Introduction: HCC shares pathways with regulators of liver development. Wound healing recapitulates early liver development (hepatoblast proliferation) while regeneration resembles late embryonic growth (hepatocyte proliferation). Our aims in this study were to investigate (1) the involvement and specificity of developmental genes in HCV-cirrhosis and HCC, and (2) “wound healing” and “regeneration” patterns in HCC. We compared microarray studies from 30 HCV-cirrhosis, 49 HCC, and 12 normal livers, and validated results with a public dataset of HCV- cirrhosis and HCC.

Results:

86/202 genes specific to liver development had differential expression (DEG) between normal and cirrhosis or HCC samples. 60 genes with paralogous function, which have known associations with other cancer types, were not expressed in adult normal liver or HCC. Of 1,339 non-developmental genes not normally expressed in livers, only 3 were differentially expressed in HCC (FDR<0.05). This suggests that mutational activation of random genes is not a major contributor to carcinogenesis.

69 liver development genes were DEG in cirrhosis, and 58 (84%) were also DEG in early HCC. 19/58 (33%) had larger changes in cirrhosis and 5 (9%) had largerchanges in early HCC. Fifteen genes were uniquely DEG in early tumors, while only 2 genes were uniquely DEG in late-stage (T3 and T4) HCC. This suggests that the master regulators of liver development are active in the pre-cancerous cirrhotic liver and in those with emerging tumors, but play a limited role in the transition to late stage HCC.

Progenitor cell markers VIM, EPCAM, and KRT19, and hepatocyte proliferation inhibitors (HPI) BMP2, CDH1, and MST1 were highly expressed in cirrhosis. Continued over-expression of HPI in HCC was associated with excellent outcomes, while their loss was associated with early recurrence and death (94% vs. 38% 2-year recurrence- free survival, p=0.0003). Loss of HPI also correlated with overexpression of hepatocyte proliferation promoter c-MET. These results suggest that cirrhosis is characterized by proliferation of progenitor cells in a process resembling early hepatoblast proliferation, while hepatocyte proliferation characteristic of late liver development and liver regeneration is actively suppressed. Tumors also display markers of progenitor-cell proliferation, at lower levels than cirrhosis, and a subset of tumors that acquire hepatocyte proliferative capacity have lower 2-year recurrence-free survival.

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