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Ying-Juan Zheng, Tian-Song Liang, Juan Wang, Jing-Yi Zhao, Sciprofile linkDao-Ke Yang, Sciprofile linkZhang-Suo Liu
Published: 6 December 2019
Molecular Therapy - Nucleic Acids, Volume 18, pp 485-495; doi:10.1016/j.omtn.2019.07.026

Abstract: Long non-coding RNAs (lncRNAs) have been widely highlighted due to their involvement in various types of cancers, including glioma; however, the exact mechanism and function by which they operate in regard to spinal cord glioma remain poorly understood. LOC101928963 was screened out for its differential expression in spinal cord glioma by microarray analysis. Therefore, this study was conducted to investigate the modulatory effects of LOC101928963 on spinal cord glioma by binding to phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1). The expression of LOC101928963 and LOC101928963 was characterized in spinal cord glioma tissues, and their interaction was examined by dual-luciferase reporter gene assay. Cells with LOC101928963 that exhibited elevated or suppressed levels of PMAIP1 were established to substantiate the mechanism between LOC101928963 and PMAIP1. qRT-PCR and western blot methods were subsequently applied to determine the expression of cell-proliferation- and apoptosis-related genes in response to the alterations of LOC101928963 and PMAIP1. Glioma cell proliferation and apoptosis were assessed by MTT assay and flow cytometry. Decreased cell apoptosis and PMAIP1 expression, as well as overexpressed LOC101928963, were exhibited among spinal cord glioma tissues. LOC101928963 overexpression was observed to promote cell proliferation and cell-cycle entry and inhibit the process of apoptosis. PMAIP1, a target of LOC101928963, displayed a downregulated level following the elevation of LOC101928963. The present results strongly emphasize the neutralization effect of PMAIP1 overexpression on spinal cord glioma progression induced by the overexpression of LOC101928963. The data obtained during the study highlighted the inhibitory role of LOC101928963 silencing in spinal cord glioma through the increase in PMAIP1, which suggests a potential target in the treatment of spinal cord glioma.
Wenming Feng, Hui Gong, Yongchun Wang, Guoliang Zhu, Tao Xue, Yao Wang, Sciprofile linkGe Cui
Published: 6 December 2019
Molecular Therapy - Nucleic Acids, Volume 18, pp 375-387; doi:10.1016/j.omtn.2019.08.024

Abstract: Circular RNAs (circRNAs), a recently identified new member of non-coding RNAs, are demonstrated to participate in diverse biological processes; however, the molecular mechanisms that link circRNAs with colorectal cancer (CRC) are not well understood. In the present study, we attempted to explore the roles of the exosomal circRNAs on CRC progression. We first compared the expression patterns of exosomal circRNAs between the plasma of CRC patients and healthy controls. We identified 448 significantly dysregulated exosomal circRNAs in CRC plasma. We focused on hsa_circ_0067835, which is located on chromosome 3 and derived from IFT80; thus, we named it circIFT80. Then, the expression of circIFT80 was detected in 58 CRC tissues and cell lines by qRT-PCR. Functional assays were performed to evaluate the effects of circIFT80 on tumor growth in vitro and in vivo. The relationship between circIFT80 and miR-1236-3p was confirmed by luciferase reporter assay. We found that circIFT80 was significantly upregulated in CRC serum exosomes, CRC tissues, and CRC cell lines compared with normal control. Silencing circIFT80 suppressed CRC cell growth both in vitro and in vivo. We further demonstrated that circIFT80/miR-1236-3p/HOXB7 axis plays an important role in regulating CRC progression. Dual-luciferase reporter system validated the direct interaction of circIFT80, miR-1236-3p, and HOXB7. Western blot verified that inhibition of circIFT80 decreased HOXB7 expression, while a miR-1236-3p inhibitor attenuated the effect of inhibition of circIFT80. In conclusion, these data suggest that circIFT80 is a central component linking circRNAs to the progression of CRC via a miR-1236-3p/HOXB7 axis.
Ming-Jian Huang, Jing-Yu Zhao, Jia-Jia Xu, Jing Li, Yi-Fu Zhuang, Sciprofile linkXiao-Ling Zhang
Published: 6 December 2019
Molecular Therapy - Nucleic Acids, Volume 18, pp 533-545; doi:10.1016/j.omtn.2019.08.027

