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© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Simple Summary

Sorafenib 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.

Abstract

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.

Details

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
Author
Ngo, Mai-Huong T 1 ; Sue-Wei, Peng 2 ; Yung-Che Kuo 3   VIAFID ORCID Logo  ; Chun-Yen, Lin 4   VIAFID ORCID Logo  ; Ming-Heng, Wu 5   VIAFID ORCID Logo  ; Chia-Hsien Chuang 4 ; Cheng-Xiang, Kao 6   VIAFID ORCID Logo  ; Han-Yin, Jeng 3   VIAFID ORCID Logo  ; Gee-Way, Lin 7   VIAFID ORCID Logo  ; Thai-Yen, Ling 8 ; Te-Sheng, Chang 9   VIAFID ORCID Logo  ; Yen-Hua, Huang 10   VIAFID ORCID Logo 

 International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; [email protected] (M.-H.T.N.); [email protected] (C.-X.K.); Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; [email protected] (S.-W.P.); [email protected] (G.-W.L.) 
 Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; [email protected] (S.-W.P.); [email protected] (G.-W.L.); TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; [email protected] (Y.-C.K.); [email protected] (H.-Y.J.) 
 TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; [email protected] (Y.-C.K.); [email protected] (H.-Y.J.) 
 Institute of Information Science, Academia Sinica, Taipei 11529, Taiwan; [email protected] (C.-Y.L.); [email protected] (C.-H.C.) 
 The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; [email protected]; Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan 
 International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; [email protected] (M.-H.T.N.); [email protected] (C.-X.K.) 
 Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; [email protected] (S.-W.P.); [email protected] (G.-W.L.); Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA 
 Department and Graduate Institute of Pharmacology, National Taiwan University, Taipei 100, Taiwan; [email protected] 
 School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33382, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan 
10  International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; [email protected] (M.-H.T.N.); [email protected] (C.-X.K.); Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; [email protected] (S.-W.P.); [email protected] (G.-W.L.); TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; [email protected] (Y.-C.K.); [email protected] (H.-Y.J.); The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; [email protected]; International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan; Comprehensive Cancer Center of Taipei Medical University, Taipei 11031, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan 
First page
3812
Publication year
2021
Publication date
2021
Publisher
MDPI AG
e-ISSN
20726694
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2558726461
Copyright
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.