Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC)

Dhanasekaran, Renumathy; Gabay-Ryan, Meital; Baylot, Virginie; Lai, Ian; Mosley, Adriane; Huang, Xinqiang; Zabludoff, Sonya; Li, Jian; Kaimal, Vivek; Karmali, Priya; Felsher, Dean W.

doi:10.18632/oncotarget.22342

Cited by 36 publications

(24 citation statements)

References 38 publications

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“…Of these, the TuD RNAs have been identified as one of the most specific and potent miRNA inhibitors [23,25]. Recently, TuDs have been exploited as therapeutic agents in in vivo mouse models [28,30], showing promising results regarding long-term target inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, an AAV-based TuD has been successfully used to restore cardiac function in a murine heart failure model by targeting miR-25 [28]. In addition, introduction of an anti-miR-17 TuD in a MYC-driven hepatocellular carcinoma mouse model significantly inhibited tumor progression [30]. These studies suggest that anti-miRNA TuDs may hold therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

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RNA accessibility impacts potency of Tough Decoy microRNA inhibitors

et al. 2018

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MicroRNAs (miRNAs) are small RNA molecules that post-transcriptionally regulate gene expression through silencing of complementary target mRNAs. miRNAs are involved in many biological processes, including cell proliferation, differentiation, cell signaling and cellular defense responses to infection. Strategies that allow for strong and stable suppression of specific microRNA activity are needed to study miRNA functions and to develop therapeutic intervention strategies aimed at interfering with miRNA activity in vivo. One of these classes of miRNA inhibitors are Tough Decoys (TuD) RNAs, which comprise of an imperfect RNA hairpin structure that harbors two opposing miRNA binding sites. Upon developing TuDs targeting Epstein-Barr virus miRNAs, we observed a strong variation in inhibitory potential between different TuD RNAs targeting the same miRNA. We show that the composition of the ‘bulge’ sequence in the miRNA binding sites has a strong impact on the inhibitory potency of the TuD. Our data implies that miRNA inhibition correlates with the thermodynamic properties of the TuD and that design aimed at lowering the TuD opening energy increases TuD potency. Our study provides specific guidelines for the design and construction of potent decoy-based miRNA inhibitors, which may be used for future therapeutic intervention strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RNA accessibility impacts potency of Tough Decoy microRNA inhibitors

et al. 2018

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“…They contain 22 nucleotides and regulates the expression of genes at the post-transcriptional level.The miRNAs can be confined found into a vesicle, especially an exosome of about 50-100 nm diameter and then excreted to the extracellular environment and transferred into recipient cells [19] . The cellular miRNAs regulate the different cell activities such as differentiation, apoptosis, proliferation and angiogenesis [20] . The nucleus contains the miRNAs genes which are similar to the proteins.…”

Section: Rna Biomarkersmentioning

confidence: 99%

“…MYC is considered as a regulator gene for the transcription factor that adjusts the expression of genes for different kinds of genes in the cancer features such as proliferation, survival, metabolism, and self-renewal. Thus, inactivation of MYC oncogene leads to tumor regression associated with differentiation, apoptosis, and proliferative arrest [20] . The gene encoding HOTTIP have also been shown to have a significant oncogenic role in HCC, by dysregulation of HOXA genes.…”

Section: Genetic Levelmentioning

confidence: 99%

Current Status Regarding Tumour Progression, Surveillance, Diagnosis, Staging, and Treatment Of HCC: A Literature Review

Ahmad¹,

Suardi²,

Shukri³

et al. 2019

Journal of Gastroenterology and Hepatology Research

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Hepatocellular carcinoma (HCC) is the most common primary malignant tumour of the liver, and is globally considered to be a major causes of cancer-associated mortality. The early diagnosis of HCC improves overall survival through the application of suitable treatment options. This article presents some of the techniques for the surveillance of HCC like ultrasonography and the use of tumour biomarkers such as α-fetoprotein (AFP), DesGamma-Carboxy Prothrombin (DCP) and others. Included in the discussion will be diagnostic methods like computed tomography (CT), magnetic resonance imaging (MRI), contrast enhancement ultrasound (CEUS), and fluorodeoxyglucose positron emission tomography hybrid with computed tomography (FDG PET/CT). Current molecular pathogenesis related to HCC and the molecular steps that determine the transition from benign to malignancy are also analysed. The HCC stages which depends on the Barcelona Clinic Liver Cancer (BCLC) algorithm are also discussed. Finally, this review article discusses the present therapeutic and treatment options for HCC such as resection, transplantation, or ablation used to treat early stage cancer. Also included will be trans-arterial chemoembolization (TACE) and Sorafenib for patients with intermediate and advanced-stage cancer, respectively.

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“…15 Based on this work there has been a growing interest in developing anti-miR drugs designed to target the miR-17~92 cluster. [16][17][18][19][20][21] miR-17~92, however, is a complex polycistronic cluster that encodes 6 individual miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a-1). Moreover, the mammalian genome encodes two additional paralogous clusters known as miR-106a~363 and miR-106b~25.…”

Section: Introductionmentioning

confidence: 99%

Anti-microRNA screen uncovers miR-17 family within miR-17~92 cluster as the primary driver of kidney cyst growth

Yheskel

Lakhia

Flaten

et al. 2018

Preprint

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Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of renal failure. We have recently shown that inhibiting miR-17~92 is a potential novel therapeutic approach for ADPKD. However, miR-17~92 is a polycistronic cluster that encodes microRNAs (miRNAs) belonging to the miR-17, miR-18, miR-19 and miR-25 families, and the relative pathogenic contribution of these miRNA families to ADPKD progression is unknown. Here we performed an in vivo anti-miR screen to identify the miRNA drug targets within the miR-17~92 miRNA cluster. We designed anti-miRs to individually inhibit miR-17, miR-18, miR-19 or miR-25 families in an orthologous ADPKD model. Treatment with anti-miRs against the miR-17 family reduced cyst proliferation, kidney-weight-to-body-weight ratio and cyst index. In contrast, treatment with anti-miRs against the miR-18, 19, or 25 families did not affect cyst growth. Anti-miR-17 treatment recapitulated the gene expression pattern observed after miR-17~92 genetic deletion and was associated with upregulation of mitochondrial metabolism, suppression of the mTOR pathway, induction of autophagy, and inhibition of cyst-associated inflammation. Our results argue against functional cooperation between the various miR-17~92 cluster families in promoting cyst growth, and instead point to miR-17 family is the primary therapeutic target for ADPKD. driver of kidney cyst growth

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Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC)

Cited by 36 publications

References 38 publications

RNA accessibility impacts potency of Tough Decoy microRNA inhibitors

RNA accessibility impacts potency of Tough Decoy microRNA inhibitors

Current Status Regarding Tumour Progression, Surveillance, Diagnosis, Staging, and Treatment Of HCC: A Literature Review

Anti-microRNA screen uncovers miR-17 family within miR-17~92 cluster as the primary driver of kidney cyst growth

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