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

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, thereby further promoting loading of miR-4312 containing miRISC to IL-8 transcript. Taken together, we propose that BAG3 promotes invasion by stabilizing IL-8 transcript via HuR recruitment, and subsequently suppressing the loading of miR-4312 containing miRISC in PDACs. Our results reveal a novel pathway linking BAG3 expression to enhanced PDAC metastasis, thus making BAG3 a potential target for intervention in pancreatic cancer.

SEMA4D under the posttranscriptional regulation of HuR and miR-4319 boosts cancer progression in esophageal squamous cell carcinoma

“…For example, circAGO2 impels cancer progression by facilitating HuR-repressed functions on AGO2-miRNA complexes; 23 LncRNA B4GALT1-AS1 attracts HuR to boost osteosarcoma cells migration and stemness by reinforcing YAP transcriptional activity; 24 BAG3 regulates IL-8 mRNA stability through the interplay between HuR and miR-4312 in PDACs. 25 Our study represented that HuR interacted with SEMA4D mRNA and further stabilized its mRNA level in ESCC.…”

The HuR CMLD-2 inhibitor exhibits antitumor effects via MAD2 downregulation in thyroid cancer cells

“…Moreover, Li et al . identified IL-8 as HuR-target in pancreatic ductal adenocarcinoma (PDAC) cells 47 . However, in a previous work 17 , we have demonstrated that IL-8 is not a HuR-target in thyroid cells, and this finding is in agreement with those published by Lebedeva et al .…”

Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease

“…However, Judge et al also reported that the accumulation of ubiquitinated protein after bortezomib treatment was the same in WT and BAG3-deficient cardiomyo-PDAC. This novel pathway links BAG3 expression to enhanced PDAC metastasis (82). In aggregate, these studies support the use of BAG3 as a target for the treatment of patients with PDAC; however, that enthusiasm must be tempered by the recognition that the regulation and function of autophagy in pancreatic cancer are complex and likely require precise targeting (83).…”