Comprehensive analysis of abnormal expression, prognostic value and oncogenic role of the hub gene FN1 in pancreatic ductal adenocarcinoma via bioinformatic analysis and in vitro experiments

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most commonly diagnosed cancers with a poor prognosis worldwide. Although the treatment of PDAC has made great progress in recent years, the therapeutic effects are still unsatisfactory. Methods. In this study, we identified differentially expressed genes (DEGs) between PDAC and normal pancreatic tissues based on four Gene Expression Omnibus (GEO) datasets (GSE15471, GSE16515, GSE28735 and GSE71729). A protein–protein interaction (PPI) network was established to evaluate the relationship between the DEGs and to screen hub genes. The expression levels of the hub genes were further validated through the Gene Expression Profiling Interactive Analysis (GEPIA), ONCOMINE and Human Protein Atlas (HPA) databases, as well as the validation GEO dataset GSE62452. Additionally, the prognostic values of the hub genes were evaluated by Kaplan–Meier plotter and the validation GEO dataset GSE62452. Finally, the mechanistic roles of the most remarkable hub genes in PDAC were examined through in vitro experiments. Results We identified the following nine hub genes by performing an integrated bioinformatics analysis: COL1A1, COL1A2, FN1, ITGA2, KRT19, LCN2, MMP9, MUC1 and VCAN. All of the hub genes were significantly upregulated in PDAC tissues compared with normal pancreatic tissues. Two hub genes (FN1 and ITGA2) were associated with poor overall survival (OS) rates in PDAC patients. Finally, in vitro experiments indicated that FN1 plays vital roles in PDAC cell proliferation, colony formation, apoptosis and the cell cycle. Conclusions In summary, we identified two hub genes that are associated with the expression and prognosis of PDAC. The oncogenic role of FN1 in PDAC was first illustrated by performing an integrated bioinformatic analysis and in vitro experiments. Our results provide a fundamental contribution for further research aimed finding novel therapeutic targets for overcoming PDAC.

A comprehensive transcriptional signature in pancreatic ductal adenocarcinoma reveals new insights into the immune and desmoplastic microenvironment

“…Furthermore, laminins LAMBC2 and LAMB3 support cancer progression and resistance to gemcitabine -one of the main chemotherapeutics used in PDAC patients [61,62]. In general, the association with poor prognosis of the stroma signature is consistent with the one described in previous studies for each gene: CEACAM5 [63], CEACAM6 [64], FN1 [65], GJB2 [66], GPRC5A [67], LAMB3 [68,69], LAMC2 [68,69], SFN [70], SLC6A14 [71], TSPAN1 [72], VCAN [65]. The meta-analysis from transcriptomic studies allows a be er understanding of the PDAC environment.…”

A Comprehensive Transcriptional Signature in Pancreatic Ductal Adenocarcinoma Reveals New Insights into the Immune and Desmoplastic Microenvironments

“…Furthermore, laminins LAMBC2 and LAMB3 support cancer progression and resistance to gemcitabine-one of the main chemotherapeutics used in PDAC patients [62,63]. In general, the association of the stroma signature with a poor prognosis is consistent with the one described in previous studies for each gene: CEACAM5 [64], CEACAM6 [65], FN1 [66], GJB2 [67], GPRC5A [68], LAMB3 [69,70], LAMC2 [69,70], SFN [71], SLC6A14 [72], TSPAN1 [73], and VCAN [66]. After, with a focus on the immune signature co-occurrence, patients could be divided into those with more S100/IL genes and those with a more IFN expressed genes.…”

Prognostic Significance of Integrin Subunit Alpha 2 (ITGA2) and Role of Mechanical Cues in Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma (PDAC)

“…ITGA2 involvement in "stiff" cancers, such as breast, prostate, colon and pancreatic cancer, has been extensively studied [20,22]. In particular, ITGA2 was reported to be a putative biomarker and poor prognostic factor for PDAC patients [21,51,52]. However, to our knowledge, this is the first study investigating its role in resistance to gemcitabine in PDAC.…”

“…However, to our knowledge, this is the first study investigating its role in resistance to gemcitabine in PDAC. Previous studies analysed ITGA2 expression on publicly available datasets reporting that high ITGA2, along with its hub genes (LAMB3, LAMC2 and FN1), is an unfavorable prognostic factor for PDAC patients [21,22]. Nevertheless, it was not investigated whether patients received a chemotherapy regimen and if there was a correlation between therapy response and ITGA2 expression level.…”

“…High expression levels of the Integrin α2 (ITGA2) subunit have been associated with aggressiveness, increased invasion and poor prognosis in several solid cancers [17][18][19][20]. In particular, ITGA2 has recently emerged as a potential prognostic biomarker and therapeutic target in PDAC [21,22]. However, the impact of ITGA2 on PDAC chemoresistance has not yet been elucidated.…”