Overexpression of HMGN3 nucleosome binding protein is associated with tumor invasion and TGF-? expression in cholangiocarcinoma

Abstract

High mobility group nucleosome binding (HMGN) protein is a non-histone protein that affects the chromatin function, leading to the regulation of gene expression. Several studies reported the aberrant expression of HMGN1-HMGN5 in variety of cancers. This study aimed to investigate a potential HMGN protein and its clinical impact in cholangiocarcinoma (CCA). Analysis of gene expression profiles of HMGNs in liver cancers from public database demonstrated the alteration of HMGN1-HMGN5 in CCA and hepatocellular carcinoma (HCC) tissues. HMGN3 was the only member that overexpressed in CCA, but not HCC, and hence was selected for further study. The immunohistochemistry of HMGN3 revealed that HMGN3 was weakly detected in normal bile ducts and hepatocytes but was gradually expressed in hyperproliferative bile ducts and CCA tissues, indicating the involvement of HMGN3 in development and progression of CCA. CCA exhibited significantly higher expression of HMGN3 than HCC, suggesting HMGN3 as a diagnostic marker distinguishing CCA from HCC. Univariate analysis revealed the association of high HMGN3 expression and tumor invasion of CCA patients. The expression of transforming growth factor β (TGF-β), a major inflammatory cytokine related to liver fluke-related CCA, was positively correlated with the expression of HMGN3 in CCA tissues. Treating CCA cell lines with recombinant TGF-β1 significantly induced the mRNA expression of HMGN3 but not the cholangiocytes. This finding signifies the positive correlation of TGF-β1 and HMGN3 observed in CCA tissues and the influence of TGF-β1 on HMGN3 expression. Further mechanistic studies are necessary to validate these findings.