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Mohammadi F, Nejatollahi M, Sheikhnia F, Ebrahimi Y, Mohammadi M, Rashidi V, Alizadeh-Fanalou S, Azizzadeh B, Majidinia M. MiRNAs: main players of cancer drug resistance target ABC transporters. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:6239-6291. [PMID: 39808313 DOI: 10.1007/s00210-024-03719-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/08/2024] [Indexed: 01/16/2025]
Abstract
Chemotherapy remains the cornerstone of cancer treatment; however, its efficacy is frequently compromised by the development of chemoresistance. Multidrug resistance (MDR), characterized by the refractoriness of cancer cells to a wide array of chemotherapeutic agents, presents a significant barrier to achieving successful and sustained cancer remission. One critical factor contributing to this chemoresistance is the overexpression of ATP-binding cassette (ABC) transporters. Furthermore, additional mechanisms, such as the malfunctioning of apoptosis, alterations in DNA repair systems, and resistance mechanisms inherent to cancer stem cells, exacerbate the issue. Intriguingly, microRNAs (miRNAs) have demonstrated potential in modulating chemoresistance by specifically targeting ABC transporters, thereby offering promising new avenues for overcoming drug resistance. This narrative review aims to elucidate the molecular underpinnings of drug resistance, with a particular focus on the roles of ABC transporters and the regulatory influence of miRNAs on these transporters.
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Affiliation(s)
- Forogh Mohammadi
- Department of Veterinary, Agriculture Faculty, Kermanshah Branch, Islamic Azad University, Kermanshah, Iran
| | - Masoumeh Nejatollahi
- Research Center for High School Students, Education System Zanjan Province, Zanjan, Iran
| | - Farhad Sheikhnia
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yaser Ebrahimi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mahya Mohammadi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Rashidi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Shahin Alizadeh-Fanalou
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Bita Azizzadeh
- Department of Biochemistry, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
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Wang Y, Tu MJ, Yu AM. Efflux ABC transporters in drug disposition and their posttranscriptional gene regulation by microRNAs. Front Pharmacol 2024; 15:1423416. [PMID: 39114355 PMCID: PMC11303158 DOI: 10.3389/fphar.2024.1423416] [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: 04/25/2024] [Accepted: 07/11/2024] [Indexed: 08/10/2024] Open
Abstract
ATP-binding cassette (ABC) transporters are transmembrane proteins expressed commonly in metabolic and excretory organs to control xenobiotic or endobiotic disposition and maintain their homeostasis. Changes in ABC transporter expression may directly affect the pharmacokinetics of relevant drugs involving absorption, distribution, metabolism, and excretion (ADME) processes. Indeed, overexpression of efflux ABC transporters in cancer cells or bacteria limits drug exposure and causes therapeutic failure that is known as multidrug resistance (MDR). With the discovery of functional noncoding microRNAs (miRNAs) produced from the genome, many miRNAs have been revealed to govern posttranscriptional gene regulation of ABC transporters, which shall improve our understanding of complex mechanism behind the overexpression of ABC transporters linked to MDR. In this article, we first overview the expression and localization of important ABC transporters in human tissues and their clinical importance regarding ADME as well as MDR. Further, we summarize miRNA-controlled posttranscriptional gene regulation of ABC transporters and effects on ADME and MDR. Additionally, we discuss the development and utilization of novel bioengineered miRNA agents to modulate ABC transporter gene expression and subsequent influence on cellular drug accumulation and chemosensitivity. Findings on posttranscriptional gene regulation of ABC transporters shall not only improve our understanding of mechanisms behind variable ADME but also provide insight into developing new means towards rational and more effective pharmacotherapies.
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Affiliation(s)
| | | | - Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA, United States
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3
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Kamiya H, Komatsu S, Takashima Y, Ishida R, Arakawa H, Nishibeppu K, Kiuchi J, Imamura T, Ohashi T, Shimizu H, Arita T, Konishi H, Shiozaki A, Kubota T, Fujiwara H, Yagyu S, Iehara T, Otsuji E. Low blood level of tumour suppressor miR-5193 as a target of immunotherapy to PD-L1 in gastric cancer. Br J Cancer 2024; 130:671-681. [PMID: 38148376 PMCID: PMC10876550 DOI: 10.1038/s41416-023-02532-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/19/2023] [Accepted: 11/30/2023] [Indexed: 12/28/2023] Open
Abstract
BACKGROUND Recent studies have identified that low levels of some tumour suppressor microRNAs (miRNAs) in the blood contribute to tumour progression and poor outcomes in various cancers. However, no study has proved these miRNAs are associated with cancer immune mechanisms. METHODS From a systematic review of the NCBI and miRNA databases, four tumour suppressor miRNA candidates were selected (miR-5193, miR-4443, miR-520h, miR-496) that putatively target programmed cell death ligand 1 (PD-L1). RESULTS Test-scale and large-scale analyses revealed that plasma levels of miR-5193 were significantly lower in gastric cancer (GC) patients than in healthy volunteers (HVs). Low plasma levels of miR-5193 were associated with advanced pathological stages and were an independent prognostic factor. Overexpression of miR-5193 in GC cells suppressed PD-L1 on the surface of GC cells, even with IFN-γ stimulation. In the coculture model of GC cells and T cells stimulated by anti-CD3/anti-CD28 beads, overexpression of miR-5193 increased anti-tumour activity of T cells by suppressing PD-L1 expression. Subcutaneous injection of miR-5193 also significantly enhanced the tumour-killing activity and trafficking of T cells in mice. CONCLUSIONS Low blood levels of miR-5193 are associated with GC progression and poor outcomes and could be a target of nucleic acid immunotherapy in GC patients.
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Affiliation(s)
- Hajime Kamiya
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
| | - Yusuke Takashima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Ryo Ishida
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hiroshi Arakawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hiroki Shimizu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takeshi Kubota
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shigeki Yagyu
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
- Center for Advanced Research of Gene and Cell Therapy in Shinshu University (CARS), Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoko Iehara
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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Yang Y, Li P, Li X, Zhu Y, Guo X. Brucine D restrains colorectal cancer tumorigenesis and autophagy by downregulating circ_0068464. Chem Biol Drug Des 2024; 103:e14407. [PMID: 38040413 DOI: 10.1111/cbdd.14407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/18/2023] [Accepted: 11/10/2023] [Indexed: 12/03/2023]
Abstract
Bruceine D (BD) from Brucea javanica (L) exerts an antitumor effect in several human cancers. At present, it has not been reported whether BD inhibits the malignancy of colorectal cancer (CRC) cells. Therefore, investigating the role and regulatory mechanisms of BD in CRC is the main thrust of this study. Effect of BD on CRC cell viability, proliferation, apoptosis, invasion, and autophagy was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide, 5-ethynyl-2'-deoxyuridine, flow cytometry, transwell invasion, and western blotting assays. Expression changes of has_circ_0068464 (circ_0068464) were detected using real time quantitative polymerase chain reaction. The molecular mechanisms related to circ_0068464 were predicted through online prediction websites Starbase 2.0, circinteractome, and CircBank and validated using dual-luciferase reporter and RNA pull-down assays. The tumorigenic ability of BD and circ_0068464 on CRC was confirmed by xenograft experiments. The results showed that BD lessened CRC cell proliferation, invasion, autophagy, and prompted cell apoptosis. Circ_0068464 was overexpressed in CRC samples and cells. BD led to a significant reduction in circ_0068464 levels in cells of this carcinoma, but circ_0068464 overexpression partially rescued these effects urged by BD. Also, the combination of BD and circ_0068464 silencing decreased xenograft tumor growth compared to BD alone. Importantly, circ_0068464 could regulate ATG5 expression by functioning as a miR-520h molecular sponge. In conclusion, BD might suppress CRC growth by inhibiting the circ_0068464/miR-520h/ATG5 axis, providing a new perspective for the molecular pathogenesis of CRC and preliminarily indicating that BD may be a promising drug for CRC treatment.
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Affiliation(s)
- Yong Yang
- Department Anus & Intestine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Peng Li
- Department Anus & Intestine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaojia Li
- Department Anus & Intestine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Zhu
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiutian Guo
- Department Anus & Intestine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Khalili E, Afgar A, Rajabpour A, Aghaee-Bakhtiari SH, Jamialahmadi K, Teimoori-Toolabi L. MiR-548c-3p through suppressing Tyms and Abcg2 increases the sensitivity of colorectal cancer cells to 5-fluorouracil. Heliyon 2023; 9:e21775. [PMID: 38045156 PMCID: PMC10692789 DOI: 10.1016/j.heliyon.2023.e21775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 10/21/2023] [Accepted: 10/27/2023] [Indexed: 12/05/2023] Open
Abstract
Background Colorectal cancer, is one of most prevalent the cancer in the world. 5-Fluorouracil is a standard chemotherapeutic drug while the acquisition of resistance to 5-Fluorouracil is one of the problems during treatment. In this study, we aimed to find the miRNAs that modulate the expression of Tyms and Abcg2 as resistance-inducing genes in the resistant cell lines to 5-Fluorouracil. Methods 5-Fluorouracil-resistant HCT116 and SW480 cell lines were generated by consecutive treatment of cells with 5-Fluorouracil. This resistance induction was validated by MTT assays. The expression of the Tyms and Abcg2 gene and miR-548c-3p were studied by quantitative real-time PCR in the cell lines. Results We hypothesized that miR-548c-3p is targeting Tyms and Abcg2 simultaneously. Increased expression Tyms gene in the two most resistant cell lines derived from HCT116 and all resistant cell lines derived from SW480 except one were seen. Increased expression of Abcg2 was observed in the most resistant HCT116-derived cell line and all resistant cell lines, derived from SW480. In all resistant cell lines, the expression of miR-548c-3p was decreased. Conclusion It can be concluded downregulation of miR548c-3p is in line with Tyms and Abcg2 overexpression in resistant cell lines to 5-Fluorouracil.
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Affiliation(s)
- Elham Khalili
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Iran
| | - Ali Afgar
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Azam Rajabpour
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Iran
| | - Seyed Hamid Aghaee-Bakhtiari
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khadijeh Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ladan Teimoori-Toolabi
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Iran
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Zhao Y, Qin C, Zhao B, Wang Y, Li Z, Li T, Yang X, Wang W. Pancreatic cancer stemness: dynamic status in malignant progression. J Exp Clin Cancer Res 2023; 42:122. [PMID: 37173787 PMCID: PMC10182699 DOI: 10.1186/s13046-023-02693-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide. Increasing evidence suggests that the capacity for self-renewal, proliferation, and differentiation of pancreatic cancer stem cells (PCSCs) contribute to major challenges with current PC therapies, causing metastasis and therapeutic resistance, leading to recurrence and death in patients. The concept that PCSCs are characterized by their high plasticity and self-renewal capacities is central to this review. We focused specifically on the regulation of PCSCs, such as stemness-related signaling pathways, stimuli in tumor cells and the tumor microenvironment (TME), as well as the development of innovative stemness-targeted therapies. Understanding the biological behavior of PCSCs with plasticity and the molecular mechanisms regulating PC stemness will help to identify new treatment strategies to treat this horrible disease.
