Abstract C87: Regulation of stemness by Hippo-YAP pathway under hypoxia in hepatocellular carcinoma

Abstract

Abstract Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death. The Hippo-YAP signaling pathway is gaining recognition as it plays an important role in both organ size control and tumorigenesis. Liver-specific ablation of WW45 in rodent models (one of the tumor suppressive Hippo pathway components in mammals) has been reported to increase liver size and expand hepatic stem/progenitor cells (oval cells) and to develop HCC eventually. The expression of YAP also has been reported as an independent poor prognostic marker for human HCCs. Amphiregulin is a downstream target of YAP and is a member of the EGF family, which is implicated in cancer stem cells in HCC. Cancer stem cells have the ability to self-renew, differentiate, and proliferate, and have greater tumorigenicity, chemoresistance, and resistance to hypoxia. HCCs expressing stem cell makers have actually been reported to be associated with poor prognosis and aggressive biological behavior. The aim of this study is to investigate the Hippo-YAP pathway and its related oncogenic signaling in HCCs expressing stem cell markers. The effect of amphiregulin on the regulation of the Hippo-YAP pathway was also studied to identify potential molecular therapeutic targets for HCCs expressing stem cell markers. Under hypoxic condition, the expression of cancer stem cell markers (EpCAM, CD133, and CK19) was upregulated in a time dependent manner and the Hippo-YAP pathway was oncogenically activated in four HCC cell lines (HepG2, Hep3B, Huh7, and SK-Hep1). In addition, the treatment of recombinant human amphiregulin dephosphorylated and activated YAP pathway. Therefore, up-regulation of cancer stem cell markers with activation of oncogenic YAP pathway in HCC cell lines might suggest the acquisition of survival advantage of tumor cells under hypoxia. The relationship between the regulatory mechanism of cancer stem cells and the Hippo-YAP pathway can be used for molecular target of chemotherapy for HCC. Citation Format: Ji Su Kim, Ei Yong Ahn, Young Nyun Park. Regulation of stemness by Hippo-YAP pathway under hypoxia in hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C87.