Abstract
Abstract Hypoxia is a common feature of hepatocellular carcinoma (HCC) due to the expansion of tumors and the inadequacy of their local vasculature and facilitates tumor metastasis. Our previous study revealed that 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. This suggests that Cav1 may play an important role in the acquisition of aggressiveness in cancer cells under hypoxic stress. To explore the molecular mechanisms by which Cav1 mediates HCC cell motility and invasiveness, a cDNA microarray analysis was employed to compare the gene expression profiles between sh-Cav1 knockdown cells and the control sh-Ctl cells. Among the differentially expressed genes, the expression of S100P, a member of the S100 calcium-binding protein family showed a 4-fold reduction. S100P has been shown to be highly expressed in several malignancies and to promote metastasis. However, the impact of S100P on HCC tumorigenesis and metastasis remains unexplored and the potential role of S100P in human cancers under hypoxic stress has never been reported. Our present study aims to investigate the functional role of Cav1-mediated S100P signaling cascade in HCC tumorigenesis and metastasis under hypoxic condition. We showed that S100P expression was well correlated with Cav1 expression in a panel of HCC cell lines by Western Blot. Both proteins were undetectable in non-tumorigenic immortalized liver cell and moderately expressed in non-metastatic HCC cell line but pronouncedly expressed in metastatic HCC cell line. In addition, S100P expression at protein and mRNA levels was largely suppressed in sh-Cav1 stable knockdown cell. 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 was suppressed in Cav1 knockdown stable clones. Same phenomenon was also noticed in S100P knockdown stable clones. Taking together, Cav1 functions as the upstream component of S100P and plays a critical role in modulation of cell motility during hypoxia. Thereafter, we examined the potential signaling underlying Cav1-modulatedS100P expression in HCC development. Our data showed Cav1 was able to activate NF-κB reporter. Transient expression of Cav1 upregulated S100P in cells and the addition of NF-κB inhibitor, IMD-0354 abolished the upregulation of S100P by Cav1 suggests that Cav1 upregulates S100P via the activation of NF-κB pathway. In conclusion, Cav1 may upregulate S100P through the activation of NF-κB cascade to confer the enhanced aggressiveness of HCC cells under hypoxic condition. Citation Format: Xiaowen Mao, Sivia Yuen-sze Wong, Frankie Chi Fat Ko, Judy Wai Ping Yam. Upregulation of S100P by caveolin-1 drives tumorigenesis and metastasis in hepatocellular carcinoma under hypoxic stress. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2997. doi:10.1158/1538-7445.AM2015-2997
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