Comprehensive bioinformatics analysis reveals the significance of forkhead box family members in pancreatic adenocarcinoma

Abstract

Background: Forkhead box proteins (FOXs) play important roles in multiple biological processes; while little is known regarding the role of FOX members in pancreatic adenocarcinoma (PAAD). This study aimed to comprehensively investigate the function of FOX family members in PAAD. Methods: Expression and prognostic value of FOXs were analyzed by R language and GEPIA. Genetic alteration and promoter methylation level were analyzed using CBioPortal and UALCAN. Protein-protein interactions and gene functions were analyzed using STRING and DAVID. TIMER and SENESCopedia were utilized to analyze the correlation of FOXs with immune cell infiltration or tumor senescence. Protein levels of FOXs were detected by immunohistochemistry. Results: Expression of 15 of 50 FOXs were significantly elevated in PAAD. Among these 15 differentially expressed FOXs (DE-FOXs), 4 were significantly associated with the clinical cancer stage and 4 were negatively associated with overall survival. Functions of DE-FOXs were related to epithelial tube morphogenesis, nuclear chromatin, and DNA-binding. Promoter methylation and genomic alterations were not major causes of FOX dysregulation. Most DE-FOX was correlated with diverse immune infiltration cells. Seven of the DE-FOXs were positively related to tumor senescence. The protein levels of FOXM1, FOXP1, and FOXN3 were negatively correlated with OS in the collected PAAD patients. Conclusions: FOXM1, FOXP1, and FOXN3 have prognostic value. Seven FOXs were related senescence, whereas most DE-FOXs were related to immune infiltration in PAAD. Our findings are instructive for future research on FOX family and provide novel insights into the selection of FOXs with potential prognostic or therapeutic target value.

XRCC1 rs1799782 Promotes DNA Damage Repair in Lung Cancer Cells by Enhancing Its Binding to FOXA1 to Facilitate FOXA1-Mediated Transcription of XRCC1

“…Several studies have proved that FOXA1 is a vital transcription factor in the occurrence and development of LC, and its overexpression can enhance cell metastasis and proliferation [27,28]. However, the effect of FOXA1 on LC cell aging has not been reported, but previous study showed that the expression of FOXA1 was negatively correlated with the aging marker IL-6 level [29]. Further, Yusuke Imamura et al [30] reported that the depletion of FOXA1 can increase P21 expression in prostate cancer cells.…”

FOXK2 targeting by the SCF-E3 ligase subunit FBXO24 for ubiquitin mediated degradation modulates mitochondrial respiration

“…The forkhead box (FOX) proteins constitute a family of transcription factors characterized by their well-preserved fork-head and winged-helix DNA binding domains, which display a specific affinity for the universally conserved DNA sequence 5ʹ-TTGTTTAC-3ʹ ( 20 , 21 , 22 ). FOXK, comprising FOXK1 and FOXK2, harbor a forkhead-associated (FHA) domain rich in phospho-threonine-residues that distinguishes it from other FOX transcription factors ( 23 ).…”