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1
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Ji R, Chang L, An C, Zhang J. Proton-sensing ion channels, GPCRs and calcium signaling regulated by them: implications for cancer. Front Cell Dev Biol 2024; 12:1326231. [PMID: 38505262 PMCID: PMC10949864 DOI: 10.3389/fcell.2024.1326231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 02/14/2024] [Indexed: 03/21/2024] Open
Abstract
Extracellular acidification of tumors is common. Through proton-sensing ion channels or proton-sensing G protein-coupled receptors (GPCRs), tumor cells sense extracellular acidification to stimulate a variety of intracellular signaling pathways including the calcium signaling, which consequently exerts global impacts on tumor cells. Proton-sensing ion channels, and proton-sensing GPCRs have natural advantages as drug targets of anticancer therapy. However, they and the calcium signaling regulated by them attracted limited attention as potential targets of anticancer drugs. In the present review, we discuss the progress in studies on proton-sensing ion channels, and proton-sensing GPCRs, especially emphasizing the effects of calcium signaling activated by them on the characteristics of tumors, including proliferation, migration, invasion, metastasis, drug resistance, angiogenesis. In addition, we review the drugs targeting proton-sensing channels or GPCRs that are currently in clinical trials, as well as the relevant potential drugs for cancer treatments, and discuss their future prospects. The present review aims to elucidate the important role of proton-sensing ion channels, GPCRs and calcium signaling regulated by them in cancer initiation and development. This review will promote the development of drugs targeting proton-sensing channels or GPCRs for cancer treatments, effectively taking their unique advantage as anti-cancer drug targets.
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Affiliation(s)
- Renhui Ji
- Foundational and Translational Medical Research Center, Department of Allergy and General Surgery, Hohhot First Hospital, Hohhot, China
- Department of Pathophysiology, Basic Medicine College of Inner Mongolia Medical University, Hohhot, China
| | - Li Chang
- Foundational and Translational Medical Research Center, Department of Allergy and General Surgery, Hohhot First Hospital, Hohhot, China
- Department of Pathophysiology, Basic Medicine College of Inner Mongolia Medical University, Hohhot, China
| | - Caiyan An
- Foundational and Translational Medical Research Center, Department of Allergy and General Surgery, Hohhot First Hospital, Hohhot, China
| | - Junjing Zhang
- Foundational and Translational Medical Research Center, Department of Allergy and General Surgery, Hohhot First Hospital, Hohhot, China
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2
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To KKW, Huang Z, Zhang H, Ashby CR, Fu L. Utilizing non-coding RNA-mediated regulation of ATP binding cassette (ABC) transporters to overcome multidrug resistance to cancer chemotherapy. Drug Resist Updat 2024; 73:101058. [PMID: 38277757 DOI: 10.1016/j.drup.2024.101058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/27/2023] [Accepted: 01/16/2024] [Indexed: 01/28/2024]
Abstract
Multidrug resistance (MDR) is one of the primary factors that produces treatment failure in patients receiving cancer chemotherapy. MDR is a complex multifactorial phenomenon, characterized by a decrease or abrogation of the efficacy of a wide spectrum of anticancer drugs that are structurally and mechanistically distinct. The overexpression of the ATP-binding cassette (ABC) transporters, notably ABCG2 and ABCB1, are one of the primary mediators of MDR in cancer cells, which promotes the efflux of certain chemotherapeutic drugs from cancer cells, thereby decreasing or abolishing their therapeutic efficacy. A number of studies have suggested that non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a pivotal role in mediating the upregulation of ABC transporters in certain MDR cancer cells. This review will provide updated information about the induction of ABC transporters due to the aberrant regulation of ncRNAs in cancer cells. We will also discuss the measurement and biological profile of circulating ncRNAs in various body fluids as potential biomarkers for predicting the response of cancer patients to chemotherapy. Sequence variations, such as alternative polyadenylation of mRNA and single nucleotide polymorphism (SNPs) at miRNA target sites, which may indicate the interaction of miRNA-mediated gene regulation with genetic variations to modulate the MDR phenotype, will be reviewed. Finally, we will highlight novel strategies that could be used to modulate ncRNAs and circumvent ABC transporter-mediated MDR.
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Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
| | - Zoufang Huang
- Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Hang Zhang
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, United States
| | - Liwu Fu
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
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3
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Singh P. MicroRNA based combinatorial therapy against TKIs resistant CML by inactivating the PI3K/Akt/mTOR pathway: a review. Med Oncol 2023; 40:300. [PMID: 37713129 DOI: 10.1007/s12032-023-02161-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023]
Abstract
Chronic myeloid leukemia (CML) is characterized by presence of Philadelphia chromosome, which harbors BCR-ABL oncogene responsible for encoding BCR-ABL oncoprotein. This oncoprotein interferes with cellular signaling pathways, resulting in tumor progression. Among these pathways, PI3K/Akt/mTOR pathway is significantly upregulated in CML. Tyrosine kinase inhibitors (TKIs) are current standard therapy for CML, and they have shown remarkable efficacy. However, emergence of TKIs drug resistance has necessitated investigation of novel therapeutic approaches. Components of PI3K/Akt/mTOR pathway have emerged as attractive targets in this context, as this pathway is known to be activated in TKIs-resistant CML cells/patients. Inhibiting this pathway may provide a complementary approach to improving TKIs' efficacy and treatment outcomes. Given previous research indicating that miRNAs play an inhibitory role in cancer, current study used computational tools to identify miRNAs that specifically target pathway's core components. A comprehensive analysis was performed, resulting in identification of 111 miRNAs that potentially target PI3K/Akt/mTOR pathway. From this extensive list, 7 miRNAs was selected for further investigation based on their consistent downregulation across leukemia subtypes. Except for hsa-miR-199a-3p, remaining six miRNAs have been extensively studied in acute myeloid leukemia (AML). Given high similarity between AML and CML, it is believed that six miRNAs which are not studied in context of CML may also be advantageous for curing chemoresistance in CML. Building upon this knowledge, it is reasonable to speculate that a combination therapy approach involving use of miRNAs alongside TKIs may offer improved therapy for TKIs-resistant CML compared to TKIs monotherapy alone.
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Affiliation(s)
- Priyanka Singh
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Ghudda, 151401, Bathinda, India.
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Soussi M, Hasselsweiller A, Gkika D. TRP Channels: The Neglected Culprits in Breast Cancer Chemotherapy Resistance? MEMBRANES 2023; 13:788. [PMID: 37755210 PMCID: PMC10536409 DOI: 10.3390/membranes13090788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 09/28/2023]
Abstract
Breast cancer is a major health concern worldwide, and resistance to therapies remains a significant challenge in treating this disease. In breast cancer, Transient Receptor Potential (TRP) channels are well studied and constitute key players in nearly all carcinogenesis hallmarks. Recently, they have also emerged as important actors in resistance to therapy by modulating the response to various pharmaceutical agents. Targeting TRP channels may represent a promising approach to overcome resistance to therapies in breast cancer patients.
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Affiliation(s)
| | | | - Dimitra Gkika
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.S.); (A.H.)
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5
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Ma L, Li C, Yin H, Huang J, Yu S, Zhao J, Tang Y, Yu M, Lin J, Ding L, Cui Q. The Mechanism of DNA Methylation and miRNA in Breast Cancer. Int J Mol Sci 2023; 24:9360. [PMID: 37298314 PMCID: PMC10253858 DOI: 10.3390/ijms24119360] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 05/17/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Breast cancer is the most prevalent cancer in the world. Currently, the main treatments for breast cancer are radiotherapy, chemotherapy, targeted therapy and surgery. The treatment measures for breast cancer depend on the molecular subtype. Thus, the exploration of the underlying molecular mechanisms and therapeutic targets for breast cancer remains a hotspot in research. In breast cancer, a high level of expression of DNMTs is highly correlated with poor prognosis, that is, the abnormal methylation of tumor suppressor genes usually promotes tumorigenesis and progression. MiRNAs, as non-coding RNAs, have been identified to play key roles in breast cancer. The aberrant methylation of miRNAs could lead to drug resistance during the aforementioned treatment. Therefore, the regulation of miRNA methylation might serve as a therapeutic target in breast cancer. In this paper, we reviewed studies on the regulatory mechanisms of miRNA and DNA methylation in breast cancer from the last decade, focusing on the promoter region of tumor suppressor miRNAs methylated by DNMTs and the highly expressed oncogenic miRNAs inhibited by DNMTs or activating TETs.
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Affiliation(s)
- Lingyuan Ma
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.M.); (C.L.); (H.Y.); (J.H.); (S.Y.); (J.Z.); (Y.T.); (M.Y.); (J.L.)
- Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
| | - Chenyu Li
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.M.); (C.L.); (H.Y.); (J.H.); (S.Y.); (J.Z.); (Y.T.); (M.Y.); (J.L.)
- Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
| | - Hanlin Yin
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.M.); (C.L.); (H.Y.); (J.H.); (S.Y.); (J.Z.); (Y.T.); (M.Y.); (J.L.)
- Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
| | - Jiashu Huang
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.M.); (C.L.); (H.Y.); (J.H.); (S.Y.); (J.Z.); (Y.T.); (M.Y.); (J.L.)
- Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
| | - Shenghao Yu
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.M.); (C.L.); (H.Y.); (J.H.); (S.Y.); (J.Z.); (Y.T.); (M.Y.); (J.L.)
- Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
| | - Jin Zhao
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.M.); (C.L.); (H.Y.); (J.H.); (S.Y.); (J.Z.); (Y.T.); (M.Y.); (J.L.)
- Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
| | - Yongxu Tang
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.M.); (C.L.); (H.Y.); (J.H.); (S.Y.); (J.Z.); (Y.T.); (M.Y.); (J.L.)
- Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
| | - Min Yu
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.M.); (C.L.); (H.Y.); (J.H.); (S.Y.); (J.Z.); (Y.T.); (M.Y.); (J.L.)
- Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
| | - Jie Lin
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.M.); (C.L.); (H.Y.); (J.H.); (S.Y.); (J.Z.); (Y.T.); (M.Y.); (J.L.)
- Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
| | - Lei Ding
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.M.); (C.L.); (H.Y.); (J.H.); (S.Y.); (J.Z.); (Y.T.); (M.Y.); (J.L.)
- Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
| | - Qinghua Cui
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.M.); (C.L.); (H.Y.); (J.H.); (S.Y.); (J.Z.); (Y.T.); (M.Y.); (J.L.)
- Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, Kunming 650214, China
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Bhootra S, Jill N, Shanmugam G, Rakshit S, Sarkar K. DNA methylation and cancer: transcriptional regulation, prognostic, and therapeutic perspective. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2023; 40:71. [PMID: 36602616 DOI: 10.1007/s12032-022-01943-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 12/25/2022] [Indexed: 01/06/2023]
Abstract
DNA methylation is one among the major grounds of cancer progression which is characterized by the addition of a methyl group to the promoter region of the gene thereby causing gene silencing or increasing the probability of mutations; however, in bacteria, methylation is used as a defense mechanism where DNA protection is by addition of methyl groups making restriction enzymes unable to cleave. Hypermethylation and hypomethylation both pose as leading causes of oncogenesis; the former being more frequent which occurs at the CpG islands present in the promoter region of the genes, whereas the latter occurs globally in various genomic sequences. Reviewing methylation profiles would help in the detection and treatment of cancers. Demethylation is defined as preventing methyl group addition to the cytosine DNA base which could cause cancers in case of global hypomethylation, however, upon further investigation; it could be used as a therapeutic tool as well as for drug design in cancer treatment. In this review, we have studied the molecules that induce and enzymes (DNMTs) that bring about methylation as well as comprehend the correlation between methylation with transcription factors and various signaling pathways. DNA methylation has also been reviewed in terms of how it could serve as a prognostic marker and the various therapeutic drugs that have come into the market for reversing methylation opening an avenue toward curing cancers.
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Affiliation(s)
- Sannidhi Bhootra
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Nandana Jill
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Geetha Shanmugam
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Sudeshna Rakshit
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India.
