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.

Prognostic value of high IMP3 expression in solid tumors: a meta-analysis

“…The 53 studies involved 8,937 patients with different cancer types, including 6 studies of RCC,8,25–29 6 lung cancer,9,30–34 4 oral cancer,10,35–37 4 urothelial carcinoma,38–41 4 ovarian cancer,16,17,42,43 3 hepatocellular carcinoma (HCC),44–46 4 colorectal cancer,12,47–49 3 prostate cancer,14,15,50 3 pancreatic cancer,51–53 2 gastric cancer,11,54 2 intrahepatic cholangiocarcinoma (ICC),55,56 and one study each of tongue cancer,57 thyroid carcinoma,58 sacral chordoma,59 pilocytic astrocytoma and pilomyxoid astrocytoma (PA/PMA),60 neuroblastoma,61 meningioma,62 melanoma,63 breast cancer,64 giant cell tumor,65 bile duct carcinoma,66 esophageal carcinoma,67 and cervical cancer 13. A total of 25 studies involved Caucasians and 28 involved Asians.…”

IGF2BP3 From Physiology to Cancer: Novel Discoveries, Unsolved Issues, and Future Perspectives

“…Other mechanisms include DNA methylation and acetylation processes. Demethylated CpG islands characterize the IGF2BP3 promoter in intrahepatic cholangiocarcinoma cases, which were in stark contrast to normal liver tissues that were heavily methylated (Gao et al, 2014). More recently, a large-scale sequencing analysis of datasets of 15 cancer types from The Cancer Genome Atlas (TCGA) confirmed these data, showing an inverse correlation between the DNA methylation status of the IGF2BP3 promoter and IGF2BP3 mRNA expression (Panebianco et al, 2017).…”

New insights into molecular diagnostic pathology of primary liver cancer: Advances and challenges

“…Studies have shown that 41% of ICC cases have a mutation in PTPN3, a protein tyrosine phosphatase family member. ICC patients with high levels of PTPN3 protein expression will have a significantly increased risk of postoperative recurrence [33], and IMP3, a novel oncoprotein expressed in 82% of ICC cases, is negatively correlated prognosis [34]. Sia et al used gene expression profiles and mutation analysis technology to classify ICC into two types.…”