ZCCHC13-mediated induction of human liver cancer is associated with the modulation of DNA methylation and the AKT/ERK signaling pathway

Zhiming Li,Linjun Wang,Xuan Zhuang,Zaozao Zheng,Chen Long,Zhi Li

doi:10.1186/s12967-019-1852-0

Abstract

BackgroundPrevious studies have shown that zinc-finger CCHC-type containing 13 (ZCCHC13) is located in an imprinted gene cluster in the X-inactivation centre, but few published studies have provided evidence of its expression in cancers. The CCHC-type zinc finger motif has numerous biological activities (such as DNA binding and RNA binding) and mediates protein–protein interactions. In an effort to examine the clinical utility of ZCCHC13 in oncology, we investigated the expression of the ZCCHC13 mRNA and protein in hepatocellular carcinoma (HCC).MethodsThe expression of the ZCCHC13 mRNA and protein was evaluated using real-time reverse transcriptase-PCR, Western blotting and immunochemistry. DNA methylation was measured by methylation-specific PCR and bisulfite sequencing. The role of ZCCHC13 methylation was further evaluated using the demethylating agent, 5-aza-2′-deoxycytidine. The presence of anti-ZCCHC13 antibodies was determined by an ELISA.ResultsZCCHC13 expression was frequently upregulated in human liver cancer cells and tissues. Compared with heathy individuals, sera from patients with HCC displayed a significant response to the recombinant ZCCHC13 protein. The overexpression of ZCCHC13 in HCC was attributed to DNA hypomethylation in the promoter region. Moreover, overexpression of ZCCHC13 in liver cancer cells promoted cell cycle progression by facilitating the G1-S transition, which was related to aberrant activation of the ATK/ERK/c-MYC/CDK pathway.ConclusionsBased on our findings, ZCCHC13 functions an oncogene for HCC, and DNA hypomethylation is a driving factor in carcinogenesis.

Highlights

Previous studies have shown that zinc-finger CCHC-type containing 13 (ZCCHC13) is located in an imprinted gene cluster in the X-inactivation centre, but few published studies have provided evidence of its expression in cancers
ZCCHC13 is expressed at high levels in hepatocellular carcinoma (HCC) cells and tissues To analyze the relationship between ZCCHC13 expression and carcinogenesis, we detected the levels of the ZCCHC13 protein in a series of different human cancer cell lines, including lung, stomach, breast, cervical, and prostate cancer cell lines
Strong immunoreactivity was observed in more aggressive human liver cancer cell lines, including Huh7, QGY-7701, PLC/PRF/5, HCC-9810, HepG2, and BEL-7402, in particular the highest levels were observed in HepG2, Huh7 and QGY-7701 cells (Fig. 1b)

Summary

Introduction

Previous studies have shown that zinc-finger CCHC-type containing 13 (ZCCHC13) is located in an imprinted gene cluster in the X-inactivation centre, but few published studies have provided evidence of its expression in cancers. The CCHC-type zinc finger motif has numerous biological activities (such as DNA binding and RNA binding) and mediates protein–protein interactions. Hepatocellular carcinoma (HCC) is one of the most common primary malignant cancers and displays a predominant increase in incidence and mortality rates in patients with cirrhosis or chronic liver diseases. The MAPK/ERK pathway is a chain of proteins that transmit a signal from a receptor on the surface of the cell to the DNA in the nucleus. Crosstalk between the ERK and AKT pathways regulates cell growth and development to a greater extent than either pathway alone. The upstream factors that trigger the AKT/ ERT pathways remain largely unexplored

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Conclusion