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7
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Meng Q, Deng Y, Lu Y, Wu C, Tang S. Tumor-derived miRNAs as tumor microenvironment regulators for synergistic therapeutic options. J Cancer Res Clin Oncol 2023; 149:423-439. [PMID: 36378341 DOI: 10.1007/s00432-022-04432-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 10/18/2022] [Indexed: 11/16/2022]
Abstract
MicroRNAs (miRNAs) are a class of non-coding RNAs that perform post-transcriptional gene regulation. This review focuses on the role of tumor cell-derived miRNAs in the regulation of the tumor microenvironment (TME) via receptor cell recoding, including angiogenesis, expression of immunosuppressive molecules, formation of radiation resistance, and chemoresistance. Furthermore, we discuss the potential of these molecules as adjuvant therapies in combination with chemotherapy, radiotherapy, or immunotherapy, as well as their advantages as efficacy predictors for personalized therapy. MiRNA-based therapeutic agents for tumors are currently in clinical trials, and while challenges remain, additional research on tumor-derived miRNAs is warranted, which may provide significant clinical benefits to cancer patients.
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Affiliation(s)
- Qiuxing Meng
- Department of Laboratory Medicine, Liuzhou People's Hospital, Liu Zhou, China.,Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Liu Zhou, China
| | - Yaoming Deng
- Department of Laboratory Medicine, Liuzhou People's Hospital, Liu Zhou, China.,Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Liu Zhou, China
| | - Yu Lu
- Department of Laboratory Medicine, Liuzhou People's Hospital, Liu Zhou, China.,Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Liu Zhou, China
| | - Chunfeng Wu
- Department of Laboratory Medicine, Liuzhou People's Hospital, Liu Zhou, China.,Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Liu Zhou, China
| | - Shifu Tang
- Department of Laboratory Medicine, Liuzhou People's Hospital, Liu Zhou, China. .,Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Liu Zhou, China.
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8
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Zhang H, Zhang Z, Liu Z, Mu G, Xie Q, Zhou S, Wang Z, Cao Y, Tan Y, Wei X, Yuan D, Xiang Q, Cui Y. Circulating miR-320a-3p and miR-483-5p level associated with pharmacokinetic-pharmacodynamic profiles of rivaroxaban. Hum Genomics 2022; 16:72. [PMID: 36578040 PMCID: PMC9795792 DOI: 10.1186/s40246-022-00445-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 12/15/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Novel biomarkers for personalizing anticoagulation remain undetermined. We aimed to investigate the association of plasma miRNAs with pharmacokinetic-pharmacodynamic (PK-PD) profiles of rivaroxaban. METHODS This is a multicenter, exploratory study of miRNAs in a Chinese population. Healthy volunteers and patients receiving rivaroxaban were enrolled in the study. The area under the plasma concentration-time curve from time 0-t h (AUC0-t) and anti-Xa activity at 3 h (AXA3h) were measured in healthy volunteers, and AXA3h was measured in patients. MiRNAs were detected by miRNA microarray in 26 healthy volunteers with 20 mg rivaroxaban, and quantitative reverse transcription polymerase chain reaction was used to exclude undetectable ones. MiR-320a-3p and miR-483-5p were then quantified in 65 healthy volunteers and 71 patients. MiRNA levels at 3 h were compared between high and low AXA3h or AUC0-t subjects and in matched patients with or without bleeding during follow-up. The miRNA targets were predicted by TargetScan, miRTarBase, and miRDB. Validated genes were included in GO enrichment and KEGG analyses. The protein-protein interaction network was established by STRING and visualized by Cytoscape. RESULTS A total of 136 Chinese subjects completed the study. In healthy volunteers taking 15 mg rivaroxaban, the miR-320a level at 3 h was significantly positively correlated with AXA3h and AUC0-t (r = 0.359, p = 0.025; r = 0.370, p = 0.02, respectively). A positive correlation was also observed between miR-483 and AXA3h or AUC0-t (r = 0.372, p = 0.02; r = 0.523, p = 0.001, respectively). MiR-320a and miR-483 levels at 3 h in the higher AUC0-t group were significantly higher than those at 0 h. MiR-483 levels at 3 h may distinguish healthy volunteers with high or low AXA3h or AUC0-t. In the 10 mg fed subgroup, higher 3 h mir-483 levels were also observed compared with the control group. No significant differences were found in the comparisons among patients. Bioinformatic analysis showed that these miRNAs may play a regulatory role by targeting ABCG2, ITGB3, PTEN, MAPK1/3, etc. CONCLUSIONS: MiR-320a and miR-483 levels were found to be associated with PK and PD profiles of rivaroxaban in healthy Chinese subjects. Further studies are required to verify these findings and explore the mechanisms.
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Affiliation(s)
- Hanxu Zhang
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034 China ,grid.11135.370000 0001 2256 9319School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhuo Zhang
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034 China
| | - Zhiyan Liu
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034 China
| | - Guangyan Mu
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034 China
| | - Qiufen Xie
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034 China
| | - Shuang Zhou
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034 China ,grid.11135.370000 0001 2256 9319School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhe Wang
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034 China
| | - Yu Cao
- grid.412521.10000 0004 1769 1119Office of Drug Clinical Trial Management, Affiliated Hospital of Qingdao University, Qingdao, Shandong China
| | - Yunlong Tan
- grid.11135.370000 0001 2256 9319Psychiatry Research Center, Beijing HuiLongGuan Hospital, Peking University, Beijing, China
| | - Xiaohua Wei
- grid.412604.50000 0004 1758 4073Clinical Trial Research Center, Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi China
| | - Dongdong Yuan
- grid.417239.aDepartment of Pharmacy, The 7Th People’s Hospital of Zhengzhou, Zhengzhou, Henan China
| | - Qian Xiang
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034 China
| | - Yimin Cui
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034 China ,grid.11135.370000 0001 2256 9319School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China ,grid.11135.370000 0001 2256 9319Institute of Clinical Pharmacology, Peking University, Beijing, China
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9
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Crosstalk between Methylation and ncRNAs in Breast Cancer: Therapeutic and Diagnostic Implications. Int J Mol Sci 2022; 23:ijms232415759. [PMID: 36555400 PMCID: PMC9779155 DOI: 10.3390/ijms232415759] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/05/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Breast cancer, as a highly heterogeneous malignant tumor, is one of the primary causes of death among females worldwide. The etiology of breast cancer involves aberrant epigenetic mechanisms and abnormal expression of certain non-coding RNA (ncRNAs). DNA methylation, N6-methyladenosine(m6A), and histone methylation are widely explored epigenetic regulation types in breast cancer. ncRNAs are a group of unique RNA transcripts, mainly including microRNA (miRNAs), long non-coding RNA (lncRNAs), circular RNA (circRNAs), small interfering RNA (siRNAs), piwi-interacting RNA (piRNAs), etc. Different types of methylation and ncRNAs mutually regulate and interact to form intricate networks to mediate precisely breast cancer genesis. In this review, we elaborate on the crosstalk between major methylation modifications and ncRNAs and discuss the role of their interaction in promoting breast cancer oncogenesis. This review can provide novel insights into establishing a new diagnostic marker system on methylation patterns of ncRNAs and therapeutic perspectives of combining ncRNA oligonucleotides and phytochemical drugs for breast cancer therapy.
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10
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Romito O, Guéguinou M, Raoul W, Champion O, Robert A, Trebak M, Goupille C, Potier-Cartereau M. Calcium signaling: A therapeutic target to overcome resistance to therapies in cancer. Cell Calcium 2022; 108:102673. [PMID: 36410063 DOI: 10.1016/j.ceca.2022.102673] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/13/2022]
Abstract
Innate and acquired resistances to therapeutic agents are responsible for the failure of cancer treatments. Due to the multifactorial nature of resistance, the identification of new therapeutic targets is required to improve cancer treatment. Calcium is a universal second messenger that regulates many cellular functions such as proliferation, migration, and survival. Calcium channels, pumps and exchangers tightly regulate the duration, location and magnitude of calcium signals. Many studies have implicated dysregulation of calcium signaling in several pathologies, including cancer. Abnormal calcium fluxes due to altered channel expression or activation contribute to carcinogenesis and promote tumor development. However, there is limited information on the role of calcium signaling in cancer resistance to therapeutic drugs. This review discusses the role of calcium signaling as a mediator of cancer resistance, and assesses the potential value of combining anticancer therapy with calcium signaling modulators to improve the effectiveness of current treatments.
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Affiliation(s)
- Olivier Romito
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
| | - Maxime Guéguinou
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
| | - William Raoul
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
| | - Ophélie Champion
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
| | - Alison Robert
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
| | - Mohamed Trebak
- Vascular Medicine Institute, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Caroline Goupille
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France; CHRU de Tours, hôpital Bretonneau, Tours, France.
| | - Marie Potier-Cartereau
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
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11
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Yang CK, Hsu HC, Liu YH, Tsai WS, Ma CP, Chen YT, Tan BCM, Lai YY, Chang IYF, Yang C, Yang CY, Yu JS, Liu H. EV-miRome-wide profiling uncovers miR-320c for detecting metastatic colorectal cancer and monitoring the therapeutic response. Cell Oncol (Dordr) 2022; 45:621-638. [PMID: 35849310 PMCID: PMC9424175 DOI: 10.1007/s13402-022-00688-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2022] [Indexed: 11/28/2022] Open
Abstract
PURPOSE Molecular composition of circulating small extracellular vesicles (EVs) does not merely reflect the cells of origin, but also is enriched in specific biomolecules directly associated with the cellular transformation. However, while most of the currently identified EV-miRs are only geared towards one-dimensional disease detection, their application for long-term tracking and treatment response monitoring has been largely elusive. METHODS We established and optimized a rapid, sensitive and robust liquid biopsy sampling method, and further used small RNA sequencing to comprehensively catalogue EV-miRomes in association with the progression and outcome of metastatic colorectal cancer (mCRC). RESULTS By cross-comparison of EV-miRomes (n = 290) from multi-stage and longitudinal cohorts, we uncovered a 15-EV-miR signature with dual detection and long-term monitoring of tumor size progression for mCRC. From this panel, EV-miR-320c was uncovered as a strong clinical marker - aside from its diagnostic power and a therapeutic monitoring performance superior to carcinoembryonic antigen (CEA), its high expression has also been linked to lower overall survival and a greater likelihood of disease recurrence. Further, integrative analyses of tissue transcriptomic and liquid biopsy implicated this 15-EV-miR signature in programming the mesenchymal-epithelial transition (MET) for distant localization of the metastasized cells and also in creating a tumor-favoring metastatic niche. CONCLUSION Our clinically-oriented delineation of the mCRC-associated circulating EV-miRomes systematically revealed the functional significance of these liquid biopsy markers and further strengthen their translational potential in mCRC therapeutic monitoring.
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Affiliation(s)
- Chan-Keng Yang
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hung-Chih Hsu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Hao Liu
- Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wen-Sy Tsai
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chung-Pei Ma
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Yi-Tung Chen
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Bertrand Chin-Ming Tan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan
- Department of Neurosurgery, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ying-Yu Lai
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ian Yi-Feng Chang
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Department of Neurosurgery, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chi Yang
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Yu Yang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Jau-Song Yu
- Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Hsuan Liu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
- Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
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12
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Zhong T, Zhang W, Guo H, Pan X, Chen X, He Q, Yang B, Ding L. The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies. Acta Pharm Sin B 2022; 12:1761-1780. [PMID: 35847486 PMCID: PMC9279634 DOI: 10.1016/j.apsb.2021.11.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/11/2021] [Accepted: 10/19/2021] [Indexed: 02/08/2023] Open
Abstract
Transient receptor potential (TRP) channels are one primary type of calcium (Ca2+) permeable channels, and those relevant transmembrane and intracellular TRP channels were previously thought to be mainly associated with the regulation of cardiovascular and neuronal systems. Nowadays, however, accumulating evidence shows that those TRP channels are also responsible for tumorigenesis and progression, inducing tumor invasion and metastasis. However, the overall underlying mechanisms and possible signaling transduction pathways that TRP channels in malignant tumors might still remain elusive. Therefore, in this review, we focus on the linkage between TRP channels and the significant characteristics of tumors such as multi-drug resistance (MDR), metastasis, apoptosis, proliferation, immune surveillance evasion, and the alterations of relevant tumor micro-environment. Moreover, we also have discussed the expression of relevant TRP channels in various forms of cancer and the relevant inhibitors' efficacy. The chemo-sensitivity of the anti-cancer drugs of various acting mechanisms and the potential clinical applications are also presented. Furthermore, it would be enlightening to provide possible novel therapeutic approaches to counteract malignant tumors regarding the intervention of calcium channels of this type.
