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Long Non-Coding Rnas Regulate Drug Resistance in Cancer Kaisheng Liu1†, Lin Gao1†, Xiaoshi Ma1†, Juan-Juan Huang2, Juan Chen1, Leli Zeng3,4, Charles R

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Long Non-Coding Rnas Regulate Drug Resistance in Cancer Kaisheng Liu1†, Lin Gao1†, Xiaoshi Ma1†, Juan-Juan Huang2, Juan Chen1, Leli Zeng3,4, Charles R Liu et al. Molecular Cancer (2020) 19:54 https://doi.org/10.1186/s12943-020-01162-0 REVIEW Open Access Long non-coding RNAs regulate drug resistance in cancer Kaisheng Liu1†, Lin Gao1†, Xiaoshi Ma1†, Juan-Juan Huang2, Juan Chen1, Leli Zeng3,4, Charles R. Ashby Jr.3, Chang Zou1* and Zhe-Sheng Chen3* Abstract Chemoresistance, whether intrinsic or acquired, is a major obstacle in the treatment of cancer. The resistance of cancer cells to chemotherapeutic drugs can result from various mechanisms. Over the last decade, it has been reported that 1ong noncoding RNAs (lncRNAs) can mediate carcinogenesis and drug resistance/sensitivity in cancer cells. This article reviews, in detail, recent studies regarding the roles of lncRNAs in mediating drug resistance. Keywords: Cancer, Drug resistance, Long non-coding RNAs Background Furthermore, drug resistance can be present in tumor Globally, cancer is the leading cause of mortality and in cells before chemotherapy, a phenomenon known as 2018, it was estimated that there were 9.6 million acquired drug resistance [5]. Overall, the underlying cancer-related deaths [1]. Currently, the primary thera- mechanisms of resistance to chemotherapeutic drugs peutic approaches for treating cancer are chemotherapy, remain to be fully elucidated. radiation and surgery [2]. However, during treatment, The development of new technologies, in combination tumor cells can become resistant to chemotherapy due with bioinformatics, has resulted in the discovery of to, but not limited to; 1) increased expression of certain additional genes associated with drug resistance [6]. Fur- ATP-binding cassette (ABC) transport proteins that thermore, it is important to note that < 2% of the human decrease the intracellular concentration of anticancer genome encodes proteins and 98% of the transcriptional drugs, thereby decreasing their efficacy; 2) alterations products are short and long non-coding RNAs that allow cancer cells to avoid cell death; 3) increase in (lncRNAs) [7, 8]. LncRNAs consist of more than 200 DNA repair; 4) mutations in specific cellular targets; 5) nucleotides and have no protein coding function [7]. alterations that allow cancer cells to tolerate adverse or LncRNAs are less conserved among species, are typically stressful conditions and 6) increasing the biotransform- expressed at low levels and often have high tissue and ation of anticancer drugs to less efficacious or inactive development specificity [9]. LncRNAs have important metabolites [3]. Consequently, drug resistance is still a regulatory roles in many aspects of genome function, major challenge as it often causes therapeutic failure [4]. including gene transcription, splicing, and epigenetics, as well as biological processes involved in the cell cycle, cell differentiation, development, and pluripotency [10]. * Correspondence: [email protected]; [email protected] †Kaisheng Liu, Lin Gao and Xiaoshi Ma contributed equally to this work. LncRNAs have recently been identified as a new mech- 1The First Affiliated Hospital of Southern University of Science and anism in drug resistance/sensitivity and has garnered Technology, The Second Clinical Medical College of Jinan University, significant attention in the area of cancer research. Shenzhen People’s Hospital, Shenzhen 518020, Guangdong, People’s Republic of China Indeed, numerous papers have been published over the 3College of Pharmacy and Health Sciences, St. John’s University, Queens, last decade regarding lncRNA and resistance to antican- New York, NY 11439, USA cer drugs. In this review, we will discuss the mechanisms Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liu et al. Molecular Cancer (2020) 19:54 Page 2 of 13 by which lncRNAs produce drug resistance in cancer intestine, brain and kidney, which play a role in protect- cells. ing tissues and organs from endogenous and xenobiotics [16, 17]. It is well established that the overexpression of LncRNA roles in mediating resistance to anticancer drugs the ABC proteins by cancer cells, which efflux anti- The