Taipei Medical University Institutional Repository:Item 987654321/61343
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    Title: A Yes-Associated Protein (YAP) and Insulin-Like Growth Factor 1 Receptor (IGF-1R) Signaling Loop Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma
    Authors: HUONG, NGO THI MAI
    Contributors: 細胞治療與再生醫學國際博士學位學程
    黃彥華
    Keywords: YAP;IGF-1R;HCC;Sorafenib resistance
    Date: 2021-07-30
    Issue Date: 2022-01-27 18:39:06 (UTC+8)
    Abstract: Background:
    The critical role of Yes-associated protein (YAP) in cancer resistance to therapies such as radiotherapy, chemotherapy and targeted therapy has been identified. Insulin like growth factor 1 receptor (IGF-1R) is closely linked to cancer stemness and sorafenib resistance properties in hepatocellular carcinoma (HCC). Nevertheless, the role and mechanism of YAP and IGF-1R involved in sorafenib resistance in HCC is still unclear.
    Method:
    The BIOSTORM-HCC, TCGA, GEPIA, and ONCOMINE databases were used to identify the role of YAP in cancers and sorafenib resistance in patients. The sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R cells) were used to confirm the role of YAP and illustrate the correlation between YAP and IGF-1R in HCC sorafenib resistance. An in vivo model used sorafenib treatment of xenografts of HepG2215_R cells in SCID mice. The Western blotting, qPCR, IHC, ICC, and knockdown genes were used as well as the cell viability assay.
    Results:
    We identified that YAP played an important role in HCC sorafenib resistance. Inhibition of YAP by a specific inhibitor (verteprofin –VP) reduced cell viability of sorafenib-resistant HCC cells to sorafenib. Besides, the synergistic effect of VP and sorafenib was shown in both sorafenib-resistant cell lines, HepG2215_R and Hep3B-R. Noticeably, the positive correlation of YAP with IGF-1R and EMT markers in tissues was demonstrated in patients with HCC and sorafenib failure, TCGA-HCC patients from the GEPIA service website, HCC cell lines, and HepG2215_R-derived xenograft tumors. Blocking YAP by specific inhibitor (Verteporfin) or YAP shRNA downregulated the expression of IGF-1R signaling and EMT markers. In contrast, knockdown of IGF1R reduced the level of YAP. Mechanically, activation of the IGF-1R/PI3K/mTOR axis enhanced nuclear translocation of YAP in HCC cells.
    Conclusion:
    1. YAP played a central role in sorafenib resistance to HCC. The high expression of YAP positively correlated with the high expression of IGF-1R and EMT markers.
    2. Mechanically, the IGF/IGF-1R/PI3K/mTOR axis activation induced the nuclear translocation of YAP in the HCC cells.
    3. Targeting the YAP-IGF-1R signaling loop might be an effective strategy for treating sorafenib-resistant HCC
    Description: 博士
    指導教授:黃彥華
    委員:楊慕華
    委員:林仲彥
    委員:吳明恒
    委員:張德生
    Data Type: thesis
    Appears in Collections:[International Ph.D. Program for Cell Therapy and Regeneration Medicine] Dissertations/Theses

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