| 摘要: | 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 |
