A two-circular RNA signature of donor circFOXN2 and circNECTIN3 predicts early allograft dysfunction after liver transplantation

Abstract

Background: Early allograft dysfunction (EAD) following liver transplantation is associated with poor recipient and graft survival. In recent years, circular RNAs (circRNAs) have emerged as important components of endogenous RNAs. This study aims to explore the expression profile and predictive value of graft circular RNAs for EAD after liver transplantation.Methods: RNA sequencing was conducted to identify the circRNA profile in donor liver tissues. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was used to identify candidate circRNAs. A novel model combining circular RNA signature was established to predict EAD based on the multivariate analysis.Results: A total of 442 circRNAs were differentially expressed between the EAD and non-EAD groups, of which, 223 were significantly upregulated and 219 were downregulated in the EAD group (Fold change >2, P<0.05). qRT-PCR validation indicated that circFOXN2 and circNECTIN3 levels in the EAD group were significantly lower than those in the non-EAD group (P=0.038, 0.024, respectively; n=115). Among the 115 recipients, 32 recipients with high circFOXN2 expression were classified as circular RNA signature A and the rest recipients with low circFOXN2 expression were categorized into circular RNA signature B (n=33, high circNECTIN3 expression) and C (n=50, low circNECTIN3 expression). The incidence rates of EAD in signature A, B and C were significantly different (3.1%, 21.2% and 42.0%, respectively; P=0.000).According to the multivariate analysis, a novel predictive model for EAD was developed based on CIT (P=0.000) and circular RNA signature (P=0.013). The novel model displayed a high predictive value for EAD with areas under the curve (AUC) of 0.870 (95% CI: 0.797-0.942).Conclusions: Donor circFOXN2 and circNEXTIN3 were associated with the incidence of EAD. The novel model combing the two-circular RNA signature had a high predictive value for EAD.

Combination of Early Allograft Dysfunction and Protein Expression Patterns Predicts Outcome of Liver Transplantation From Donation After Cardiac Death

“…Further research has revealed that PPARα is downregulated after LT, which might be an adaptive response to oxidative stress and hepatocellular damage during LT ( 16 ). Moreover, microRNAs and circular RNAs, such as miRNA-122, circFOXN2, and circNEXTIN3, that are expressed in the liver have been found to be potential early predictors of the onset of EAD ( 6 , 7 ). In addition, serum protein profiles of recipients associated with EAD have been widely studied, and several serum proteins have been identified, such as monocyte chemoattractant protein 1, interleukin 8, factor V, and soluble CD163 ( 8 , 9 , 17 ).…”

“…Many factors could contribute to the onset of EAD, such as donor age, donor body mass index (BMI), graft steatosis, cold ischemic time (CIT), warm ischemic time (WIT), donor serum sodium, and model for end-stage liver disease (MELD) score (5). Recently, multiple molecular markers of EAD have been introduced and improved the predicting profiles of EAD, such as microRNAs, circRNAs, and serum proteins (6)(7)(8)(9). However, the role of protein expression patterns in pretransplant liver grafts in predicting the onset of EAD and recipients' prognosis remains poorly studied.…”

Past, Present and Future: The Relationship Between Circular RNA and Immunity

“…However, because the contents and categories of current related studies are relatively similar, there are only a few examples, which are no longer explained in detail here. For instance, circHIPK3 was proven to modulate the proliferation of airway smooth muscle cells by the miR-326/STIM1 axis in asthma ( 69 ), a group of ample circRNAs and ceRNA networks were found to likely contribute to acquired immune deficiency syndrome (AIDS) ( 70 ), and a two-circular RNA signature of donors was thought to be a biomarker of early allograft dysfunction after liver transplantation ( 71 ). In addition to the above diseases, circRNAs play vital roles in a variety of immunological diseases and immune cells.…”

Single-cell analysis reveals a pathogenic cellular module associated with early allograft dysfunction after liver transplantation

“…1 However, apart from the organ shortage as the major limitation of LT, 2 early allograft dysfunction (EAD) following LT is considered a critical complication, with an incidence of approximately 20-40%, seriously affecting the long-term survival rate of allografts and recipients. [3][4][5][6][7] EAD is a multifactorial complication of LT, and its risk factors include the donor risk index, surgery-related factors, and Model for End-stage Liver Disease score. [7][8][9] Liver ischemia-reperfusion (IR) injury after surgery, a key factor for EAD development, is a complex process involving immune responses, inflammation, cell damage, and cell death, all of which are regulated by multiple cell lineages.…”