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Key Words
- 4α-PDD, 4α-phorbol-12,13-didecanoate
- ABCB, ATP-binding cassette B1
- AKT, protein kinase B
- ALA, alpha lipoic acid
- AMPK, AMP-activated protein kinase
- APB, aminoethoxydiphenyl borate
- ATP, adenosine triphosphate
- CBD, cannabidiol
- CRAC, Ca2+ release-activated Ca2+ channel
- CaR, calcium-sensing receptor
- CaSR, calcium sensing receptor
- Cancer progression
- DAG, diacylglycerol
- DBTRG, Denver Brain Tumor Research Group
- ECFC, endothelial colony-forming cells
- ECM, enhanced extracellular matrix
- EGF, epidermal growth factor
- EMT, epithelial–mesenchymal transition
- ER, endoplasmic reticulum
- ERK, extracellular signal-regulated kinase
- ETS, erythroblastosis virus E26 oncogene homolog
- FAK, focal adhesion kinase
- GADD, growth arrest and DNA damage-inducible gene
- GC, gastric cancer
- GPCR, G-protein coupled receptor
- GSC, glioma stem-like cells
- GSK, glycogen synthase kinase
- HCC, hepatocellular carcinoma
- HIF, hypoxia-induced factor
- HSC, hematopoietic stem cells
- IP3R, inositol triphosphate receptor
- Intracellular mechanism
- KO, knockout
- LOX, lipoxygenase
- LPS, lipopolysaccharide
- LRP, lipoprotein receptor-related protein
- MAPK, mitogen-activated protein kinase
- MLKL, mixed lineage kinase domain-like protein
- MMP, matrix metalloproteinases
- NEDD4, neural precursor cell expressed, developmentally down-regulated 4
- NFAT, nuclear factor of activated T-cells
- NLRP3, NLR family pyrin domain containing 3
- NO, nitro oxide
- NSCLC, non-small cell lung cancer
- Nrf2, nuclear factor erythroid 2-related factor 2
- P-gp, P-glycoprotein
- PCa, prostate cancer
- PDAC, pancreatic ductal adenocarcinoma
- PHD, prolyl hydroxylases
- PI3K, phosphoinositide 3-kinase
- PKC, protein kinase C
- PKD, polycystic kidney disease
- PLC, phospholipase C
- Programmed cancer cell death
- RNS/ROS, reactive nitrogen species/reactive oxygen species
- RTX, resiniferatoxin
- SMAD, Caenorhabditis elegans protein (Sma) and mothers against decapentaplegic (Mad)
- SOCE, store operated calcium entry
- SOR, soricimed
- STIM1, stromal interaction molecules 1
- TEC, tumor endothelial cells
- TGF, transforming growth factor-β
- TNF-α, tumor necrosis factor-α
- TRP channels
- TRPA/C/M/ML/N/P/V, transient receptor potential ankyrin/canonical/melastatin/mucolipon/NOMPC/polycystin/vanilloid
- Targeted tumor therapy
- Tumor microenvironment
- Tumor-associated immunocytes
- UPR, unfolded protein response
- VEGF, vascular endothelial growth factor
- VIP, vasoactive intestinal peptide
- VPAC, vasoactive intestinal peptide receptor subtype
- mTOR, mammalian target of rapamycin
- pFRG/RTN, parafacial respiratory group/retrotrapezoid nucleus
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13
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Kukal S, Guin D, Rawat C, Bora S, Mishra MK, Sharma P, Paul PR, Kanojia N, Grewal GK, Kukreti S, Saso L, Kukreti R. Multidrug efflux transporter ABCG2: expression and regulation. Cell Mol Life Sci 2021; 78:6887-6939. [PMID: 34586444 PMCID: PMC11072723 DOI: 10.1007/s00018-021-03901-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/24/2021] [Accepted: 07/15/2021] [Indexed: 12/15/2022]
Abstract
The adenosine triphosphate (ATP)-binding cassette efflux transporter G2 (ABCG2) was originally discovered in a multidrug-resistant breast cancer cell line. Studies in the past have expanded the understanding of its role in physiology, disease pathology and drug resistance. With a widely distributed expression across different cell types, ABCG2 plays a central role in ATP-dependent efflux of a vast range of endogenous and exogenous molecules, thereby maintaining cellular homeostasis and providing tissue protection against xenobiotic insults. However, ABCG2 expression is subjected to alterations under various pathophysiological conditions such as inflammation, infection, tissue injury, disease pathology and in response to xenobiotics and endobiotics. These changes may interfere with the bioavailability of therapeutic substrate drugs conferring drug resistance and in certain cases worsen the pathophysiological state aggravating its severity. Considering the crucial role of ABCG2 in normal physiology, therapeutic interventions directly targeting the transporter function may produce serious side effects. Therefore, modulation of transporter regulation instead of inhibiting the transporter itself will allow subtle changes in ABCG2 activity. This requires a thorough comprehension of diverse factors and complex signaling pathways (Kinases, Wnt/β-catenin, Sonic hedgehog) operating at multiple regulatory levels dictating ABCG2 expression and activity. This review features a background on the physiological role of transporter, factors that modulate ABCG2 levels and highlights various signaling pathways, molecular mechanisms and genetic polymorphisms in ABCG2 regulation. This understanding will aid in identifying potential molecular targets for therapeutic interventions to overcome ABCG2-mediated multidrug resistance (MDR) and to manage ABCG2-related pathophysiology.
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Affiliation(s)
- Samiksha Kukal
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Debleena Guin
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Main Bawana Road, Delhi, 110042, India
| | - Chitra Rawat
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shivangi Bora
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Main Bawana Road, Delhi, 110042, India
| | - Manish Kumar Mishra
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Main Bawana Road, Delhi, 110042, India
| | - Priya Sharma
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
| | - Priyanka Rani Paul
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Neha Kanojia
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Gurpreet Kaur Grewal
- Department of Biotechnology, Kanya Maha Vidyalaya, Jalandhar, Punjab, 144004, India
| | - Shrikant Kukreti
- Nucleic Acids Research Lab, Department of Chemistry, University of Delhi (North Campus), Delhi, 110007, India
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, P. le Aldo Moro 5, 00185, Rome, Italy
| | - Ritushree Kukreti
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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14
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Garrido-Cano I, Pattanayak B, Adam-Artigues A, Lameirinhas A, Torres-Ruiz S, Tormo E, Cervera R, Eroles P. MicroRNAs as a clue to overcome breast cancer treatment resistance. Cancer Metastasis Rev 2021; 41:77-105. [PMID: 34524579 PMCID: PMC8924146 DOI: 10.1007/s10555-021-09992-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 09/02/2021] [Indexed: 12/31/2022]
Abstract
Breast cancer is the most frequent cancer in women worldwide. Despite the improvement in diagnosis and treatments, the rates of cancer relapse and resistance to therapies remain higher than desirable. Alterations in microRNAs have been linked to changes in critical processes related to cancer development and progression. Their involvement in resistance or sensitivity to breast cancer treatments has been documented by different in vivo and in vitro experiments. The most significant microRNAs implicated in modulating resistance to breast cancer therapies are summarized in this review. Resistance to therapy has been linked to cellular processes such as cell cycle, apoptosis, epithelial-to-mesenchymal transition, stemness phenotype, or receptor signaling pathways, and the role of microRNAs in their regulation has already been described. The modulation of specific microRNAs may modify treatment response and improve survival rates and cancer patients' quality of life. As a result, a greater understanding of microRNAs, their targets, and the signaling pathways through which they act is needed. This information could be useful to design new therapeutic strategies, to reduce resistance to the available treatments, and to open the door to possible new clinical approaches.
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Affiliation(s)
| | | | | | - Ana Lameirinhas
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain
| | | | - Eduardo Tormo
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain.,Center for Biomedical Network Research On Cancer, CIBERONC-ISCIII, 28029, Madrid, Spain
| | | | - Pilar Eroles
- INCLIVA Biomedical Research Institute, 46010, Valencia, Spain. .,Center for Biomedical Network Research On Cancer, CIBERONC-ISCIII, 28029, Madrid, Spain. .,Department of Physiology, University of Valencia, 46010, Valencia, Spain.
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15
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Liang Y, Li S, Tang L. MicroRNA 320, an Anti-Oncogene Target miRNA for Cancer Therapy. Biomedicines 2021; 9:biomedicines9060591. [PMID: 34071109 PMCID: PMC8224659 DOI: 10.3390/biomedicines9060591] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/18/2021] [Accepted: 05/20/2021] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs are a set of highly conserved non-coding RNAs that control gene expression at the post-transcriptional/translational levels by binding to the 3′-UTR of diverse target genes. Increasing evidence indicates that miRNAs not only play a vital role in many biological processes, but they are also frequently deregulated in pathological conditions, including cancer. The miR-320 family is one of many tumor suppressor families and is composed of five members, which has been demonstrated to be related to the repression of epithelial-mesenchymal transition (EMT) inhibition, cell proliferation, and apoptosis. Moreover, this family has been shown to regulate drug resistance, and act as a potential biomarker for the diagnosis, prognosis, and prediction of cancer. In this review, we summarized recent research with reference to the tumor suppressor function of miR-320 and the regulation mechanisms of miR-320 expression. The collected evidence shown here supports that miR-320 may act as a novel biomarker for cancer prognosis and therapeutic response to cancer treatment.
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Affiliation(s)
- Yuanyuan Liang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China;
| | - Shun Li
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
- Non-Coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu 610500, China
- Correspondence: (S.L.); (L.T.)
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China;
- Correspondence: (S.L.); (L.T.)
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16
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Singh S, Raza W, Parveen S, Meena A, Luqman S. Flavonoid display ability to target microRNAs in cancer pathogenesis. Biochem Pharmacol 2021; 189:114409. [PMID: 33428895 DOI: 10.1016/j.bcp.2021.114409] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/01/2021] [Accepted: 01/05/2021] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are non-coding, conserved, single-stranded nucleotide sequences involved in physiological and developmental processes. Recent evidence suggests an association between miRNAs' deregulation with initiation, promotion, progression, and drug resistance in cancer cells. Besides, miRNAs are known to regulate the epithelial-mesenchymal transition, angiogenesis, autophagy, and senescence in different cancer types. Previous reports proposed that apart from the antioxidant potential, flavonoids play an essential role in miRNAs modulation associated with changes in cancer-related proteins, tumor suppressor genes, and oncogenes. Thus, flavonoids can suppress proliferation, help in the development of drug sensitivity, suppress metastasis and angiogenesis by modulating miRNAs expression. In the present review, we summarize the role of miRNAs in cancer, drug resistance, and the chemopreventive potential of flavonoids mediated by miRNAs. The potential of flavonoids to modulate miRNAs expression in different cancer types demonstrate their selectivity and importance as regulators of carcinogenesis. Flavonoids as chemopreventive agents targeting miRNAs are extensively studied in vitro, in vivo, and pre-clinical studies, but their efficiency in targeting miRNAs in clinical studies is less investigated. The evidence presented in this review highlights the potential of flavonoids in cancer prevention/treatment by regulating miRNAs, although further investigations are required to validate and establish their clinical usefulness.
