Distinct gene signatures linked to acute phase injury and tumor invasiveness in tumor development after liver transplantation using small-for-size grafts

Abstract

BACKGROUND: As living donors theoretically offer an unlimited supply of liver grafts, there is immense interest in the clinical efficacy of adult-to-adult living donor liver transplantation (LDLT). A liver graft from a live donor is almost always small-for-size for an adult recipient. We hypothesize that the early response to acute-phase injury and the subsequent regeneration of a small-for-size graft can potentially provide a favorable environment for tumor recurrence. OBJECTIVES: We aim to study the gene expression profiles associated with acute phase graft injury and tumor invasiveness at early or late phase after liver transplantation using small-for-size grafts. MATERIALS AND METHODS: Orthotopic liver transplantation was applied using whole (100%) grafts (Group W) and small-for-size (50%) grafts (Group S) in a rat transplantation model. The recipients were injected with hepatoma cell lines (CRL1601, 2´105 ) via the portal vein after reperfusion, and were sacrificed on days 1, 3, 14, and 21 after transplantation for histological examination. Gene signatures of acute graft injury (days 1, 3, 7) and tumor recurrence (days 14, 21) were screened using cDNA Microarray and confirmed by quantitative RT-PCR. Results Significant liver regeneration was present in Group S. This was associated with histological hallmarks of severe acute graft injury. Early development of liver tumors and significantly larger tumor sizes were also noted in Group S, accompanied by invasive growth patterns. Numbers of genes linked to inflammatory responses and tumor invasiveness were found to be over-expressed in small-for-size liver grafts and/or the tumor developed in small liver grafts by cDNA microarray screening. After confirmation by real-time RT PCR, the gene (Cdc2-a) leading to acute phase liver graft injury were found over-expressed in small-for-size liver grafts at day 1 after liver transplantation. At 3 weeks after transplantation, mRNA expression levels of Fosl-1, MAPK13 and MMP12 both in the tumor and non-tumor tissues were significantly higher in Group S. On the contrary, Spin-2b, a tumor suppressive gene, was presented with lower level in Group S. CONCLUSION: Distinct gene signatures linked to acute phase injury and tumor invasiveness in the small-for-size liver graft may contribute to early tumor recurrence after liver transplantation.