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Affiliation(s)
- Yutong Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Bangbo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Yuanyang Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Zeru Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Tianyu Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Xiaoying Yang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Weibin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China.
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Damiani D, Tiribelli M. ABCG2 in Acute Myeloid Leukemia: Old and New Perspectives. Int J Mol Sci 2023; 24:ijms24087147. [PMID: 37108308 PMCID: PMC10138346 DOI: 10.3390/ijms24087147] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/05/2023] [Accepted: 04/10/2023] [Indexed: 04/29/2023] Open
Abstract
Despite recent advances, prognosis of acute myeloid leukemia (AML) remains unsatisfactory due to poor response to therapy or relapse. Among causes of resistance, over-expression of multidrug resistance (MDR) proteins represents a pivotal mechanism. ABCG2 is an efflux transporter responsible for inducing MDR in leukemic cells; through its ability to extrude many antineoplastic drugs, it leads to AML resistance and/or relapse, even if conflicting data have been reported to date. Moreover, ABCG2 may be co-expressed with other MDR-related proteins and is finely regulated by epigenetic mechanisms. Here, we review the main issues regarding ABCG2 activity and regulation in the AML clinical scenario, focusing on its expression and the role of polymorphisms, as well as on the potential ways to inhibit its function to counteract drug resistance to, eventually, improve outcomes in AML patients.
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Affiliation(s)
- Daniela Damiani
- Division of Hematology and Stem Cell Transplantation, Udine Hospital, P.le Santa Maria della Misericordia, 5, 33100 Udine, Italy
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy
| | - Mario Tiribelli
- Division of Hematology and Stem Cell Transplantation, Udine Hospital, P.le Santa Maria della Misericordia, 5, 33100 Udine, Italy
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy
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Wang C, Jiang H, Peng J, Weng D, Zhang Y, Zhou Y, Zhang Q. Circular RNA circ_SKA3 enhances gastric cancer development by targeting miR-520h. Histol Histopathol 2023; 38:317-328. [PMID: 36134741 DOI: 10.14670/hh-18-521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
PURPOSE To explore the mechanisms of action of circ_SKA3 in gastric cancer (GC), which are still not fully understood. METHODS Subcellular localization assay was used to analyze the localization of circ_SKA3, and Actinomycin D assay was applied to confirm the stability of circ_SKA3. The levels of circ_SKA3, microRNA (miR)-520h, and cell division cycle 42 (CDC42) mRNA were gauged by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of CDC42 and proliferating cell nuclear antigen (PCNA) were assessed by western blot. Cell proliferation, colony formation, cell cycle distribution, apoptosis, migration, and invasion were detected by 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT), 5-Ethynyl-2'-Deoxyuridine (EdU) incorporation, colony formation, flow cytometry, and transwell assays, respectively. Directed relationship between miR-520h and circ_SKA3 or CDC42 was verified by a dual-luciferase reporter assay. Mouse xenograft experiments were used to elucidate the impact of circ_SKA3 in vivo. RESULTS Overexpression of circ_SKA3 was validated in GC tissues and cells. The down-regulation of circ_SKA3 suppressed proliferation, cell cycle progression, colony formation, migration, invasion, and promoted cell apoptosis in vitro, as well as weakening tumor growth in vivo. Circ_SKA3 directly bound to miR-520h, and circ_SKA3 regulated CDC42 expression through miR-520h. Circ_SKA3 exerted regulatory effects on GC cell behaviors by inhibiting miR-520h. Furthermore, CDC42 was a functional target of miR-520h in regulating GC cell behaviors. CONCLUSION Our findings established a strong molecular mechanism, the miR-520h/CDC42 axis, at least in part, for the oncogenic role of circ_SKA3 in GC.
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Affiliation(s)
- Chuntao Wang
- Department of Thyroid Gastroenterology and Thoracic Surgery, Suizhou Central Hospital, Suizhou, Hubei, China
| | - Hao Jiang
- Department of Hepatopancreatobiliary Surgery, Suizhou Central Hospital, Suizhou, Hubei, China
| | - Jiaqun Peng
- Department of Thyroid Gastroenterology and Thoracic Surgery, Suizhou Central Hospital, Suizhou, Hubei, China
| | - Duanshun Weng
- Department of Thyroid Gastroenterology and Thoracic Surgery, Suizhou Central Hospital, Suizhou, Hubei, China
| | - Yu Zhang
- Department of Thyroid Gastroenterology and Thoracic Surgery, Suizhou Central Hospital, Suizhou, Hubei, China
| | - Yanxun Zhou
- Department of Gastroenterology, Suizhou Central Hospital, Suizhou, Hubei, China
| | - Qin Zhang
- Department of Thyroid Gastroenterology and Thoracic Surgery, Suizhou Central Hospital, Suizhou, Hubei, China.
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Funamizu N, Honjo M, Tamura K, Sakamoto K, Ogawa K, Takada Y. microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer. Cancers (Basel) 2023; 15:1230. [PMID: 36831572 PMCID: PMC9953943 DOI: 10.3390/cancers15041230] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Despite extensive research, pancreatic cancer remains a lethal disease with an extremely poor prognosis. The difficulty in early detection and chemoresistance to therapeutic agents are major clinical concerns. To improve prognosis, novel biomarkers, and therapeutic strategies for chemoresistance are urgently needed. microRNAs (miRNAs) play important roles in the development, progression, and metastasis of several cancers. During the last few decades, the association between pancreatic cancer and miRNAs has been extensively elucidated, with several miRNAs found to be correlated with patient prognosis. Moreover, recent evidence has revealed that miRNAs are intimately involved in gemcitabine sensitivity and resistance through epithelial-to-mesenchymal transition, the tumor microenvironment, and drug metabolism. Gemcitabine is the gold standard drug for pancreatic cancer treatment, but gemcitabine resistance develops easily after chemotherapy initiation. Therefore, in this review, we summarize the gemcitabine resistance mechanisms associated with aberrantly expressed miRNAs in pancreatic cancer, especially focusing on the mechanisms associated with epithelial-to-mesenchymal transition, the tumor microenvironment, and metabolism. This novel evidence of gemcitabine resistance will drive further research to elucidate the mechanisms of chemoresistance and improve patient outcomes.
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Affiliation(s)
- Naotake Funamizu
- Department of Hepatobiliary Pancreatic and Transplantation Surgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
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Jaszczuk I, Winkler I, Koczkodaj D, Skrzypczak M, Filip A. The Role of Cluster C19MC in Pre-Eclampsia Development. Int J Mol Sci 2022; 23:ijms232213836. [PMID: 36430313 PMCID: PMC9699419 DOI: 10.3390/ijms232213836] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/03/2022] [Accepted: 11/06/2022] [Indexed: 11/12/2022] Open
Abstract
Pre-eclampsia is a placenta-related complication occurring in 2-10% of all pregnancies. miRNAs are a group of non-coding RNAs regulating gene expression. There is evidence that C19MC miRNAs are involved in the development of the placenta. Deregulation of chromosome 19 microRNA cluster (C19MC) miRNAs expression leads to impaired cell differentiation, abnormal trophoblast invasion and pathological angiogenesis, which can lead to the development of pre-eclampsia. Information was obtained through a review of articles available in PubMed Medline. Articles on the role of the C19MC miRNA in the development of pre-eclampsia published in 2009-2022 were analyzed. This review article summarizes the current data on the role of the C19MC miRNA in the development of pre-eclampsia. They indicate a significant increase in the expression of most C19MC miRNAs in placental tissue and a high level of circulating fractions in serum and plasma, both in the first and/or third trimester in women with PE. Only for miR-525-5p, low levels of plasma expression were noted in the first trimester, and in the placenta in the third trimester. The search for molecular factors indicating the development of pre-eclampsia before the onset of clinical symptoms seems to be a promising diagnostic route. Identifying women at risk of developing pre-eclampsia at the pre-symptomatic stage would avoid serious complications in both mothers and fetuses. We believe that miRNAs belonging to cluster C19MC could be promising biomarkers of pre-eclampsia development.
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Affiliation(s)
- Ilona Jaszczuk
- Department of Cancer Genetics with Cytogenetic Laboratory, Medical University of Lublin, Radziwillowska Street 11, 20-080 Lublin, Poland
| | - Izabela Winkler
- Second Department of Gynecological Oncology, St. John’s Center of Oncology of the Lublin Region, Jaczewski Street 7, 20-090 Lublin, Poland
- Correspondence:
| | - Dorota Koczkodaj
- Department of Cancer Genetics with Cytogenetic Laboratory, Medical University of Lublin, Radziwillowska Street 11, 20-080 Lublin, Poland
| | - Maciej Skrzypczak
- Second Department of Gynecology, Lublin Medical University, Jaczewski Street 8, 20-954 Lublin, Poland
| | - Agata Filip
- Department of Cancer Genetics with Cytogenetic Laboratory, Medical University of Lublin, Radziwillowska Street 11, 20-080 Lublin, Poland
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A Systematic Review of Clinical Validated and Potential miRNA Markers Related to the Efficacy of Fluoropyrimidine Drugs. DISEASE MARKERS 2022; 2022:1360954. [PMID: 36051356 PMCID: PMC9427288 DOI: 10.1155/2022/1360954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 07/15/2022] [Accepted: 07/29/2022] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) is becoming increasingly prevalent worldwide. Fluoropyrimidine drugs are the primary chemotherapy regimens in routine clinical practice of CRC. However, the survival rate of patients on fluoropyrimidine-based chemotherapy varies significantly among individuals. Biomarkers of fluoropyrimidine drugs'' efficacy are needed to implement personalized medicine. This review summarized fluoropyrimidine drug-related microRNA (miRNA) by affecting metabolic enzymes or showing the relevance of drug efficacy. We first outlined 42 miRNAs that may affect the metabolism of fluoropyrimidine drugs. Subsequently, we filtered another 41 miRNAs related to the efficacy of fluoropyrimidine drugs based on clinical trials. Bioinformatics analysis showed that most well-established miRNA biomarkers were significantly enriched in the cancer pathways instead of the fluoropyrimidine drug metabolism pathways. The result also suggests that the miRNAs screened from metastasis patients have a more critical role in cancer development than those from non-metastasis patients. There are five miRNAs shared between these two lists. The miR-21, miR-215, and miR-218 can suppress fluoropyrimidine drugs'' catabolism. The miR-326 and miR-328 can reduce the efflux of fluoropyrimidine drugs. These five miRNAs could jointly act by increasing intracellular levels of fluoropyrimidine drugs'' cytotoxic metabolites, leading to better chemotherapy responses. In conclusion, we demonstrated that the dynamic changes in the transcriptional regulation via miRNAs might play significant roles in the efficacy and toxicity of the fluoropyrimidine drug. The reported miRNA biomarkers would help evaluate the efficacy of fluoropyrimidine drug-based chemotherapy and improve the prognosis of colorectal cancer patients.
