Hsa-circ-0029407 promotes inflammation in acute pancreatitis cells by binding with hsa-miR-3613-3p to upregulate MMP9

We previously found that hsa-circ-0029407 was increased in the circulation of patients with acute pancreatitis (AP) and contains a binding site for hsa-miR-3613-3p. In this study, we investigated the mechanisms by which hsa-circ-0029407 directly binds hsa-miR-3613-3p via sequence complementarity and induces inflammatory processes of AP through upregulating matrix metallopeptidase 9 (MMP9). Human pancreatic stellate cells (HPSCs) were induced to form AP cells as an in vitro model. AP cells showed decreased proliferation and increased necrosis/apoptosis compared to uninduced HPSCs. We demonstrated interactions between hsa-circ-0029407 and hsa-miR-3613-3p as well as hsa-miR-3613-3p and MMP9 3′UTR. hsa-miR-3613-3p suppressed MMP9 expression and inflammation while hsa-circ-0029407 promoted them. As AP patients have lung involvement, co-culturing AP cells with human alveolar epithelia cells (AECs, type II) or treating AECs with exosomes isolated from AP cells upregulated inflammatory markers MMP9, interleukin-1β (IL-1β), C-C chemokine 2 (CCL2) and interleukin-6 (IL-6). The inflammatory effects exhibited by hsa-circ-0029407 and hsa-miR-3613-3p were also reported in AECs. Our study suggests that inflammatory conditions cause AP cells to produce exosomes containing hsa-circ-0029407, which are released into distant cells such as AECs. hsa-miR-3613-3p binds to the 3′UTR of MMP9 to suppress its expression at the post-transcriptional level, but this is alleviated by the addition of hsa-circ-0029407. The released MMP9 transcripts are then released and MMP9 activates NF-κB signaling to amplify pro-inflammatory cytokine production (e.g., IL-1β, IL-6).