Molecular Therapy - Nucleic Acids

Journal Information
ISSN / EISSN : 21622531 / 21622531
Current Publisher: Elsevier BV (10.1016)
Former Publisher: Springer Science and Business Media LLC (10.1038)
Total articles ≅ 1,237
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Latest articles in this journal

Ting Deng, Haiyang Zhang, Haiou Yang, Huiya Wang, Ming Bai, Wu Sun, Xinyi Wang, Yiran Si, Tao Ning, Le Zhang, et al.
Molecular Therapy - Nucleic Acids, Volume 19, pp 1449-1459; doi:10.1016/j.omtn.2020.01.024

Abstract:
Exosomes, membranous nanovesicles, naturally carry proteins, mRNAs, and microRNAs (miRNAs) and play important roles in tumor pathogenesis. Here we showed that gastric cancer (GC) cell-derived exosomes can function as vehicles to deliver miR-155 to promote angiogenesis in GC. In this study, we first detected that the expression of miR-155 and c-MYB was negatively correlated in GC and that c-MYB was a direct target of miR-155. We next characterized the promotional effect of exosome-delivered miR-155 on angiogenesis and tumor growth in GC. We found that miR-155 could inhibit c-MYB but increase vascular endothelial growth factor (VEGF) expression and promote growth, metastasis, and tube formation of vascular cells, causing the occurrence and development of tumors. We also used a tumor implantation mouse model to show that exosomes containing miR-155 significantly augment the growth rate of the vasculature and tumors in vivo. Our results illustrate the potential mechanism between miR-155 and angiogenesis in GC. These findings contribute to our understanding of the function of miR-155 and exosomes for GC therapy.
Zhaolin Chen, Tingting Pan, Duochen Jiang, Le Jin, Yadi Geng, Xiaojun Feng, Aizong Shen, Lei Zhang
Molecular Therapy - Nucleic Acids, Volume 19, pp 1434-1448; doi:10.1016/j.omtn.2020.01.030

Abstract:
Drug resistance, including adriamycin (ADR)-based therapeutic resistance, is a crucial cause of chemotherapy failure in breast cancer treatment. Acquired chemoresistance has been identified to be closely associated with the overexpression of P-glycoprotein (P-gp/ABCB1). Long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) can be involved in carcinogenesis; however, its roles in ABCB1-mediated ADR resistance are poorly understood. In this study, we identified a panel of differentially expressed lncRNAs, mRNAs, and microRNAs (miRNAs) in MCF-7 and MCF-7/ADR cell lines through RNA sequencing (RNA-seq) technologies. GAS5 level was downregulated whereas ABCB1 level was upregulated in the resistant breast cancer tissues and cells. Overexpression of GAS5 significantly enhanced the ADR sensitivity and apoptosis, and it inhibited the efflux function and expression of ABCB1 in vitro, while knockdown of GAS5 had the opposite effects. Further mechanism-related investigations indicated that GAS5 acted as an endogenous "sponge" by competing for miR-221-3p binding to regulate its target dickkopf 2 (DKK2), and then it inhibited the activation of the Wnt/β-catenin pathway. Functionally, GAS5 enhanced the anti-tumor effect of ADR in vivo. Collectively, our findings reveal that GAS5 exerted regulatory function in ADR resistance possibly through the miR-221-3p/DKK2 axis, providing a novel approach to develop promising therapeutic strategy for overcoming chemoresistance in breast cancer patients.
Taejin Kim, Mathias Viard, Kirill A. Afonin, Kshitij Gupta, Mary Popov, Jacqueline Salotti, Peter F. Johnson, Charles Linder, Eliahu Heldman, Bruce A. Shapiro
Molecular Therapy - Nucleic Acids, Volume 20, pp 359-372; doi:10.1016/j.omtn.2020.02.011

