IMP3 expression is associated with poor outcome and epigenetic deregulation in intrahepatic cholangiocarcinoma

Abstract

IMP3 is a fetal protein not expressed in normal adult tissues. IMP3 is an oncoprotein and a useful biomarker for a variety of malignancies and is associated with reduced overall survival of a number of them. IMP3 expression and its prognostic value for patients with intrahepatic cholangiocarcinoma (ICC) have not been well investigated. The molecular mechanism underlying IMP3 expression in human cancer cells remains to be elucidated. Here we investigated IMP3 expression in ICC and adjacent nonneoplastic liver in 72 unifocal primary ICCs from a single institute by immunohistochemistry, immunoblotting, and real-time polymerase chain reaction. IMP3 was specifically expressed in cancer cells but not in the surrounding normal tissue, and 59 (82%) of 72 ICCs were IMP3 positive by immunohistochemistry. Among 35 cases with lymphovascular invasion, 26 (74%) showed IMP3 positivity in lymph node metastases. IMP3 expression was significantly correlated with tumor size, pathological grade, metastasis, and clinical stage. Kaplan-Meier analysis demonstrated an inverse correlation between IMP3 expression and overall survival rate. Multivariate analysis revealed that IMP3 was the only risk factor associated with survival. To further explore the mechanism of IMP3 expression in cancers, we identified 2 CpG islands at IMP3 proximal promoter. Interestingly, the IMP3 promoter was almost completely demethylated in ICCs in contrast to densely methylated promoter in normal liver tissues. IMP3 expression is a useful biomarker for ICCs and can provide an independent prognostic value for patients with ICC. To our knoweldge, this is the first direct evidence of epigenetic deregulation of IMP3 in human cancer.

Keywords: Cholangiocarcinoma; Epigenetic; IMP3; Intrahepatic; Methylation; Outcome.