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

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

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

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 language	English
Article number	3812
Journal	Cancers
Volume	13
Issue number	15
DOIs	https://doi.org/10.3390/cancers13153812
Publication status	Published - Aug 1 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

EMT markers
HCC
IGF-1R
Sorafenib resistance
YAP

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.3390/cancers13153812

Cite this

Ngo, M. H. T., Peng, S. W., Kuo, Y. C., Lin, C. Y., Wu, M. H., Chuang, C. H., Kao, C. X., Jeng, H. Y., Lin, G. W., Ling, T. Y., Chang, T. S., & Huang, Y. H. (2021). 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, 13(15), Article 3812. https://doi.org/10.3390/cancers13153812

@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",

}

TY - JOUR

T1 - A yes-associated protein (YAP) and insulin-like growth factor 1 receptor (IGF-1R) signaling loop is involved in Sorafenib resistance in hepatocellular carcinoma

AU - Ngo, Mai Huong T.

AU - Peng, Sue Wei

AU - Kuo, Yung Che

AU - Lin, Chun Yen

AU - Wu, Ming Heng

AU - Chuang, Chia Hsien

AU - Kao, Cheng Xiang

AU - Jeng, Han Yin

AU - Lin, Gee Way

AU - Ling, Thai Yen

AU - Chang, Te Sheng

AU - Huang, Yen Hua

N1 - 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: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/8/1

Y1 - 2021/8/1

N2 - 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.

AB - 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.

KW - EMT markers

KW - HCC

KW - IGF-1R

KW - Sorafenib resistance

KW - YAP

UR - https://www.scopus.com/pages/publications/85111430059

UR - https://www.scopus.com/pages/publications/85111430059#tab=citedBy

U2 - 10.3390/cancers13153812

DO - 10.3390/cancers13153812

M3 - Article

AN - SCOPUS:85111430059

SN - 2072-6694

VL - 13

JO - Cancers

JF - Cancers

IS - 15

M1 - 3812

ER -

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

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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