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Affiliation(s)
- Shilpi Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Waseem Raza
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Jawahar Lal Nehru University, New Delhi 110067, India
| | - Shahnaz Parveen
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India.
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17
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Dobre EG, Dinescu S, Costache M. Connecting the Missing Dots: ncRNAs as Critical Regulators of Therapeutic Susceptibility in Breast Cancer. Cancers (Basel) 2020; 12:E2698. [PMID: 32967267 PMCID: PMC7565380 DOI: 10.3390/cancers12092698] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/10/2020] [Accepted: 09/14/2020] [Indexed: 12/24/2022] Open
Abstract
Whether acquired or de novo, drug resistance remains a significant hurdle in achieving therapeutic success in breast cancer (BC). Thus, there is an urge to find reliable biomarkers that will help in predicting the therapeutic response. Stable and easily accessible molecules such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are regarded as valuable prognostic biomarkers and therapeutic targets since they act as crucial regulators of the various mechanisms involved in BC drug resistance. Here, we reviewed the current literature on ncRNAs as mediators of resistance to systemic therapies in BC. Interestingly, upon integrating data results from individual studies, we concluded that miR-221, miR-222, miR-451, Urothelial Carcinoma Associated 1 (UCA1), and Growth arrest-specific 5 (GAS5) are strong candidates as prognostic biomarkers and therapeutic targets since they are regulating multiple drug resistance phenotypes in BC. However, further research around their clinical implications is needed to validate and integrate them into therapeutic applications. Therefore, we believe that our review may provide relevant evidence for the selection of novel therapeutic targets and prognostic biomarkers for BC and will serve as a foundation for future translational research in the field.
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Affiliation(s)
- Elena-Georgiana Dobre
- AMS Genetic Lab, 030882 Bucharest, Romania;
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania;
| | - Sorina Dinescu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania;
- The Research Institute of the University of Bucharest, 050095 Bucharest, Romania
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania;
- The Research Institute of the University of Bucharest, 050095 Bucharest, Romania
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18
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Romero-Garcia S, Prado-Garcia H, Carlos-Reyes A. Role of DNA Methylation in the Resistance to Therapy in Solid Tumors. Front Oncol 2020; 10:1152. [PMID: 32850327 PMCID: PMC7426728 DOI: 10.3389/fonc.2020.01152] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022] Open
Abstract
Despite the recent advances in chemotherapeutic treatments against cancer, some types of highly aggressive and invasive cancer develop drug resistance against conventional therapies, which continues to be a major problem in the fight against cancer. In recent years, studies of alterations of DNA methylome have given us a better understanding of the role of DNA methylation in the development of tumors. DNA methylation (DNAm) is an epigenetic change that promotes the covalent transfer of methyl groups to DNA. This process suppresses gene expression through the modulation of the transcription machinery access to the chromatin or through the recruitment of methyl binding proteins. DNAm is regulated mainly by DNA methyltransferases. Aberrant DNAm contributes to tumor progression, metastasis, and resistance to current anti-tumoral therapies. Aberrant DNAm may occur through hypermethylation in the promoter regions of tumor suppressor genes, which leads to their silencing, while hypomethylation in the promoter regions of oncogenes can activate them. In this review, we discuss the impact of dysregulated methylation in certain genes, which impact signaling pathways associated with apoptosis avoidance, metastasis, and resistance to therapy. The analysis of methylome has revealed patterns of global methylation, which regulate important signaling pathways involved in therapy resistance in different cancer types, such as breast, colon, and lung cancer, among other solid tumors. This analysis has provided gene-expression signatures of methylated region-specific DNA that can be used to predict the treatment outcome in response to anti-cancer therapy. Additionally, changes in cancer methylome have been associated with the acquisition of drug resistance. We also review treatments with demethylating agents that, in combination with standard therapies, seem to be encouraging, as tumors that are in early stages can be successfully treated. On the other hand, tumors that are in advanced stages can be treated with these combination schemes, which could sensitize tumor cells that are resistant to the therapy. We propose that rational strategies, which combine specific demethylating agents with conventional treatment, may improve overall survival in cancer patients.
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Affiliation(s)
- Susana Romero-Garcia
- Department of Chronic-Degenerative Diseases, National Institute of Respiratory Diseases "Ismael Cosío Villegas", Mexico City, Mexico
| | - Heriberto Prado-Garcia
- Department of Chronic-Degenerative Diseases, National Institute of Respiratory Diseases "Ismael Cosío Villegas", Mexico City, Mexico
| | - Angeles Carlos-Reyes
- Department of Chronic-Degenerative Diseases, National Institute of Respiratory Diseases "Ismael Cosío Villegas", Mexico City, Mexico
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19
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Santoni G, Morelli MB, Marinelli O, Nabissi M, Santoni M, Amantini C. Calcium Signaling and the Regulation of Chemosensitivity in Cancer Cells: Role of the Transient Receptor Potential Channels. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1131:505-517. [PMID: 31646523 DOI: 10.1007/978-3-030-12457-1_20] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cancer cells acquire the ability to modify the calcium signaling network by altering the expression and functions of cation channels, pumps or transporters. Calcium signaling pathways are involved in proliferation, angiogenesis, invasion, immune evasion, disruption of cell death pathways, ECM remodelling, epithelial-mesenchymal transition (EMT) and drug resistance. Among cation channels, a pivotal role is played by the Transient Receptor Potential non-selective cation-permeable receptors localized in plasma membrane, endoplasmic reticulum, mitochondria and lysosomes. Several findings indicate that the dysregulation in calcium signaling induced by TRP channels is responsible for cancer growth, metastasis and chemoresistance. Drug resistance represents a major limitation in the application of current therapeutic regimens and several efforts are spent to overcome it. Here we describe the ability of Transient Receptor Potential Channels to modify, by altering the intracellular calcium influx, the cancer cell sensitivity to chemotherapeutic drugs.
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Affiliation(s)
- Giorgio Santoni
- School of Pharmacy, Immunopathology and Molecular Medicine Laboratory, University of Camerino, Camerino, Italy
| | - Maria Beatrice Morelli
- School of Pharmacy, Immunopathology and Molecular Medicine Laboratory, University of Camerino, Camerino, Italy.,School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
| | - Oliviero Marinelli
- School of Pharmacy, Immunopathology and Molecular Medicine Laboratory, University of Camerino, Camerino, Italy.,School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
| | - Massimo Nabissi
- School of Pharmacy, Immunopathology and Molecular Medicine Laboratory, University of Camerino, Camerino, Italy
| | - Matteo Santoni
- Clinic and Oncology Unit, Macerata Hospital, Macerata, Italy
| | - Consuelo Amantini
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
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20
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Santoni G, Morelli MB, Santoni M, Nabissi M, Marinelli O, Amantini C. Targeting Transient Receptor Potential Channels by MicroRNAs Drives Tumor Development and Progression. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1131:605-623. [PMID: 31646527 DOI: 10.1007/978-3-030-12457-1_24] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Transient receptor potential (TRP) cation channel superfamily plays important roles in a variety of cellular processes such polymodal cellular sensing, adhesion, polarity, proliferation, differentiation and apoptosis. The expression of TRP channels is strictly regulated and their de-regulation can stimulate cancer development and progression.In human cancers, specific miRNAs are expressed in different tissues, and changes in the regulation of gene expression mediated by specific miRNAs have been associated with carcinogenesis. Several miRNAs/TRP channel pairs have been reported to play an important role in tumor biology. Thus, the TRPM1 gene regulates melanocyte/melanoma behaviour via TRPM1 and microRNA-211 transcripts. Both miR-211 and TRPM1 proteins are regulated through microphthalmia-associated transcription factor (MIFT) and the expression of miR-211 is decreased during melanoma progression. Melanocyte phenotype and melanoma behaviour strictly depend on dual TRPM1 activity, with loss of TRPM1 protein promoting melanoma aggressiveness and miR-211 expression supporting tumour suppressor. TRPM3 plays a major role in the development and progression of human clear cell renal cell carcinoma (ccRCC) with von Hippel-Lindau (VHL) loss. TRPM3, a direct target of miR-204, is enhanced in ccRCC with inactivated or deleted VHL. Loss of VHL inhibits miR-204 expression that lead to increased oncogenic autophagy. Therefore, the understanding of specific TRP channels/miRNAs molecular pathways in distinct tumors could provide a clinical rationale for target therapy in cancer.
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Affiliation(s)
- Giorgio Santoni
- School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy.
| | - Maria Beatrice Morelli
- School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy
| | - Matteo Santoni
- Clinic and Oncology Unit, Macerata Hospital, Macerata, Italy
| | - Massimo Nabissi
- School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy
| | - Oliviero Marinelli
- School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
| | - Consuelo Amantini
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
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21
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Transient Receptor Potential Cation Channels in Cancer Therapy. Med Sci (Basel) 2019; 7:medsci7120108. [PMID: 31801263 PMCID: PMC6950741 DOI: 10.3390/medsci7120108] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/08/2019] [Accepted: 11/26/2019] [Indexed: 02/06/2023] Open
Abstract
In mammals, the transient receptor potential (TRP) channels family consists of six different families, namely TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPA (ankyrin), that are strictly connected with cancer cell proliferation, differentiation, cell death, angiogenesis, migration, and invasion. Changes in TRP channels' expression and function have been found to regulate cell proliferation and resistance or sensitivity of cancer cells to apoptotic-induced cell death, resulting in cancer-promoting effects or resistance to chemotherapy treatments. This review summarizes the data reported so far on the effect of targeting TRP channels in different types of cancer by using multiple TRP-specific agonists, antagonists alone, or in combination with classic chemotherapeutic agents, microRNA specifically targeting the TRP channels, and so forth, and the in vitro and in vivo feasibility evaluated in experimental models and in cancer patients. Considerable efforts have been made to fight cancer cells, and therapies targeting TRP channels seem to be the most promising strategy. However, more in-depth investigations are required to completely understand the role of TRP channels in cancer in order to design new, more specific, and valuable pharmacological tools.
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22
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Li YS, Zou Y, Dai DQ. MicroRNA-320a suppresses tumor progression by targeting PBX3 in gastric cancer and is downregulated by DNA methylation. World J Gastrointest Oncol 2019; 11:842-856. [PMID: 31662823 PMCID: PMC6815930 DOI: 10.4251/wjgo.v11.i10.842] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 06/19/2019] [Accepted: 07/28/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Ectopic expression of miRNAs promotes tumor development and progression. miRNA (miR)-320a is downregulated in many cancers, including gastric cancer (GC). However, the mechanism underlying its downregulation and the role of miR-320a in GC are unknown.
AIM To determine expression and biological functions of miR-320a in GC and investigate the underlying molecular mechanisms.
METHODS Quantitative real-time polymerase chain reaction (PCR) was used to determine expression of miR-320a in GC cell lines and tissues. TargetScanHuman7.1, miRDB, and microRNA.org were used to predict the possible targets of miR-320a, and a dual luciferase assay was used to confirm the findings. Western blotting was used to detect the protein levels of pre-B-cell leukemia homeobox 3 (PBX3) in GC cells and tissue samples. Cell Counting Kit-8 proliferation, Transwell, wound healing, and apoptosis assays were performed to analyze the biological functions of miR-320a in GC cells. Methylation-specific PCR was used to analyze the methylation level of the miR-320a promoter CpG islands. 5-Aza-2’-deoxycytidine (5-Aza-CdR) and trichostatin A (TSA) were used to treat GC cells.
RESULTS miR-320a expression was lower in GC cell lines and tissues than in the normal gastric mucosa cell line GES-1 and matched adjacent normal tissues. miR-320a overexpression suppressed GC cell proliferation, invasion and migration, and induced apoptosis. PBX3 was a target of miR-320a in GC. The methylation level of the miR-320a promoter CpG islands was elevated and this was partly reversed by 5-Aza-CdR and TSA.
CONCLUSION miR-320a acts as a tumor suppressor and inhibits malignant behavior of GC cells, partly by targeting PBX3. DNA methylation is an important mechanism associated with low expression of miR-320a.
