A Yes-Associated Protein (YAP) and Insulin-Like Growth Factor 1 Receptor (IGF-1R) Signaling Loop Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma

Mai-Huong T Ngo; Sue-Wei Peng; Yung-Che Kuo; Chun-Yen Lin; Ming-Heng Wu; Chia-Hsien Chuang; Cheng-Xiang Kao; Han-Yin Jeng; Gee-Way Lin; Thai-Yen Ling; Te-Sheng Chang; Yen-Hua Huang

doi:10.3390/cancers13153812

A Yes-Associated Protein (YAP) and Insulin-Like Growth Factor 1 Receptor (IGF-1R) Signaling Loop Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma

Cancers (Basel). 2021 Jul 29;13(15):3812. doi: 10.3390/cancers13153812.

Authors

Mai-Huong T Ngo^{1

2}, Sue-Wei Peng^{2

3}, Yung-Che Kuo³, Chun-Yen Lin⁴, Ming-Heng Wu^{5

6

7}, Chia-Hsien Chuang⁴, Cheng-Xiang Kao¹, Han-Yin Jeng³, Gee-Way Lin^{2

8}, Thai-Yen Ling⁹, Te-Sheng Chang^{10

11}, Yen-Hua Huang^{1

2

3

5

7

12

13

14

15}

Affiliations

¹ International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
² Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
³ TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan.
⁴ Institute of Information Science, Academia Sinica, Taipei 11529, Taiwan.
⁵ The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
⁶ Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
⁷ International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
⁸ Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁹ Department and Graduate Institute of Pharmacology, National Taiwan University, Taipei 100, Taiwan.
¹⁰ School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33382, Taiwan.
¹¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
¹² Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
¹³ Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan.
¹⁴ Comprehensive Cancer Center of Taipei Medical University, Taipei 11031, Taiwan.
¹⁵ TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.

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.

Keywords: EMT markers; HCC; IGF-1R; YAP; sorafenib resistance.

Abstract

Grants and funding