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12
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Dai H, Abdullah R, Wu X, Li F, Ma Y, Lu A, Zhang G. Pancreatic Cancer: Nucleic Acid Drug Discovery and Targeted Therapy. Front Cell Dev Biol 2022; 10:855474. [PMID: 35652096 PMCID: PMC9149368 DOI: 10.3389/fcell.2022.855474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 04/07/2022] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most lethal cancers with an almost 10% 5-year survival rate. Because PC is implicated in high heterogeneity, desmoplastic tumor-microenvironment, and inefficient drug-penetration, the chemotherapeutic strategy currently recommended for the treatment of PC has limited clinical benefit. Nucleic acid-based targeting therapies have become strong competitors in the realm of drug discovery and targeted therapy. A vast evidence has demonstrated that antibody-based or alternatively aptamer-based strategy largely contributed to the elevated drug accumulation in tumors with reduced systematic cytotoxicity. This review describes the advanced progress of antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), messenger RNA (mRNAs), and aptamer-drug conjugates (ApDCs) in the treatment of PC, revealing the bright application and development direction in PC therapy.
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Affiliation(s)
- Hong Dai
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Razack Abdullah
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute for the Advancement of Chinese medicine (IACM) .Ltd, Shatin, Hong Kong SAR, China
| | - Xiaoqiu Wu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Fangfei Li
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
| | - Yuan Ma
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
| | - Aiping Lu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
| | - Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
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13
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Wang H, Jiang Y, Liang Y, Wei L, Zhang W, Li L. Observation of the cervical microbiome in the progression of cervical intraepithelial neoplasia. BMC Cancer 2022; 22:362. [PMID: 35379200 PMCID: PMC8981842 DOI: 10.1186/s12885-022-09452-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 03/21/2022] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Cervical microbial community in the cervical intraepithelial neoplasia and cervical cancer patients was analysed to study its composition, diversity and signalling pathways by high-throughput 16S rDNA sequencing,and the candidate genes associated with occurrence and progression of cervical intraepithelial neoplasia were screened out and the model was established to predict the evolution of cervical intraepithelial neoplasia malignant transformation from the cervical microbial genes aspect. METHODS Cervical tissues of normal, cervical intraepithelial neoplasia and cervical cancer patients without receiving any treatment were collected. The correlation between candidate genes and cervical intraepithelial neoplasia progression was initially determined by analyzing the microbial flora. Real-time fluorescence quantitative PCR was used to detect the expression of candidate genes in different cervical tissues, ROC curve and logistic regression was used to analyse and predict the risk factors related to the occurrence and progression of cervical intraepithelial neoplasia. Finally, the early warning model of cervical intraepithelial neoplasia occurrence and progression is established. RESULTS Cervical tissues from normal, cervical intraepithelial neoplasia and cervical cancer patients were collected for microbial community high-throughput 16S rDNA sequencing. The analysis revealed five different pathways related to cervical intraepithelial neoplasia. 10 candidate genes were selected by further bioinformatics analysis and preliminary screening. Real time PCR, ROC curve and Logistic regression analysis showed that human papillomavirus infection, TCT severity, ABCG2, TDG, PCNA were independent risk factors for cervical intraepithelial neoplasia. We used these indicators to establish a random forest model. Seven models were built through different combinations. The model 4 (ABCG2 + PCNA + TDG) was the best early warning model for the occurrence and progression of CIN. CONCLUSIONS A total of 5 differential pathways and 10 candidate genes related to occurrence and progression of cervical intraepithelial neoplasia were found in cervical microbial community. This study firstly identified the genes from cervical microbial community that play an important role in the occurrence and progression of cervical intraepithelial neoplasia. At the same time, the early warning model including ABCG2 + PCNA+TDG genes provided a new idea and target for clinical prediction and blocking the evolution of cervical intraepithelial neoplasia malignant transformation from the aspect of cervical microbiological related genes.
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Affiliation(s)
- He Wang
- Department of gynecologic oncology, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, 530021, Guangxi, China
| | - Yanming Jiang
- Department of Obstetrics and Gynecology, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yuejuan Liang
- Department of Obstetrics and Gynecology, Liuzhou People's Hospital, Liuzhou, China
| | - Lingjia Wei
- Department of Obstetrics and Gynecology, Guangxi Medical University, Nanning, China
| | - Wei Zhang
- Department of gynecologic oncology, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, 530021, Guangxi, China
| | - Li Li
- Department of gynecologic oncology, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, 530021, Guangxi, China.
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MiR-520h inhibits viability and facilitates apoptosis of KGN cells through modulating IL6R and the JAK/STAT pathway. Reprod Biol 2022; 22:100607. [DOI: 10.1016/j.repbio.2022.100607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/10/2022] [Accepted: 01/11/2022] [Indexed: 12/22/2022]
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Pavlíková L, Šereš M, Breier A, Sulová Z. The Roles of microRNAs in Cancer Multidrug Resistance. Cancers (Basel) 2022; 14:cancers14041090. [PMID: 35205839 PMCID: PMC8870231 DOI: 10.3390/cancers14041090] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/16/2022] [Accepted: 02/20/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary The resistance of neoplastic cells to multiple drugs is a serious problem in cancer chemotherapy. The molecular causes of multidrug resistance in cancer are largely known, but less is known about the mechanisms by which cells deliver phenotypic changes that resist the attack of anticancer drugs. The findings of RNA interference based on microRNAs represented a breakthrough in biology and pointed to the possibility of sensitive and targeted regulation of gene expression at the post-transcriptional level. Such regulation is also involved in the development of multidrug resistance in cancer. The aim of the current paper is to summarize the available knowledge on the role of microRNAs in resistance to multiple cancer drugs. Abstract Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes in cell cycle checkpoints; elevated DNA repair mechanisms. Although these mechanisms of MDR are well described, information on their molecular interaction in overall multidrug resistance is still lacking. MicroRNA (miRNA) expression and subsequent RNA interference are candidates that could be important players in the interplay of MDR mechanisms. The regulation of post-transcriptional processes in the proteosynthetic pathway is considered to be a major function of miRNAs. Due to their complementarity, they are able to bind to target mRNAs, which prevents the mRNAs from interacting effectively with the ribosome, and subsequent degradation of the mRNAs can occur. The aim of this paper is to provide an overview of the possible role of miRNAs in the molecular mechanisms that lead to MDR. The possibility of considering miRNAs as either specific effectors or interesting targets for cancer therapy is also analyzed.
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Affiliation(s)
- Lucia Pavlíková
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
| | - Mário Šereš
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Correspondence: (M.Š.); (A.B.); (Z.S.)
| | - Albert Breier
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovakia
- Correspondence: (M.Š.); (A.B.); (Z.S.)
| | - Zdena Sulová
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Correspondence: (M.Š.); (A.B.); (Z.S.)
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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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17
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Wu Y, Fan T, Zhao Y, Hu R, Yan D, Sun D, Gao L, Qin L, Xue X. Circular RNA hsa_circ_0001306 Functions as a Competing Endogenous RNA to Regulate FBXW7 Expression by Sponging miR-527 in Hepatocellular Carcinoma. J Cancer 2021; 12:6531-6542. [PMID: 34659544 PMCID: PMC8489137 DOI: 10.7150/jca.61381] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 09/01/2021] [Indexed: 01/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide. Circular RNAs (circRNAs) have been reported to regulate many types of cancers, including HCC. The purpose of this study was to investigate the potential roles of hsa_circ_0001306 in HCC. Firstly, the downregulation of hsa_circ_0001306 was identified by high‑throughput RNA sequencing and further verified by qRT-PCR. Secondly, we evaluated the effects of hsa_circ_0001306 on HCC cell proliferation, invasion, cell cycle. Finally, we used an animal model to validate the in vitro experimental results. The expression of hsa_circ_0001306 was closely related to tumor size. Knockdown of hsa_circ_0001306 could downregulate F-box and WD repeat domain containing 7(FBXW7), a target of miR-527, thereby promoting HCC cell proliferation and invasion. Furthermore, hsa_circ_0001306 siRNA increased the multiplication rate of HCC tumors. Mechanistic studies indicated that hsa_circ_0001306 acts as a ceRNA for miR-527, which resulted in the reduction of its endogenous target, FBXW7. Hsa_circ_001306 is significantly downregulated in HCC, and the hsa_circ_0001306/miR-527/FBXW7 axis plays an important role in HCC progression.
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Affiliation(s)
- Yufan Wu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, JiangSu Province, China.,Kunshan Hospital of Traditional Chinese Medicine, Kunshan, JiangSu Province, China
| | - Taihe Fan
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, JiangSu Province, China.,Department of General Surgery, Changshu NO.1 People's Hospital Affiliated to Soochow University, Changshu, JiangSu Province, China
| | - Yubin Zhao
- Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Rongkuan Hu
- College of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Dongdong Yan
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, JiangSu Province, China
| | - Ding Sun
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, JiangSu Province, China
| | - Ling Gao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, JiangSu Province, China
| | - Lei Qin
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, JiangSu Province, China
| | - Xiaofeng Xue
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, JiangSu Province, China
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Huang J, Chen J, Huang Q. The profile analysis of circular RNAs in cervical cancer. Medicine (Baltimore) 2021; 100:e27404. [PMID: 34596168 PMCID: PMC8483823 DOI: 10.1097/md.0000000000027404] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 09/16/2021] [Indexed: 01/05/2023] Open
Abstract
Cervical cancer (CC) is the third most common cancer among women and has a high mortality rate at the advanced stage. The mechanisms underlying the development and progression of CC are still elusive. Circular RNAs (circRNAs) play an important role in various physiological and pathological processes. The aim of this study was to identify the circRNAs significantly associated with cervical squamous cell carcinoma (CSCC), in order to discover novel diagnostic markers and elucidate their mechanistic basis.The circRNA expression profiles of CSCC and paired para-cancerous cervical tissues was downloaded from the Gene Expression Omnibus. Bioinformatics analysis were used to screen for the differentially expressed circRNAs (DECRs). The expression levels of hsa_circ_0000745, hsa_circ_0084927, hsa_circ_0002762, hsa_circ_0075341, hsa_circ_0007905, hsa_circ_0031027, hsa_circ_0065898, hsa_circ_0070190, and hsa_circ_0078383 were verified in CC and normal cervical tissues by quantitative real-time PCR.A total of 197 DECRs were identified between the CSCC and normal tissues, including 87 upregulated and 110 downregulated circRNAs. In addition, 37 miRNAs were predicted for the upregulated circRNAs and 39 for the downregulated circRNAs. Functional analysis showed that the DECRs were associated with positive regulation of substrate adhesion-dependent cell spreading, metabolism, positive regulation of GTPase activity, protein regulation, and intercellular adhesion. The MAPK signaling pathway that plays a significant role in the progression of CC, was also enriched. Consistent with the in-silico analysis, hsa_circ_0000745, hsa_circ_0084927, hsa_circ_0002762, hsa_circ_0007905 were upregulated and hsa_circ_0078383 was downregulated in CC tissues (P < .001), whereas hsa_circ_0075341 (P < .001) and hsa_circ_0031027 (P = .001) showed opposite trends.We identified novel diagnostic and therapeutic biomarkers of CSCC along with the mechanistic basis.
