Serum Anti-14-3-3 Zeta Autoantibody as a Biomarker for Predicting Hepatocarcinogenesis

Ting Wang; Xue-Ying Huang; Su-Jun Zheng; Ye-Ying Liu; Si-Si Chen; Feng Ren; Jun Lu; Zhong-Ping Duan; Mei Liu

doi:10.3389/fonc.2021.733680

Serum Anti-14-3-3 Zeta Autoantibody as a Biomarker for Predicting Hepatocarcinogenesis

Front Oncol. 2021 Oct 15:11:733680. doi: 10.3389/fonc.2021.733680. eCollection 2021.

Authors

Ting Wang¹, Xue-Ying Huang², Su-Jun Zheng³, Ye-Ying Liu², Si-Si Chen², Feng Ren⁴, Jun Lu², Zhong-Ping Duan⁵, Mei Liu²

Affiliations

¹ Department of Respiratory and Infectious Diseases, Beijing You'an Hospital, Capital Medical University, Beijing, China.
² Department of Oncology, Beijing You'an Hospital, Capital Medical University, Beijing, China.
³ First Department of Hepatology Center, Beijing You'an Hospital, Capital Medical University, Beijing, China.
⁴ Beijing Institute of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, China.
⁵ Fourth Department of Hepatology Center, Beijing You'an Hospital, Capital Medical University, Beijing, China.

Abstract

Hepatocellular carcinoma (HCC) is a common malignancy worldwide. Alpha-fetoprotein (AFP) is still the only serum biomarker widely used in clinical settings. However, approximately 40% of HCC patients exhibit normal AFP levels, including very early HCC and AFP-negative HCC; for these patients, serum AFP is not applicable as a biomarker of early detection. Thus, there is an urgent need to identify novel biomarkers for patients for whom disease cannot be diagnosed early. In this study, we screened and identified novel proteins in AFP-negative HCC and evaluated the feasibility of using autoantibodies to those protein to predict hepatocarcinogenesis. First, we screened and identified differentially expressed proteins between AFP-negative HCC tissue and adjacent non-tumor liver tissue using SWATH-MS proteome technology. In total, 2,506 proteins were identified with a global false discovery rate of 1%, of which 592 proteins were expressed differentially with 175 upregulated and 417 downregulated (adjusted p-value <0.05, fold-change FC ≥1.5 or ≤0.67) between the tumor and matched benign samples, including 14-3-3 zeta protein. For further serological verification, autoantibodies against 14-3-3 zeta in serum were evaluated using enzyme-linked immunosorbent, Western blotting, and indirect immunofluorescence assays. Five serial serum samples from one patient with AFP-negative HCC showed anti-14-3-3 zeta autoantibody in sera 9 months before the diagnosis of HCC, which gradually increased with an increase in the size of the nodule. Based on these findings, we detected the prevalence of serum anti-14-3-3 zeta autoantibody in liver cirrhosis (LC) patients, which is commonly considered a premalignant liver disease of HCC. We found that the prevalence of autoantibodies against 14-3-3 zeta protein was 16.1% (15/93) in LC patient sera, which was significantly higher than that in patients with chronic hepatitis (0/75, p = 0.000) and normal human sera (1/60, 1.7%, p = 0.01). Therefore, we suggest that anti-14-3-3 zeta autoantibody might be a biomarker for predicting hepatocarcinogenesis. Further follow-up and research of patients with positive autoantibodies will be continued to confirm the relationship between anti-14-3-3 zeta autoantibody and hepatocarcinogenesis.

Keywords: 14-3-3 zeta; SWATH-MS proteome technology; biomarker; hepatocarcinogenesis; premalignant liver disease.