The FGFR4-388arg Variant Promotes Lung Cancer Progression by N-Cadherin Induction

Overview

Journal Sci Rep

Specialty Science

Date 2018 Feb 7

PMID 29402970

Citations 19

Authors

Alvaro Quintanal-Villalonga

Laura Ojeda-Marquez

Angela Marrugal

Patricia Yague

Santiago Ponce-Aix

Ana Salinas

Amancio Carnero

Irene Ferrer

Sonia Molina-Pinelo

Luis Paz-Ares

Affiliations

Soon will be listed here.

Abstract

The FGFR4-388Arg variant has been related to poor prognosis in several types of cancer, including lung cancer. The mechanism underlying this association has not been addressed in detail in patients with this pathology. Here, we report that this FGFR4 variant induces MAPK and STAT3 activation and causes pro-oncogenic effects in NSCLC in vitro and in vivo. This variant induces the expression of EMT-related genes, such as N-cadherin, vimentin, Snail1 and Twist1. Indeed, the induction of N-cadherin protein expression by this variant is essential for its pro-tumorigenic role. The presence of the FGFR4-388Arg variant correlates with higher N-cadherin expression levels in clinical NSCLC samples and with poorer outcome in patients with FGFR expression. These results support the prognostic role of this FGFR variant in lung cancer and show that these effects may be mediated by the induction of N-cadherin expression and an EMT phenotype.

Citing Articles

Synthesis of coumarin derivatives and investigation of their inhibitory effects on lung cancer cell motility.

Zhou R, Yu Y, Kim H, Ha H Sci Rep. 2022; 12(1):21635.

PMID: 36517633 PMC: 9751305. DOI: 10.1038/s41598-022-26212-z.

Comprehensive analysis of lncRNA-mRNAs co-expression network identifies potential lncRNA biomarkers in cutaneous squamous cell carcinoma.

Hu Y, Li R, Chen H, Chen L, Zhou X, Liu L BMC Genomics. 2022; 23(1):274.

PMID: 35392800 PMC: 8988344. DOI: 10.1186/s12864-022-08481-0.

New developments in the biology of fibroblast growth factors.

Ornitz D, Itoh N WIREs Mech Dis. 2022; 14(4):e1549.

PMID: 35142107 PMC: 10115509. DOI: 10.1002/wsbm.1549.

Fibroblast growth factor receptor 4 as a prognostic indicator in triple-negative breast cancer.

Wei W, Cao S, Liu J, Wang Y, Song Q, A L Transl Cancer Res. 2022; 9(11):6881-6888.

PMID: 35117296 PMC: 8797274. DOI: 10.21037/tcr-20-1756.

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance.

Szymczyk J, Sluzalska K, Materla I, Opalinski L, Otlewski J, Zakrzewska M Cancers (Basel). 2021; 13(22).

PMID: 34830951 PMC: 8616288. DOI: 10.3390/cancers13225796.

References

Nitta T, Mitsuhashi T, Hatanaka Y, Miyamoto M, Oba K, Tsuchikawa T . Prognostic significance of epithelial-mesenchymal transition-related markers in extrahepatic cholangiocarcinoma: comprehensive immunohistochemical study using a tissue microarray. Br J Cancer. 2014; 111(7):1363-72. PMC: 4183847. DOI: 10.1038/bjc.2014.415. View

Morimoto Y, Ozaki T, Ouchida M, Umehara N, Ohata N, Yoshida A . Single nucleotide polymorphism in fibroblast growth factor receptor 4 at codon 388 is associated with prognosis in high-grade soft tissue sarcoma. Cancer. 2003; 98(10):2245-50. DOI: 10.1002/cncr.11778. View

Zhang C, Guo F, Xu G, Ma J, Shao F . STAT3 cooperates with Twist to mediate epithelial-mesenchymal transition in human hepatocellular carcinoma cells. Oncol Rep. 2015; 33(4):1872-82. DOI: 10.3892/or.2015.3783. View

Quintanal-Villalonga A, Carranza-Carranza A, Melendez R, Ferrer I, Molina-Pinelo S, Paz-Ares L . Prognostic Role of the FGFR4-388Arg Variant in Lung Squamous-Cell Carcinoma Patients With Lymph Node Involvement. Clin Lung Cancer. 2017; 18(6):667-674.e1. DOI: 10.1016/j.cllc.2017.05.008. View

Moore H, Kelly A, Jewell S, McShane L, Clark D, Greenspan R . Biospecimen reporting for improved study quality (BRISQ). Cancer Cytopathol. 2011; 119(2):92-101. DOI: 10.1002/cncy.20147. View