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19
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Liu F, Zhang X, Wu F, Peng H. Hsa_circ_0088212-mediated miR-520 h/APOA1 axis inhibits osteosarcoma progression. Transl Oncol 2021; 14:101219. [PMID: 34555726 PMCID: PMC8461379 DOI: 10.1016/j.tranon.2021.101219] [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] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/27/2021] [Accepted: 09/07/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND It has been known for decades that circRNAs are deregulated in cancer. Here, we characterized the role and underlying mechanism of circ_0088212 in osteosarcoma. METHODS The expression levels of circ_0088212, miR-520 h, and APOA1 were determined by RT-qPCR. RNase R digestion was performed to verify the circular structure of circ_0088212. CCK8 and transwell invasion assays were conducted to examine the in vitro malignancy of osteosarcoma. Caspase-3 activity was also measured. An in vivo model of osteosarcoma was constructed to examine the in vivo effect of circ_0088212 on osteosarcoma. Luciferase reporter, RNA RIP, and RNA pull-down assays were performed to verify the interaction between miR-520 h and APOA1 or circ_0088212. RESULTS Circ_0088212 and APOA1 were expressed at low levels in osteosarcoma tissues and cells, while miR-520 h was highly expressed. Overexpression of circ_0088212 was found to inhibit the in vitro and in vivo growth of osteosarcoma. Mechanistically, miR-520 h was the target of circ_0088212 and APOA1 was the target of miR-520 h. Circ_0088212 downregulated miR-520 h expression, while miR-520 h overexpression abolished the inhibitory effect of circ_0088212 on osteosarcoma cell proliferation and migration. Furthermore, miR-520 h overexpression led to reduced APOA1 expression, while APOA1 overexpression counteracted the oncogenic effect of miR-520 h in osteosarcoma cells. CONCLUSION Our findings demonstrated that circ_0088212 might exert a tumor-suppressive activity in osteosarcoma by sponging and sequestering miR-520 h away from APOA1. This suggests that the circ_0088212/miR-520 h/APOA1 axis may be a promising therapeutic target for osteosarcoma intervention.
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Affiliation(s)
- Feng Liu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Xiangyang Zhang
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Fei Wu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Hao Peng
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China.
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Li P, Wang H, Tang Y, Sun S, Ma Y, Xu Y, Chen G. Knockdown of LINC00657 inhibits the viability, migration and invasion of pancreatic cancer cells by regulating the miR-520h/CKS1B axis. Exp Ther Med 2021; 22:1142. [PMID: 34504588 DOI: 10.3892/etm.2021.10576] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 05/13/2021] [Indexed: 12/13/2022] Open
Abstract
Long non-coding RNA LINC00657 has a critical role in multiple cancers. The aim of the present study was to investigate the regulatory effect of LINC00657 in pancreatic cancer (PC) and reveal its molecular mechanism of function. The expression levels of LINC00657 and microRNA (miR)-520h were detected by reverse transcription-quantitative PCR in PC tissues and cell lines. MTT, wound healing and Transwell assays were used to detect cell viability, migration and invasion, respectively. Dual-luciferase reporter assay was utilized to examine the relationship between LINC00657 and miR-520h and that between miR-520h and cyclin-dependent kinases regulatory subunit 1 (CKS1B). Western blotting was performed to detect CKS1B expression. The expression levels of LINC00657 and CKS1B were enhanced and miR-520h expression level was reduced in PC tissues and cell lines compared with adjacent normal tissues or HPDE6 cells. LINC00657 knockdown decreased the viability, migration and invasion of PC cells. Additionally, LINC00657 targeted miR-520h and negatively modulated miR-520h expression. Furthermore, miR-520h overexpression inhibited the viability, migration and invasion of PC cells. In addition, miR-520h targeted CKS1B and reversely regulated CKS1B expression. miR-520h inhibition and CKS1B overexpression alleviated the inhibition effect of LINC00657 knockdown on the viability, migration and invasion of PACA-2 PC cells. In conclusion, the results of the present study demonstrated that LINC00657 knockdown repressed the viability, migration and invasion of PC cells via targeting the miR-520h/CKS1B axis, which may offer a future target for PC therapy.
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Affiliation(s)
- Peng Li
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Hongsheng Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Ying Tang
- Department of Nursing, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Shuo Sun
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Yue Ma
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Yansong Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Guangyu Chen
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
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21
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Lü JM, Liang Z, Liu D, Zhan B, Yao Q, Chen C. Two Antibody-Guided Lactic-co-Glycolic Acid-Polyethylenimine (LGA-PEI) Nanoparticle Delivery Systems for Therapeutic Nucleic Acids. Pharmaceuticals (Basel) 2021; 14:841. [PMID: 34577541 PMCID: PMC8470087 DOI: 10.3390/ph14090841] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/14/2021] [Accepted: 08/23/2021] [Indexed: 01/10/2023] Open
Abstract
We previously reported a new polymer, lactic-co-glycolic acid-polyethylenimine (LGA-PEI), as an improved nanoparticle (NP) delivery for therapeutic nucleic acids (TNAs). Here, we further developed two antibody (Ab)-conjugated LGA-PEI NP technologies for active-targeting delivery of TNAs. LGA-PEI was covalently conjugated with a single-chain variable fragment antibody (scFv) against mesothelin (MSLN), a biomarker for pancreatic cancer (PC), or a special Ab fragment crystallizable region-binding peptide (FcBP), which binds to any full Ab (IgG). TNAs used in the current study included tumor suppressor microRNA mimics (miR-198 and miR-520h) and non-coding RNA X-inactive specific transcript (XIST) fragments; green fluorescence protein gene (GFP plasmid DNA) was also used as an example of plasmid DNA. MSLN scFv-LGA-PEI NPs with TNAs significantly improved their binding and internalization in PC cells with high expression of MSLN in vitro and in vivo. Anti-epidermal growth factor receptor (EGFR) monoclonal Ab (Cetuximab) binding to FcBP-LGA-PEI showed active-targeting delivery of TNAs to EGFR-expressing PC cells.
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Affiliation(s)
- Jian-Ming Lü
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA; (J.-M.L.); (Z.L.); (D.L.); (Q.Y.)
| | - Zhengdong Liang
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA; (J.-M.L.); (Z.L.); (D.L.); (Q.Y.)
| | - Dongliang Liu
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA; (J.-M.L.); (Z.L.); (D.L.); (Q.Y.)
| | - Bin Zhan
- National School of Tropical Medicine and Department of Pediatrics, Section of Tropical Medicine, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA;
| | - Qizhi Yao
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA; (J.-M.L.); (Z.L.); (D.L.); (Q.Y.)
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
| | - Changyi Chen
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Plaza, Houston, TX 77030, USA; (J.-M.L.); (Z.L.); (D.L.); (Q.Y.)
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22
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Apoptotic effects of valproic acid on miR-34a, miR-520h and HDAC1 gene in breast cancer. Life Sci 2021; 269:119027. [PMID: 33453248 DOI: 10.1016/j.lfs.2021.119027] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 12/17/2022]
Abstract
Identifying miRNAs involved in cancer and devising strategies to control their expression is a new therapeutic approach. Valproic acid (VPA) has attracted a lot of interest in cancer research. We evaluated the impact of VPA on the expression of miR-34a, miR-520h, and their target gene histone deacetylase 1 (HDAC1), as well as their relationship with apoptosis in breast cancer. First, through bioinformatics analyses, the possible target genes of miR-34a and miR-520h and their roles in apoptosis regulation were investigated. Then, miR-34a, miR-520h, and HDAC1 gene expression in tissues of breast cancer patients were determined using the qRT-PCR method. The anticancer impact of VPA on apoptosis and the expression levels of miR-34a, miR-520h, and HDAC1 gene were measured in MCF-7 and MDA-MB-231 cell lines. The bioinformatics analyses indicated that miR-34a and miR-520h might make a unique contribution in regulating the apoptosis pathway. The relative expression of miR-34a and miR-520h significantly decreased in cancer tissues, while the relative expression of HDAC1 increased. In the in vitro study, VPA led to apoptosis induction and increased lipid peroxidation products in breast cancer cells. Moreover, VPA increased the expression of miR- 34a and miR-520h and decreased HDAC1 expression in MCF-7 cells. In MDA-MB-231 cells, VPA decreased the expression of these miRNAs and increased the expression of HDAC1. It can be concluded that miR-34a and miR-520h are implicated in the apoptosis pathways, and thus, VPA can recruit as a possible option in breast cancer research due to its interference with epigenetic processes.
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23
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Sarkadi B, Homolya L, Hegedűs T. The ABCG2/BCRP transporter and its variants - from structure to pathology. FEBS Lett 2020; 594:4012-4034. [PMID: 33015850 DOI: 10.1002/1873-3468.13947] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/27/2020] [Accepted: 09/21/2020] [Indexed: 12/13/2022]
Abstract
The ABCG2 protein has a key role in the transport of a wide range of structurally dissimilar endo- and xenobiotics in the human body, especially in the tissue barriers and the metabolizing or secreting organs. The human ABCG2 gene harbors a high number of polymorphisms and mutations, which may significantly modulate its expression and function. Recent high-resolution structural data, complemented with molecular dynamic simulations, may significantly help to understand intramolecular movements and substrate handling, as well as the effects of mutations on the membrane transporter function of ABCG2. As reviewed here, structural alterations may result not only in direct alterations in drug binding and transporter activity, but also in improper folding or problems in the carefully regulated process of trafficking, including vesicular transport, endocytosis, recycling, and degradation. Here, we also review the clinical importance of altered ABCG2 expression and function in general drug metabolism, cancer multidrug resistance, and impaired uric acid excretion, leading to gout.
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Affiliation(s)
- Balázs Sarkadi
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.,Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - László Homolya
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
| | - Tamás Hegedűs
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
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24
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Wang W, Yang Y, Chen X, Shao S, Hu S, Zhang T. MAGI1 mediates tumor metastasis through c-Myb/miR-520h/MAGI1 signaling pathway in renal cell carcinoma. Apoptosis 2020; 24:837-848. [PMID: 31352641 DOI: 10.1007/s10495-019-01562-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Renal cell carcinoma (RCC) is the third most common urological cancer with highly metastatic potential. MAGI1 plays an important role in stabilization of the adherens junctions and has been confirmed to suppress invasiveness and metastasis in multiple cancers in clinic. However, its expression and anti-metastatic ability in RCC are still unclear. In this study, we demonstrated that MAGI1 was markedly decreased in the RCC and indicated poor survival. Furthermore, we found that MAGI1 suppressed the invasion and migration of human RCC cells. Mechanistic investigations revealed that MAGI1 stabilized the PTEN/MAGI1/β-catenin complex to inhibit β-catenin signaling pathway. Moreover, MAGI1 was targeted by miR-520h which was transcriptionally activated by c-Myb. Collectively, our findings suggested that MAGI1mediated tumor metastasis through c-Myb/miR-520h/MAGI1 signaling pathway in RCC.
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Affiliation(s)
- Wei Wang
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong, China.,Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yanhua Yang
- Department of Pathology, Qingdao Municipal Hospital, Qingdao, Shandong, China
| | - Xinyi Chen
- Department of Pathology, Qingdao Central Hospital, Qingdao, Shandong, China.,Department of Pathology, The Second Affiliated Hospital of Qingdao University Medical College, Qingdao, Shandong, China
| | - Shihong Shao
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Shasha Hu
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Tingguo Zhang
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong, China. .,Department of Pathology, School of Basic Medical Sciences, Shandong University, NO. 44, Wenhuaxi Road, Jinan, Shandong, China.
