BAG3 regulates stability of IL-8 mRNA via interplay between HuR and miR-4312 in PDACs

Cell Death & Disease
Chao LiHua-Qin Wang

Abstract

Bcl-2 associated athanogene 3 (BAG3) is highly expressed in pancreatic ductal adenocarcinoma (PDAC), and its high expression appears to be a poor prognostic factor for patients with PDAC. In this study, we show that BAG3 knockdown significantly decreases migration and invasion of PDACs via reduction of interleukine-8 (IL-8) production. BAG3 knockdown regulates IL-8 expression at the posttranscriptional levels via interplay between recruitment of RNA-binding protein HuR and miR-4312. HuR binds to the cis-elements located in the 3'-untranslational region (UTR) of the IL-8 transcript to stabilize it, whereas miR-4312-containing miRNA-induced silencing complex (miRISC) is recruited to the adjacent seed element to destabilize it. The binding of HuR prevents the recruitment of Argonaute (Ago2), overriding miR-4312-mediated translation inhibition of IL-8. BAG3 knockdown decreases cytoplasmic distribution of HuR via increasing its phosphorylation at Ser202, therefore compromising its recruitment while promoting recruitment of miR-4312 containing miRISC to IL-8 transcript. Furthermore, our data indicate that only phosphorylated Ago2 at Ser387 interacts with IL-8 transcript. BAG3 knockdown increases phosphorylation of Ago2 at Ser387, the...Continue Reading

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Citations

May 15, 2021·Journal of Cellular Biochemistry·Heng LinGail V W Johnson
Jun 9, 2021·British Journal of Cancer·Margot De MarcoLiberato Marzullo
Aug 17, 2021·The Journal of Clinical Investigation·Jonathan A KirkArthur M Feldman

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Methods Mentioned

BETA
antibody array
ELISA
immunoprecipitation
pull down
PCR
protein assay
electrophoresis
transfection
RIP

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