Abstract:
Small interfering RNAs (siRNAs) are potential therapeutic substances due to their gene silencing capability as exemplified by the recent approval by the US Food and Drug Administration (FDA) of the first siRNA therapeutic agent (patisiran). However, the delivery of naked siRNAs is challenging because of their short plasma half-lives and poor cell penetrability. In this study, we used vesicles made from bolaamphiphiles (bolas), GLH-19 and GLH-20, to investigate their ability to protect siRNA from degradation by nucleases while delivering it to target cells, including cells in the brain. Based on computational and experimental studies, we found that GLH-19 vesicles have better delivery characteristics than do GLH-20 vesicles in terms of stability, binding affinity, protection against nucleases, and transfection efficiency, while GLH-20 vesicles contribute to efficient release of the delivered siRNAs, which become available for silencing. Our studies with vesicles made from a mixture of the two bolas (GLH-19 and GLH-20) show that they were able to deliver siRNAs into cultured cancer cells, into a flank tumor and into the brain. The vesicles penetrate cell membranes and the blood-brain barrier (BBB) by endocytosis and transcytosis, respectively, mainly through the caveolae-dependent pathway. These results suggest that GLH-19 strengthens vesicle stability, provides protection against nucleases, and enhances transfection efficiency, while GLH-20 makes the siRNA available for gene silencing.
Yu-Chan Yang, Yu-Hsiang Chen, Jia-Horng Kao, Chi Ching, I-Jung Liu, Chih-Chiang Wang, Cheng-Hsueh Tsai, Fang-Yi Wu, Chun-Jen Liu, Pei-Jer Chen, et al.
Molecular Therapy - Nucleic Acids; doi:10.1016/j.omtn.2020.03.005

Rui Jiang, Hui Li, Jiameng Yang, Xuemei Shen, Chengchuang Song, Zhaoxin Yang, Xiaogang Wang, Yongzhen Huang, Xianyong Lan, Chuzhao Lei, et al.
Molecular Therapy - Nucleic Acids; doi:10.1016/j.omtn.2020.03.011

Ana Teresa Barros-Viegas, Vítor Carmona, Elisabete Ferreiro, Joana Guedes, Ana Maria Cardoso, Pedro Cunha, Luís Pereira De Almeida, Catarina Resende De Oliveira, João Pedro De Magalhães, João Peça, et al.
Molecular Therapy - Nucleic Acids, Volume 19, pp 1219-1236; doi:10.1016/j.omtn.2020.01.010

Abstract:
Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive memory impairment, behavioral changes, and, ultimately, loss of consciousness and death. Recently, microRNA (miRNA) dysfunction has been associated with increased production and impaired clearance of amyloid-β (Aβ) peptides, whose accumulation is one of the most well-known pathophysiological markers of this disease. In this study, we identified several miRNAs capable of targeting key proteins of the amyloidogenic pathway. The expression of one of these miRNAs, miR-31, previously found to be decreased in AD patients, was able to simultaneously reduce the levels of APP and Bace1 mRNA in the hippocampus of 17-month-old AD triple-transgenic (3xTg-AD) female mice, leading to a significant improvement of memory deficits and a reduction in anxiety and cognitive inflexibility. In addition, lentiviral-mediated miR-31 expression significantly ameliorated AD neuropathology in this model, drastically reducing Aβ deposition in both the hippocampus and subiculum. Furthermore, the increase of miR-31 levels was enough to reduce the accumulation of glutamate vesicles in the hippocampus to levels found in non-transgenic age-matched animals. Overall, our results suggest that miR-31-mediated modulation of APP and BACE1 can become a therapeutic option in the treatment of AD.
Hao Li, Shan Wang, Xue Dong, Qiao Li, Min Li, Junfeng Li, Yan Guo, Xia Jin, Yusen Zhou, HongBin Song, et al.
Molecular Therapy - Nucleic Acids, Volume 19, pp 1460-1469; doi:10.1016/j.omtn.2020.01.028

Abstract:
The CRISPR-Cas9 system has been applied to DNA editing with precision in eukaryotic and prokaryotic systems, but it is unable to edit RNA directly. A recently developed CRISPR-Cas13a system has been shown to be capable of effectively knocking down RNA expression in mammalian and plant cells. In this study, we employ the CRISPR-Cas13a system to achieve reprogrammable inactivation of dengue virus in mammalian cells. Quantitative reverse transcription PCR (qRT-PCR), fluorescence-activated cell sorting (FACS), and plaque assays showed that CRISPR RNA (crRNA) targeting the NS3 region led to the greatest viral inhibition among 10 crRNAs targeting different regions along the dengue viral genomic RNA. Deletions and insertions had also been found adjacent to the NS3 region after NS3-crRNA/Cas13a complex transfection. Our results demonstrate that the CRISPR-Cas13a system is a novel and effective technology to inhibit dengue viral replication, suggesting that such a programmable method may be further developed into a novel therapeutic strategy for dengue and other RNA viruses.
Xiang Jin, Xiuhua Liu, Zhen Zhang, Yinghui Guan
Molecular Therapy - Nucleic Acids, Volume 19, pp 1266-1275; doi:10.1016/j.omtn.2020.01.006