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25
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Huang Y, Dai Y, Wen C, He S, Shi J, Zhao D, Wu L, Zhou H. circSETD3 Contributes to Acquired Resistance to Gefitinib in Non-Small-Cell Lung Cancer by Targeting the miR-520h/ABCG2 Pathway. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 21:885-899. [PMID: 32805491 PMCID: PMC7452060 DOI: 10.1016/j.omtn.2020.07.027] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 07/16/2020] [Accepted: 07/21/2020] [Indexed: 12/24/2022]
Abstract
Gefitinib is a first-line treatment for patients with non-small-cell lung cancer (NSCLC), but acquired resistance is a major obstacle to its therapeutic efficacy, and the underlying mechanisms are not fully elucidated. Recent studies have indicated that circular RNAs play a crucial role in chemoresistance, but their expression and function in NSCLC cells with acquired resistance to gefitinib are largely unknown. In this study, we determined that circSETD3 was significantly upregulated in gefitinib-resistant NSCLC cell lines and the plasma of gefitinib-resistant NSCLC patients. circSETD3 markedly decreased the gefitinib sensitivity of NSCLC cells both in vitro and in nude mice xenografts. It could directly bind to miR-520h and lead to the upregulation of ATP-binding cassette subfamily G member 2 (ABCG2), an efflux transporter of gefitinib, resulting in a reduced intracellular gefitinib concentration. Moreover, we reported that the downregulation of serine/arginine splicing factor 1 (SRSF1) contributed to, at least in part, the increased expression of circSETD3 in NSCLC cells with acquired resistance to gefitinib. Taken together, our findings indicated that circSETD3 may serve as a prognostic biomarker and a potential therapeutic target for acquired resistance to gefitinib in NSCLC.
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Affiliation(s)
- Yutang Huang
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Yi Dai
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China; Wangjia Community Health Service Center, Chongqing 401120, China
| | - Chunjie Wen
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Shuai He
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Jingjing Shi
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Dezhang Zhao
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Lanxiang Wu
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China.
| | - Honghao Zhou
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China; Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha 410078, China
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26
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miR-520h Stimulates Drug Resistance to Paclitaxel by Targeting the OTUD3-PTEN Axis in Breast Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9512793. [PMID: 32775453 PMCID: PMC7391095 DOI: 10.1155/2020/9512793] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 03/30/2020] [Accepted: 04/01/2020] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) have been identified as negative posttranscriptional regulators of target genes and are involved directly in the pathological processes of tumors, including drug resistance. However, the exact function of miR-520h in breast cancer remains poorly understood. The aim of this study was to investigate the molecular mechanisms of miR-520h in paclitaxel resistance in the MCF-7 breast cancer cell line. Ectopic expression of miR-520h could promote the proliferation of breast cancer cells and inhibit paclitaxel-induced cell apoptosis. Inhibiting the expression of miR-520h could enhance the sensitivity to paclitaxel in paclitaxel-resistant MCF-7/Taxol cells. Furthermore, luciferase reporter assays showed that OTUD3 was a direct target of miR-520h. OTUD3 plays a necessary role in the paclitaxel resistance effect of miR-520h, and cotreatment with a miR-520h inhibitor and OTUD3 overexpression significantly enhanced MCF-7 cell sensitivity to paclitaxel. Moreover, miR-520h substantially inhibited the protein expression of PTEN via OTUD3 and subsequently affected downstream p-AKT pathway activity. In a clinical study, we also found that high miR-520h expression was associated with more aggressive pathological characteristic and poor prognosis. Therefore, our findings showed that miR-520h targeted the OTUD3-PTEN axis to drive paclitaxel resistance, and this miR might be an important potential target for breast cancer treatment.
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27
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Gorczyca L, Aleksunes LM. Transcription factor-mediated regulation of the BCRP/ ABCG2 efflux transporter: a review across tissues and species. Expert Opin Drug Metab Toxicol 2020; 16:239-253. [PMID: 32077332 DOI: 10.1080/17425255.2020.1732348] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Introduction: The breast cancer resistance protein (BCRP/ABCG2) is a member of the ATP-binding cassette superfamily of transporters. Using the energy garnered from the hydrolysis of ATP, BCRP actively removes drugs and endogenous molecules from the cell. With broad expression across the liver, kidney, brain, placenta, testes, and small intestines, BCRP can impact the pharmacokinetics and pharmacodynamics of xenobiotics.Areas covered: The purpose of this review is to summarize the transcriptional signaling pathways that regulate BCRP expression across various tissues and mammalian species. We will cover the endobiotic- and xenobiotic-activated transcription factors that regulate the expression and activity of BCRP. These include the estrogen receptor, progesterone receptor, peroxisome proliferator-activated receptor, constitutive androstane receptor, pregnane X receptor, nuclear factor e2-related factor 2, and aryl hydrocarbon receptor.Expert opinion: Key transcription factors regulate BCRP expression and function in response to hormones and xenobiotics. Understanding this regulation provides an opportunity to improve pharmacotherapeutic outcomes by enhancing the efficacy and reducing the toxicity of drugs that are substrates of this efflux transporter.
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Affiliation(s)
- Ludwik Gorczyca
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ, USA
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ, USA.,Division of Toxicology, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, USA
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28
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Kovacsics D, Brózik A, Tihanyi B, Matula Z, Borsy A, Mészáros N, Szabó E, Németh E, Fóthi Á, Zámbó B, Szüts D, Várady G, Orbán TI, Apáti Á, Sarkadi B. Precision-engineered reporter cell lines reveal ABCG2 regulation in live lung cancer cells. Biochem Pharmacol 2020; 175:113865. [PMID: 32142727 DOI: 10.1016/j.bcp.2020.113865] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/18/2020] [Indexed: 12/19/2022]
Abstract
Expression of the ABCG2 multidrug transporter is a marker of cancer stem cells and a predictor of recurrent malignant disease. Understanding how human ABCG2 expression is modulated by pharmacotherapy is crucial in guiding therapeutic recommendations and may aid rational drug development. Genome edited reporter cells are useful in investigating gene regulation and visualizing protein activity in live cells but require precise targeting to preserve native regulatory regions. Here, we describe a fluorescent reporter assay that allows the noninvasive assessment of ABCG2 regulation in human lung adenocarcinoma cells. Using CRISPR-Cas9 gene editing coupled with homology-directed repair, we targeted an EGFP coding sequence to the translational start site of ABCG2, generating ABCG2 knock-out and in situ tagged ABCG2 reporter cells. Using the engineered cell lines, we show that ABCG2 is upregulated by a number of anti-cancer medications, HDAC inhibitors, hypoxia-mimicking agents and glucocorticoids, supporting a model in which ABCG2 is under the control of a general stress response. To our knowledge, this is the first description of a fluorescent reporter assay system designed to follow the endogenous regulation of a human ABC transporter in live cells. The information gained may guide therapy recommendations and aid rational drug design.
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Affiliation(s)
- Daniella Kovacsics
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Anna Brózik
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Borbála Tihanyi
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Zsolt Matula
- South-Pest Hospital Centre, National Institute of Hematology and Infectious Diseases, Laboratory of Molecular and Cytogenetics, Budapest, Hungary
| | - Adrienn Borsy
- South-Pest Hospital Centre, National Institute of Hematology and Infectious Diseases, Laboratory of Molecular and Cytogenetics, Budapest, Hungary
| | - Nikolett Mészáros
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Edit Szabó
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Eszter Németh
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Ábel Fóthi
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Boglárka Zámbó
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Dávid Szüts
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - György Várady
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Tamás I Orbán
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Ágota Apáti
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Balázs Sarkadi
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary.
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29
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Shi H, Li H, Zhen T, Dong Y, Pei X, Zhang X. The Potential Therapeutic Role of Exosomal MicroRNA-520b Derived from Normal Fibroblasts in Pancreatic Cancer. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 20:373-384. [PMID: 32200272 PMCID: PMC7090279 DOI: 10.1016/j.omtn.2019.12.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 11/11/2019] [Accepted: 12/09/2019] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer (PC) remains a major health concern, with conventional cancer treatments exerting little influence on the disease course. MicroRNA-520b (miR-520b) functions as a tumor suppressor in several types of human cancers, whereas its anti-tumor property in the context of PC is still fundamental. The aim of this study is to identify the potential therapeutic role of miR-520b, transferred by exosomes, derived from normal fibroblasts (NFs) in PC progression. A gain-of-function study was performed to examine the roles of miR-520b in PC cell line SW1990, which suggested that miR-520b served as a tumor suppressor in PC. In order to confirm the role of exosomal miR-520b, exosomes were isolated from NF culture medium and cocultured with SW1990 cells. During the coculture experiments, we disrupted exosome secretion and upregulated exosomal miR-520b. The in vitro coculture studies revealed that miR-520b was transferred from NF-derived exosomes to PC cells and thereby suppressed PC cell proliferation, invasion, migration, and stimulated apoptosis. Furthermore, inhibited tumor growth and live metastasis upon elevated miR-520b in exosomes were observed in vivo. Conjointly, our study demonstrates that NF-derived exosomal miR-520b impedes the progression of PC, which contributes to a novel, therapeutic role of exosomal miR-520b for treating PC.
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Affiliation(s)
- Huijuan Shi
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Hui Li
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Tiantian Zhen
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Yu Dong
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Xiaojuan Pei
- Department of Pathology, Shenzhen Hospital of Southern Medical University, Shenzhen 518110, P.R. China.
| | - Xiangliang Zhang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, P.R. China.
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30
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Zhang H, Lang TY, Zou DL, Zhou L, Lou M, Liu JS, Li YZ, Ding DY, Li YC, Zhang N, Zheng XD, Zeng XH, Zhou Q, Li L. miR-520b Promotes Breast Cancer Stemness Through Hippo/YAP Signaling Pathway. Onco Targets Ther 2019; 12:11691-11700. [PMID: 32021247 PMCID: PMC6942529 DOI: 10.2147/ott.s236607] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 12/14/2019] [Indexed: 11/23/2022] Open
Abstract
Introduction The breast cancer stem cells contribute to the initiation, progression, recurrence, metastasis as well as resistance of breast cancer. However, the mechanisms underlying the maintenance of breast cancer stemness have not been fully understood. Materials and methods TCGA and GEO data were used for measuring miR-520b expression in breast cancer tissues. Kaplan-meier analysis was used for determining the relationship between miR-520b expression level and the prognosis of patients. Genetic manipulation was performed by lentivirus system and miR-520b inhibitor was used for knockdown of miR-520b. qRT-PCR and Western blot were employed to determine the mRNA and protein levels, respectively. The stemness and EMT (Epithelial to mesenchymal transition) were assessed by sphere-formation and transwell assay as well as the expression of the related markers. The target genes of miR-520b were identified using the online database starBase V3.0. Results miR-520b is upregulated in cancer tissues of breast cancer patients and predicts poor prognosis. Upregulation of miR-520b was found in breast cancer stem cells. Ectopic expression of miR-520b promotes the stemness of the breast cancer cells, conversely, depletion of miR-520b attenuates the stemness of these cells. miR-520b positively regulates Hippo/YAP signaling pathway and overexpression of LAST2 abolished the effect of miR-520b on the stemness of breast cancer cells. Conclusion miR-520b promotes the stemness of breast cancer patients by activating Hippo/YAP signaling via targeting LATS2.