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Affiliation(s)
- Yong-Shuang Li
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Ying Zou
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Dong-Qiu Dai
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
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23
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Clinical Theragnostic Relationship between Drug-Resistance Specific miRNA Expressions, Chemotherapeutic Resistance, and Sensitivity in Breast Cancer: A Systematic Review and Meta-Analysis. Cells 2019; 8:cells8101250. [PMID: 31615089 PMCID: PMC6830093 DOI: 10.3390/cells8101250] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/20/2019] [Accepted: 09/21/2019] [Indexed: 12/12/2022] Open
Abstract
Awareness of breast cancer has been increasing due to early detection, but the advanced disease has limited treatment options. There has been growing evidence on the role of miRNAs involved in regulating the resistance in several cancers. We performed a comprehensive systematic review and meta-analysis on the role of miRNAs in influencing the chemoresistance and sensitivity of breast cancer. A bibliographic search was performed in PubMed and Science Direct based on the search strategy, and studies published until December 2018 were retrieved. The eligible studies were included based on the selection criteria, and a detailed systematic review and meta-analysis were performed based on PRISMA guidelines. A random-effects model was utilised to evaluate the combined effect size of the obtained hazard ratio and 95% confidence intervals from the eligible studies. Publication bias was assessed with Cochran’s Q test, I2 statistic, Orwin and Classic fail-safe N test, Begg and Mazumdar rank correlation test, Duval and Tweedie trim and fill calculation and the Egger’s bias indicator. A total of 4584 potential studies were screened. Of these, 85 articles were eligible for our systematic review and meta-analysis. In the 85 studies, 188 different miRNAs were studied, of which 96 were upregulated, 87 were downregulated and 5 were not involved in regulation. Overall, 24 drugs were used for treatment, with doxorubicin being prominently reported in 15 studies followed by Paclitaxel in 11 studies, and 5 drugs were used in combinations. We found only two significant HR values from the studies (miR-125b and miR-4443) and our meta-analysis results yielded a combined HR value of 0.748 with a 95% confidence interval of 0.508–1.100; p-value of 0.140. In conclusion, our results suggest there are different miRNAs involved in the regulation of chemoresistance through diverse drug genetic targets. These biomarkers play a crucial role in guiding the effective diagnostic and prognostic efficiency of breast cancer. The screening of miRNAs as a theragnostic biomarker must be brought into regular practice for all diseases. We anticipate that our study serves as a reference in framing future studies and clinical trials for utilising miRNAs and their respective drug targets.
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Zong L, Hattori N, Yasukawa Y, Kimura K, Mori A, Seto Y, Ushijima T. LINC00162 confers sensitivity to 5-Aza-2'-deoxycytidine via modulation of an RNA splicing protein, HNRNPH1. Oncogene 2019; 38:5281-5293. [PMID: 30914798 DOI: 10.1038/s41388-019-0792-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/12/2019] [Accepted: 03/14/2019] [Indexed: 12/13/2022]
Abstract
DNA demethylation therapy is now expanding from hematological tumors to solid tumors. To exploit its maximum efficacy, long-term treatment is needed, and stratification of sensitive patients is critically important. Here, we identified a long non-coding RNA, LINC00162, as highly and frequently expressed in gastric cancer cell lines sensitive to 5-aza-2'-deoxycytidine (5-aza-dC). Knockdown of LINC00162 decreased the sensitivity while its overexpression increased the sensitivity. In vivo experiments also showed that LINC00162 overexpression increased the sensitivity. LINC00162 enhanced cell cycle arrest and apoptosis induced by 5-aza-dC, but did not affect its DNA demethylation effect. Mechanistically, LINC00162 interacted with an RNA splicing protein, HNRNPH1, and decreased splicing of an anti-apoptotic splicing variant, BCL-XL. LINC00162 may have translational value to predict patients who will respond to 5-aza-dC.
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Affiliation(s)
- Liang Zong
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Naoko Hattori
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yoshimi Yasukawa
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kana Kimura
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akiko Mori
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
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25
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The role and mechanisms of action of microRNAs in cancer drug resistance. Clin Epigenetics 2019; 11:25. [PMID: 30744689 PMCID: PMC6371621 DOI: 10.1186/s13148-018-0587-8] [Citation(s) in RCA: 482] [Impact Index Per Article: 80.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 11/19/2018] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs with a length of about 19–25 nt, which can regulate various target genes and are thus involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. Drug resistance in cancer chemotherapy is one of the main obstacles to curing this malignant disease. Statistical data indicate that over 90% of the mortality of patients with cancer is related to drug resistance. Drug resistance of cancer chemotherapy can be caused by many mechanisms, such as decreased antitumor drug uptake, modified drug targets, altered cell cycle checkpoints, or increased DNA damage repair, among others. In recent years, many studies have shown that miRNAs are involved in the drug resistance of tumor cells by targeting drug-resistance-related genes or influencing genes related to cell proliferation, cell cycle, and apoptosis. A single miRNA often targets a number of genes, and its regulatory effect is tissue-specific. In this review, we emphasize the miRNAs that are involved in the regulation of drug resistance among different cancers and probe the mechanisms of the deregulated expression of miRNAs. The molecular targets of miRNAs and their underlying signaling pathways are also explored comprehensively. A holistic understanding of the functions of miRNAs in drug resistance will help us develop better strategies to regulate them efficiently and will finally pave the way toward better translation of miRNAs into clinics, developing them into a promising approach in cancer therapy.
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26
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Regional methylome profiling reveals dynamic epigenetic heterogeneity and convergent hypomethylation of stem cell quiescence-associated genes in breast cancer following neoadjuvant chemotherapy. Cell Biosci 2019; 9:16. [PMID: 30774927 PMCID: PMC6367786 DOI: 10.1186/s13578-019-0278-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 01/28/2019] [Indexed: 12/17/2022] Open
Abstract
Background Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~ 30% of patients with breast cancer. However, aberrant DNA methylation alterations are frequent events during breast cancer progression and acquisition of chemoresistance. We aimed to characterize the inter- and intra-tumor methylation heterogeneity (MH) in breast cancer following NAC. Methods DNA methylation profiles of spatially separated regions of breast tumors before and after NAC treatment were investigated using high-density methylation microarray. Methylation levels of genes of interest were further examined using multiplexed MethyLight droplet digital PCR (ddPCR). Results We have discovered different levels of intra-tumor MH in breast cancer patients. Moreover, NAC dramatically altered the methylation profiles and such changes were highly heterogeneous between the patients. Despite the high inter-patient heterogeneity, we identified that stem cell quiescence-associated genes ALDH1L1, HOPX, WNT5A and SOX9 were convergently hypomethylated across all the samples after NAC treatment. Furthermore, by using MethyLight ddPCR, we verified that the methylation levels of these 4 genes were significantly lower in breast tumor samples after NAC than those before NAC. Conclusions Our study has revealed that NAC dramatically alters epigenetic heterogeneity in breast cancer and induces convergent hypomethylation of stem cell quiescence-associated genes, ALDH1L1, HOPX, WNT5A and SOX9, which can potentially be developed as therapeutic targets or biomarkers for chemoresistance. Electronic supplementary material The online version of this article (10.1186/s13578-019-0278-y) contains supplementary material, which is available to authorized users.
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27
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Loginov VI, Filippova EA, Kurevlev SV, Fridman MV, Burdennyy AM, Braga EA. Suppressive and Hypermethylated MicroRNAs in the Pathogenesis of Breast Cancer. RUSS J GENET+ 2018. [DOI: 10.1134/s1022795418070086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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28
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Wei JH, Luo QQ, Tang YJ, Chen JX, Huang CL, Lu DG, Tang QL. Upregulation of microRNA-320 decreases the risk of developing steroid-induced avascular necrosis of femoral head by inhibiting CYP1A2 both in vivo and in vitro. Gene 2018; 660:136-144. [DOI: 10.1016/j.gene.2018.03.045] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 03/15/2018] [Indexed: 12/15/2022]
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29
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Zhu G, Xie C, Yang Z, Wang Y, Chen D, Wang X. Expression of TRPC5 is decreased in the sperm of patients with varicocele-associated asthenozoospermia. Biomed Rep 2018; 8:529-534. [PMID: 29774143 DOI: 10.3892/br.2018.1089] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 03/28/2018] [Indexed: 12/21/2022] Open
Abstract
The present study aimed to determine whether the expression of transient receptor potential channel 5 (TRPC5) protein is altered in spermatozoa of patients with varicocele-associated asthenozoospermia. TRPC5 expression in spermatozoa was determined by polymerase chain reaction and western blotting analyses, and indirect immunofluorescence was used for identification and immunolocalization of the TRPC5 channel in human sperm. Sperm motility and superoxide dismutase (SOD) activity were also determined with a computer-assisted semen analysis system and assay kit, respectively. Compared with levels in control subjects, it was identified that TRPC5 protein expression, SOD activity and cellular motility in the sperm of patients with varicocele-associated asthenozoospermia were reduced (P<0.001). Furthermore, the expression of TRPC5 was positively correlated with sperm motility (r=0.781, P<0.001) and SOD activity (r=0.933, P<0.001), indicated by partial correlation analysis. The present study may provide a novel target for the study and treatment of varicocele-associated asthenozoospermia.
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Affiliation(s)
- Guangbin Zhu
- Department of Urology, Daqing Oilfield General Hospital, Daqing, Heilongjiang 163000, P.R. China.,Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Changying Xie
- Department of Urology, Daqing Oilfield General Hospital, Daqing, Heilongjiang 163000, P.R. China
| | - Zhonghua Yang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yongzhi Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Dong Chen
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Xinghuan Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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30
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Li YL, Jin YF, Liu XX, Li HJ. A comprehensive analysis of Wnt/β-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As 2O 3 in renal cancer. Ren Fail 2018; 40:331-339. [PMID: 29633893 PMCID: PMC6014489 DOI: 10.1080/0886022x.2018.1456461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
We aimed to investigate the effect of As2O3 treatment on Wnt/β-catenin signaling pathway-related genes and pathways in renal cancer. Illumina-based RNA-seq of 786-O cells with or without As2O3 treatment was performed, and differentially expressed genes (DEGs) were identified using Cuffdiff software. TargetMine was utilized to perform Gene Ontology (GO) pathway and Disease Ontology enrichment analyses. Furthermore, TRANSFAC database and LPIA method were applied to select differentially expressed transcription factors (TFs) and pathways related to Wnt/β-catenin signaling pathway, respectively. Additionally, transcriptional regulatory and pathway crosstalk networks were constructed. In total, 1684 DEGs and 69 TFs were screened out. The 821 up-regulated DEGs were mainly enriched in 67 pathways, 70 GO terms, and 46 disease pathways, while only 1 pathway and 5 GO terms were enriched for 863 down-regulated DEGs. A total of 18 DEGs (4 up-regulated and 14 down-regulated genes) were involved in the Wnt/β-catenin signaling pathway. Among the 18 DEGs, 4 ones were TFs. Furthermore, 211 pathways were predicted to be linked to the Wnt/β-catenin signaling pathway. In conclusion, As2O3 may have a significant effect on the Wnt/β-catenin signaling pathway for renal cancer treatment. The potential key DEGs are expected to be used as therapeutic targets.
