/16/2019] [Accepted: 12/19/2019] [Indexed: 12/12/2022] Open
Abstract
The susceptibility of cancer cells to different types of treatments can be restricted by intrinsic and acquired therapeutic resistance, leading to the failure of cancer regression and remission. To overcome this problem, a combination therapy has been proposed as a fundamental strategy to improve therapeutic responses; however, resistance is still unavoidable. MicroRNA (miRNAs) are associated with cancer therapeutic resistance. The modulation of dysregulated miRNA levels through miRNA-based therapy comprising a replacement or inhibition approach has been proposed to sensitize cancer cells to other anti-cancer therapies. The combination of miRNA-based therapy with other anti-cancer therapies (miRNA-based combinatorial cancer therapy) is attractive, due to the ability of miRNAs to target multiple genes associated with the signaling pathways controlling therapeutic resistance. In this article, we present an overview of recent findings on the role of therapeutic resistance-related miRNAs in different types of cancer. We review the feasibility of utilizing dysregulated miRNAs in cancer cells and extracellular vesicles as potential candidates for miRNA-based combinatorial cancer therapy. We also discuss innate properties of miRNAs that need to be considered for more effective combinatorial cancer therapy.
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Affiliation(s)
- Hyun Ah Seo
- Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (H.A.S.); (S.M.); (S.Y.C.)
| | - Sokviseth Moeng
- Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (H.A.S.); (S.M.); (S.Y.C.)
| | - Seokmin Sim
- Generoath, Seachang-ro, Mapo-gu, Seoul 04168, Korea;
| | - Hyo Jeong Kuh
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Soo Young Choi
- Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (H.A.S.); (S.M.); (S.Y.C.)
| | - Jong Kook Park
- Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (H.A.S.); (S.M.); (S.Y.C.)
- Correspondence: or ; Tel.: +82-33-248-2114
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29
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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: 13] [Impact Index Per Article: 2.2] [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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30
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Tan BB, Li Y. Role of microRNAs in drug resistance of gastric cancer cells. Shijie Huaren Xiaohua Zazhi 2019; 27:913-917. [DOI: 10.11569/wcjd.v27.i15.913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Drug therapy is an important component of comprehensive treatments for gastric cancer (GC), but drug resistance of cancer cells often leads to treatment failure. It is significant to explore the drug resistance mechanism of GC cells. It has been reported that microRNAs (miRNAs) are closely related to drug resistance in GC. However, there are many kinds of microRNAs, which possess complex mechanisms and are not widely applied in clinical patients, so there are still many areas to be investigated about the relationship between microRNAs and drug resistance in GC. In this review, we review the role of miRNAs in the formation of drug resistance and discuss the existing problems and future directions.
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Affiliation(s)
- Bi-Bo Tan
- Third Department of Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Yong Li
- Third Department of Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
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RNA Binding Protein HuR Promotes Autophagosome Formation by Regulating Expression of Autophagy-Related Proteins 5, 12, and 16 in Human Hepatocellular Carcinoma Cells. Mol Cell Biol 2019; 39:MCB.00508-18. [PMID: 30602494 PMCID: PMC6399664 DOI: 10.1128/mcb.00508-18] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 12/18/2018] [Indexed: 12/16/2022] Open
Abstract
Autophagy is a process of lysosomal self-degradation of cellular components by forming autophagosomes. Autophagosome formation is an essential process in autophagy and is fine-tuned by various autophagy-related gene (ATG) products, including ATG5, ATG12, and ATG16. Although several reports have shown that numerous factors affect multiple levels of gene regulation to orchestrate cellular autophagy, the detailed mechanism of autophagosome formation still needs further investigation. In this study, we demonstrate that the RNA binding protein HuR (human antigen R) performs an essential function in autophagosome formation. We observe that HuR silencing leads to inhibition of autophagosome formation and autophagic flux in liver cells. Ribonucleoprotein immunoprecipitation (RIP) assay allows the identification of ATG5, ATG12, and ATG16 mRNAs as the direct targets of HuR. We further show that HuR mediates the translation of ATG5, ATG12, and ATG16 mRNAs by binding to their 3' untranslated regions (UTRs). In addition, we show that HuR expression positively correlates with the levels of ATG5 and ATG12 in hepatocellular carcinoma (HCC) cells. Collectively, our results suggest that HuR functions as a pivotal regulator of autophagosome formation by enhancing the translation of ATG5, ATG12, and ATG16 mRNAs and that augmented expression of HuR and ATGs may participate in the malfunction of autophagy in HCC cells.
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