| Summary: | 碩士 === 國立陽明大學 === 臨床醫學研究所 === 100 === Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related death worldwide and the second one in Taiwan. Because of high mortality and poor prognosis of this cancer, more effective treatment, in addition to surgery and current target therapy, is needed. Recently “cancer stem cell” or “tumor-initiating cell” hypothesis has attracted much attention. The tumor-initiating cells are minor population which can lead tumor cells to become a bulky tumor. Recent studies also indicated a close relationship of tumor-initiating cells with tumor progression and metastasis in HCC and various kinds of cancers. Many stemness genes, including Sox2, Oct4, and Nanog, are involved in these processes. However, it is controversial whether cancer cells isolated by cell surface markers or side populations identified by the efflux of Hoechst33342 dye really represent tumor initiating cells. In this study, we isolated HCC tumor-initiating cell-like cells by functional isolation via ultra-low attachment environment. The tumor-initiating cell-like tumor spheres formed by human HCC cell line Mahlavu displayed enhanced Oct4 expression, colony-forming ability and invasion ability when compared with their adherent counterpart. Furthermore, overexpressing Oct4 increased the sphere-forming ability, colony-forming ability and invasion ability of Mahlavu, while knocking down Oct4 decreased the properties of self-renewal, in vitro tumorigenesis and invasiveness. Oct4 overexpression also enhanced EMT characteristics as shown by increasing Slug expression, while knocking down Slug abolished Oct4-induced augmentation on self-renewal, in vitro tumorigenesis and invasiveness. In conclusion, this study identifies Oct4 as an important factor in tumorigenesis of HCC from functionally isolated tumor spheres and Oct4 enhances HCC tumor formation in a Slug-dependent manner.
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