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Affiliation(s)
- Yan-Lei Li
- a Medical Examination Center , China-Japan Union Hospital of Jilin University , Changchun , China
| | - Yu-Fen Jin
- b Clinical Laboratory , The Second Hospital of Jilin University , Changchun , China
| | - Xiu-Xia Liu
- b Clinical Laboratory , The Second Hospital of Jilin University , Changchun , China
| | - Hong-Jun Li
- a Medical Examination Center , China-Japan Union Hospital of Jilin University , Changchun , China
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31
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Jahangiri R, Mosaffa F, Emami Razavi A, Teimoori‐Toolabi L, Jamialahmadi K. Altered DNA methyltransferases promoter methylation and mRNA expression are associated with tamoxifen response in breast tumors. J Cell Physiol 2018; 233:7305-7319. [DOI: 10.1002/jcp.26562] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 02/23/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Rosa Jahangiri
- Department of Medical BiotechnologyFaculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Fatemeh Mosaffa
- Biotechnology Research CenterPharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran
- Department of Pharmaceutical BiotechnologySchool of PharmacyMashhad University of Medical SciencesMashhadIran
| | - Amirnader Emami Razavi
- Iran National Tumor BankCancer Biology Research CenterCancer Institute of IranTehran University of Medical SciencesTehranIran
| | | | - Khadijeh Jamialahmadi
- Biotechnology Research CenterPharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran
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32
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Interplay between regulation by methylation and noncoding RNAs in cancers. Eur J Cancer Prev 2018; 27:418-424. [PMID: 29557800 DOI: 10.1097/cej.0000000000000433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Cancer is one of the most important health problems today; therefore, many researchers are focusing on exploring the mechanisms underlying its development and treatment. The field of cancer epigenetics has flourished in recent decades, and studies have shown that different epigenetic events, such as DNA methylation, histone modification, and noncoding RNA regulation, work together to influence cancer development and progression. In this short review, we summarize the interactions between methylation and noncoding RNAs that affect cancer development.
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Alfano L, Costa C, Caporaso A, Antonini D, Giordano A, Pentimalli F. HUR protects NONO from degradation by mir320, which is induced by p53 upon UV irradiation. Oncotarget 2018; 7:78127-78139. [PMID: 27816966 PMCID: PMC5363649 DOI: 10.18632/oncotarget.13002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 10/12/2016] [Indexed: 12/13/2022] Open
Abstract
UV radiations challenge genomic stability and are a recognized cancer risk factor. We previously found that the RNA-binding protein NONO regulates the intra-S phase checkpoint and its silencing impaired HeLa and melanoma cell response to UV-induced DNA damage. Here we investigated the mechanisms underlying NONO regulation upon UVC treatment. We found that UVC rays induce the expression of mir320a, which can indeed target NONO. However, despite mir320a induction, NONO mRNA and protein expression are not affected by UVC. We found through RNA immunoprecipitation that UVC rays induce the ubiquitous RNA-binding protein HUR to bind NONO 5′UTR in a site overlapping mir320a binding site. Both HUR silencing and its pharmacological inhibition induced NONO downregulation following UVC exposure, whereas concomitant mir320a silencing restored NONO stability. UVC-mediated mir320a upregulation is triggered by p53 binding to its promoter, which lies within a region marked by H3K4me3 and H3K27ac signals upon UVC treatment. Silencing mir320a sensitizes cells to DNA damage. Overall our findings reveal a new mechanism whereby HUR protects NONO from mir320-mediated degradation upon UVC exposure and identify a new component within the complex network of players underlying the DNA damage response adding mir320a to the list of p53-regulated targets upon genotoxic stress.
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Affiliation(s)
- Luigi Alfano
- Oncology Research Center of Mercogliano (CROM), Istituto Nazionale Per Lo Studio E La Cura Dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, 80131, Italy
| | - Caterina Costa
- Oncology Research Center of Mercogliano (CROM), Istituto Nazionale Per Lo Studio E La Cura Dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, 80131, Italy
| | - Antonella Caporaso
- Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, 53100, Italy
| | | | - Antonio Giordano
- Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, 53100, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia PA, 19122, USA
| | - Francesca Pentimalli
- Oncology Research Center of Mercogliano (CROM), Istituto Nazionale Per Lo Studio E La Cura Dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, 80131, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia PA, 19122, USA
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34
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Endothelial Ca 2+ Signaling and the Resistance to Anticancer Treatments: Partners in Crime. Int J Mol Sci 2018; 19:ijms19010217. [PMID: 29324706 PMCID: PMC5796166 DOI: 10.3390/ijms19010217] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 01/08/2018] [Accepted: 01/10/2018] [Indexed: 02/06/2023] Open
Abstract
Intracellular Ca2+ signaling drives angiogenesis and vasculogenesis by stimulating proliferation, migration, and tube formation in both vascular endothelial cells and endothelial colony forming cells (ECFCs), which represent the only endothelial precursor truly belonging to the endothelial phenotype. In addition, local Ca2+ signals at the endoplasmic reticulum (ER)-mitochondria interface regulate endothelial cell fate by stimulating survival or apoptosis depending on the extent of the mitochondrial Ca2+ increase. The present article aims at describing how remodeling of the endothelial Ca2+ toolkit contributes to establish intrinsic or acquired resistance to standard anti-cancer therapies. The endothelial Ca2+ toolkit undergoes a major alteration in tumor endothelial cells and tumor-associated ECFCs. These include changes in TRPV4 expression and increase in the expression of P2X7 receptors, Piezo2, Stim1, Orai1, TRPC1, TRPC5, Connexin 40 and dysregulation of the ER Ca2+ handling machinery. Additionally, remodeling of the endothelial Ca2+ toolkit could involve nicotinic acetylcholine receptors, gasotransmitters-gated channels, two-pore channels and Na⁺/H⁺ exchanger. Targeting the endothelial Ca2+ toolkit could represent an alternative adjuvant therapy to circumvent patients' resistance to current anti-cancer treatments.
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Bulkowska M, Rybicka A, Senses KM, Ulewicz K, Witt K, Szymanska J, Taciak B, Klopfleisch R, Hellmén E, Dolka I, Gure AO, Mucha J, Mikow M, Gizinski S, Krol M. MicroRNA expression patterns in canine mammary cancer show significant differences between metastatic and non-metastatic tumours. BMC Cancer 2017; 17:728. [PMID: 29115935 PMCID: PMC5678797 DOI: 10.1186/s12885-017-3751-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 11/01/2017] [Indexed: 01/12/2023] Open
Abstract
Background MicroRNAs may act as oncogenes or tumour suppressor genes, which make these small molecules potential diagnostic/prognostic factors and targets for anticancer therapies. Several common oncogenic microRNAs have been found for canine mammary cancer and human breast cancer. On account of this, large-scale profiling of microRNA expression in canine mammary cancer seems to be important for both dogs and humans. Methods Expression profiles of 317 microRNAs in 146 canine mammary tumours of different histological type, malignancy grade and clinical history (presence/absence of metastases) and in 25 control samples were evaluated. The profiling was performed using microarrays. Significance Analysis of Microarrays test was applied in the analysis of microarray data (both unsupervised and supervised data analyses were performed). Validation of the obtained results was performed using real-time qPCR. Subsequently, predicted targets for the microRNAs were searched for in miRBase. Results Results of the unsupervised analysis indicate that the primary factor separating the samples is the metastasis status. Predicted targets for microRNAs differentially expressed in the metastatic vs. non-metastatic group are mostly engaged in cell cycle regulation, cell differentiation and DNA-damage repair. On the other hand, the supervised analysis reveals clusters of differentially expressed microRNAs unique for the tumour type, malignancy grade and metastasis factor. Conclusions The most significant difference in microRNA expression was observed between the metastatic and non-metastatic group, which suggests a more important role of microRNAs in the metastasis process than in the malignant transformation. Moreover, the differentially expressed microRNAs constitute potential metastasis markers. However, validation of cfa-miR-144, cfa-miR-32 and cfa-miR-374a levels in blood samples did not follow changes observed in the non-metastatic and metastatic tumours. Electronic supplementary material The online version of this article (10.1186/s12885-017-3751-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Malgorzata Bulkowska
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Agata Rybicka
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Kerem Mert Senses
- Department of Molecular Biology and Genetics, Faculty of Science, SB Building, Bilkent University, 06800, Ankara, Turkey
| | - Katarzyna Ulewicz
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Katarzyna Witt
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Joanna Szymanska
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Bartlomiej Taciak
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Robert Klopfleisch
- Institute of Veterinary Pathology, Freie Universitaet Berlin, Robert-von-Ostertag-Strasse 15, Building 31, 14163, Berlin, Germany
| | - Eva Hellmén
- Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Box 7011, 75007, Uppsala, Sweden
| | - Izabella Dolka
- Department of Pathology and Veterinary Diagnostics, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Ali O Gure
- Department of Molecular Biology and Genetics, Faculty of Science, SB Building, Bilkent University, 06800, Ankara, Turkey
| | - Joanna Mucha
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Mariusz Mikow
- Veterinary Clinic 'Elwet', Niepodleglosci 24/30, 02-653 Warsaw, Poland
| | - Slawomir Gizinski
- Department of Large Animal Diseases with Clinic, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 100, 02-797, Warsaw, Poland
| | - Magdalena Krol
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776, Warsaw, Poland.
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He DX, Wu XL, Lu CX, Gu XT, Zhang GY, Ma X, Liu DQ. Genome-wide analysis of the three-way interplay among gene expression, estrogen receptor expression and chemotherapeutic sensitivity in breast cancer. Oncol Rep 2017; 38:3392-3402. [PMID: 29039577 PMCID: PMC5783585 DOI: 10.3892/or.2017.6033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 09/26/2017] [Indexed: 01/04/2023] Open
Abstract
The expression of estrogen receptor α (ER) in breast cancers may be indicative of a favorable prognosis and most of these cancers respond to anti-estrogens or aromatase inhibitors. However, ER-positive (ER+) breast cancers receiving anti-hormone and/or chemotherapy sometimes lose their ER expression, which leads to the evolution of the disease to higher aggressiveness and drug resistance. In the present study, an ER-modified signature (EMS) was developed from the expression profile of a chemoresistant MCF-7 breast cancer cell line that lost ER expression during long-term treatment with a chemotherapeutic agent. The EMS could discriminate the ER-negative (ER-) breast cancer cells from the ER+ ones, which included seven pathways essential for the ER- cell development. Furthermore, the EMS indicated a more malignant subgroup of the ER- cells by discriminating the chemoresistant ER- cells from the chemosensitive ones. In addition, the classified chemoresistant ER- patients demonstrated worse prognosis. In conclusion, we developed a new method to discriminate subgroups of ER- breast cancer cells.
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Affiliation(s)
- Dong-Xu He
- National Engineering Laboratory for Cereal Fermentation Technology and Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Xiao-Li Wu
- National Engineering Laboratory for Cereal Fermentation Technology and Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Chun-Xiao Lu
- National Engineering Laboratory for Cereal Fermentation Technology and Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Xiao-Ting Gu
- National Engineering Laboratory for Cereal Fermentation Technology and Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Guang-Yuan Zhang
- National Engineering Laboratory for Cereal Fermentation Technology and Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Xin Ma
- National Engineering Laboratory for Cereal Fermentation Technology and Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - De-Quan Liu
- Department of Breast Surgery, The Third Affiliated Hospital, Kunming Medical University, Kunming, Yunnan 650031, P.R. China
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miR-320a functions as a suppressor for gliomas by targeting SND1 and β-catenin, and predicts the prognosis of patients. Oncotarget 2017; 8:19723-19737. [PMID: 28160566 PMCID: PMC5386717 DOI: 10.18632/oncotarget.14975] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 01/03/2017] [Indexed: 11/30/2022] Open
Abstract
miR-320a downexpression contributes to tumorigenesis in several human cancers. However, the relevance of miR-320a to prognosis, proliferation and invasion in gliomas remains unclear. In this study, we demonstrated that miR-320a expression was decreased in human glioma tissues and cell lines. Moreover, miR-320a expression was inversely correlated with glioma grades and Ki-67 index, but positively correlated with patients’ survival. Contrarily, SND1 and β-catenin expressions were positively correlated with glioma grades and Ki-67 index, but inversely correlated with miR-320a expression and patients’ survival. Furthermore, two subgroups with distinct prognoses in our glioma patients of different grade, IDH status, age and KPS were identified according to expression of miR-320a, SND1 or β-catenin. Cox regression showed that miR-320a and SND1 were independent predictors and β-catenin was an auxiliary predictor for patients’ survival. miR-320a overexpression suppressed the G1/S phase transition, proliferation, migration and invasion of glioblastoma cells. Mechanistically, we validated SND1 and β-catenin as direct targets of miR-320a, and found that miR-320a overexpression increased SND1-inhibited tumor suppressor p21WAF1 and decreased Smad2, Smad4, MMP2, MMP7 and cyclinD1, the pivotal downstream effectors of SND1 or β-catenin. Our findings demonstrate the potential values of miR-320a, SND1 and β-catenin as prognostic biomarkers and therapeutic candidates for malignant gliomas.
