ZFAND5 Is an Independent Prognostic Biomarker of Perihilar Cholangiocarcinoma

Abstract

Background: Cholangiocarcinoma (CCA) is a highly aggressive malignancy with extremely poor prognosis. Perihilar CCA (pCCA) is the most common subtype of CCA, but its biomarker study is much more lagged behind other subtypes. ZFAND5 protein can interact with ubiquitinated proteins and promote protein degradation. However, the function of ZFAND5 in cancer progression is rarely investigated, and the role of ZFAND5 in pCCA is never yielded.

Materials and methods: In this study, we established a pCCA cohort consisting of 72 patients. The expression of ZFAND5 in pCCAs, and the paired liver tissues, intrahepatic bile duct tissues and common bile ducts (CBD) tissues were detected with IHC. ZFAND5 mRNA in pCCAs and CBDs was detected with qRT-PCR. The pCCA cohort was divided into ZFAND5^low and ZFAND5^high subsets according to the IHC score. The correlations between ZFAND5 expression and clinicopathological parameters were assessed bychi-square test. The prognostic significance of ZFAND5 expression and clinicopathological parameters was estimated by univariate analysis with Kaplan-Meier method, and by multivariate analysis with Cox-regression model.

Results: Expression of ZFAND5 in pCCAs was substantially higher than that in interlobular bile ducts and common bile ducts, but lower than that in liver tissues. The ZFAND5^low and ZFAND5^high subsets accounted for 44.4% and 55.6% of all pCCAs respectively. ZFAND5 ^high patients had much lower survival rates than the ZFAND5^low patients, with the average survival time as 31.2 months and 19.5 months respectively. ZFAND5 was identified as an independent unfavorable prognostic biomarker of pCCA with multivariate analysis.

Conclusion: ZFAND5 expression was up-regulated in pCCAs compared with the CBDs. We identified ZFAND5 as an independent biomarker of pCCA, which could provide more evidence for the molecular classification of pCCA, and help stratify the high-risk patients based on the molecular features.

Keywords: ZFAND5; biomarker; cohort; perihilar cholangiocarcinoma; prognosis.

Figure 1

The expressions of ZFAND5 in pCCAs, liver tissues, interlobar bile ducts tissues, and common bile ducts tissues. (A) The expressions of ZFAND5 in pCCAs, liver tissues, interlobar bile ducts tissues, common bile ducts tissues were detected by IHC. Scale bar: 100 μm. The arrow indicates the interlobar bile duct. (B) The expressions of ZFAND5 in pCCAs, liver tissues, interlobar bile ducts tissues, and common bile ducts tissues were estimated by the IHC scores. *** represents P < with one-way ANOVA test. (C) mRNAs of ZFAND5 in pCCAs and common bile ducts were detected with qRT-PCR. The statistical significance was analyzed by paired t test.

Figure 2

The cohort was divided into ZFAND5low and ZFAND5high subsets. The representative images of low and high ZFAND5 expression. Scale bar: 100 μm.

Figure 3

The correlation between clinicopathological factors and overall survival rates. The patients were divided into different subsets according to ZFAND5 expression (A), histological grade (B), T stage (C), TNM stage (D) and tumor size (E). The survival curves were plotted by Kaplan-Meier method, and the statistical significance was analyzed with the log-rank test.