FGF18–FGFR2 signaling triggers the activation of c-Jun–YAP1 axis to promote carcinogenesis in a subgroup of gastric cancer patients and indicates translational potential

• Published in: Oncogene 2020-10, Vol.39 (43), p.6647-6663
• Main Authors: Zhang, Jinglin, Wong, Chi Chun, Leung, Kam Tong, Wu, Feng, Zhou, Yuhang, Tong, Joanna H. M., Chan, Ronald C. K., Li, Hui, Wang, Yifei, Yan, Huan, Liu, Liping, Wu, William K. K., Chan, Michael W. Y., Cheng, Alfred S. L., Yu, Jun, Wong, Nathalie, Lo, Kwok Wai, To, Ka Fai, Kang, Wei
• Format: Article
• Language: English
• Subjects: 14/105; 38/91; 631/67/1504/1829; 631/67/1857; 631/80/86/2368; 64/60; 82/51; 96/21; 96/31; 96/95; Actin; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor activity; Apoptosis; Benzamides - pharmacology; Benzamides - therapeutic use; c-Jun protein; Cancer patients; Carcinogenesis; Carcinogenesis - drug effects; Carcinogenesis - pathology; Care and treatment; Cell Biology; Cell cycle; Cell Line, Tumor; Cellular signal transduction; Cohort Studies; Datasets as Topic; Development and progression; DNA Copy Number Variations; Female; Fibroblast growth factor 18; Fibroblast growth factor receptor 2; Fibroblast growth factor receptors; Fibroblast growth factors; Fibroblast Growth Factors - metabolism; Gastric cancer; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Health aspects; Human Genetics; Humans; Internal Medicine; Kaplan-Meier Estimate; Male; MAP kinase; MAP Kinase Signaling System - drug effects; Medicine; Medicine & Public Health; Mice; Middle Aged; Molecular modelling; Muscle proteins; Neoplasm Staging; Oncology; Piperazines - pharmacology; Piperazines - therapeutic use; Prognosis; Progression-Free Survival; Proto-Oncogene Proteins c-jun - metabolism; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Receptor, Fibroblast Growth Factor, Type 2 - antagonists & inhibitors; Receptor, Fibroblast Growth Factor, Type 2 - genetics; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; Ribonucleic acid; RNA; RNA-Seq; Signal transduction; Stomach cancer; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - mortality; Stomach Neoplasms - pathology; Transcription factors; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Translation; Tumors; Up-Regulation; Verteporfin; Verteporfin - pharmacology; Verteporfin - therapeutic use; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yes-associated protein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01458-x

Fibroblast growth factor receptor type 2 (FGFR2) has emerged as a key oncogenic factor that regulates gastric cancer (GC) progression, but the underlying mechanism of FGF–FGFR2 signaling pathway remains largely unknown. To identify the potential molecular mechanisms of the oncogenic FGFR2 in gastric carcinogenesis and convey a novel therapeutic strategy, we profiled the FGFR alterations and analyzed their clinical associations in TCGA and Hong Kong GC cohorts. We found that FGFR2 overexpression in GC cell lines and primary tumors predicted poor survival and was associated with advanced stages of GC. Functionally, growth abilities and cell cycle progression of GC were inhibited by inactivation of ERK–MAPK signal transduction after FGFR2 knockdown, while apoptosis was promoted. Meanwhile, the first-line anti-cancer drug sensitivity was enhanced. RNA-seq analysis further revealed that YAP1 signaling serves as a significant downstream modulator and mediates the oncogenic signaling of FGFR2. When stimulating FGFR2 by rhFGF18, we observed intensified F-actin, nuclear accumulation of YAP1, and overexpression of YAP1 targets, but these effects were attenuated by either FGFR2 depletion or AZD4547 administration. Additionally, the FGF18–FGFR2 signaling upregulated YAP1 expression through activating c-Jun, an effector of MAPK signaling. In our cohort, 28.94% of GC cases were characterized as FGFR2, c-Jun, and YAP1 co-positive and demonstrated worse clinical outcomes. Remarkably, we also found that co-targeting FGFR2 and YAP1 by AZD4547 and Verteporfin synergistically enhanced the antitumor effects in vitro and in vivo. In conclusion, we have identified the oncogenic FGF–FGFR2 regulates YAP1 signaling in GC. The findings also highlight the translational potential of FGFR2–c-Jun–YAP1 axis, which may serve as a prognostic biomarker and therapeutic target for GC.