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38
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Chen Y, Luo D, Tian W, Li Z, Zhang X. Demethylation of miR-495 inhibits cell proliferation, migration and promotes apoptosis by targeting STAT-3 in breast cancer. Oncol Rep 2017; 37:3581-3589. [PMID: 28498478 DOI: 10.3892/or.2017.5621] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 04/18/2017] [Indexed: 11/06/2022] Open
Abstract
In breast cancer (BC), silencing of miRNA genes due to miRNA gene promoter methylation are the important mechanisms directly contributing to tumorigenesis and tumor progression. miRNA-495 (miR-495) has been reported to be a tumor suppressor gene in various cancers, but its role and regulation in BC remains unclear. In the present study, the level of miR-495 was inversely correlated with the expression of STAT-3 in BC tissues and cell lines. miR-495 can directly target 3'-UTR of STAT-3 mRNA and thereby decrease the expression of STAT-3 in MCF-7 and HCC1973 cells by Targetscan and Dual-luciferase assay. We further analyzed miR-495 promoter methylation by sodium bisulfite sequencing method (BSP), and found DNA methyltransferase inhibitor, 5-AzaC concomitantly upregulated expression of miR-495 and downregulated its target gene STAT-3 and its downstream target VEGF. Furthermore, we further observed that 5-AzaC treatment, miR-495 mimics and STAT-3 knockdown significantly inhibited cell function in breast cancer by Transwell assay, EdU flow cytometry, Annexin V-FITC/PI combined with flow cytometry and Hoechst staining. Taken together, our data are first to demonstrate that the miR-495 is silenced due to promoter methylation in breast cancer. DNA methyltransferase inhibitor 5-AzaC could reverse miR‑495 (suppressor gene) and STAT-3 (oncogene). The anticancer properties of 5-AzaC were preliminarily confirmed in breast cancer.
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Affiliation(s)
- Yi Chen
- Department of General (Breast and Thyroid), Daping Hospital of the Third Military Medical University, No. 10 Yangtze River Branch, Yuzhong, Chongqing 400042, P.R. China
| | - Donglin Luo
- Department of General (Breast and Thyroid), Daping Hospital of the Third Military Medical University, No. 10 Yangtze River Branch, Yuzhong, Chongqing 400042, P.R. China
| | - Wuguo Tian
- Department of General (Breast and Thyroid), Daping Hospital of the Third Military Medical University, No. 10 Yangtze River Branch, Yuzhong, Chongqing 400042, P.R. China
| | - Zhirong Li
- Department of General (Breast and Thyroid), Daping Hospital of the Third Military Medical University, No. 10 Yangtze River Branch, Yuzhong, Chongqing 400042, P.R. China
| | - Xiaohua Zhang
- Department of General (Breast and Thyroid), Daping Hospital of the Third Military Medical University, No. 10 Yangtze River Branch, Yuzhong, Chongqing 400042, P.R. China
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Kang DW, Yang ES, Noh YN, Hwang WC, Jo SY, Suh YA, Park WS, Choi KY, Min DS. MicroRNA-320a and microRNA-4496 attenuate Helicobacter pylori cytotoxin-associated gene A (CagA)-induced cancer-initiating potential and chemoresistance by targeting β-catenin and ATP-binding cassette, subfamily G, member 2. J Pathol 2017; 241:614-625. [PMID: 28008607 DOI: 10.1002/path.4866] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 12/01/2016] [Accepted: 12/15/2016] [Indexed: 01/04/2023]
Abstract
Infection with Helicobacter pylori is closely linked to an increased risk of gastric cancer. Although cytotoxin-associated gene A (CagA), a major virulence factor of H. pylori, is known to be a causal factor for gastric carcinogenesis, the molecular link between CagA and gastric cancer-initiating cell (CIC)-like properties remains elusive. Here, we demonstrate that CagA is required for increased expression of β-catenin and its target CIC markers via downregulation of microRNA (miR)-320a and miR-4496. CagA promoted gastric CIC properties and was responsible for chemoresistance. miR-320a and miR-4496 attenuated the in vitro self-renewal and tumour-initiating capacity of CagA-expressing CICs by targeting β-catenin. Moreover, miR-320a and miR-4496 decreased CagA-induced chemoresistance by targeting ATP-binding cassette, subfamily G, member 2 (ABCG2) at the transcriptional and post-transcriptional levels, respectively. Combination therapy with 5-fluorouracil and miR-320a/miR-4496 suppressed gastric tumourigenesis and metastatic potential in an orthotopic mouse model, probably via suppression of CagA-induced CIC properties and chemoresistance. Our results provide novel evidence that CIC properties, chemoresistance and tumourigenesis associated with H. pylori are linked to CagA-induced upregulation of β-catenin and ABCG2. These data provide novel insights into the molecular mechanisms of CagA-induced carcinogenisis and the therapeutic potential of of miR-320a and miR-4496. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Dong Woo Kang
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea
- Institute of Innovative Cancer Research, Asan Institute for Life Science, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eun Sun Yang
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea
| | - Yu Na Noh
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea
| | - Won Chan Hwang
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea
| | - Se-Young Jo
- Institute of Innovative Cancer Research, Asan Institute for Life Science, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Ah Suh
- Institute of Innovative Cancer Research, Asan Institute for Life Science, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Won Sang Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kang-Yell Choi
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
- Translational Research Centre for Protein Function Control, Yonsei University, Seoul, Republic of Korea
| | - Do Sik Min
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea
- Translational Research Centre for Protein Function Control, Yonsei University, Seoul, Republic of Korea
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Ayers D, Vandesompele J. Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance. Genes (Basel) 2017; 8:genes8030095. [PMID: 28273813 PMCID: PMC5368699 DOI: 10.3390/genes8030095] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 02/15/2017] [Accepted: 02/24/2017] [Indexed: 12/16/2022] Open
Abstract
Innate and acquired chemoresistance exhibited by most tumours exposed to conventional chemotherapeutic agents account for the majority of relapse cases in cancer patients. Such chemoresistance phenotypes are of a multi-factorial nature from multiple key molecular players. The discovery of the RNA interference pathway in 1998 and the widespread gene regulatory influences exerted by microRNAs (miRNAs) and other non-coding RNAs have certainly expanded the level of intricacy present for the development of any single physiological phenotype, including cancer chemoresistance. This review article focuses on the latest research efforts in identifying and validating specific key molecular players from the two main families of non-coding RNAs, namely miRNAs and long non-coding RNAs (lncRNAs), having direct or indirect influences in the development of cancer drug resistance properties and how such knowledge can be utilised for novel theranostics in oncology.
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Affiliation(s)
- Duncan Ayers
- Centre for Molecular Medicine and Biobanking, University of Malta, Msida MSD2080, Malta.
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M1 7DN, UK.
| | - Jo Vandesompele
- Center for Medical Genetics Ghent, Ghent University, Ghent 9000, Belgium.
- Cancer Research Institute Ghent (CRIG), Ghent University, Ghent 9000, Belgium.
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41
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Chang JTH, Wang F, Chapin W, Huang RS. Identification of MicroRNAs as Breast Cancer Prognosis Markers through the Cancer Genome Atlas. PLoS One 2016; 11:e0168284. [PMID: 27959953 PMCID: PMC5154569 DOI: 10.1371/journal.pone.0168284] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 11/29/2016] [Indexed: 12/21/2022] Open
Abstract
Breast cancer is the second-most common cancer and second-leading cause of cancer mortality in American women. The dysregulation of microRNAs (miRNAs) plays a key role in almost all cancers, including breast cancer. We comprehensively analyzed miRNA expression, global gene expression, and patient survival from the Cancer Genomes Atlas (TCGA) to identify clinically relevant miRNAs and their potential gene targets in breast tumors. In our analysis, we found that increased expression of 12 mature miRNAs-hsa-miR-320a, hsa-miR-361-5p, hsa-miR-103a-3p, hsa-miR-21-5p, hsa-miR-374b-5p, hsa-miR-140-3p, hsa-miR-25-3p, hsa-miR-651-5p, hsa-miR-200c-3p, hsa-miR-30a-5p, hsa-miR-30c-5p, and hsa-let-7i-5p -each predicted improved breast cancer survival. Of the 12 miRNAs, miR-320a, miR-361-5p, miR-21-5p, miR-103a-3p were selected for further analysis. By correlating global gene expression with miRNA expression and then employing miRNA target prediction analysis, we suggest that the four miRNAs may exert protective phenotypes by targeting breast oncogenes that contribute to patient survival. We propose that miR-320a targets the survival-associated genes RAD51, RRP1B, and TDG; miR-361-5p targets ARCN1; and miR-21-5p targets MSH2, RMND5A, STAG2, and UBE2D3. The results of our stringent bioinformatics approach for identifying clinically relevant miRNAs and their targets indicate that miR-320a, miR-361-5p, and miR-21-5p may contribute to breast cancer survival.
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Affiliation(s)
- Jeremy T-H. Chang
- Biological Sciences Collegiate Division, University of Chicago, Chicago, Illinois, United States of America
| | - Fan Wang
- Department of Medicine, University of Chicago, Chicago, Illinois, United States of America
| | - William Chapin
- Pritzker School of Medicine, University of Chicago, Chicago, Illinois, United States of America
| | - R. Stephanie Huang
- Department of Medicine, University of Chicago, Chicago, Illinois, United States of America
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da Silva Oliveira KC, Thomaz Araújo TM, Albuquerque CI, Barata GA, Gigek CO, Leal MF, Wisnieski F, Rodrigues Mello Junior FA, Khayat AS, de Assumpção PP, Rodriguez Burbano RM, Smith MC, Calcagno DQ. Role of miRNAs and their potential to be useful as diagnostic and prognostic biomarkers in gastric cancer. World J Gastroenterol 2016; 22:7951-7962. [PMID: 27672290 PMCID: PMC5028809 DOI: 10.3748/wjg.v22.i35.7951] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Revised: 06/14/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Alterations in epigenetic control of gene expression play an important role in many diseases, including gastric cancer. Many studies have identified a large number of upregulated oncogenic miRNAs and downregulated tumour-suppressor miRNAs in this type of cancer. In this review, we provide an overview of the role of miRNAs, pointing to their potential to be useful as diagnostic and/or prognostic biomarkers in gastric cancer. Moreover, we discuss the influence of polymorphisms and epigenetic modifications on miRNA activity.
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43
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He DX, Zhang GY, Gu XT, Mao AQ, Lu CX, Jin J, Liu DQ, Ma X. Genome-wide profiling of long non-coding RNA expression patterns in anthracycline-resistant breast cancer cells. Int J Oncol 2016; 49:1695-1703. [PMID: 27633960 DOI: 10.3892/ijo.2016.3665] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 07/29/2016] [Indexed: 11/05/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are involved in cancer progression. In the present study, we analyzed the lncRNA profiles in adriamycin-resistant and -sensitive breast cancer cells and found a group of dysregulated lncRNAs in the adriamycin-resistant cells. Expression of the dysregulated lncRNAs was correlated with dysregulated mRNAs, and these were enriched in GO and KEGG pathways associated with cancer progression and chemoresistance development. Among these lncRNA-mRNA interactions, some lncRNAs may cis‑regulate neighboring protein-coding genes and be involved in chemoresistance. We then validated that the lncRNA NONHSAT028712 regulated nearby CDK2 and interfered with the cell cycle and chemoresistance. Furthermore, we identified another group of lncRNAs that trans-regulated genes by interacting with different transcription factors. For example, NONHSAT057282 and NONHSAG023333 modulated chemoresistance and most likely interacted with the transcription factors ELF1 and E2F1, respectively. In conclusion, in the present study, we report for the first time the lncRNA expression patterns in adriamycin-resistant breast cancer cells, and provide a group of novel lncRNA targets that mediate chemoresistance development in both cis- and trans-action modes.
