Characterization of Target mRNA Reduction Through <i>In Situ</i> RNA Hybridization in Multiple Organ Systems Following Systemic Antisense Treatment in Animals

Hung, Gene; Xiao, Xiaokun; Peralta, Raechel; Bhattacharjee, Gourab; Murray, Sue; Norris, Dan; Guo, Shuling; Monia, Brett P.

doi:10.1089/nat.2013.0443

Cited by 112 publications

(110 citation statements)

References 22 publications

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“…These ASO reduced Lxr␣ 40 -90% in multiple tissues, including liver, white adipose tissue, kidney, spleen, and heart (data not shown), consistent with prior literature (27).…”

Section: Resultssupporting

confidence: 90%

Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation

Sun

Haas

Miao

et al. 2016

Journal of Biological Chemistry

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Diabetes is characterized by increased lipogenesis as well as increased endoplasmic reticulum (ER) stress and inflammation. The nuclear hormone receptor liver X receptor (LXR) is induced by insulin and is a key regulator of lipid metabolism. It promotes lipogenesis and cholesterol efflux, but suppresses endoplasmic reticulum stress and inflammation. The goal of these studies was to dissect the effects of insulin on LXR action. We used antisense oligonucleotides to knock down Lxr␣ in mice with hepatocytespecific deletion of the insulin receptor and their controls. We found, surprisingly, that knock-out of the insulin receptor and knockdown of Lxr␣ produced equivalent, non-additive effects on the lipogenic genes. Thus, insulin was unable to induce the lipogenic genes in the absence of Lxr␣, and LXR␣ was unable to induce the lipogenic genes in the absence of insulin. However, insulin was not required for LXR␣ to modulate the phospholipid profile, or to suppress genes in the ER stress or inflammation pathways. These data show that insulin is required specifically for the lipogenic effects of LXR␣ and that manipulation of the insulin signaling pathway could dissociate the beneficial effects of LXR on cholesterol efflux, inflammation, and ER stress from the negative effects on lipogenesis.

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“…These ASO reduced Lxr␣ 40 -90% in multiple tissues, including liver, white adipose tissue, kidney, spleen, and heart (data not shown), consistent with prior literature (27).…”

Section: Resultssupporting

confidence: 90%

Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation

Sun

Haas

Miao

et al. 2016

Journal of Biological Chemistry

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“…ASOs are currently in clinical trials for many diseases, including spinal muscular atrophy and Duchenne muscular dystrophy (Aartsma-Rus et al 2004;Rigo et al 2012). The in vivo efficacies of Malat1 ASOs have been tested in primates, where >80% knockdown efficiency was achieved (Koller et al 2011;Hung et al 2013). Here we show that Malat1 knockdown results in slower tumor proliferation and differentiation and significant reduction in metastasis, all recapitulating the phenotype of the MMTV-PyMT; Malat1…”

Section: Malat1 Asos Are a Promising Therapeuticmentioning

confidence: 99%

Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss

et al. 2015

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Genome-wide analyses have identified thousands of long noncoding RNAs (lncRNAs). Malat1 (metastasisassociated lung adenocarcinoma transcript 1) is among the most abundant lncRNAs whose expression is altered in numerous cancers. Here we report that genetic loss or systemic knockdown of Malat1 using antisense oligonucleotides (ASOs) in the MMTV (mouse mammary tumor virus)-PyMT mouse mammary carcinoma model results in slower tumor growth accompanied by significant differentiation into cystic tumors and a reduction in metastasis. Furthermore, Malat1 loss results in a reduction of branching morphogenesis in MMTV-PyMTand Her2/neu-amplified tumor organoids, increased cell adhesion, and loss of migration. At the molecular level, Malat1 knockdown results in alterations in gene expression and changes in splicing patterns of genes involved in differentiation and protumorigenic signaling pathways. Together, these data demonstrate for the first time a functional role of Malat1 in regulating critical processes in mammary cancer pathogenesis. Thus, Malat1 represents an exciting therapeutic target, and Malat1 ASOs represent a potential therapy for inhibiting breast cancer progression.

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“…When oligonucleotides, such as 2¢-O-methoxyethyl phosphorothioates, are systemically delivered in vivo, they reach many tissues and cell types but predominantly the liver [102]. However, uptake by itself is not sufficient for an effective cleavage of the target RNA.…”

Section: Uptakementioning

confidence: 99%

Phosphorothioates, Essential Components of Therapeutic Oligonucleotides

Eckstein

2014

Nucleic Acid Therapeutics

525

385

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Phosphorothioates have found their usefulness in the general area of oligonucleotide therapeutic applications. Initially this modification was introduced into the antisense methodology because of the nuclease resistance of the phosphorothioate linkage in comparison with that of the phosphate linkage. However, as experimental data accumulated, it was detected that this chemical modification also facilitates cellular uptake and bioavailibity in vivo. Thus, today the majority of therapeutic oligonucleotides contain this modification. This review will discuss the historical development of this modification and present some of its chemical properties where they differ from those of the phosphate group. The antisense application will be discussed in the original context with cleavage of the target mRNA, but other target RNAs such as microRNAs and long noncoding RNAs will also be covered. It continues with applications where the target RNA should not be cleaved. A brief presentation of decoy oligonucleotides will be included, as well as some miscellaneous applications. Cellular uptake is a crucial step for oligonucleotides to reach their target and will be briefly reviewed. Lastly, a most surprising recent observation is the presence of phosphorothioate groups in bacterial DNA where functions still remain to be fully determined.

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Characterization of Target mRNA Reduction Through In Situ RNA Hybridization in Multiple Organ Systems Following Systemic Antisense Treatment in Animals

Cited by 112 publications

References 22 publications

Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation

Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation

Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss

Phosphorothioates, Essential Components of Therapeutic Oligonucleotides

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