effect of lncRNA on phase I and phase II enzymes cancer drugs from the cancer cells, thereby attenuat- Alterations in drug metabolism are one of the important ing or abrogating their efficacy, mediates resistance to and most studied mechanisms that mediate drug resist- certain anticancer drugs [18, 19]. Numerous studies ance. The mechanisms of drug metabolism and dispos- indicate that the members of the ABC transporter ition can be categorized as: phase I, phase II and phase family associated with multidrug resistance (MDR) in III [11]. LncRNAs can regulate certain phase I enzymes cancer cells include p-glycoprotein (P-gp/ABCB1), and affect drug resistance in cancer cells. For example, MRP1/ABCC1, MRP2/ABCC2, MRP4/ABCC4, and lncRNA H19 is overexpressed in colorectal cancer and BCRP/ABCG2 [20](Fig.1). increases the intracellular aldehyde dehydrogenase Recent studies have shown that specific lncRNAs can (ALDH) activity in colorectal tumors [12]. LncRNA H19 affect various ABC transporters, thereby producing drug activates the β-catenin pathway by sequestering miR- resistance. For example, in hepatocellular cancer (HCC), 141, which contributes to tumor development and knockdown of lncRNA H19 significantly increased the chemoresistance in colorectal cancer tumors [12]. methylation of the MDR1 promoter methylation and de- LncRNAs have been shown to affect the regulation of creased MDR1/P-glycoprotein expression in doxorubicin specific phase II enzymes [13, 14]. The expression of the (DOX)-resistant R-HepG2 cells [21]. In addition, the lncRNA, HOX transcript antisense intergenic RNA levels of lncRNA very low density lipoprotein receptor (HOTAIR), is positively correlated with the level of the (VLDLR) are significantly increased in HCC, and the carbohydrate sulfotransferase (CHST15) protein in pri- knockdown of lncRNA VLDLR significantly reduced mary, as well as the number of metastatic tumor lesions HCC proliferation and the expression of BCRP/ABCG2, [13]. In addition, HOTAIR promotes the invasion of while overexpression of BCRP/ABCG2 decreased the ef- breast cancer cells by affecting the expression of cell sur- fect of lncRNA VLDLR1 knockdown on sorafenib- face glycosaminoglycans [13]. The lncRNA Homo sapi- induced cell death in HepG2 cells [22]. The lncRNA ens glutathione S-transferase mu 3, transcript variant 2 plasmacytoma variant translocation 1 (PVT1) is highly and noncoding RNA (GSTM3TV2) levels are signifi- expressed in gastric cancer tissues of cisplatin-resistant cantly increased in pancreatic tumor tissues and it upre- patients and cisplatin-resistant cells [23]. The up- gulates the L-type amino acid transporter 2 (LAT2) and regulation of lncRNA PVT1 increased the expression of oxidized low-density lipoprotein receptor 1(OLR1) by MDR1, MRP, mammalian target of rapamycin (mTOR) competitively sequestering let-7 (a mRNA targeting c- and hypoxia-inducible factor alpha (HIF-1α) and de- Myc, HMGA2 and Ras) to induce gemcitabine resistance creased the apoptosis produced by cisplatin in BGC823 in pancreatic cancer [15]. and SGC7901 cancer cells [23]. The lncRNA MDR- related and upregulated lncRNA (MRUL) was signifi- Altered drug efflux and related lncRNAs cantly upregulated in the multidrug-resistant gastric In phase III drug disposition, the metabolites of the cancer cell sublines, SGC7901/ADR [resistant to doxo- drugs are eliminated and excreted by various endogen- rubicin/adriamycin (DOX/ADR)] and SGC7901/VCR ous transporters that are found in the liver, small [resistant to vincristine (VCR)], and its expression Fig. 1 Schematic illustration of lncRNA-induced resistance to anticancer drugs by altering drug metabolism and drug efflux Liu et al. Molecular Cancer (2020) 19:54 Page 3 of 13 significantly decreased the anti-proliferative efficacy of the expression levels of lncRNAs have been reported to ADR or VCR [24]. The expression of lncRNA MRUL in- be significantly correlated with drug resistance in various creases the expression of P-gp/ABCB1 in an orientation- tumors. The lncRNA E2F1-regulated inhibitor of cell and position-independent manner and the depletion of death (ERIC) is a 1.7 kb transcript up-regulated by E2F1 MRUL decreased ABCB1 mRNA levels in a concentra- [34]. The knockdown of ERIC significantly increases tion - and time-dependent manner [24]. In addition, the etoposide-induced apoptosis in osteosarcoma cells incu- knockdown of
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