@article{1c038a5d5188469e80c83646079eb5db,
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",
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 na{\"i}ve 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, Sorafenib resistance, YAP",
author = "Ngo, {Mai Huong T.} and Peng, {Sue Wei} and Kuo, {Yung Che} and Lin, {Chun Yen} and Wu, {Ming Heng} and Chuang, {Chia Hsien} and Kao, {Cheng Xiang} and Jeng, {Han Yin} and Lin, {Gee Way} and Ling, {Thai Yen} and Chang, {Te Sheng} and Huang, {Yen Hua}",
note = "Funding Information: This study is supported by research grants from Ministry of Science and Technology, Taiwan (Grant numbers: MOST 107-2321-B-038-002, MOST 107-2314-B-038-061, MOST 108-2314-B-038-006, MOST 108-2321-B-038-003, MOST 109-2314-B-038-135, MOST 109-2321-B-038-003, MOST 110-2314-B-038-034, and MOST 110-2314-B-038-132 to Y.-H.H., and MOST 109-2314-B-182-025 and MOST 110-2314-B-182-043 to T.S.C.); Taipei Medical University (Grant number: TMU109-AE1-B02). The authors gratefully acknowledge Chau-Ting Yeh (Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan) and Feng-Che Kuan (Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan) for their assistance in obtaining clinical specimens. The authors also gratefully acknowledge English editing service from Anita Infante. The results published here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga (accessed on 4 January 2021). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2021",
month = aug,
day = "1",
doi = "10.3390/cancers13153812",
language = "English",
volume = "13",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "15",
}
