IDENTIFICATION OF THE FGF FAMILY AS THERAPEUTIC TARGETS AND PROGNOSTIC BIOMARKERS IN THE MICROENVIRONMENT OF HEADAND NECK SQUAMOUS CELL CARCINOMA

Abstract

Background: Almost 90% of head and neck malignancies are squamous cell carcinomas, head and neck squamous cell carcinoma (HNSC) is the sixth most common malignant tumor in the world, with a five-year overall survival rate about 40%-50%. Early diagnosis and treatment can bring a better prognosis. Fibroblast growth factor (FGF) is an important polypeptide in vivo. Studies have found that FGF signal has carcinogenic potential and participates in a variety of carcinogenic behaviors. Some experiments have proved that FGF signal has the function of tumor inhibition in some cases, and the importance of FGF signal in tissue development and homeostasis suggests the role of FGF in targeted therapy and prognosis. However, its expression and prognostic value in HNSC have not been clearly defined. Methods: Genome-wide expression analysis of Oncomine evaluated the expression of FGF family in HNSC. Expression analysis and HNSC data set were used to obtain FGF family expression data and T test was used for analysis. GEPIA single-gene analysis was used to analyze the difference of mRNA expression between tumor and normal tissues, pathological staging and prognosis of FGF family. FGF family altered CO expression and network modules were obtained from cBioportal and analyzed in 520 HNSC samples. Pro-pro interaction(PPI) network analysis was performed on the differentially expressed FGF family using STRING, Gene Ontology(GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were performed on FGF family and adjacent genes by DAVID6.8, key transcriptional factors (TF) of FGF family was analyzed by TRRUST, correlation between FGF family level and immune cell infiltration was evaluated by TIMER, and biological analysis of FGF family kinase target enrichment was performed using Link Interpreter. Results: Only the expression of FGF6 in HNSC was down-regulated in all FGF family (FC=2), Transcriptional level of FGF1, FGF2, FGF5, FGF7-14, FGF17-19, FGF21 and FGF22 was upregulated in HNSC. In terms of the relative level of FGF family in HNSC, the relative level of FGF11 was the highest. In different pathological stages of HNSC, the expression of FGF was meaningless (P＞0.05), and FGF3-6, FGF8-10, FGF14, FGF16, FGF17, FGF19 -21, FGF23 showed no significant difference in different HNSC stages. Low expression of FGF5 and high expression of FGF22 had low overall survival (OS) rate of HNSC (P =0.012, P =0.0015). In addition, enrichment analysis of FGF family in HNSC showed that it was significantly enriched in PI3K-Akt signaling pathway, MAPK signaling pathway, and Raspberry signaling pathway. Our data showed that ATF4, STAT, RELA, NFKB1 are key transcription target of the FGF family, NLK, LOCK1, LYN, ZAP70, MAP2K3, RPS6KA4, AURKB, ATR, ROCK1, MYLK2, CAMK2A, EGFR, MAPK3, MAP3K8, SYK, LCK, HCK, PKN2, RPS6KA1, BUB1, CDK5, ITK, FYN, TBK1, ATM, CDK2, PTK2 are kinase targets of the FGF family. We found a significant correlation between the expression of FGF and cell infiltration, such as B lymphocyte, CD4+T cells and Macrophages dendritic cells. Conclusions: Our results may provide new perspectives for the selection of immune therapy targets and prognostic biomarkers for HNSC.