YAP promotes sorafenib resistance in hepatocellular carcinoma by upregulating survivin
Ting Sun1, Wenhao Mao2, Hui Peng2
1Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. sunting@zzu.edu.cn.
Background:
Sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), but its use is hampered by secondary drug resistance. Yes-associated protein (YAP) is a downstream effector of the Hippo signaling pathway, which is crucial for liver tumorigenesis. As yet, however, the mechanism underlying sorafenib resistance and the role of YAP therein is not fully understood and needs to be explored further.
Methods:
Western blotting, flow cytometry and CCK-8 assays were used to assess the role of YAP in HCC sorafenib resistance. Next, qRT-PCR and Western blotting were performed to identify survivin as a YAP downstream effector, and rescue experiments were performed to confirm that YAP induces sorafenib resistance via survivin. Additionally, Western blotting, flow cytometry and in vivo xenograft models were used to evaluate the effect of verteporfin in combination with sorafenib on HCC.
Results:
We found that sorafenib enhances YAP nuclear accumulation and activation, thereby promoting sorafenib resistance through inhibiting apoptosis in HCC cells. In addition, we found that survivin acts as a downstream mediator of YAP to resist sorafenib-induced apoptosis. Pharmacological inhibition of YAP by verteporfin increased the sensitivity of HCC cells to sorafenib and reversed sorafenib resistance. Moreover, verteporfin in combination with sorafenib significantly suppressed in vivo HCC tumor growth.
Conclusions:
Our data indicate that YAP promotes sorafenib resistance through upregulation of survivin expression in HCC cells. Targeting YAP may be a therapeutic strategy to improve the antitumor effects of sorafenib in HCC.
Insights
Yes-associated protein (YAP) promotes sorafenib resistance in hepatocellular carcinoma (HCC) by upregulating survivin. Targeting YAP with verteporfin enhances sorafenib
Area of Science:
- Oncology
- Molecular Biology
- Hepatology
Background:
- Sorafenib is a first-line treatment for advanced hepatocellular carcinoma (HCC).
- Secondary drug resistance limits sorafenib efficacy in HCC.
- The role of Yes-associated protein (YAP) in sorafenib resistance is not fully understood.
Purpose of the Study:
- To investigate the mechanism of sorafenib resistance in HCC.
- To explore the role of YAP in mediating sorafenib resistance.
- To evaluate YAP inhibition as a therapeutic strategy for HCC.
Main Methods:
- Western blotting, flow cytometry, and CCK-8 assays were used.
- Quantitative reverse transcription polymerase chain reaction (qRT-PCR) identified survivin as a YAP effector.
- In vivo xenograft models assessed combined sorafenib and verteporfin treatment.
Main Results:
- Sorafenib treatment increased YAP nuclear accumulation and activation, leading to apoptosis inhibition and resistance.
- YAP promotes sorafenib resistance by upregulating survivin expression.
- Verteporfin, a YAP inhibitor, sensitized HCC cells to sorafenib and suppressed tumor growth in vivo.
Conclusions:
- YAP drives sorafenib resistance in HCC via survivin upregulation.
- Targeting YAP represents a potential therapeutic strategy to overcome sorafenib resistance in HCC.
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