Abstract
Simple SummarySorafenib is the first approved targeted therapy for the treatment of advanced hepatocellular carcinoma (HCC). However, HCC resistance to sorafenib has greatly reduced its utility. Yes-associated protein (YAP) is overexpressed in cancers, including HCC. We observed a positive correlation in expression levels of insulin-like growth factor-1 receptor (IGF-1R) and YAP in sorafenib-resistant HCCs. Therefore, the interplay between YAP and IGF-1R signaling and its role in HCC sorafenib resistance will be examined in this study. We found that the YAP-IGF-1R signaling loop was involved in sorafenib resistance in HCC. IGF-1/2 treatment enhanced YAP nuclear translocation. In turn, YAP regulated expression of IGF-1R and epithelial mesenchymal transition (EMT)-related proteins in vitro. Targeting YAP with a specific inhibitor, verteporfin (VP), significantly increased HCC cell sensitivity to sorafenib, with a potential synergistic combination index. These findings highlight the significance of the YAP-IGF-1R signaling loop as a potential therapeutic target for HCC, especially in terms of overcoming sorafenib resistance.The role of a YAP-IGF-1R signaling loop in HCC resistance to sorafenib remains unknown. Method: Sorafenib-resistant cells were generated by treating naïve cells (HepG2215 and Hep3B) with sorafenib. Different cancer cell lines from databases were analyzed through the ONCOMINE web server. BIOSTORM–LIHC patient tissues (46 nonresponders and 21 responders to sorafenib) were used to compare YAP mRNA levels. The HepG2215_R-derived xenograft in SCID mice was used as an in vivo model. HCC tissues from a patient with sorafenib failure were used to examine differences in YAP and IGF-R signaling. Results: Positive associations exist among the levels of YAP, IGF-1R, and EMT markers in HCC tissues and the levels of these proteins increased with sorafenib failure, with a trend of tumor-margin distribution in vivo. Blocking YAP downregulated IGF-1R signaling-related proteins, while IGF-1/2 treatment enhanced the nuclear translocation of YAP in HCC cells through PI3K-mTOR regulation. The combination of YAP-specific inhibitor verteporfin (VP) and sorafenib effectively decreased cell viability in a synergistic manner, evidenced by the combination index (CI). Conclusion: A YAP-IGF-1R signaling loop may play a role in HCC sorafenib resistance and could provide novel potential targets for combination therapy with sorafenib to overcome drug resistance in HCC.
Highlights
The number of new liver cancer cases ranked seventh among all cancers, while deaths attributable to liver cancer ranked second, accounting for 8.2% of all cancer deaths in 2018 [1]
YAP expression levels were significantly higher in tumors from Hepatocellular carcinoma (HCC) patients who did not respond to sorafenib than that of in HCC patients who responded to sorafenib
We found significantly higher levels of YAP in both of the TCGA-liver cancer cell lines (Figure 1A) and in the tissues from HCC patients who did not respond to sorafenib (Figure 1B)
Summary
The number of new liver cancer cases ranked seventh among all cancers, while deaths attributable to liver cancer ranked second, accounting for 8.2% of all cancer deaths in 2018 [1]. The gap between the incidence and mortality rates of liver cancer is due to the aggressiveness of the disease and the lack of effective treatments. Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers. Drug resistance is the major reason for the unsatisfactory response to targeted therapies, including sorafenib and lenvatinib, in the treatment of advanced HCC. In the Phase 3 SHARP clinical trial and the REFLECT clinical trial, disease progression in the sorafenib treatment group was 27% and. The low response rate to sorafenib in HCC treatment is a current clinical challenge
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