Abstract: Long noncoding RNAs (lncRNAs) have emerged as key regulators of cell differentiation and development. However, potential roles for lncRNAs in chondrogenic differentiation have remained poorly understood. Here we identify lncRNA ADAMTS9 antisense RNA 2, ADAMTS9-AS2, which controls the chondrogenic differentiation by acting as a competing endogenous RNA (ceRNA) in human mesenchymal stem cells (hMSCs). We screen out ADAMTS9-AS2 of undifferentiated and differentiated cells during chondrogenic differentiation by microarrays. Suppression or overexpression of lncRNA ADAMTS9-AS2 correlates with inhibition and promotion of hMSC chondrogenic differentiation, respectively. We find that ADAMTS9-AS2 can sponge miR-942-5p to regulate the expression of Scrg1, a transcription factor promoting chondrogenic gene expression. Finally, we confirm the function of ADAMTS9-AS2 to cartilage repair in the absence of transforming growth factor β (TGF-β) in vivo. In conclusion, ADAMTS9-AS2 plays an important role in chondrogenic differentiation as a ceRNA, so that it can be regarded as a therapy target for cartilage repair.
Rajib Kumar Dutta, Srinivasan Chinnapaiyan, Sciprofile linkHoshang Unwalla
Published: 6 December 2019
Molecular Therapy - Nucleic Acids, Volume 18, pp 413-431; doi:10.1016/j.omtn.2019.09.007

Abstract: Over the last few decades, evolutionarily conserved molecular networks have emerged as important regulators in the expression and function of eukaryotic genomes. Recently, miRNA (miRNA), a large family of small, non-coding regulatory RNAs were identified in these networks as regulators of endogenous genes by exerting post-transcriptional gene regulation activity in a broad range of eukaryotic species. Dysregulation of miRNA expression correlates with aberrant gene expression and can play an essential role in human health and disease. In the context of the lung, miRNA have been implicated in organogenesis programming, such as proliferation, differentiation, and morphogenesis. Gain- or loss-of-function studies revealed their pivotal roles as regulators of disease development, potential therapeutic candidates/targets, and clinical biomarkers. An altered microRNAome has been attributed to several pulmonary diseases, such as asthma, chronic pulmonary obstructive disease, cystic fibrosis, lung cancer, and idiopathic pulmonary fibrosis. Considering the relevant roles and functions of miRNA under physiological and pathological conditions, they may lead to the invention of new diagnostic and therapeutic tools. This review will focus on recent advances in understanding the role of miRNA in lung development, lung health, and diseases, while also exploring the progress and prospects of their application as therapeutic leads or as biomarkers.
Gina Barkowsky, Anna-Lena Lemster, Roberto Pappesch, Anette Jacob, Selina Krüger, Anne Schröder, Bernd Kreikemeyer, Sciprofile linkNadja Patenge
Published: 6 December 2019
Molecular Therapy - Nucleic Acids, Volume 18, pp 444-454; doi:10.1016/j.omtn.2019.09.010

Abstract: Streptococcus pyogenes is an exclusively human pathogen causing a wide range of clinical manifestations from mild superficial infections to severe, life-threatening, invasive diseases. S. pyogenes is consistently susceptible toward penicillin, but therapeutic failure of penicillin treatment has been reported frequently. At the same time, streptococcal resistance to alternative antibiotics, e.g., macrolides, is common. To reduce the application of antibiotics for treatment of S. pyogenes infections, it is mandatory to develop novel therapeutic strategies. Antisense peptide nucleic acids (PNAs) are synthetic DNA derivatives widely applied for hybridization-based microbial diagnostics. They have a high potential as therapeutic agents, because PNA antisense targeting of essential genes was shown to reduce growth of several pathogenic bacterial species. Spontaneous cellular uptake of PNAs is restricted in eukaryotes and in bacteria. To overcome this problem, PNAs can be coupled to cell-penetrating peptides (CPPs) that support PNA translocation over the cell membrane. In bacteria, the efficiency of CPP-mediated PNA uptake is species specific. Previously, HIV-1 transactivator of transcription (HIV-1 TAT) peptide-coupled anti-gyrA PNA was shown to inhibit growth of S. pyogenes. Here, we investigate the effect of 18 CPP-coupled anti-gyrA PNAs on S. pyogenes growth and virulence. HIV-1 TAT, oligolysine (K8), and (RXR)4XB peptide-coupled anti-gyrA PNAs efficiently abolished bacterial growth in vitro. Consistently, treatment with these three CPP-PNAs increased survival of larvae in a Galleria mellonella infection model.
Keman Liao, Yingying Lin, Weizhen Gao, Zhipeng Xiao, Rogelio Medina, Pauline Dmitriev, Jing Cui, ZhengPing Zhuang, Xiaochun Zhao, Yongming Qiu, et al.
Published: 6 December 2019
Molecular Therapy - Nucleic Acids, Volume 18, pp 388-399; doi:10.1016/j.omtn.2019.09.005

