Significant correlation between intragraft gene expression profiles linking to acute phase injury and angoneness with HCC recurrence after LDLT

Abstract

Objective We aim to investigate the impact of intragraft gene expression profi les linking to acute phase injury and angiogenesis on liver tumor recurrence of HCC patients after LDLT. Methods From May 2000 to Sep 2005, 378 adult-to-adult liver transplants were included in the current study. Liver biopsies were taken in the donors before graft harvesting and 2 hours after reperfusion in the recipients. The intragraft gene expression profi les of the grafts greater (Group 1) and less than 60% (Group 2) of standard liver weight (SLW) were compared by cDNA microarray analysis. The mRNA expression of the over-expressed genes was further confi rmed by quantitative RT-PCR. Hepatic stellate cell activation and intragraft gene/protein expression of Rac, FAK and CAK after reperfusion were detected. Clinical-pathological data including the incidence of tumor recurrence and metastases were also compared. Results The patients were grouped into Group 1 (>= 60% SLW, n=175) and Group 2 (<60%SLW, n=203). There were more HCC recipients in Group 2 [59 (29%) vs 31 (17.7%), p=0.01]. There was no difference of the incidence of higher tumor staging [21/59(35.6%) vs 13/31(41.9%), p=0.555) and patients beyond Milan [22/59(37.3%) vs 12/31(38.7%), p=0.895] or UCSF [14/59(23.7%) vs 7/31(22.6%), p=0.903] criteria between the two groups. The incidence of liver tumor recurrence together with lung metastasis was 22% (13/59) in Group 2. Most of the patients with tumor recurrence had hepatic sinusoidal injury at early phase after liver transplantation. There was no liver tumor recurrence in Group 1 (p=0.003). Signifi cant activation of hepatic stellate cells was found in Group 2 together with stronger intragraft protein expression of FAK and CAK compared to that of Group 1. Intragraft mRNA levels of Egr-1, RhoA, FAK and VEGF were also signifi cantly higher in Group 2. Distinct gene expression profi les linking to acute phase liver graft injury (Egr-1, G-protein signaling 5, ET-1, TGFR-b, FGFR, TNF-a and MMP-9) and angiogenesis (angiopoietin and angiopoietin-related protein 1) were found over-expressed in smaller liver grafts (Group 2). Conclusion Distinct intragraft gene expression profi les linking to acute phase injury and angiongenesis signifi cantly correlated with higher incidence of liver tumor recurrence and metastases in LDLT using the liver graft less than 60% of SLW.