Bioinformatics Analysis On The Role And Clinical Significance Of The Forkhead Box Family In Cervical Cancer

BACKGROUND:Forkhead-box family is a large family of transcription factors,which are characterized by forkhead-box-liked or wing-helix-shaped special conserved sequences that can bind to DNA.They participate in a variety of key biological processes,and play an important role in tumor development,invasion and metastasis.Therefore,we hope to explore the biological role and clinical significance of FOX family in cervical cancer by means of bioinformatics.METHODS:The gene expression profiles of 304 cervical cancer tissues,3 paracancerous tissues and 78 normal cervical tissues were downloaded from TCGA and GTEX database.The differentially expressed FOXs genes were screened by limma package of R.The biological effects of FOX family in cervical cancer were studied by GO,KEGG and protein interaction analysis.Kaplan Meier method and univariate analysis were used to analyze the relationship among clinical parameters,FOXs expression and prognosis.Cox proportional hazards model was used for multivariate analysis.The difference was statistically significant(P<0.05).RESULTS:Gene difference analysis showed that 6 FOXs were up-regulated and 2 FOXs were down-regulated in cervical cancer,p<1-4e.Bioinformatics results showed that up-regulated FOXs were associated with 14 biological processes such as keratinization and 8 cellular localizations such as nucleolus;The down-regulated FOXs mainly included 12 biological processes,such as RNA polymerase Ⅱ promoter transcription.The cells were located in 3 places,such as collagen trimer.The molecular function mainly included cGMP binding.The signal pathway was most significantly enriched in cancer-related pathways,p<0.05.The key genes related to FOX family are BUB1 and so on.Kruskal Wallis test results showed that FOXN1 expression was higher in patients with multiple pregnancy(p=0.031),advanced stage(p=0.032)and moderately&well differentiated(p=0.045)squamous cell carcinoma(p=0.000);FOXE1 expression was higher in patients with squamous cell carcinoma(p=0.000)and pelvic lymph node metastasis(p=0.025);FOXF1 was highly expressed in perimenopausal group(p=0.040),and significantly decreased in squamous cell carcinoma group(p=0.005),advanced cervical carcinoma group(p=0.002)and pelvic lymph node metastasis group(p=0.006).The results of survival analysis showed that the advanced cervical cancer(p=0.018),distant metastasis(p=0.000)and lymphatic vascular space invasion(p=0.001)were associated with poor prognosis of cervical cancer while high expression of FOXN1 and other five FOXs have significantly better prognosis.There results of univariate analysis were also significant.Multivariate analysis showed that FOXN1,FOXE1,FOXD1 mRNA expression(p=0.026,p=0.005,p=0.027)were independent prognostic factors of cervical cancer.The results of subgroup analysis showed that the high expression of FOXN1 mRNA in multiple pregnancy subgroup,clinical stage subgroups,squamous cell carcinoma subgroup and G2 subgroup was significantly correlated with the prolongation of overall survival,and the high expression of FOXE1 mRNA in each pelvic lymph node metastasis group and squamous cell carcinoma subgroup was significantly correlated with the prolongation of overall survival,p<0.05.CONCLUSIONS:1.FOX family is closely related to the occurrence of cervical cancer:FOXM1,FOXA1,FOXN1,FOXQ1,FOXE1 and FOXD1 are significantly up-regulated in cervical cancer,which may participate in the occurrence and development of cervical cancer through keratinization,cell adhesion,protein crosslinking,mitosis and cell cycle regulation;FOXF1,FOXL2 and FOXP2 are significantly down-regulated,which may participate in the process of cervical cancer through cell proliferation,cell migration and cell aging.These FOXs are mainly enriched in cancer-related pathways,and have co expression and protein interaction with BUB1,PRC1,KIF4A,PBK,CDCA8,KIF23,KIF11,CCNA2,BUB1B,CCNB2.2.High expression of FOXN1,FOXE1 and FOXD1 mRNA is an independent protective factor for the prognosis of cervical cancer,especially FOXN1 in multiple pregnancies,squamous cell carcinoma,moderate differentiation and FOXE1 in squamous cell carcinoma.In conclusion,FOXN1,FOXE1 and FOXD1 may play a biological role in inhibiting the development of cervical cancer.