Abstract: Zinc fingers and homeoboxes 1 (ZHX1) is a transcription repressor that has been implicated in the tumorigenesis and progression of diverse tumors. The functional role and regulating mechanism of ZHX1 has not been elucidated in glioblastoma (GBM). Previous reports have suggested that a large number of non-coding RNAs play a vital role in glioma initiation and progression. This study aimed to investigate the functional role and co-regulatory mechanisms of the metastasis-associated lung adenocarcinoma transcript-1 (MALAT1)/ microRNA-199a (miR-199a)/ZHX1 axis in GBM. We analyzed the expression of the MALAT1/miR-199a/ZHX1 axis and its correlation with patients' overall survival using two different glioma gene-expression datasets. A series of in vitro and in vivo studies including dual luciferase reporter assay, fluorescence in situ hybridization (FISH), RNA immunoprecipitation, and pull-down experiments were completed to elucidate the biological significance of the MALAT1/miR-199a/ZHX1 axis in promoting glioma proliferation and progression. Elevated ZHX1 expression correlated with poor prognosis in GBM patients, and in vitro studies demonstrated that ZHX1 attenuated GBM cell apoptosis by downregulation of pro-apoptotic protein (Bax) and upregulation of anti-apoptotic protein (Bcl-2). Furthermore, knockdown of MALAT1 inhibited GBM proliferation and progression in vitro and reduced tumor volume and prolonged survival in an orthotopic GBM murine model. Finally, we demonstrated that MALAT1 promoted ZHX1 expression via acting as a competing endogenous RNA by sponging miR-199a. The MALAT1/miR-199a/ZHX1 axis promotes GBM cell proliferation and progression in vitro and in vivo, and its expression negatively correlates with GBM patient survival. Blocking the MALAT1/miR-199a/ZHX1 axis can serve as a novel therapeutic strategy for treating GBM.
Thomas Kocher, Roland N. Wagner, Alfred Klausegger, Christina Guttmann-Gruber, Stefan Hainzl, Johann W. Bauer, Julia Reichelt, Sciprofile linkUlrich Koller
Published: 6 December 2019
Molecular Therapy - Nucleic Acids, Volume 18, pp 496-507; doi:10.1016/j.omtn.2019.09.011

Abstract: Current gene-editing approaches for treatment of recessive dystrophic epidermolysis bullosa (RDEB), an inherited, severe form of blistering skin disease, suffer from low efficiencies and safety concerns that complicate implementation in clinical settings. We present a strategy for efficient and precise repair of RDEB-associated mutations in the COL7A1 gene. We compared the efficacy of double-strand breaks (induced by CRISPR/Cas9), single nicks, or double nicks (induced by Cas9n) in mediating repair of a COL7A1 splice-site mutation in exon 3 by homologous recombination (HR). We accomplished remarkably high HR frequencies of 89% with double nicking while at the same time keeping unwanted repair outcomes, such as non-homologous end joining (NHEJ), at a minimum (11%). We also investigated the effects of subtle differences in repair template design on HR rates and found that strategic template-nicking can enhance COL7A1-editing efficiency. In RDEB patient keratinocytes, application of double-nicking led to restoration and subsequent secretion of type VII collagen at high efficiency. Comprehensive analysis of 25 putative off-target sites revealed no off-target activity for double-nicking, while usage of Cas9 resulted in 54% modified alleles at one site. Taken together, our work provides a framework for efficient, precise, and safe repair of COL7A1, which lies at the heart of a future curative therapy of RDEB.
Sciprofile linkJeroen Bremer, Elisabeth H. Van Der Heijden, Daryll S. Eichhorn, Rowdy Meijer, Henny H. Lemmink, Hans Scheffer, Richard J. Sinke, Marcel F. Jonkman, Anna M.G. Pasmooij, Peter C. Van Den Akker
Published: 6 December 2019
Molecular Therapy - Nucleic Acids, Volume 18, pp 465-475; doi:10.1016/j.omtn.2019.09.009