Abstract:
Long non-coding RNA (lncRNA) colon cancer-associated transcript-1 (CCAT1) has been reported to play important roles in the development and progression of multiple human malignancies. However, the functional role and molecular mechanism of CCAT1 on gefitinib resistance in non-small cell lung cancer (NSCLC) are largely unclear. The aim of this study is to explore the roles of CCAT1 on gefitinib resistance in NSCLC and to explore the underlying mechanisms. The quantitative real-time PCR (qRT-PCR) analysis was to investigate the expression pattern of CCAT1 in gefitinib-resistant NSCLC patient tissues and cell lines, and then the effects of CCAT1 on gefitinib resistance of NSCLC in vitro and in vivo. Furthermore, bioinformatics online program predictions and luciferase reporter assay were used to validate the association of CCAT1 and miR-218 in NSCLC cells. In this study, CCAT1 was observed to be upregulated in gefitinib-resistant patient tissues and cell lines. In vitro and in vivo experiments demonstrated that CCAT1 knockdown impaired cell proliferation and promoted the gefitinib-induced cell apoptosis. Furthermore, we demonstrated that CCAT1 acts as a sponge for miR-218, and verified that HOXA1 is a novel target of miR-218. These results suggest that CCAT1 may serve as a promising therapeutic target for the treatment of epidermal growth factor receptor (EGFR) plus NSCLC patients.
Xuemei Shen, Xiaoyan Zhang, Wenxiu Ru, Yongzhen Huang, Xianyong Lan, Chuzhao Lei, Hong Chen
Molecular Therapy - Nucleic Acids, Volume 19, pp 986-999; doi:10.1016/j.omtn.2019.12.032

Abstract:
As a diverse and abundant class of endogenous RNAs, circular RNAs (circRNAs) participate in processes including cell proliferation and apoptosis. Nevertheless, few researchers have investigated the function of circRNAs in bovine muscle development. Based on existing sequencing data, we identified circINSR. The localization of circINSR in bovine myoblasts was investigated by fluorescence in situ hybridization. Molecular and biochemical assays were used to confirm the role of circINSR in myoblast proliferation and the cell cycle. Mitochondrial membrane potential and annexin V-PE/7-AAD staining assays were performed to assess cell apoptosis. Additionally, interactions between circINSR, miR-34a, and target mRNAs were examined using bioinformatics, a luciferase assay, and RNA immunoprecipitation. We found that circINSR was highly expressed in embryonic muscle tissue. Overexpression of circINSR significantly promoted proliferation and reduced apoptosis of embryonic myoblasts. Our data suggested that circINSR may act as a sponge of miR-34a and could function through de-repression of target genes in muscle cells. This study proposes that circINSR may function as a regulator of embryonic muscle development. circINSR regulates cells proliferation and apoptosis through miR-34a-modulated Bcl-2 and CyclinE2 expression.
Si-Ning Shen, Ke Li, Ying Liu, Cheng-Liang Yang, Chun-Yu He, Hao-Rang Wang
Molecular Therapy - Nucleic Acids, Volume 19, pp 668-682; doi:10.1016/j.omtn.2019.11.030

Abstract:
Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) is correlated to various malignant tumors. Consequently, we explored effects of lncRNA PVT1 on esophageal carcinoma (EC) targeting microRNA-145 (miR-145). EC tissues, adjacent normal tissues, and EC-related cell lines were collected and cultured. Expression of lncRNA PVT1, miR-145, fascin-1 (FSCN1), and related genes with intervening expression of PVT1 and miR-145 was determined. Bioinformatic website, dual-luciferase reporter assay, and RNA immunoprecipitation (RIP) were carried to verify target relationship among lncRNA PVT1, FSCN1, and miR-145. Scratch test, Transwell assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and flow cytometry were performed for detection of migration, invasion, viability, and apoptosis of transfected cells, respectively. Finally, tumor formation in nude mice was measured. After database analysis, lncRNA PVT1, miR-145, and FSCN1 were selected for study. lncRNA PVT1 and FSCN1 can bind to miR-145. After overexpressing miR-145 or inhibiting lncRNA PVT1, EC cell viability, migration, and invasion were inhibited, while volume and weight of tumor formation in nude mice decreased. Expression of lncRNA PVT1, FSCN1, Bcl-2, CD147, VEGFR2, and MTA1 decreased and expression of miR-145 and Bax increased. Silencing lncRNA PVT1 can upregulate miR-145, which is a tumor suppressor in EC via knockdown of FSCN1. Thus, we might provide a potential theoretical basis for EC treatment.