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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer
Downregulation of Bcl-2 associated athanogene 3 (BAG3) significantly deceased migration (Fig. 1b) and invasion (Fig. 1c) of PDACs in transwell assays. Both cell migratory and invasive (Supplementary Figure 1A–B) capacity of PDACs with BAG3 knockdown were rescued by addition of conditional medium (CM) derived from control Cytokines antibody microarrays demonstrated that IL-6, IL-8, PDGF-BB release was decreased, whereas ICAM-1 release was increased in BxPC3 and SW1990 cells with BAG3 knockdown, and BAG3 knockdown decreased secretion of TNFγ and TNFβ, whereas increased release of TNFα and TNF RII in SW1990 cells (Fig. 1d)
BAG3 upregulation has been correlated with poor prognosis in patients with PDACs13
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer. It is one of the leading causes of cancer-related mortality worldwide[1]. It is important to fully elucidate the underlying mechanisms that implicated in PDAC invasion. BAG3 expression is inducible by multiple stressful stimuli in many other cell types. BAG3 is expressed in many cancers and correlated with the poor prognosis of some cancers, including pancreatic[4,5,6,7,8,9,10,11,12]. The oncogenic potential of BAG3 are not yet fully elucidated
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