Abstract: Dystrophic epidermolysis bullosa (DEB) is a devastating blistering disease affecting skin and mucous membranes. It is caused by pathogenic variants in the COL7A1 gene encoding type VII collagen, and can be inherited dominantly or recessively. Recently, promising proof-of-principle has been shown for antisense oligonucleotide (AON)-mediated exon skipping as a therapeutic approach for DEB. However, the precise phenotypic effect to be anticipated from exon skipping, and which patient groups could benefit, is not yet clear. To answer these questions, we studied new clinical and molecular data on seven patients from the Dutch EB registry and reviewed the literature on COL7A1 exon skipping variants. We found that phenotypes associated with dominant exon skipping cannot be distinguished from phenotypes caused by other dominant DEB variants. Recessive exon skipping phenotypes are generally relatively mild in the spectrum of recessive DEB. Therefore, for dominant DEB, AON-mediated exon skipping is unlikely to ameliorate the phenotype. In contrast, the overall severity of phenotypes associated with recessive natural exon skipping pivots toward the milder end of the spectrum. Consequently, we anticipate AON-mediated exon skipping for recessive DEB caused by bi-allelic null variants should lead to a clinically relevant improvement of this devastating phenotype.
Gianluca Fontana, Hannah L. Martin, Jae Sung Lee, Kristen Schill, Peiman Hematti, Sciprofile linkWilliam L. Murphy
Published: 6 December 2019
Molecular Therapy - Nucleic Acids, Volume 18, pp 455-464; doi:10.1016/j.omtn.2019.09.004

Abstract: The regenerative potential of bone marrow cells could be harnessed for tissue engineering applications. Bone marrow can be easily collected from patients, providing a valuable autologous source of therapeutic cells. However, years of delivery of bone marrow cells have highlighted the need for their genetic manipulation to overcome heterogeneity and to confer specificity to the regenerative process. In this study, we optimized the use of condensed mRNA as a non-viral alternative. As a proof of concept, we used mRNA encoding for reporter proteins such as EGFP or Firefly luciferase, which was condensed by complexing agents and delivered to human bone marrow cells using mineral-coated microparticles. We demonstrated that human bone marrow cells could be transfected with complexed mRNA, and that this approach was more efficient than the delivery of complexed plasmid DNA. In addition, human bone marrow cells were vulnerable to the toxicity of mRNA complexing agents, but these deleterious effects were mitigated by using mineral-coated microparticles as a carrier of complexed mRNA. Microparticle-mediated delivery of complexed mRNA also enabled higher cell metabolic activity and higher transfection in multiple in vitro culture conditions, including suspension culture and three-dimensional culture.
Sheng-Yan Lin, Fei-Fei Hu, Ya-Ru Miao, Hui Hu, Qian Lei, Qiong Zhang, Qiubai Li, Hongxiang Wang, Sciprofile linkZhichao Chen, Sciprofile linkAn-Yuan Guo
Published: 6 December 2019
Molecular Therapy - Nucleic Acids, Volume 18, pp 476-484; doi:10.1016/j.omtn.2019.09.014

Abstract: Cytogenetically normal acute myeloid leukemia (CN-AML) presents with diverse outcomes in different patients and is categorized as an intermediate prognosis group. It is important to identify prognostic factors for CN-AML risk stratification. In this study, using the TCGA CN-AML dataset, we found that the scavenger receptor stabilin-1 (STAB1) is a prognostic factor for poor outcomes and validated it in three other independent CN-AML datasets. The high STAB1 expression (STAB1high) group had shorter event-free survival compared with the low STAB1 expression (STAB1low) group in both the TCGA dataset (n = 79; p = 0.0478) and GEO: GSE6891 dataset (n = 187; p = 0.0354). Differential expression analysis between the STAB1high and STAB1low groups revealed that upregulated genes in the STAB1high group were enriched in pathways related to cell adhesion and migration and immune responses. We confirmed that STAB1 suppression inhibits cell growth in KG1a and NB4 leukemia cells. Expression correlation analyses between STAB1 and cancer drug targets suggested that patients in the STAB1low group are more sensitive to the BCL2 inhibitor venetoclax, and we confirmed it in cell lines. In conclusion, we identified STAB1 as a prognostic factor for CN-AML in multiple datasets, explored its underlying mechanism, and provided potential therapeutic indications.
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