Sasaki H, Okuda K, Kawano O, Yukiue H, Yano M, Fujii Y . Fibroblast growth factor receptor 4 mutation and polymorphism in Japanese lung cancer. Oncol Rep. 2008; 20(5):1125-30. View

Cho S, Hong C, Kim H, Shin M, Kim K, Shim H . Arg388 Is Correlated with Poor Survival in Resected Colon Cancer Promoting Epithelial to Mesenchymal Transition. Cancer Res Treat. 2016; 49(3):766-777. PMC: 5512371. DOI: 10.4143/crt.2016.457. View

Matakidou A, el Galta R, Rudd M, Webb E, Bridle H, Eisen T . Further observations on the relationship between the FGFR4 Gly388Arg polymorphism and lung cancer prognosis. Br J Cancer. 2007; 96(12):1904-7. PMC: 2359960. DOI: 10.1038/sj.bjc.6603816. View

Araki K, Shimura T, Suzuki H, Tsutsumi S, Wada W, Yajima T . E/N-cadherin switch mediates cancer progression via TGF-β-induced epithelial-to-mesenchymal transition in extrahepatic cholangiocarcinoma. Br J Cancer. 2011; 105(12):1885-93. PMC: 3251878. DOI: 10.1038/bjc.2011.452. View

10.

Hulit J, Suyama K, Chung S, Keren R, Agiostratidou G, Shan W . N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation. Cancer Res. 2007; 67(7):3106-16. DOI: 10.1158/0008-5472.CAN-06-3401. View

11.

Zhang J, Shemezis J, McQuinn E, Wang J, Sverdlov M, Chenn A . AKT activation by N-cadherin regulates beta-catenin signaling and neuronal differentiation during cortical development. Neural Dev. 2013; 8:7. PMC: 3658902. DOI: 10.1186/1749-8104-8-7. View

12.

Lafitte M, Moranvillier I, Garcia S, Peuchant E, Iovanna J, Rousseau B . FGFR3 has tumor suppressor properties in cells with epithelial phenotype. Mol Cancer. 2013; 12:83. PMC: 3750311. DOI: 10.1186/1476-4598-12-83. View

13.

Altman D, McShane L, Sauerbrei W, Taube S . Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): explanation and elaboration. PLoS Med. 2012; 9(5):e1001216. PMC: 3362085. DOI: 10.1371/journal.pmed.1001216. View

14.

Sugiyama N, Varjosalo M, Meller P, Lohi J, Chan K, Zhou Z . FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex. Proc Natl Acad Sci U S A. 2010; 107(36):15786-91. PMC: 2936587. DOI: 10.1073/pnas.0914459107. View

15.

Huang H, Feng H, Qiao H, Ren Z, Zhu G . The prognostic significance of fibroblast growth factor receptor 4 in non-small-cell lung cancer. Onco Targets Ther. 2015; 8:1157-64. PMC: 4447177. DOI: 10.2147/OTT.S81659. View

16.

Herbst R, Heymach J, Lippman S . Lung cancer. N Engl J Med. 2008; 359(13):1367-80. PMC: 10662965. DOI: 10.1056/NEJMra0802714. View

17.

Bange J, Prechtl D, Cheburkin Y, Specht K, Harbeck N, Schmitt M . Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. Cancer Res. 2002; 62(3):840-7. View

18.

Yu W, Feng S, Dakhova O, Creighton C, Cai Y, Wang J . FGFR-4 Arg³⁸⁸ enhances prostate cancer progression via extracellular signal-related kinase and serum response factor signaling. Clin Cancer Res. 2011; 17(13):4355-66. PMC: 3131485. DOI: 10.1158/1078-0432.CCR-10-2858. View

19.

Tran N, Adams D, Vaillancourt R, Heimark R . Signal transduction from N-cadherin increases Bcl-2. Regulation of the phosphatidylinositol 3-kinase/Akt pathway by homophilic adhesion and actin cytoskeletal organization. J Biol Chem. 2002; 277(36):32905-14. DOI: 10.1074/jbc.M200300200. View

20.

Lu M, Tian H, Yue W, Li L, Li S, Qi L . TFIIB-related factor 2 over expression is a prognosis marker for early-stage non-small cell lung cancer correlated with tumor angiogenesis. PLoS One. 2014; 9(2):e88032. PMC: 3921153. DOI: 10.1371/journal.pone.0088032. View