Abstract
Poly (ADP-ribose) polymerase 1 (PARP-1) is a crucial contributor to exacerbate ischemia and reperfusion (IR) injury and cancer process. However, there is little research into whether PARP-1 affects the hepatocellular carcinoma (HCC) recurrence after liver transplantation. In this study, we investigated the influence of PARP-1 on hepatic neutrophil mobilizing and phenotype shifting which may lead to HCC recurrence after liver transplantation. We found that rats received the grafts with warm ischemic injury had higher risk of HCC recurrence, which was markedly prevented by pharmacological inhibition of PARP-1 after liver transplantation. In mouse models, the up-regulation of PARP-1 was closely related to the greater tumor burden and increased hepatic susceptibility to recurrence after IR injury. The reason was that high hepatic PARP-1 led to increased liver CXCL1 levels, which in turn promoted recruitment of neutrophils. Both blocking CXCL1/CXCR2 signaling pathway and depleting neutrophils decreased tumor burden. Moreover, these infiltrating neutrophils were programmed to a proangiogenic phenotype under the influence of PARP-1 in vivo after hepatic IR injury. In conclusion, IR-induced PARP-1 up-regulation increased the hepatic recruitment of neutrophils through regulation of CXCL1/CXCR2 signaling and polarized hepatic neutrophils to proangiogenic phenotype, which further promoted HCC recurrence after transplantation.
Highlights
Primary liver cancer is the sixth most frequent cancer and the second leading cause of cancer-related death worldwide
Considering that Poly (ADP-ribose) polymerase 1 (PARP-1) promoted apoptosis/necrosis during ischemia and reperfusion (IR) injury [20] and high Poly (ADP-ribose) polymerase (PARP)-1 expression was associated with tumor malignant potential [21], we adopted the PARP-1 inhibitor PJ34 to explore its role in hepatocellular carcinoma (HCC) recurrence after liver transplantation
We show for the first time that PARP-1 up-regulated by hepatic IR injury could increase the hepatic susceptibility to post-liver transplantation HCC recurrence through regulation of neutrophil recruitment and phenotype shifting (Figure 8)
Summary
Primary liver cancer is the sixth most frequent cancer and the second leading cause of cancer-related death worldwide. It is reported that China has about 55% liver cancer deaths worldwide due to the high incidence of chronic hepatitis B [3]. Simple living donor liver transplantation is difficult to meet the growing demands for availability of organs. The lack of organs has led to an increase in the use of extended criteria grafts, such as donation after cardiac death (DCD) donors. It is reported that DCD allograft tended to increase the rates of recurrence for HCC candidates [7] and Oldani G, et al has proved it in rodent DCD models for HCC recurrence after liver transplantation [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
