CircHIPK3 Promotes Pyroptosis in Acinar Cells Through Regulation of the miR-193a-5p/GSDMD Axis

Abstract

Acute pancreatitis (AP), especially severe acute pancreatitis (SAP), is an extremely dangerous illness with a high mortality rate. Pyroptotic cells release their cellular contents and inflammatory factors, aggravating the inflammatory response. Pyroptosis may be the main mode of acinar cell death during AP. The circular RNA circHIPK3 is expressed in pancreatic tissue and is associated with inflammatory response. In this study, we focused on the role and underlying mechanism of circHIPK3 in AP. We found that the expression of circHIPK3 was significantly elevated in serum of patients with AP and in caerulein-stimulated AR42J cells and was associated with caspase-1 and caspase-11 activation. circHIPK3 silencing ameliorated caerulein-induced cell damage and reduced the release of inflammatory factors IL-1β, IL-6, IL-8, and TNF-α and inhibited the activation of caspase-1 and caspase-11. In addition, circHIPK3 bound to miR-193a-5p and negatively regulated its expression. Inhibition of miR-193a-5p increased the release of IL-1β, IL-6, IL-8, and TNF-α and activated caspase-1 and caspase-11, thereby counteracting the effect of circHIPK3 silencing on caerulein-induced cell damage. Furthermore, we identified GSDMD as a target gene of miR-193a-5p, which is the key gene for pyroptosis. Interfering with the expression of GSDMD can increase cell viability, reduce the secretion of inflammatory cytokines, and suppress the activation of cleaved caspase-1 and caspase-11. Silencing GSDMD reversed the effects of miR-193a-5p inhibitors on caerulein-induced damage. In conclusion, circHIPK3 promotes pyroptosis in acinar cells through regulation of the miR-193a-5p/GSDMD axis, which eventually aggravates AP disease.

CircHIPK3: Key Player in Pathophysiology and Potential Diagnostic and Therapeutic Tool

“…In addition, circHIPK3 was shown to regulate the expression level of IGF1 through miR-379 to promote the proliferation of non-small cell lung cancer cell lines, NCI-H1299 and NCI-H2170 ( 43 ). According to Jiale Wang et al, circHIPK3 promoted acinar cell carcinoma apoptosis by regulating the miR-193a-5p/GSDMD pathway ( 41 , 44 ). Jinjin Lai et al showed that circHIPK3 promotes the proliferation and metastasis of renal cancer cells by downregulating miR-485-3p ( 45 ).…”

“…High blood glucose levels led to downregulated circHIPK3 expression, promoting damage to vascular endothelial cells, while the overexpression of circHIPK3 inhibited vascular endothelial cell damage ( 66 ). Other studies have found that circHIPK3 is involved in the pathophysiological processes of diseases such as diabetic neuropathic pain, type 2 diabetes, diabetic nephropathy, acute pancreatitis, osteoarthritis, myocardial ischemia reperfusion injury, and age-related cataract, and plays an important role in these conditions ( 24 , 44 , 67 – 70 ). Although circHIPK3 is downregulated in age-related cataracts, and it is upregulated in all other fibrotic diseases.…”

MiR-146b-3p protects against AR42J cell injury in cerulein-induced acute pancreatitis model through targeting Anxa2

“…More importantly, we first showed that Anxa2 was a functionally important target of miR-146b-3p in regulating cerulein-induced AR42J cell injury. Similarly, the examples of the miRNAs protecting against AP progression included miR-148a and miR-193a-5p, which regulated the expression of their targets [ 9 , 34 ]. Conversely, some miRNAs, such as miR-155 and miR-551b-5p, promoted AP progression by silencing target mRNAs [ 10 , 35 ].…”

Emerging landscape of circHIPK3 and its role in cancer and other diseases (Review)

“…Thus, silencing miR-193a-5p reversed the effects of GSDMD. These findings suggest that circHIPK3 may promote pyroptosis and inflammation via regulation of the miR-193a-5p/GSDMD axis in AR42J cells (100). circHIPK3 and cardiac fibrosis (CF).…”

“…Silencing its expression inhibited the release of IL-1β and TNF-α ( 99 ). Additionally, a recent study demonstrated that circHIPK3 expression was upregulated in the serum of patients compared with AP and in caerulein-stimulated AR42J cells ( 100 ). Furthermore, it was revealed that circHIPK3 sponged miR-193a-5p to negatively regulate its expression.…”