The expression of keratin 19 (K19) has been proposed as a novel predictor for poor prognosis in patients with hepatocellular carcinoma (HCC). However, the cell origin of K19-proficient HCC remains unclear. Herein we tried to reveal the cell origin of K19-proficient HCC by tracing epigenetic footprints in cultured cells and clinical materials.
The KRT19 gene, which encodes K19, has a CpG island in promoter region and therefore implicates DNA methylation as a potential epigenetic process for K19 expression. Firstly, we examined epigenetic alterations in K19-positive HCC cell lines. Next, from a panel of 564 surgically resected HCCs, we clarify the clinicopathological relevance of K19-preficent HCCs by analyzing robust methylation analyses in KRT19 promoter region and LINE-1 in comparison with other cholangiocytic (K7), hepatocytic markers (HepPar-1 and Arginase-1), EMT markers (E-cadherin and vimentin), and a signal pathway associate with biliary differentiation (NOTCH-1).
In vitro, although methylation in KRT19 promoter was associated with K19 deficiency, 5-aza-dC treatment failed to re-expression of K19. From 564 surgically resected HCCs, a cohort of 125 HCC patients was selected and analyzed after exclusion of HCC with recurrence, TNM stage as IIIB or more, preoperative therapy, transplantation, and combined hepatocellular-cholangiocarcinoma. In this cohort, K19 expression was found in 29 HCCs (23.2%), and corresponded with poor survival following surgery (P = 0.025) and extrahepatic recurrence free survival (P = 0.017). Compared with K19-deficient HCCs, the lower methylation level in KRT19 promoter was observed in K19-proficient HCCs (P
K19-proficient HCC showed the poor prognosis owing to extrahepatic recurrence and the molecular signatures were different from K19-deficeint HCC, providing novel insights of heterogeneity underlying development of HCC with extrahepatic metastasis.
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All authors have declared no conflicts of interest.