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Affiliation(s)
- Dong-Xu He
- National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Guang-Yuan Zhang
- National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Xiao-Ting Gu
- Department of Cellular and Molecular Pharmacology, School of Medicine and Pharmaceutics, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Ai-Qin Mao
- Department of Cellular and Molecular Pharmacology, School of Medicine and Pharmaceutics, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Chun-Xiao Lu
- Department of Cellular and Molecular Pharmacology, School of Medicine and Pharmaceutics, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Jian Jin
- Department of Cellular and Molecular Pharmacology, School of Medicine and Pharmaceutics, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - De-Quan Liu
- Department of Breast Surgery, The Third Affiliated Hospital, Kunming Medical University, Kunming, Yunnan 650031, P.R. China
| | - Xin Ma
- Department of Cellular and Molecular Pharmacology, School of Medicine and Pharmaceutics, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
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Arrigoni E, Galimberti S, Petrini M, Danesi R, Di Paolo A. ATP-binding cassette transmembrane transporters and their epigenetic control in cancer: an overview. Expert Opin Drug Metab Toxicol 2016; 12:1419-1432. [PMID: 27459275 DOI: 10.1080/17425255.2016.1215423] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Members of the ATP-binding cassette (ABC) transmembrane transporters control the passage of several substrates across cell membranes, including drugs. This means that ABC transporters may exert a significant influence on the kinetics and dynamics of pharmacological agents, being responsible for the occurrence of multidrug-resistant (MDR) phenotype. Pharmacogenetic analyses have shed light on gene expression and polymorphisms as possible markers predictive of transporter activity. However, a non-negligible part of the variability in drug pharmacokinetics and pharmacodynamics still remains. Further research has demonstrated that different epigenetic mechanisms exert a coordinated control over ABC genes, and on the corresponding MDR phenotype. Areas covered: DNA methylation and histone modifications (namely acetylation, methylation, phosphorylation, etc.) significantly impact gene expression, as well as noncoding RNA molecules that are involved in the post-transcriptional control of the ABC transporters ABCB1, ABCC1 and ABCG2. We describe the epigenetic mechanisms of gene expression control for ABC transporters and their relevant association with the MDR phenotype in human cancer. Expert opinion: The clinical meaning of those observations is discussed in the review, highlighting the importance of the epigenetic control of the ABC transporters for the clinical therapeutic outcomes that despite their effects and applications, requires further investigation.
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Affiliation(s)
- Elena Arrigoni
- a Section of Pharmacology, Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
| | - Sara Galimberti
- b Section of Hematology, Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
| | - Mario Petrini
- b Section of Hematology, Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
| | - Romano Danesi
- a Section of Pharmacology, Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
| | - Antonello Di Paolo
- a Section of Pharmacology, Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
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Mechanisms of breast cancer resistance to anthracyclines or taxanes: an overview of the proposed roles of noncoding RNA. Curr Opin Oncol 2016; 27:457-65. [PMID: 26371779 DOI: 10.1097/cco.0000000000000235] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
PURPOSE OF REVIEW Anthracyclines and taxanes are the two most active classes of cytotoxic agents that are commonly used for the treatment of breast cancer. However, resistance to these agents has become a major clinical obstacle. The aim of the present review is to define the roles of noncoding RNA (ncRNA) in breast cancer progression and the development of chemotherapy resistance. The ultimate goal is to exploit ncRNAs as new therapeutic tools to overcome resistance. RECENT FINDINGS Two important types of ncRNA include microRNA (miRNA) and long noncoding RNA (lncRNA). Both miRNA and lncRNA have recently impacted the field of breast cancer research as important pieces in the mechanistic puzzle of the genes and pathways involved in breast cancer development and progression. SUMMARY Herein, we review the roles of miRNA and lncRNA in breast cancer progression and the development of chemotherapy resistance. Future research should include identification of ncRNAs that could be potential therapeutic targets in chemotherapy-resistant tumors, as well as ncRNA biomarkers that facilitate more tumor-specific treatment options for chemotherapy-resistant breast cancer patients.
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He DX, Gu F, Gao F, Hao JJ, Gong D, Gu XT, Mao AQ, Jin J, Fu L, Ma X. Genome-wide profiles of methylation, microRNAs, and gene expression in chemoresistant breast cancer. Sci Rep 2016; 6:24706. [PMID: 27094684 PMCID: PMC4837395 DOI: 10.1038/srep24706] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 03/30/2016] [Indexed: 12/17/2022] Open
Abstract
Cancer chemoresistance is regulated by complex genetic and epigenetic networks. In this study, the features of gene expression, methylation, and microRNA (miRNA) expression were investigated with high-throughput sequencing in human breast cancer MCF-7 cells resistant to adriamycin (MCF-7/ADM) and paclitaxel (MCF-7/PTX). We found that: ① both of the chemoresistant cell lines had similar, massive changes in gene expression, methylation, and miRNA expression versus chemosensitive controls. ② Pairwise integration of the data highlighted sets of genes that were regulated by either methylation or miRNAs, and sets of miRNAs whose expression was controlled by DNA methylation in chemoresistant cells. ③ By combining the three sets of high-throughput data, we obtained a list of genes whose expression was regulated by both methylation and miRNAs in chemoresistant cells; ④ Expression of these genes was then validated in clinical breast cancer samples to generate a 17-gene signature that showed good predictive and prognostic power in triple-negative breast cancer patients receiving anthracycline-taxane-based neoadjuvant chemotherapy. In conclusion, our results have generated a new workflow for the integrated analysis of the effects of miRNAs and methylation on gene expression during the development of chemoresistance.
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Affiliation(s)
- Dong-Xu He
- National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China
| | - Feng Gu
- Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, PR China
| | - Fei Gao
- Agricultural Genomes Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China
| | - Jun-jun Hao
- State Key Lab of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Desheng Gong
- Agricultural Genomes Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China
| | - Xiao-Ting Gu
- Department of Cellular and Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
| | - Ai-Qin Mao
- Department of Cellular and Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
| | - Jian Jin
- Department of Cellular and Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
| | - Li Fu
- Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, PR China
| | - Xin Ma
- Department of Cellular and Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
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Ohya S, Kito H, Hatano N, Muraki K. Recent advances in therapeutic strategies that focus on the regulation of ion channel expression. Pharmacol Ther 2016; 160:11-43. [PMID: 26896566 DOI: 10.1016/j.pharmthera.2016.02.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A number of different ion channel types are involved in cell signaling networks, and homeostatic regulatory mechanisms contribute to the control of ion channel expression. Profiling of global gene expression using microarray technology has recently provided novel insights into the molecular mechanisms underlying the homeostatic and pathological control of ion channel expression. It has demonstrated that the dysregulation of ion channel expression is associated with the pathogenesis of neural, cardiovascular, and immune diseases as well as cancers. In addition to the transcriptional, translational, and post-translational regulation of ion channels, potentially important evidence on the mechanisms controlling ion channel expression has recently been accumulated. The regulation of alternative pre-mRNA splicing is therefore a novel therapeutic strategy for the treatment of dominant-negative splicing disorders. Epigenetic modification plays a key role in various pathological conditions through the regulation of pluripotency genes. Inhibitors of pre-mRNA splicing and histone deacetyalase/methyltransferase have potential as potent therapeutic drugs for cancers and autoimmune and inflammatory diseases. Moreover, membrane-anchoring proteins, lysosomal and proteasomal degradation-related molecules, auxiliary subunits, and pharmacological agents alter the protein folding, membrane trafficking, and post-translational modifications of ion channels, and are linked to expression-defect channelopathies. In this review, we focused on recent insights into the transcriptional, spliceosomal, epigenetic, and proteasomal regulation of ion channel expression: Ca(2+) channels (TRPC/TRPV/TRPM/TRPA/Orai), K(+) channels (voltage-gated, KV/Ca(2+)-activated, KCa/two-pore domain, K2P/inward-rectifier, Kir), and Ca(2+)-activated Cl(-) channels (TMEM16A/TMEM16B). Furthermore, this review highlights expression of these ion channels in expression-defect channelopathies.
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Affiliation(s)
- Susumu Ohya
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
| | - Hiroaki Kito
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Noriyuki Hatano
- Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya 464-8650, Japan
| | - Katsuhiko Muraki
- Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya 464-8650, Japan.
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Casey MC, Sweeney KJ, Brown JAL, Kerin MJ. Exploring circulating micro-RNA in the neoadjuvant treatment of breast cancer. Int J Cancer 2016; 139:12-22. [PMID: 26756433 PMCID: PMC5066681 DOI: 10.1002/ijc.29985] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 11/04/2015] [Accepted: 12/22/2015] [Indexed: 12/18/2022]
Abstract
Breast cancer is the most frequently diagnosed malignancy amongst females worldwide. In recent years the management of this disease has transformed considerably, including the administration of chemotherapy in the neoadjuvant setting. Aside from increasing rates of breast conserving surgery and enabling surgery via tumour burden reduction, use of chemotherapy in the neoadjuvant setting allows monitoring of in vivo tumour response to chemotherapeutics. Currently, there is no effective means of identifying chemotherapeutic responders from non‐responders. Whilst some patients achieve complete pathological response (pCR) to chemotherapy, a good prognostic index, a proportion of patients derive little or no benefit, being exposed to the deleterious effects of systemic treatment without any knowledge of whether they will receive benefit. The identification of predictive and prognostic biomarkers could confer multiple benefits in this setting, specifically the individualization of breast cancer management and more effective administration of chemotherapeutics. In addition, biomarkers could potentially expedite the identification of novel chemotherapeutic agents or increase their efficacy. Micro‐RNAs (miRNAs) are small non‐coding RNA molecules. With their tissue‐specific expression, correlation with clinicopathological prognostic indices and known dysregulation in breast cancer, miRNAs have quickly become an important avenue in the search for novel breast cancer biomarkers. We provide a brief history of breast cancer chemotherapeutics and explore the emerging field of circulating (blood‐borne) miRNAs as breast cancer biomarkers for the neoadjuvant treatment of breast cancer. Established molecular markers of breast cancer are outlined, while the potential role of circulating miRNAs as chemotherapeutic response predictors, prognosticators or potential therapeutic targets is discussed.
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Affiliation(s)
- Máire-Caitlín Casey
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
| | - Karl J Sweeney
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
| | | | - Michael J Kerin
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
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49
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Transient receptor potential channel C5 in cancer chemoresistance. Acta Pharmacol Sin 2016; 37:19-24. [PMID: 26657058 DOI: 10.1038/aps.2015.109] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Accepted: 11/01/2015] [Indexed: 12/25/2022]
Abstract
The transient receptor potential (TRP) superfamily contains at least 28 homologs in mammalian. These proteins form TRP channels are permeable to monovalent and divalent cations and participate in a variety of physiological functions. Dysregulation of TRP channels is responsible for numerous diseases. This review provides a brief short overview of mammalian TRP channels with a focus on TRPC5 and its role in cancers. Dysregulation of TRPC5 interrupts Ca(2+) homeostasis in cancer cells, which activates signaling pathways that are highly associated with cancer progression, especially cancer chemoresistance. Based on the important role of TRPC5, we also discuss the potential of TRPC5 as a target for therapeutic intervention. Either direct targeting of TRPC5 or indirect interruption of TRPC5-related signaling pathways may effectively overcome cancer chemoresistance.
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50
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Nair S, Kong ANT. Architecture of Signature miRNA Regulatory Networks in Cancer Chemoprevention. ACTA ACUST UNITED AC 2015. [DOI: 10.1007/s40495-014-0014-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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