The Oncogenic and Diagnostic Potential of Stanniocalcin 2 in Hepatocellular Carcinoma

Zhixian Wu,1,2,* Hongwei Cheng,1,* Jie Liu,1,* Shuaishuai Zhang,1 Minda Zhang,1 Fangzhou Liu,1 Yinghui Li,2 Qian Huang,2 Yi Jiang,3 Shaohua Chen,3 Lizhi Lv,3 Dongliang Li,2 Jin-Zhang Zeng1 1Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China; 2Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China; 3Department of Hepatobiliary Surgery, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jin-Zhang Zeng; Dongliang Li, Email jzzeng@xmu.edu.cn; dongliangli93@163.comPurpose: Early detection and prognostic prediction of hepatocellular carcinoma (HCC) remain a great challenge. In this study, we explored the role and diagnostic significance of stanniocalcin 2 (STC2), recently identified as a secretory protein, in HCC.Methods: STC2 mRNA and protein in HCC tissues were examined by qRT-PCR and immunohistochemistry. The regulatory role of HCC growth by STC2 was evaluated in vitro and in vivo. Serum STC2 levels were determined in HCC patients and compared to those with liver cirrhosis (LC) and normal controls (NC). The difference and significance of STC2 levels between groups were analyzed by Mann–Whitney U-test. The diagnostic value of serum STC2 in detecting early HCC was assayed with receiver operating characteristics (ROC). The association of STC2 with overall survival (OS) was determined with Kaplan–Meier method.Results: STC2 was elevated in about 77.1% HCC patients and correlated with advanced tumor progression. Overexpression or knockdown of STC2 stimulated or suppressed HCC colony formation and xenograft tumor growth. AKT activation played a critical role in tumor-promoting effect of STC2. The median level of serum STC2 in HCC patients (n = 98, 2086.6 ng/L) was 2.6-fold and 4.2-fold that in LC patients (n = 42, 801.9 ng/L) and NC (n = 26, 496.9 ng/L), respectively. A cut-off value 1493 ng/L for STC2 could distinguish early HCC from LC with a sensitivity of 76.9% and a specificity of 76.2%, both of which were superior to AFP at 20 μg/L (sensitivity 69.2%, specificity 52.4%). STC2 was positive in 77.8% (14/18) AFP-negative patients. High STC2 level was correlated with poor overall and disease specific survival.Conclusion: STC2 is upregulated in both tumor and serum of HCC patients, and its overexpression promotes HCC via AKT pathway. STC2 possesses a diagnostic significance and may serve as an auxiliary biomarker of AFP for detecting early HCC.Keywords: biological marker, serological diagnosis, early diagnosis, prognosis