Functional role of caveolin-1-mediated S100P signaling in liver cancer metastasis under hypoxia

Abstract

Hypoxia is a common feature of hepatocellular carcinoma (HCC) and facilitates tumor metastasis. High level of Caveolin-1 (Cav1) was exclusively expressed in primary HCC and metastatic tissues and its level was further enhanced under hypoxic stress. Suppression of Cav1 reduced HCC growth and metastasis. However, the potential role of Cav1 in human cancers under hypoxic stress has never been reported. A cDNA array profiling identified S100P calcium binding protein as a downstream target of Cav1. S100P is highly expressed in several malignancies and promote metastasis. In the present study, we showed that S100P expression was well correlated with Cav1 expression in a panel of HCC cell lines. In addition, S100P expression at protein and mRNA levels was largely suppressed in sh-Cav1 knockdown cells. Suppression of S100P expression largely inhibited tumorigenesis in subcutaneous injection and orthotopic liver implantation models. Furthermore, hypoxia significantly enhanced the migration and invasion of control and such enhancement was not prominent when Cav1 or S100P was suppressed. Taking together, Cav1 functions as the upstream component of S100P and plays a critical role in modulation of cell motility during hypoxia. Thereafter, our data showed Cav1 was able to activate NF-jB reporter and transient expression of Cav1 upregulated S100P in cells. Addition of NF-jB inhibitor, IMD-0354 abolished the upregulation of S100P by Cav1 suggests that Cav1 upregulates S100P via the activation of NFjB pathway. In conclusion, Cav1 may upregulate S100P through the activation of NF-jB cascade to confer the enhanced aggressiveness of HCC cells under hypoxic condition.