Cancer Res Treat.  2017 Jul;49(3):766-777. 10.4143/crt.2016.457.

FGFR4 Arg388 Is Correlated with Poor Survival in Resected Colon Cancer Promoting Epithelial to Mesenchymal Transition

• Cho SH
• Hong CS
• Kim HN
• Shin MH
• Kim KR
• Shim HJ
• Hwang JE
• Bae WK
• Chung IJ

• KMID: 2388322
• DOI: http://doi.org/10.4143/crt.2016.457

Abstract

PURPOSE
Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cancer progression during tumor proliferation, invasion, and metastasis. This study evaluated the prognostic role of FGFR4 polymorphism in patients with resected colon cancer, including the underlying mechanism.
MATERIALS AND METHODS
FGFR4 polymorphism was characterized in patientswho received curative resection for stage III colon cancer. FGFR4-dependent signal pathways involving cell proliferation, invasion, and migration according to genotypes were also evaluated in transfected colon cancer cell lines.
RESULTS
Among a total of 273 patients, the GG of FGFR4 showed significantly better overall survival than the AG or AA, regardless of adjuvant treatment. In the group of AG or AA, combination of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) resulted in better survival than fluorouracil/leucovorin or no adjuvant chemotherapy. However, in GG, there was no difference among treatment regimens. Using multivariate analyses, the Arg388 carriers, together with age, N stage, poor differentiation, absence of a lymphocyte response, and no adjuvant chemotherapy, had a significantly worse OS than patients with the Gly388 allele. In transfected colon cancer cells, overexpression of Arg388 significantly increased cell proliferation and changes in epithelial to mesenchymal transition markers compared with cells overexpressing the Gly388 allele.
CONCLUSION
The Arg388 allele of FGFR4 may be a biomarker and a candidate target for adjuvant treatment of patients with resected colon cancer.

Keyword

Adjuvant chemotherapy; Biomarkers; Colonic neoplasms; FGFR4; Polymorphism; Prognosis

MeSH Terms

Alleles
Biomarkers
Cell Line
Cell Proliferation
Chemotherapy, Adjuvant
Colon*
Colonic Neoplasms*
Fluorouracil
Genotype
Humans
Leucovorin
Lymphocytes
Multivariate Analysis
Neoplasm Metastasis
Prognosis
Receptor, Fibroblast Growth Factor, Type 4
Signal Transduction
Biomarkers
Fluorouracil
Leucovorin
Receptor, Fibroblast Growth Factor, Type 4

Figure

• 

  Fig. 1. (A, B) Survival outcomes according to FGFR4 genotype.

• 

  Fig. 2. (A-D) Survival outcomes after adjuvant chemotherapy according to FGFR4 genotype. FGFR4, fibroblast growth factor receptor 4; FL, fluorouracil and leucovorin; FOLFOX, combination of folinic acid, fluorouracil, and oxaliplatin.

• 

  Fig. 3. Fibroblast growth factor receptor 4 (FGFR4) dependent downstream signal and cell proliferation. (A) The expression of downstream signals of FGFR4, including pSTAT3, pAKT, and pERK, were increased more in overexpressed Arg388 than in overexpressed Gly388 cells. (B) However, the growth rate of overexpressed Arg388 cells was similar to that of overexpressed Gly388 cells. *p < 0.01 compared with vector control.

• 

  Fig. 4. Effect of fibroblast growth factor receptor 4 (FGFR4) genoypte on epithelial-mesenchymal transition (EMT) signals, invasion, and migraion. (A) The Arg388 allele of FGFR4 induces the EMT markers including, vimentin and Twist, while it decreased E-cadherin. (B) When compared with control cells, the Gly388- and Arg388-transfected cells showed significantly more cell invasion. In addition, Arg388-transfected cells were more invasive than Gly388-transfected cells. (C) Similar results were also seen using a wound healing assay. *p < 0.01.

Reference

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