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Fibroblast growth factor receptor 1 and 3 expression is associated with regulatory PI3K/AKT kinase activity, as well as invasion and prognosis, in human laryngeal cancer

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Abstract

Purpose

Aberrant fibroblast growth factor receptor (FGFR) expression is thought to contribute to the development of many types of cancer. As yet, however, their impact on the course and prognosis of head and neck cancer remains to be determined. Here, we aimed to investigate the effects of expression of the FGFR family members FGFR1 and FGFR3, as well as their downstream PI3K/AKT signal-regulated kinases, on the aggressiveness and prognosis of laryngeal cancer.

Methods

In total 137 surgically removed squamous cell laryngeal cancer (SCLC) and 100 matched non-cancerous laryngeal mucosa (NCLM) samples were assessed for mRNA expression using quantitative real-time PCR. The corresponding proteins were analyzed by Western blotting. SLUG expression was assessed by immunohistochemistry. The expression data were subsequently related to tumor front grading (TFG), local/nodal recurrences, prognosis and overall survival.

Results

The FGFR1, FGFR3 and PI3K/AKT kinase mRNA and protein levels were found to be significantly higher in the SCLC than the NCLM samples (p < 0.05). A high FGFR1 mRNA/protein expression level was found to be associated with an increased invasion rate, according to TFG scale and SLUG level, a high local/nodal recurrence rate and a poor prognosis (p < 0.05). Similarly, we found that a high FGFR3 mRNA/protein expression level was associated with a shorter survival time (p < 0.05). In addition, we found that high PI3K/AKT kinase mRNA/protein levels were associated with a high TFG (p < 0.05). We also found that FGFR1/3 mRNA and FGFR1 protein levels were inversely associated with overall survival (log-rank test: FGFR1 mRNA p = 0.03, FGFR3 mRNA p = 0.04, FGFR1 protein p = 0.03). Subsequent multivariate analyses revealed that high FGFR3 mRNA expression may serve as an independent poor prognostic factor (HR 2.32, 95% CI 1.03–6.59; p = 0.04). We also found that the p-PI3K regulatory kinase protein level was significantly associated with survival in the cohort studied (HR 1.78, 95% CI 0.64–8.53; p = 0.03).

Conclusions

From our data we conclude that FGFR1 and FGFR3, as well as its downstream regulatory PI3K/AKT kinases, may serve as potential biomarkers for the invasiveness and prognosis of laryngeal cancer. The expression of FGFR1/3-PI3K/AKT regulatory pathway members may be instrumental for the identification of patients at risk for an unfavorable clinical outcome.

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Acknowledgements

This work was supported, in part, by a grant from the statutory fund of the Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Łódź, Poland (506/811) and by the National Science Council, Poland (N403 043 32/2326).

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Authors and Affiliations

  1. I Department of Otolaryngology and Laryngological Oncology, Medical University of Łódź, Kopcińskiego 22, 90-153, Łódź, Poland

    Katarzyna Starska

  2. Department of Cytobiochemistry, University of Łódź, Pomorska 142/143, 90-236, Łódź, Poland

    Ewa Forma & Magdalena Bryś

  3. Department of Pathology, Medical University of Łódź, Pomorska 251, 92-213, Łódź, Poland

    Iwona Lewy-Trenda

  4. Department of Nephropathology, Medical University of Łódź, Pomorska 251, 92-213, Łódź, Poland

    Olga Stasikowska-Kanicka

  5. Department of Otolaryngology, Żeromski Specialist Hospital, os. Na Skarpie 66, 31-913, Kraków, Poland

    Michał Skóra

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  1. Katarzyna Starska
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Correspondence to Katarzyna Starska.

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The study was approved by the Bioethical Commission of the Medical University of Łódź, Poland (approval No RNN/80/16/KE). Informed consent was obtained from all participants included in the study.

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Electronic supplementary material

Supplementary Fig. 1

Spearman rank analysis results for FGFR1 and FGFR3 mRNA/protein expression level in relation to PI3K/AKT measured by real-time PCR and Western blotting analyses in laryngeal cancers. a Spearman rank analysis results for FGFR1 gene level in relation to PI3K and b AKT genes. c Spearman rank analysis results for FGFR1 protein level in relation to total-PI3K and d AKT proteins as well as for e phospho-PI3K and f AKT proteins. g Spearman rank analysis results for FGFR3 mRNA expression level in relation to PI3K and h AKT genes. i Spearman rank analysis results for FGFR3 protein expression level in relation to total-PI3K and j AKT proteins as well as for k phospho-PI3K and l AKT proteins. (EPS 4571 kb)

High resolution (GIF 33 kb)

Supplementary Fig. 2

Expression of FGFR1, FGFR3, PI3K and AKT mean mRNA measured by real-time PCR in laryngeal cancers. a A comparison between subgroups with tumor size (pT status) according to FGFR1 and g FGFR3 genes. b A comparison between subgroups with total score of tumor front grading according to FGFR1 and h FGFR3 transcripts. c A comparison between subgroups with depth of invasion according to to FGFR1 and i FGFR3 genes. d A comparison between subgroups with mode of invasion according to FGFR1 and j FGFR3 transcripts. e A comparison between subgroups with local recurrences according to FGFR1 and k FGFR3 genes. f A comparison between subgroups with five-year disease-free (5y–DF) survival according to FGFR1 and l FGFR3 transcripts. Graphs represent mean ± standard deviation. P values were calculated by the Mann-Whitney U-test. *P < 0.05, **p < 0.01 (EPS 4428 kb)

High resolution (GIF 69 kb)

Supplementary Fig. 3

Expression of FGFR1/3 and phospho-PI3K/AKT mean protein levels measured by Western blotting in laryngeal cancers. a A comparison between subgroups with tumor size (pT status) according to FGFR1 and g FGFR3 proteins. b A comparison between subgroups with total score of tumor front grading according to FGFR1 and h FGFR3 proteins. c A comparison between subgroups with depth of invasion according to to FGFR1 and i FGFR3 proteins. d A comparison between subgroups with mode of invasion according to FGFR1 and j FGFR3 proteins. e A comparison between subgroups with local recurrences according to FGFR1 and k FGFR3 proteins. f A comparison between subgroups with five-year disease-free (5y–DF) survival according to FGFR1 and l FGFR3 proteins. Graphs represent mean ± standard deviation. P values were calculated by the Mann-Whitney U-test. *P < 0.05, **p < 0.01 (EPS 4186 kb)

High resolution (GIF 52 kb)

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Starska, K., Forma, E., Lewy-Trenda, I. et al. Fibroblast growth factor receptor 1 and 3 expression is associated with regulatory PI3K/AKT kinase activity, as well as invasion and prognosis, in human laryngeal cancer. Cell Oncol. 41, 253–268 (2018). https://doi.org/10.1007/s13402-017-0367-z

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