Serum copper, zinc and metallothionein serve as potential biomarkers for hepatocellular carcinoma.

Yasuyuki Tamai,Motoh Iwasa,Yoshiyuki Takei,Hiroshi Hasegawa,Kazushi Sugimoto,Akiko Eguchi,Ryuta Shigefuku,Gianfranco D. Alpini

doi:10.1371/journal.pone.0237370

Yasuyuki Tamai, Motoh Iwasa + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0237370

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Journal: PloS one	Publication Date: Aug 28, 2020
Citations: 26	License type: CC BY 4.0

Affiliation: Mie University

Abstract

BackgroundCopper (Cu) and zinc (Zn) are essential nutrients and cofactors of enzymatic reactions with their binding partner. Metallothionein (MT) plays an important role in protecting against heavy metals and oxidative injury, however it may also portend drug resistance and a worse prognosis for hepatocellular carcinoma (HCC) patients. The aim of this study was to determine the amount of Cu, Zn, Cu/Zn and MT in evaluating a group of patients with HCC, including those treated with lenvatinib.MethodsWe enrolled 175 patients with HCC (139 men, 36 women; mean age 71.1 years; hepatitis C virus n = 85, hepatitis B virus n = 19, hepatitis C virus and hepatitis B virus n = 2, non-alcoholic steatohepatitis n = 39, alcohol n = 25, others n = 5; Child-Pugh A n = 141, Child-Pugh B n = 30, Child-Pugh C n = 4; Barcelona clinic liver cancer (BCLC) stage 0 n = 38, stage A n = 56, stage B n = 39, stage C n = 38, stage D n = 4). We evaluated the associations between Cu, Zn and MT. The study outcome was liver cancer-specific survival. Moreover, we treated 12 HCC patients with lenvatinib and investigated the changes in MT during lenvatinib therapy.ResultsThe serum level of Cu was positively correlated with alanine aminotransferase and the BCLC stage. The serum level of Zn decreased concordant with liver disease progression. Patients with a Cu/Zn ratio≥0.999 had significantly improved rates of survival when compared to patients with a Cu/Zn ratio<0.999 (45.3 vs. 30.1 months, p<0.001). MT was significantly correlated with the Cu/Zn ratio and increased after the administration of lenvatinib. Using multivariate Cox regression analyses, it was determined that the Cu/Zn ratio (hazard ratio [HR]: 1.442, p = 0.008), alpha-fetoprotein (HR: 1.000, p<0.001) and BCLC stage (HR: 2.087, p<0.001) were independent predictors of survival.ConclusionsThe Cu/Zn ratio could serve as a useful predictive marker for survival in cases of HCC. MT levels increased in HCC patients receiving lenvatinib therapy, and maybe a predictor of reduced survival.

Highlights

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide [1]
MT was significantly correlated with the Cu/Zn ratio and increased after the administration of lenvatinib
Using multivariate Cox regression analyses, it was determined that the Cu/Zn ratio, alpha-fetoprotein (HR: 1.000, p

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide [1]. Zn deficiency was reported to be associated with increased liver fibrosis [6, 7] and hepatocarcinogenesis in patients with hepatitis C-related liver cirrhosis [8]. Hiraoka et al reported that Zn deficiency is an independent prognostic factor for early stage HCC patients infected with viral hepatitis who are receiving antiviral therapy [9]. The Cu/Zn ratio has been observed to be elevated in patients with hepatitis, liver cirrhosis or HCC and appears to be correlated with the overall severity of liver disease [4, 10, 11]. Fang et al reported that a higher Cu/Zn ratio was associated with a reduced HCC rate of survival in their prospective cohort study [13].

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