Abstract
Abstract Human hepatocellular carcinoma (HCC) is characterized by frequent local invasion and recurrence, which are strongly associated with poor overall survival of HCC patients. Epithelial-mesenchymal transition (EMT) is an initiating event driving tumour invasion and metastasis. However, the molecular mechanisms of EMT in HCC remains largely unknown. We have performed a human kinome/phosphatome RNAi screen to identify novel genes that are involved in invasion and metastasis of HCC cells using Hep3B, a low motile HCC cell line, and identified TIS1 (Tumor Invasion Suppressor 1) as a potential cell motility suppressor. Mechanistic studies revealed that TIS1 was a novel actin binding protein that sequestrated globular actins and prevented actin filament (F-actin) formation, thereby suppressing the formation of filopodia, lamillepodia and invadopodia. Silencing of TIS1 enhanced EMT and tumor cell migration and invasion. Notably, F-actin polymerization induced by TIS1 silencing led to activation of the NOTCH signalling via induction of HIF1A, which in turn further supports EMT for sustaining tumor invasion and metastasis. Clinically, TIS1 was frequently downregulated in many human cancers including HCC and strongly associated with tumor recurrence, local invasion, and poor prognosis. In conclusion, a novel TIS1-HIF/NOTCH signaling forms a positive feedback loop sustainingly driving mesenchymal transition of cancer cells for invasion and metastasis. This TIS1-mediated tumor invasion and metastasis signaling may serve as therapeutic targets for prevention and treatment of HCC invasion and metastasis. Citation Format: Sen-Yung Hsieh. Functional genomics identifying a TIS1-HIF-NOTCH signaling orchestrating epithelial-mesenchymal transition for tumor invasion. [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 1447. doi:10.1158/1538-7445.AM2015-1447
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