Stanniocalcin 1 Promotes Metastasis Of Hepatocellular Carcinoma Through Activation Of Jnk Signaling

Abstract

Introduction: The hypoxic tumor microenvironment of hepatocellular carcinoma (HCC) is a major contributor to tumor progression and the aggressive biological behavior of the cancer. Thus identification and characterization of hypoxia-responsive genetic events is an integral part to understand the pathogenesis of HCC. Stanniocalcin 1 (STC1) is a glycoprotein of which the physiological functions in the human are poorly understood. Notably STC1 was found upregulated by hypoxia in some cancer cell lines (1). In this study we investigated the role of STC1 in HCC. Methods: Transcript and secreted protein expression levels of STC1 in clinical samples and HCC cell lines were measured by qPCR and ELISA assay respectively. Cell motility assay and Matrigel invasion assay were employed to examine the functional effects in vitro. Metastatic potential in vivo was investigated by orthotopic implantation model with nude mice. Results: Hypoxia induced mRNA expression of STC1 in HCC cells and triggered extracellular secretion of STC1 protein. Functionally, recombinant STC1 protein promoted metastatic potential of HCC by enhancing cell migration and cell invasion in vitro; and the effect was abolished by cotreatment of anti-STC1 neutralizing antibody. In vivo, silencing of STC1 in HCC cells inhibited STC1 protein secretion and suppressed lung metastasis. On the molecular mechanism, we found that recombinant STC1 activated the JNK pathway, as evidenced by altered expression of key molecular targets of the pathway pJNK and p-c-Jun. The above results were further supported by the findings using our HCC clinical samples, in which STC1 transcript level was overexpressed in HCC tissues as compared to the corresponding non-tumoral liver. The clinical significance of STC1 was further substantiated by the significantly higher secreted protein level in HCC patient sera. Moreover, a higher serum STC1 level was correlated with larger tumor size and a poorer 5-year disease-free survival. Conclusion: Our findings demonstrated that secreted STC1 protein enhances HCC metastasis through JNK signaling. STC1 potentially serves as a prognostic serum biomarker and a therapeutic target for HCC. References: (1) Yeung HY, et al. Hypoxia-inducible factor-1-mediated activation of stanniocalcin-1 in human cancer cells. Endocrinology. 2005 Nov;146(11):4951-60.