Expression of fibroblast growth factor 9 is associated with poor prognosis in patients with resected non-small cell lung cancer
Introduction
Despite recent improvements in diagnosis and treatment, lung cancer is one of the leading causes of cancer-related death worldwide, and long-term survival remains very poor [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung malignancies. Approximately 40% of NSCLCs are at an advanced stage at the time of diagnosis. The overall survival rate is only approximately 15% at 5 years, and the recurrence rates remain high [2]. Therefore, further characterization of key molecular alterations in NSCLC is anticipated.
The fibroblast growth factor (FGF) family consists of at least 23 polypeptides that have important functions in embryonic development, tissue repair, and tumorigenesis [3], [4], [5]. FGF receptors (FGFRs) are encoded by 4 genes (FGFR1–FGFR4), and numerous isoforms exist due to alternative RNA splicing [6]. Binding of FGF to FGFR leads to a conformational shift in the FGFR structure, resulting in intermolecular transphosphorylation of the intracellular tyrosine kinase domain and carboxy-terminal tail. Subsequent downstream signaling occurs through 4 main pathways: the RAS–RAF–MAP kinase pathway, the PI3K–AKT pathway, the signal transducer and activator of transcription pathway, and the phospholipase pathway [5], [7].
The proliferation of a subset of NSCLC cells is reported to be dependent on FGF/FGFR signaling. Several studies suggest that specific FGFs and FGFRs, such as FGF2, FGF9, FGFR1, and FGFR2, are expressed in NSCLC cell lines and patient-derived lung cancer tissues [8]. Additionally, inhibition of FGF/FGFR signals by shRNA, anti-FGF2 antibody, or an FGFR-tyrosine kinase inhibitor (TKI) has been reported to suppress the proliferation of cancer cells [8], [9].
In recent years, activation of FGF/FGFR signals through FGF9 has been reported in some cancers. Leushacke et al. reported that the expression level of FGF9 mRNA was high in a subset of advanced colon cancers and that FGF9 overexpression was negatively correlated with patient survival [10]. In prostate cancer, Teishima et al. reported that the 3-year biochemical relapse-free survival rate was significantly lower for patients with FGF9-positive cancer than for those with FGF9-negative cancer [11].
FGF9 is expressed in epithelium primordium during the developmental stage of the lung and plays an important role in the differentiation and proliferation of the epithelium and interstitium; however, its expression is repressed in the mature lung [12]. In lung cancer, by using immunohistochemistry, Wang et al. demonstrated that FGF9 was highly expressed in adenocarcinoma patients and that alteration of FGF9 function might reduce the development of lung adenocarcinoma [13]. However, data confirming the relationship between FGF9 expression and prognosis in lung cancer is not available.
To date, many prognostic indicators in NSCLC patients have been identified. However, the impact of FGF9 on the prognosis of NSCLC patients is not reported. The purpose of this study was to characterize NSCLC with FGF9 expression and to evaluate the effect of FGF9 on the prognosis of NSCLC patients.
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Study population
A total of 95 patients underwent surgical resection under the diagnosis of NSCLC at the Department of Thoracic Surgery, Keio University Hospital, from 2001 to 2006. Approval for institutional review of all samples was obtained in accordance with the requirements of Keio University Institutional Review Board (Institutional Review Board #16-90-1).
cDNA microarray analysis
We used GeneChip Human Genome 2.0 Array (Affymetrix, Inc., Santa Clara, CA) to monitor the expression profiles of the samples. Total RNA was extracted
Overexpression of FGF9 mRNA in NSCLC patients
Of the 95 patients who underwent resection for a pretreatment diagnosis of NSCLC, 90 were evaluated in this study. Five patients were excluded from the study because they were found to have small cell lung cancer (2 patients) or their clinical data could not be retrieved (3 patients) (Fig. 1A). Although most tumor samples from NSCLC patients did not show high expression levels of FGF9 compared to the average level in normal lung tissues according to cDNA microarray data, we found that in 9 out
Discussion
With the molecular analysis performed in recent years, many molecular characteristics of cancers have been elucidated. In particular, the FGF/FGFR pathway has long attracted attention as a potential therapeutic target in this context. Activating mutations of FGFR1, FGFR2, and FGFR3 have been reported in melanoma, endometrial cancer, and bladder cancer, respectively [15], [16], [17]. The existence of amplification and translocation of FGFRs in several cancers has also been discovered in rapid
Conflict of interest statement
The authors declare that they have no conflict of interest.
Acknowledgement
We thank Ms. Mikiko Shibuya for her excellent technical assistance. This study was supported in part by Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan to K.S. (Grant #22590870) and T.B. (Grant #60333605).
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