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*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

10 Scopus citations

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.

Original languageEnglish
Article number3812
JournalCancers
Volume13
Issue number15
DOIs
StatePublished - 01 08 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • EMT markers
  • HCC
  • IGF-1R
  • Sorafenib resistance
  • YAP

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