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Affiliation(s)
- Hui Zhang
- Department of Gynecologic Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People's Republic of China.,Breast Cancer Center, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Chongqing, People's Republic of China.,Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Chongqing, People's Republic of China.,Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, Chongqing, 400030, People's Republic of China
| | - Ting-Yuan Lang
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Chongqing, People's Republic of China
| | - Dong-Ling Zou
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Chongqing, People's Republic of China
| | - Lei Zhou
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.,Singapore Eye Research Institute, Singapore 169856, Singapore.,Ophthalmology and Visual Sciences Academic Clinical Research Program, Duke-NUS Medical School, Singapore 169867, Singapore
| | - Meng Lou
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Chongqing, People's Republic of China
| | - Jing-Shu Liu
- Bioengineering College of Chongqing University, Chongqing University, Chongqing 400030, Chongqing, People's Republic of China
| | - Yun-Zhe Li
- Bioengineering College of Chongqing University, Chongqing University, Chongqing 400030, Chongqing, People's Republic of China
| | - Dong-Yan Ding
- Bioengineering College of Chongqing University, Chongqing University, Chongqing 400030, Chongqing, People's Republic of China
| | - Yu-Cong Li
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Chongqing, People's Republic of China.,Bioengineering College of Chongqing University, Chongqing University, Chongqing 400030, Chongqing, People's Republic of China
| | - Na Zhang
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Chongqing, People's Republic of China
| | - Xiao-Dong Zheng
- Breast Cancer Center, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Chongqing, People's Republic of China
| | - Xiao-Hua Zeng
- Breast Cancer Center, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Chongqing, People's Republic of China
| | - Qi Zhou
- Department of Gynecologic Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People's Republic of China.,Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Chongqing, People's Republic of China.,Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, Chongqing, 400030, People's Republic of China.,Department of Gynecologic Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Chongqing, People's Republic of China
| | - Li Li
- Department of Gynecologic Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People's Republic of China
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Xu WX, Liu Z, Deng F, Wang DD, Li XW, Tian T, Zhang J, Tang JH. MiR-145: a potential biomarker of cancer migration and invasion. Am J Transl Res 2019; 11:6739-6753. [PMID: 31814885 PMCID: PMC6895535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 10/30/2019] [Indexed: 06/10/2023]
Abstract
MircoRNAs (miRNAs) are a diverse family of highly-conserved small non-coding RNAs, which range from approximately 18 to 25 nucleotides in size. They regulate gene expression transcriptionally or post-transcriptionally via binding to the 3'-untranslated region (3'-UTR) of target message RNAs (mRNAs). MiRNAs have emerged as molecular regulators that participate in physiological and pathological processes of diverse malignancies. Among them, miRNA-145 (miR-145) played a profound role in tumorigenesis and progression of various neoplasms. In this review, we summarized the recent findings regarding miR-145, to elucidate its functional roles in cell invasion and migration of diverse human malignancies, and considered it a potential biomarker for cancer diagnosis, screening, and prognosis.
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Affiliation(s)
- Wen-Xiu Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, P. R. China
- The First Clinical School of Nanjing Medical UniversityNanjing 210029, P. R. China
| | - Zhen Liu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, P. R. China
- The First Clinical School of Nanjing Medical UniversityNanjing 210029, P. R. China
| | - Fei Deng
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, P. R. China
- The First Clinical School of Nanjing Medical UniversityNanjing 210029, P. R. China
| | - Dan-Dan Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, P. R. China
| | - Xing-Wang Li
- School of Clinical Medicine, Xuzhou Medical University209 Tongshan Road, Xuzhou 221004, P. R. China
| | - Tian Tian
- School of Clinical Medicine, Xuzhou Medical University209 Tongshan Road, Xuzhou 221004, P. R. China
| | - Jian Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, P. R. China
| | - Jin-Hai Tang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, P. R. China
- The First Clinical School of Nanjing Medical UniversityNanjing 210029, P. R. China
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Breast Cancer Resistance Protein (BCRP/ ABCG2) Inhibits Extra Villous Trophoblast Migration: The Impact of Bacterial and Viral Infection. Cells 2019; 8:cells8101150. [PMID: 31561453 PMCID: PMC6829363 DOI: 10.3390/cells8101150] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 09/18/2019] [Accepted: 09/24/2019] [Indexed: 11/16/2022] Open
Abstract
Extravillous trophoblasts (EVT) migration into the decidua is critical for establishing placental perfusion and when dysregulated, may lead to pre-eclampsia (PE) and intrauterine growth restriction (IUGR). The breast cancer resistance protein (BCRP; encoded by ABCG2) regulates the fusion of cytotrophoblasts into syncytiotrophoblasts and protects the fetus from maternally derived xenobiotics. Information about BCRP function in EVTs is limited, however placental exposure to bacterial/viral infection leads to BCRP downregulation in syncitiotrophoblasts. We hypothesized that BCRP is involved in the regulation of EVT function and is modulated by infection/inflammation. We report that besides syncitiotrophoblasts and cytotrophoblasts, BCRP is also expressed in EVTs. BCRP inhibits EVT cell migration in HTR8/SVneo (human EVT-like) cells and in human EVT explant cultures, while not affecting cell proliferation. We have also shown that bacterial-lipopolysaccharide (LPS)-and viral antigens-single stranded RNA (ssRNA)-have a profound effect in downregulating ABCG2 and BCRP levels, whilst simultaneously increasing the migration potential of EVT-like cells. Our study reports a novel function of BCRP in early placentation and suggests that exposure of EVTs to maternal infection/inflammation could disrupt their migration potential via the downregulation of BCRP. This could negatively influence placental development/function, contribute to existing obstetric pathologies, and negatively impact pregnancy outcomes and maternal/neonatal health.
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Ceballos MP, Rigalli JP, Ceré LI, Semeniuk M, Catania VA, Ruiz ML. ABC Transporters: Regulation and Association with Multidrug Resistance in Hepatocellular Carcinoma and Colorectal Carcinoma. Curr Med Chem 2019; 26:1224-1250. [PMID: 29303075 DOI: 10.2174/0929867325666180105103637] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/19/2017] [Accepted: 11/21/2017] [Indexed: 02/07/2023]
Abstract
For most cancers, the treatment of choice is still chemotherapy despite its severe adverse effects, systemic toxicity and limited efficacy due to the development of multidrug resistance (MDR). MDR leads to chemotherapy failure generally associated with a decrease in drug concentration inside cancer cells, frequently due to the overexpression of ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2), which limits the efficacy of chemotherapeutic drugs. The aim of this review is to compile information about transcriptional and post-transcriptional regulation of ABC transporters and discuss their role in mediating MDR in cancer cells. This review also focuses on drug resistance by ABC efflux transporters in cancer cells, particularly hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cells. Some aspects of the chemotherapy failure and future directions to overcome this problem are also discussed.
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Affiliation(s)
- María Paula Ceballos
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - Juan Pablo Rigalli
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.,Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Lucila Inés Ceré
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - Mariana Semeniuk
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - Viviana Alicia Catania
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - María Laura Ruiz
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
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Kong J, Qiu Y, Li Y, Zhang H, Wang W. TGF-β1 elevates P-gp and BCRP in hepatocellular carcinoma through HOTAIR/miR-145 axis. Biopharm Drug Dispos 2019; 40:70-80. [DOI: 10.1002/bdd.2172] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 01/13/2019] [Accepted: 01/23/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Jiehong Kong
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences; Soochow University; Suzhou 215123 China
| | - Yajing Qiu
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences; Soochow University; Suzhou 215123 China
| | - Yuan Li
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences; Soochow University; Suzhou 215123 China
| | - Hongjian Zhang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences; Soochow University; Suzhou 215123 China
| | - Weipeng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences; Soochow University; Suzhou 215123 China
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Ding M, Zhang H, Liu L, Liang R. Effect of NOS1 regulating ABCG2 expression on proliferation and apoptosis of cervical cancer cells. Oncol Lett 2019; 17:1531-1536. [PMID: 30675209 PMCID: PMC6341600 DOI: 10.3892/ol.2018.9786] [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] [Received: 04/27/2018] [Accepted: 11/05/2018] [Indexed: 01/12/2023] Open
Abstract
The expression of nitric oxide synthase 1 (NOS1) and adenosine triphosphate-binding cassette sub-family G member 2 (ABCG2) in cervical cancer tissues was investigated. The messenger ribonucleic acid (mRNA) levels of NOS1 and ABCG2 in 40 cervical cancer specimens and 20 normal cervical specimens were detected via reverse transcription-polymerase chain reaction, and the correlation between them was analyzed via Pearsons correlation analysis. The protein expression levels were detected via western blotting. Moreover, the regulatory mode between NOS1 and ABCG2 and the effects on proliferation and apoptosis of cervical cancer cells were analyzed using the lentiviral transfection technique. The mRNA levels of NOS1 and ABCG2 in the cervical cancer group were significantly increased compared with those in the normal cervical control group (P<0.05). There was a positive correlation between NOS1 and ABCG2 mRNA expression levels in cervical cancer tissues (r=1.246, P=0.014). HeLa and C-33A cell lines with relatively high expression levels of NOS1 and ABCG2 were selected for the in vitro study. After interference in the NOS1 expression in HeLa and C-33A cells with sh-NOS1, the protein expression of ABCG2 was also decreased. However, the protein expression level of NOS1 remained unchanged after interference in the ABCG2 expression (P<0.05). After interference in the NOS1 expression, the proliferation capacities of HeLa and C-33A cells were significantly decreased, but the apoptosis levels were obviously increased (P<0.05). The mRNA expression of NOS1 and ABCG2 in cervical cancer tissues is significantly increased. NOS1, as an upstream signal regulator of ABCG2, regulates the growth and apoptosis of tumor cells. Both NOS1 and ABCG2 are important proliferation-promoting oncogenes in cervical cancer, which are expected to provide a certain theoretical basis for the treatment of cervical cancer.
