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

Quintanal-Villalonga, Àlvaro; Ojeda-Márquez, Laura; Marrugal, Ángela; Yagüe, Patricia; Ponce-Aix, Santiago; Salinas, Ana; Carnero, Amancio; Ferrer, Irene; Molina-Pinelo, Sonia; Paz‐Ares, Luis

doi:10.1038/s41598-018-20570-3

Cited by 28 publications

(32 citation statements)

References 40 publications

(45 reference statements)

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“…Tumoural area from the samples was identified by pathologists following haematoxylin-eosin staining [ 19 , 32 ]. Tissue microarrays (TMAs) were constructed from the preselected tumoural area from every biopsy.…”

Section: Methodsmentioning

confidence: 99%

MAP17 predicts sensitivity to platinum-based therapy, EGFR inhibitors and the proteasome inhibitor bortezomib in lung adenocarcinoma

Ferrer

Quintanal-Villalonga

Molina-Pinelo

et al. 2018

J Exp Clin Cancer Res

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BackgroundThe high incidence and mortality of lung tumours is a major health problem. Therefore, the identification both of biomarkers predicting efficacy for therapies in use and of novel efficacious therapeutic agents is crucial to increase patient survival. MAP17 (PDZK1IP1) is a small membrane-bound protein whose upregulation is reported as a common feature in tumours from diverse histological origins. Furthermore, MAP17 is correlated with tumour progression.MethodsWe assessed the expression of MAP17 in preclinical models, including cell lines and patient-derived xenografts (PDXs), assessing its correlation with sensitivity to different standard-of-care drugs in lung adenocarcinoma, as well as novel drugs. At the clinical level, we subsequently correlated MAP17 expression in human tumours with patient response to these therapies.ResultsWe show that MAP17 expression is induced during lung tumourigenesis, particularly in lung adenocarcinomas, and provide in vitro and in vivo evidence that MAP17 levels predict sensitivity to therapies currently under clinical use in adenocarcinoma tumours, including cisplatin, carboplatin and EGFR inhibitors. In addition, we show that MAP17 expression predicts proteasome inhibitor efficacy in this context and that bortezomib, an FDA-approved drug, may be a novel therapeutic approach for MAP17-overexpressing lung adenocarcinomas.ConclusionsOur results indicate a potential prognostic role for MAP17 in lung tumours, with particular relevance in lung adenocarcinomas, and highlight the predictive pot0065ntial of this membrane-associated protein for platinum-based therapy and EGFR inhibitor efficacy. Furthermore, we propose bortezomib treatment as a novel and efficacious therapy for lung adenocarcinomas exhibiting high MAP17 expression.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0871-7) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

MAP17 predicts sensitivity to platinum-based therapy, EGFR inhibitors and the proteasome inhibitor bortezomib in lung adenocarcinoma

Ferrer

Quintanal-Villalonga

Molina-Pinelo

et al. 2018

J Exp Clin Cancer Res

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“…In addition, N-cadherin induces cell survival, migration, and invasion by modulating intracellular signaling molecules. As shown by Quintanal-Villalonga et al ( 35 ), the FGFR4-388arg variant promotes lung cancer progression through N-cadherin induction. Reducing miR-22 expression promotes epithelial-mesenchymal transition (EMT) and invasion of lung cancer cells by elevating Snail expression ( 36 ).…”

Section: Discussionmentioning

confidence: 83%

Silencing of BRF2 inhibits the growth and metastasis of lung cancer cells

Bian

Pan

2020

Mol Med Rep

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Transcription factor II B (TFIIB)-related factor 2 (BRF2) is involved in the development of cancer, but its role in lung cancer is underreported. The present study aimed to explore the role of BRF2 in the regulation of lung cancer cells. Immunofluorescence staining and immunohistochemistry were performed to detect BRF2 protein expression in human lung cancer cells and tissues. Following cell transfection with small interfering RNA for silencing BRF2, the cell proliferation was examined by Cell Counting Kit-8 and MTT assays. Cell apoptosis, migration and invasion were determined by flow cytometry, wound-healing and Transwell assay. The expression levels of Akt, phosphorylated (p)-Akt, Bax, E-cadherin, Bcl-2, N-cadherin, Snail and epidermal growth factor receptor (EGFR) in human lung cancer A549 cells were detected by western blotting. The results demonstrated that BRF2 expression was increased in human lung cancer cells and tissues, and that silencing of BRF2 promoted cell apoptosis but inhibited cell proliferation and migration. The protein expression levels of Akt, E-cadherin, p-Akt, Bcl-2, N-cadherin, Snail and EGFR in A549 cells were inhibited by silencing of BRF2, while expression levels of Bax and E-cadherin were increased by silencing BRF2. In conclusion, BRF2 demonstrates high expression in lung cancer and silencing of BRF2 inhibits the growth and metastasis of lung cancer cells. The current findings provide a novel approach for the treatment of lung cancer.

