The Hippo/YAP1 pathway interacts with FGFR1 signaling to maintain stemness in lung cancer.

Abstract

The Hippo pathway plays a critical role in organ size control, tissue homeostasis and tumor genesis through its key transcription regulator Yes-associated protein1 (YAP1), but the mechanism underlying its role in lung cancer is unclear. We hypothesized that YAP1 influences FGFR1 signaling to maintain cancer stem-like cell (CSC) properties in FGFR1-amplified lung cancer. In support of this, our data confirms that expression levels of YAP1 are positively associated with those of FGFR1 in clinical lung carcinoma samples as measured by real-time PCR, western blot, and immunohistochemistry (IHC) staining. Mechanistically, YAP1 up-regulates FGFR1 expression at the level of promoter through the TEAD binding site while bFGF/FGFR1 induces YAP1 expression via large tumor suppressors 1(LATS1). In addition, the absence of YAP1 abolishes self-renewal ability in lung cancer. Furthermore, an orthotropic mouse model highlights the function of YAP1 in the initiation and metastasis of lung cancer. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and FGFR1 expression in lung cancer. Thus, we conclude that YAP1 is a potential therapeutic target for lung cancer. Combined targeting of YAP1 and FGFR1 may provide benefits to patients with FGFR1-amplified lung cancer.

• Authors: Tingting Lu, Ziming Li, Ying Yang, Wenxiang Ji, Yongfeng Yu, Xiaomin Niu, Qingyu Zeng, Weiliang Xia, Shun Lu
• Journal: Cancer letters (Cancer Lett) Vol. 423 Pg. 36-46 (06 01 2018) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 29452146 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Phosphoproteins
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• LATS1 protein, human
• FGFR1 protein, human
• Receptor, Fibroblast Growth Factor, Type 1
• Protein Serine-Threonine Kinases

Topics

• Adaptor Proteins, Signal Transducing (chemistry, genetics, metabolism)
• Animals
• Binding Sites
• Cell Line, Tumor
• Cell Proliferation
• Cell Self Renewal
• Gene Amplification
• Gene Expression Regulation, Neoplastic
• Hippo Signaling Pathway
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• Mice
• Neoplasm Transplantation
• Neoplastic Stem Cells (metabolism)
• Phosphoproteins (chemistry, genetics, metabolism)
• Promoter Regions, Genetic
• Protein Serine-Threonine Kinases (metabolism)
• Receptor, Fibroblast Growth Factor, Type 1 (chemistry, genetics, metabolism)
• Signal Transduction
• Transcription Factors
• Up-Regulation
• YAP-Signaling Proteins