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Affiliation(s)
- Mingde Ding
- Department of Gynaecology, Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000, P.R. China
| | - Hui Zhang
- Department of Gynaecology, Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000, P.R. China
| | - Lei Liu
- Department of Pathology, Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000, P.R. China
| | - Ruilan Liang
- Department of Gynaecology, Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000, P.R. China
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An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:240. [PMID: 30285798 PMCID: PMC6169080 DOI: 10.1186/s13046-018-0899-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 08/31/2018] [Indexed: 01/05/2023]
Abstract
Background Pancreatic cancer is a deadly disease with a very low 5-year patient survival rate of 6–8%. The major challenges of eliminating pancreatic cancer are treatment resistance and stromal barriers to optimal drug access within the tumor. Therefore, effective molecular targeting drugs with high intra-tumor access and retention are urgently needed for managing this devastating disease in the clinic. Methods This study has used the following in vitro and in vivo techniques for the investigation of exceptional anticancer drug FL118’s efficacy in treatment of resistant pancreatic cancer: cell culture; immunoblotting analysis to test protein expression; DNA sub-G1 flow cytometry analyses to test cell death; MTT assay to test cell viability; pancreatic cancer stem cell assays (fluorescence microscopy tracing; matrigel assay; CD44-positive cell colony formation assay); human luciferase-labeled pancreatic tumor orthotopic animal model in vivo imaging; pancreatic cancer patient-derived xenograft (PDX) animal models; and toxicology studies with immune-competent BALB/cj mice and beagle dogs. Results Our studies found that FL118 alone preferentially killed cisplatin-resistant cancer cells, while a combination of FL118 with cisplatin synergistically killed resistant pancreatic cancer cells and reduced spheroid formation of treatment-resistant pancreatic cancer stem-like cells. Furthermore, using in vivo-imaging, we found that FL118 in combination with cisplatin strongly inhibited both drug-resistant pancreatic xenograft tumor growth and metastasis. In PDX model, we demonstrated that FL118 alone effectively eliminated PDX tumors, while FL118 in combination with gemcitabine eliminated PDX tumors that showed relative resistance (less sensitivity) to treatment with FL118. These FL118 efficacy results are consistent with our molecular-targeting data showing that FL118 inhibited the expression of multiple antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) and ERCC6, a critical regulator of DNA repair, in treatment-resistant pancreatic stem-like cancer cells. Furthermore, FL118 toxicity studies in BALB/cj mice and beagle dogs indicated that FL118 exhibits favorable hematopoietic and biochemical toxicities. Conclusion Together, our studies suggest that FL118 is a promising anticancer drug for further clinical development to effectively treat drug-resistant pancreatic cancer alone or in combination with other pancreatic cancer chemotherapeutic drugs.
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Adamska A, Falasca M. ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward? World J Gastroenterol 2018; 24:3222-3238. [PMID: 30090003 PMCID: PMC6079284 DOI: 10.3748/wjg.v24.i29.3222] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/31/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATP-binding cassette (ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance (MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.
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Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
| | - Marco Falasca
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
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38
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Yao L, Gu J, Mao Y, Zhang X, Wang X, Jin C, Fu D, Li J. Dynamic quantitative detection of ABC transporter family promoter methylation by MS-HRM for predicting MDR in pancreatic cancer. Oncol Lett 2018; 15:5602-5610. [PMID: 29552197 PMCID: PMC5840752 DOI: 10.3892/ol.2018.8041] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 09/01/2017] [Indexed: 12/11/2022] Open
Abstract
The main focus of the present study was to evaluate whether ABC transporter family promoter methylation predicted multidrug resistance in gemcitabine-resistant cancer cell lines (BxPC-3/Gem and PANC-1/Gem). Using low concentrations of gemcitabine, the cell lines acquired drug resistance with different initial gemcitabine concentrations. A novel technology, methylation-sensitive high-resolution melting, was used to monitor the dynamic changes of ABC transporter family promoter methylation, including ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C (ABCC) and ATP binding cassette subfamily G member 2 (ABCG2) mRNA expression. It was revealed that, with elevation of initial gemcitabine concentration, expression of ABCB1, ABCC and ABCG2 mRNA and corresponding downstream proteins was increased while promoter methylation was decreased. These discoveries indicate that promoter methylation of ABCB1, ABCC and ABCG2 may be a valuable indicator of drug-resistance characteristics in BxPC-3/Gem and PANC-1/Gem cells via quantitative and simultaneous detection. These results also implied that MDR in pancreatic cancer not only arises from gene mutation, but also originates from promoter methylation.
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Affiliation(s)
- Lie Yao
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jichun Gu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Yishen Mao
- Department of Clinical Medicine, Fudan University, Shanghai 200082, P.R. China
| | - Xinju Zhang
- Central Laboratory, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Xiaoyi Wang
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Chen Jin
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Ji Li
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
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Hosseinahli N, Aghapour M, Duijf PHG, Baradaran B. Treating cancer with microRNA replacement therapy: A literature review. J Cell Physiol 2018. [PMID: 29521426 DOI: 10.1002/jcp.26514] [Citation(s) in RCA: 231] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally by interfering with the translation of one or more target mRNAs. The unique miRNA sequences are involved in many physiological and pathological processes. Dysregulation of miRNAs contributes to the pathogenesis of all types of cancer. Notably, the diminished expression of tumor suppressor miRNAs, such as members of the Let-7 and miR-34 family, promotes tumor progression, invasion and metastasis. The past lustrum in particular, has witnessed substantial improvement of miRNA replacement therapy. This approach aims to restore tumor suppressor miRNA function in tumor cells using synthetic miRNA mimics or miRNA expression plasmids. Here, we provide a comprehensive review of recent advances in miRNA replacement therapy for treatment of cancer and its advantages over conventional gene therapy. We discuss a wide variety of delivery methods and vectors, as well as obstacles that remain to be overcome. Lastly, we review efforts to reverse epigenetic alterations, which affect miRNA expression in cancer cells, and the promising observation that restoring miRNA function re-sensitizes resistant tumor cells to chemotherapeutic drugs. The fact that various miRNA replacement therapies are currently in clinical trial demonstrates the great potential of this approach to treat cancer.
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Affiliation(s)
- Nayer Hosseinahli
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahyar Aghapour
- Department of Pathobiology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Pascal H G Duijf
- University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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MiR-520b as a novel molecular target for suppressing stemness phenotype of head-neck cancer by inhibiting CD44. Sci Rep 2017; 7:2042. [PMID: 28515423 PMCID: PMC5435724 DOI: 10.1038/s41598-017-02058-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 04/12/2017] [Indexed: 01/16/2023] Open
Abstract
Cancer stem cells preferentially acquire the specific characteristics of stress tolerance and high mobility, allowing them to progress to a therapy-refractive state. To identify a critical molecule to regulate cancer stemness is indispensable to erratically cure cancer. In this study, we identified miR-520b as a novel molecular target to suppress head-neck cancer (HNC) with stemness phenotype. MiR-520b inhibited cellular migration and invasion via the mechanism of epithelial-mesenchymal transition. It also sensitized cells to therapeutic drug and irradiation. Significantly, miR-520b suppressed spheroid cell formation, as well as reduced expressions of multiple stemness regulators (Nestin, Twist, Nanog, Oct4). The CD44 molecule was identified as a direct target of miR-520b, as shown by the reverse correlative expressions, the response to miR-520 modulation, the luciferase reporter assay, and the functional rescue analyses. These cellular results were confirmed by a tumor xenograft mice study. Administration of miR-520b dramatically restrained tumorigenesis and liver colonization. Conversely, miR-520b silencing led to an acceleration of tumor growth. Taken together, our study demonstrated that miR-520b inhibits the malignancy of HNC through regulation of cancer stemness conversion by targeting CD44. MiR-520b may serve as an emerging therapeutic target that may be further developed for the intervention of refractory HNC.
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Sobek KM, Cummings JL, Bacich DJ, O'Keefe DS. Contrasting roles of the ABCG2 Q141K variant in prostate cancer. Exp Cell Res 2017; 354:40-47. [PMID: 28300564 PMCID: PMC5424544 DOI: 10.1016/j.yexcr.2017.03.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 03/09/2017] [Accepted: 03/10/2017] [Indexed: 01/24/2023]
Abstract
ABCG2 is a membrane transport protein that effluxes growth-promoting molecules, such as folates and dihydrotestosterone, as well as chemotherapeutic agents. Therefore it is important to determine how variants of ABCG2 affect the transporter function in order to determine whether modified treatment regimens may be necessary for patients harboring ABCG2 variants. Previous studies have demonstrated an association between the ABCG2 Q141K variant and overall survival after a prostate cancer diagnosis. We report here that in patients with recurrent prostate cancer, those who carry the ABCG2 Q141K variant had a significantly shorter time to PSA recurrence post-prostatectomy than patients homozygous for wild-type ABCG2 (P=0.01). Transport studies showed that wild-type ABCG2 was able to efflux more folic acid than the Q141K variant (P<0.002), suggesting that retained tumoral folate contributes to the decreased time to PSA recurrence in the Q141K variant patients. In a seemingly conflicting study, it was previously reported that docetaxel-treated Q141K variant prostate cancer patients have a longer survival time. We found this may be due to less efficient docetaxel efflux in cells with the Q141K variant versus wild-type ABCG2. In human prostate cancer tissues, confocal microscopy revealed that all genotypes had a mixture of cytoplasmic and plasma membrane staining, with noticeably less staining in the two homozygous KK patients. In conclusion, the Q141K variant plays contrasting roles in prostate cancer: 1) by decreasing folate efflux, increased intracellular folate levels result in enhanced tumor cell proliferation and therefore time to recurrence decreases; and 2) in patients treated with docetaxel, by decreasing its efflux, intratumoral docetaxel levels and tumor cell drug sensitivity increase and therefore patient survival time increases. Taken together, these data suggest that a patient's ABCG2 genotype may be important when determining a personalized treatment plan.
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Affiliation(s)
- Kathryn M Sobek
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jessica L Cummings
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Dean J Bacich
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Urology, University of Texas Health Science Center, San Antonio, TX, USA
| | - Denise S O'Keefe
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Urology, University of Texas Health Science Center, San Antonio, TX, USA.
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Roh YJ, Kim JH, Kim IW, Na K, Park JM, Choi MG. Photodynamic Therapy Using Photosensitizer-Encapsulated Polymeric Nanoparticle to Overcome ATP-Binding Cassette Transporter Subfamily G2 Function in Pancreatic Cancer. Mol Cancer Ther 2017; 16:1487-1496. [PMID: 28416605 DOI: 10.1158/1535-7163.mct-16-0642] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 02/01/2017] [Accepted: 04/05/2017] [Indexed: 12/27/2022]
Abstract
Chlorin-based photosensitizers are commonly used in photodynamic therapy (PDT). These drugs are effluxed by cell membrane transporters, such as the ATP-binding cassette subfamily G member 2 (ABCG2). PDT efficacy is limited in tumor cells expressing high levels of these proteins. Pancreatic cancer cell lines AsPC-1 and MIA PaCa-2, which have high and low ABCG2 expression, respectively, were used, and ABCG2-overexpressing MIA PaCa-2 cells were generated. We compared PDT efficacy between chlorin e6 (Ce6) and cationic photosensitizer-encapsulated polymeric nanoparticle (PS-pNP), which is comprised with Ce6, polyethylene glycol, and polyethylenimine. The intracellular concentration of Ce6 was significantly higher in MIA PaCa-2 cells than in AsPC-1 or ABCG2-overexpressing MIA PaCa-2 cells. PS-pNP increased intracellular levels of the photosensitizer in all cell lines. The cell viability experiments indicated increased Ce6 resistance in ABCG2-overexpressing cells. In contrast, PS-pNP produced similar levels of cytotoxicity in each of the cancer cell lines tested. Singlet oxygen production was higher in cells treated with PS-pNP than in those treated with Ce6. Furthermore, in heterotopic and orthotopic AsPC-1 xenograft mouse models, PDT using PS-pNP significantly reduced tumor volume in comparison with that of Ce6 treatment. PS-pNP could increase intracellular Ce6 concentration, which was related with reduced ABCG2-mediated efflux of Ce6, thereby enhancing the effects of PDT in pancreatic cancer cells. Mol Cancer Ther; 16(8); 1487-96. ©2017 AACR.