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“…This study consisted of cases comprising 9 different entities of cancer showing a statistically significant association between the Arg388Arg genotype and nodal involvement (odds ratio = 1.33, 95% confidence interval 1.01-1.74) indicating a relevance for disease progression. Also, Ipenburg et al [36] carried out a thorough meta-analysis in 2016, where they evaluated the impact of FGFR4 Gly388 SNP in 8 studies comprising 1159 patients with high rates of FGFR4 Gly388Arg polymorphisms (32.5%-54.2%) and FGFR4 protein overexpression (16%-35%) correlating with worse overall and disease-free survival[37].…”

Section: Discussionmentioning

confidence: 99%

“…In aggregate, this supports the implication of FGFR signaling in several oncogenic behaviours, including proliferation, survival, migration, invasion and angiogenesis. Recently, Quintanal-Villalonga, Quintanal-Villalonga et al [37] reported on the pro-oncogenic role of the FGFR4-388Arg variant in lung cancer; this variant correlated with greater STAT3 and MAPK activation and higher expression of EMT markers in vitro . This pro-tumorigenic role was mediated by the induction of N-cadherin expression, which required STAT3 overactivation[37].…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor receptor 4 single nucleotide polymorphism Gly388Arg in head and neck carcinomas

Wimmer

Ihrler

Gires

et al. 2019

WJCO

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BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is considered to be a progressive disease resulting from alterations in multiple genes regulating cell proliferation and differentiation like receptor tyrosine kinases (RTKs) and members of the fibroblast growth factor receptors (FGFR)-family. Single-nucleotide polymorphism (SNP) Arg388 of the FGFR4 is associated with a reduced overall survival in patients with cancers of various types. We speculate that FGFR4 expression and SNP is associated with worse survival in patients with HSNCC. AIM To investigate the potential clinical significance of FGFR4 Arg388 in the context of tumors arising in HNSCC, a comprehensive analysis of FGFR4 receptor expression and genotype in tumor tissues and correlated results with patients’ clinical data in a large cohort of patients with HNSCC was conducted. METHODS Surgical specimens from 284 patients with HNSCC were retrieved from the Institute of Pathology at the Ludwig-Maximilian-University in Germany. Specimens were analyzed using immunohistochemistry and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The expression of FGFR4 was analyzed in 284 surgical specimens of HNSCC using immunohistochemstry. FGFR4 polymorphism was detected by PCR-RFLP. Patients’ clinical data with a minimum follow-up of 5 years were statistically evaluated with a special emphasis on survival analysis employing Kaplan-Meier estimator and Cox regression analysis. RESULTS Concerning the invasive tumor areas the intensity of the FGFR4 expression was evaluated in a four-grade system: no expression, low expression, intermediate and high expression. FGFR4 expression was scored as “high” (+++) in 74 (26%), “intermediate” (++) in 103 (36.3%), and “low” (+) in 107 (36.7%) cases. Analyzing the FGFR4 mutation it was found in 96 tumors (33.8%), 84 of them (29.6%) having a heterozygous and 12 (4.2%) homozygous mutated Arg388 allele. The overall frequency concerning the mutant alleles demonstrated 65% vs 34% mutated alleles in general. FGFR4 Arg388 was significantly associated with advanced tumor stage ( P < 0.004), local metastasis ( P < 0.0001) and reduced disease-free survival ( P < 0.01). Furthermore, increased expression of FGFR4 correlated significantly with worse overall survival ( P < 0.003). CONCLUSION In conclusion, the FGFR4 Arg388 genotype and protein expression of FGFR4 impacts tumor progression in patients with HNSCC and may present a useful target within a multimodal therapeutic intervention.

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

Cited by 28 publications

References 40 publications

MAP17 predicts sensitivity to platinum-based therapy, EGFR inhibitors and the proteasome inhibitor bortezomib in lung adenocarcinoma

MAP17 predicts sensitivity to platinum-based therapy, EGFR inhibitors and the proteasome inhibitor bortezomib in lung adenocarcinoma

Silencing of BRF2 inhibits the growth and metastasis of lung cancer cells

Fibroblast growth factor receptor 4 single nucleotide polymorphism Gly388Arg in head and neck carcinomas

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