OncomiR-10b hijacks the small molecule inhibitor linifanib in human cancers

Scientific Reports
Paloma Del C Monroig-BosqueGeorge A Calin

Abstract

The pervasive role of microRNAs (miRNAs) in cancer pathobiology drives the introduction of new drug development approaches such as miRNA inhibition. In order to advance miRNA-therapeutics, meticulous screening strategies addressing specific tumor targets are needed. Small molecule inhibitors represent an attractive goal for these strategies. In this study, we devised a strategy to screen for small molecule inhibitors that specifically inhibit, directly or indirectly, miR-10b (SMIRs) which is overexpressed in metastatic tumors. We found that the multi-tyrosine kinase inhibitor linifanib could significantly inhibit miR-10b and reverse its oncogenic function in breast cancer and liver cancer both in vitro and in vivo. In addition, we showed that the efficacy of linifanib to inhibit tyrosine kinases was reduced by high miR-10b levels. When the level of miR-10b is high, it can "hijack" the linifanib and reduce its kinase inhibitory effects in cancer resulting in reduced anti-tumor efficacy. In conclusion, our study describes an effective strategy to screen for small molecule inhibitors of miRNAs. We further propose that miR-10b expression levels, due to the newly described "hijacking" effect, may be used as a biomarker to select pat...Continue Reading

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Citations

Aug 23, 2019·Genome Research·Muller FabbriGeorge A Calin
Sep 21, 2018·Non-coding RNA·Hua XiaoShuxing Zhang
Aug 15, 2020·Frontiers in Immunology·Elena DaveriVeronica Huber
Feb 12, 2021·Pharmaceuticals·Eunsun JungTae-Su Han
Mar 7, 2021·International Journal of Molecular Sciences·Rebecca RaueBernhard Brüne
May 2, 2021·Advances in Biological Regulation·Jaehyeon JeongHeeyoun Bunch
Jun 20, 2021·Nature Reviews. Drug Discovery·Melanie WinkleGeorge A Calin
Jul 8, 2021·Cell Cycle·Fang LiuWei Xu

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Methods Mentioned

BETA
xenograft
transfection
Assay
nuclear
isothermal
surface plasmon resonance
FACS
transfections
electrophoresis
PCR

Software Mentioned

R
GraphPad Prism
AutoCAD

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