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Affiliation(s)
- Yoon Jin Roh
- Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
| | - Ju Hee Kim
- Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
| | - In-Wook Kim
- Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
| | - Kun Na
- Department of Biotechnology, Center for Photomedicine, The Catholic University of Korea, Bucheon-si, Gyeonggi-do, Korea
| | - Jae Myung Park
- Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea. .,Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Myung-Gyu Choi
- Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea. .,Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Abstract
Chemotherapy is widely used for cancer treatment, but its effectiveness is limited by drug resistance. Here, we report a mechanism by which cell density activates the Hippo pathway, which in turn inactivates YAP, leading to changes in the regulation of genes that control the intracellular concentrations of gemcitabine and several other US Food and Drug Administration (FDA)-approved oncology drugs. Hippo inactivation sensitizes a diverse panel of cell lines and human tumors to gemcitabine in 3D spheroid, mouse xenografts, and patient-derived xenograft models. Nuclear YAP enhances gemcitabine effectiveness by down-regulating multidrug transporters as well by converting gemcitabine to a less active form, both leading to its increased intracellular availability. Cancer cell lines carrying genetic aberrations that impair the Hippo signaling pathway showed heightened sensitivity to gemcitabine. These findings suggest that "switching off" of the Hippo-YAP pathway could help to prevent or reverse resistance to some cancer therapies.
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First trimester screening of circulating C19MC microRNAs and the evaluation of their potential to predict the onset of preeclampsia and IUGR. PLoS One 2017; 12:e0171756. [PMID: 28182660 PMCID: PMC5300267 DOI: 10.1371/journal.pone.0171756] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 01/25/2017] [Indexed: 12/17/2022] Open
Abstract
Objectives A nested case control study of a longitudinal cohort comparing pregnant women enrolled at 10 to 13 gestational weeks was carried out to evaluate risk assessment for preeclampsia and IUGR based on circulating placental specific C19MC microRNAs in early pregnancy. Methods The expression of placental specific C19MC microRNAs (miR-516b-5p, miR-517-5p, miR-518b, miR-520a-5p, miR-520h, and miR-525-5p) was determined in plasma samples from pregnancies that subsequently developed preeclampsia (n = 21), IUGR (n = 18), and 58 normal pregnancies using real-time PCR and comparative Ct method relative to synthetic Caenorhabditis elegans microRNA (cel-miR-39). Results Circulating C19MC microRNAs were up-regulated (miR-517-5p, p = 0.005; miR-518b, p = 0.013; miR-520h, p = 0.021) or showed a trend toward up-regulation in patients destined to develop preeclampsia (miR-520a-5p, p = 0.067; miR-525-5p, p = 0.073). MiR-517-5p had the best predictive performance for preeclampsia with a sensitivity of 42.9%, a specificity of 86.2%, a PPV of 52.9% and a NPV of 80.6%. The combination of all examined circulating C19MC microRNAs had no advantage over using only the miR-517-5p biomarker to predict the occurrence of preeclampsia (a sensitivity of 20.6%, a specificity of 90.8%, a PPV of 44.8%, and a NPV of 76.0%). Conclusions Up-regulation of miR-517-5p, miR-518b and miR-520h was associated with a risk of later development of preeclampsia. First trimester screening of extracellular miR-517-5p identified a proportion of women with subsequent preeclampsia. No circulating C19MC microRNA biomarkers were identified that could predict later occurrence of IUGR.
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Francois LN, Gorczyca L, Du J, Bircsak KM, Yen E, Wen X, Tu MJ, Yu AM, Illsley NP, Zamudio S, Aleksunes LM. Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling. Placenta 2017; 51:57-63. [PMID: 28292469 DOI: 10.1016/j.placenta.2017.01.125] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 12/30/2016] [Accepted: 01/22/2017] [Indexed: 12/31/2022]
Abstract
INTRODUCTION The BCRP/ABCG2 efflux transporter protects the developing fetus by limiting the transplacental transfer of drugs and chemicals and prevents the apoptosis of trophoblasts. The purpose of this study was to determine whether hypoxia-related signaling alters placental BCRP expression and function in vitro and in human pregnancies. METHODS Human BeWo choriocarcinoma cells were treated with the hypoxia mimetic, cobalt chloride (CoCl2), or 3% oxygen for 24-48 h. Activation of HIF-1α signaling and regulation of BCRP was assessed using qPCR, ELISA, western blotting and a fluorescent substrate transport assay. In addition, healthy term placentas from high altitude pregnancies with chronic hypoxia were assessed for BCRP expression. RESULTS CoCl2 and 3% oxygen increased HIF-1α protein signaling and decreased the mRNA and protein expression of BCRP by 30-75% in BeWo cells. Reduced BCRP expression corresponded with impaired efflux activity during hypoxia as evidenced by accumulation of the substrate Hoechst 33342. A number of transcription factors known to regulate BCRP, including AHR, NRF2 and PPARγ, were also coordinately down-regulated by 3% oxygen in BeWo cells. Moreover, women who gave birth at a high altitude (3100 m) exhibited signs of chronic placental hypoxia, including enhanced protein expression of the HIF-1α target GLUT1, and had reduced BCRP levels in microvillous membranes compared to women at a moderate altitude (1600 m). DISCUSSION This study provides novel insight into the regulation of the placental BCRP transporter by hypoxia, which may be important for exposure of the fetus to chemicals during early development and in hypoxia-related pregnancy disorders.
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Affiliation(s)
- Lissa N Francois
- Rutgers University, Robert Wood Johnson Medical School, Department of Obstetrics, Gynecology and Reproductive Sciences, Maternal-Fetal Medicine Division, 125 Paterson St., New Brunswick, NJ 08091, USA
| | - Ludwik Gorczyca
- Rutgers University, Ernest Mario School of Pharmacy, Department of Pharmacology and Toxicology, 170 Frelinghuysen Rd., Piscataway, NJ 08854, USA
| | - Jianyao Du
- China Pharmaceutical University, Gulou, Nanjing, Jiangsu, China
| | - Kristin M Bircsak
- Rutgers University, Ernest Mario School of Pharmacy, Department of Pharmacology and Toxicology, 170 Frelinghuysen Rd., Piscataway, NJ 08854, USA
| | - Elizabeth Yen
- Rutgers University, Robert Wood Johnson Medical School, Department of Pediatrics, Division of Neonatology, 1 Robert Wood Johnson Place, New Brunswick, NJ 08903, USA
| | - Xia Wen
- Rutgers University, Ernest Mario School of Pharmacy, Department of Pharmacology and Toxicology, 170 Frelinghuysen Rd., Piscataway, NJ 08854, USA
| | - Mei-Juan Tu
- University of California, Davis, Department of Biochemistry and Molecular Medicine, 2700 Stockton Blvd., Sacramento, CA 95817, USA
| | - Ai-Ming Yu
- University of California, Davis, Department of Biochemistry and Molecular Medicine, 2700 Stockton Blvd., Sacramento, CA 95817, USA
| | - Nicholas P Illsley
- Hackensack University Medical Center, Department of Obstetrics and Gynecology, 30 Prospect Ave, Hackensack, NJ 07601, USA
| | - Stacy Zamudio
- Hackensack University Medical Center, Department of Obstetrics and Gynecology, 30 Prospect Ave, Hackensack, NJ 07601, USA
| | - Lauren M Aleksunes
- Rutgers University, Ernest Mario School of Pharmacy, Department of Pharmacology and Toxicology, 170 Frelinghuysen Rd., Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, 170 Frelinghuysen Rd., Piscataway, NJ 08854, USA; Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USA.
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Konrad CV, Murali R, Varghese BA, Nair R. The role of cancer stem cells in tumor heterogeneity and resistance to therapy. Can J Physiol Pharmacol 2017; 95:1-15. [DOI: 10.1139/cjpp-2016-0079] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cancer is a heterogenous disease displaying marked inter- and intra-tumoral diversity. The existence of cancer stem cells (CSCs) has been experimentally demonstrated in a number of cancer types as a subpopulation of tumor cells that drives the tumorigenic and metastatic properties of the entire cancer. Thus, eradication of the CSC population is critical for the complete ablation of a tumor. This is, however, confounded by the inherent resistance of CSCs to standard anticancer therapies, eventually leading to the outgrowth of resistant tumor cells and relapse in patients. The cellular mechanisms of therapy resistance in CSCs are ascribed to several factors including a state of quiescence, an enhanced DNA damage response and active repair mechanisms, up-regulated expression of drug efflux transporters, as well as the activation of pro-survival signaling pathways and inactivation of apoptotic signaling. Understanding the mechanisms underlying the acquisition of resistance to therapy may hold the key to targeting the CSC population.
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Affiliation(s)
- Christina Valbirk Konrad
- Cancer Research Division & Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
| | - Reshma Murali
- Cancer Research Program, Rajiv Gandhi Center for Biotechnology, Kerala, India
| | | | - Radhika Nair
- Cancer Research Program, Rajiv Gandhi Center for Biotechnology, Kerala, India
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Li MP, Hu YD, Hu XL, Zhang YJ, Yang YL, Jiang C, Tang J, Chen XP. MiRNAs and miRNA Polymorphisms Modify Drug Response. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2016; 13:ijerph13111096. [PMID: 27834829 PMCID: PMC5129306 DOI: 10.3390/ijerph13111096] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 10/17/2016] [Accepted: 10/31/2016] [Indexed: 12/13/2022]
Abstract
Differences in expression of drug response-related genes contribute to inter-individual variation in drugs’ biological effects. MicroRNAs (miRNAs) are small noncoding RNAs emerging as new players in epigenetic regulation of gene expression at post-transcriptional level. MiRNAs regulate the expression of genes involved in drug metabolism, drug transportation, drug targets and downstream signal molecules directly or indirectly. MiRNA polymorphisms, the genetic variations affecting miRNA expression and/or miRNA-mRNA interaction, provide a new insight into the understanding of inter-individual difference in drug response. Here, we provide an overview of the recent progress in miRNAs mediated regulation of biotransformation enzymes, drug transporters, and nuclear receptors. We also describe the implications of miRNA polymorphisms in cancer chemotherapy response.
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Affiliation(s)
- Mu-Peng Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
| | - Yao-Dong Hu
- Department of Cardiology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi 046000, China.
| | - Xiao-Lei Hu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
| | - Yan-Jiao Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
| | - Yong-Long Yang
- Haikou People's Hospital and Affiliated Haikou Hospital of Xiangya Medical School, Central South University, Haikou 570311, China.
| | - Chun Jiang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
| | - Jie Tang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
| | - Xiao-Ping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, 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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Wang J, Xin B, Wang H, He X, Wei W, Zhang T, Shen X. Gastrin regulates ABCG2 to promote the migration, invasion and side populations in pancreatic cancer cells via activation of NF-κB signaling. Exp Cell Res 2016; 346:74-84. [PMID: 27264047 DOI: 10.1016/j.yexcr.2016.06.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 05/07/2016] [Accepted: 06/01/2016] [Indexed: 12/19/2022]
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