Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal-Cell Carcinoma to Topotecan

Naro, Yuta; Ankenbruck, Nicholas; Thomas, Melvin E.; Tivon, Yaniv; Connelly, Colleen M.; Gardner, Laura; Deiters, Alexander

doi:10.1021/acs.jmedchem.7b01891

Cited by 47 publications

(34 citation statements)

References 63 publications

(101 reference statements)

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“…MicroRNAs (miRNAs) are master gene regulators that may silence genes at the post-transcriptional level via transcript degradation or translational repression. miRNAs are extensively implicated in fundamental biological processes and aberrant microRNA profiles have been reported in various cancers including RCC [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

miR-124 and miR-203 synergistically inactivate EMT pathway via coregulation of ZEB2 in clear cell renal cell carcinoma (ccRCC)

Chen

Zhong

2020

J Transl Med

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Background: Clear cell renal cell carcinoma (ccRCC) is one of the most aggressive urological malignancies. Micro-RNAs (miRNAs) are post-transcriptional gene regulators in tumor pathophysiology. As miRNAs exert cooperative repressive effects on target genes, studying the miRNA synergism is important to elucidate the regulation mechanism of miRNAs. Methods: We first created a miRNA-mRNA association network based on sequence complementarity and coexpression patterns of miRNA-targets. The synergism between miRNAs was then defined based on their expressional coherence and the concordance between target genes. The miRNA and mRNA expression were detected in RCC cell lines (786-O) using quantitative RT-PCR. Potential miRNA-target interaction was identified by Dual-Luciferase Reporter assay. Cell proliferation and migration were assessed by CCK-8 and transwell assay. Results: A synergistic miRNA-miRNA interaction network of 28 miRNAs (52 miRNA pairs) with high coexpression level were constructed, among which miR-124 and miR-203 were identified as most tightly connected. ZEB2 expression is inversely correlated with miR-124 and miR-203 and verified as direct miRNA target. Cotransfection of miR-124 and miR-203 into 786-O cell lines effectively attenuated ZEB2 level and normalized renal cancer cell proliferation and migration. The inhibitory effects were abolished by ZEB2 knockdown. Furthermore, pathway analysis suggested that miR-124 and miR-203 participated in activation of epithelial-to-mesenchymal transition (EMT) pathway via regulation of ZEB2. Conclusions: Our findings provided insights into the role of miRNA-miRNA collaboration as well as a novel therapeutic approach in ccRCC.

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Section: Introductionmentioning

confidence: 99%

miR-124 and miR-203 synergistically inactivate EMT pathway via coregulation of ZEB2 in clear cell renal cell carcinoma (ccRCC)

Chen

Zhong

2020

J Transl Med

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“…In CC, miR-21 is demonstrated to participate in DDP plus PTX resistance and indicates a poor prognosis [146]. What's more, the silencing of miR-21 can rescue the expression of tumor suppressor proteins and reverse topotecan resistance in renal cell carcinoma (RCC) [147]. Additionally, in papillary thyroid carcinoma (PTC), upregulation of miR-206 contributes to euthyrox resistance by blocking the p38 and JNK signaling pathway via targeting MAP 4 K3 [135].…”

Section: Other Cancersmentioning

confidence: 99%

Role of non-coding RNAs and RNA modifiers in cancer therapy resistance

et al. 2020

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As the standard treatments for cancer, chemotherapy and radiotherapy have been widely applied to clinical practice worldwide. However, the resistance to cancer therapies is a major challenge in clinics and scientific research, resulting in tumor recurrence and metastasis. The mechanisms of therapy resistance are complicated and result from multiple factors. Among them, non-coding RNAs (ncRNAs), along with their modifiers, have been investigated to play key roles in regulating tumor development and mediating therapy resistance within various cancers, such as hepatocellular carcinoma, breast cancer, lung cancer, gastric cancer, etc. In this review, we attempt to elucidate the mechanisms underlying ncRNA/modifier-modulated resistance to chemotherapy and radiotherapy, providing some therapeutic potential points for future cancer treatment.

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“…Experiments that assess off-target interactions and RNA selectivity are clearly important when it comes to testing novel RNA-binders in vitro and in vivo (Naro et al 2018;Zhang et al 2020;Costales et al 2017;Abulwerdi et al 2019;Donlic et al 2018). However, our survey of the HIV-1 TAR literature ( Supplementary Table S2) revealed that these controls are not always performed (Gelus et al 1999;He et al 2005;Hwang et al 2003).…”

Section: Rnasmentioning

confidence: 99%

“…Such compounds with demonstrated cellular activity have been enumerated in the R-BIND database (Morgan et al 2019). Some of these compounds have been shown to bind specific RNAs and inhibit their cellular activities with well-validated selectivity (Costales et al 2017(Costales et al , 2019Zhang et al 2020;Shi et al 2019;Haga et al 2015;Naro et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Revealing the high propensity of RNAs to non-specifically bind drug-like small molecules

Kelly

Chu²,

Shi

et al. 2020

Preprint

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Identifying small molecules that selectively bind a single RNA target while discriminating against all other cellular RNAs is an important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like small molecules that minimize electrostatic and stacking interactions that lead to non-specific binding of aminoglycosides and intercalators to a variety of RNAs. Many such compounds have been reported to bind RNAs and inhibit their cellular activities, however the ability of such compounds to discriminate against RNA stem-loops commonly found in the transcriptome has not been thoroughly assessed in all cases. Here, we examined the propensities of three drug-like compounds, previously shown to bind and inhibit the cellular activity of three distinct RNAs, to non-specifically bind two HIV-1 stem-loop RNAs: the transactivation response element (TAR) and stem IIB in the rev response element (RREIIB). All three compounds bound to TAR and RREIIB in vitro, and two inhibited TAR-dependent transactivation and RRE-dependent viral export in cell-based assays while also exhibiting substantial off-target interactions consistent with non-specific cellular activity. A survey of X-ray and NMR structures of RNA-small molecule complexes revealed that drug-like molecules form hydrogen bonds with functional groups commonly accessible in canonical stem-loop RNA motifs, much like aminoglycosides, and in contrast to ligands that specifically bind riboswitches. Our results support extending the group of non-selective RNA-binders beyond aminoglycosides and intercalators to encompass drug-like compounds with capacity for non-specific hydrogen-bonding and reinforce the importance of assaying for off-target interactions and RNA selectivity in vitro and in cells when assessing novel RNA-binders.

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Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal-Cell Carcinoma to Topotecan

Cited by 47 publications

References 63 publications

miR-124 and miR-203 synergistically inactivate EMT pathway via coregulation of ZEB2 in clear cell renal cell carcinoma (ccRCC)

miR-124 and miR-203 synergistically inactivate EMT pathway via coregulation of ZEB2 in clear cell renal cell carcinoma (ccRCC)

Role of non-coding RNAs and RNA modifiers in cancer therapy resistance

Revealing the high propensity of RNAs to non-specifically bind drug-like small molecules

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