PC is an aggressive malignant tumor that often lacks early symptoms and is associated with a poor prognosis (Hruban et al. 2019). Although significant progress has been achieved in surgical resection and chemotherapy, these advancements have not translated into effective therapies for the majority of patients. Consequently, there is an immediate need to explore new biomarkers and therapeutic strategies for PC patients. Currently, the mechanisms underlying gene regulation that contribute to disease progression are not fully understood, and prognostic evaluations for PC patients remain unsatisfactory.
With the development of bioinformatics, several studies have explored potential prognostic and diagnostic biomarkers related to PC (Muramatsu et al. 2024, Xu et al. 2023, Zhou et al. 2019). Furthermore, researchers identified a set of prognostic RNA expression signatures based on a large-scale meta-analysis (Kordshouli et al. 2024, Klett et al. 2018, Haider et al. 2014). Therefore, we performed an initial investigation aimed at identifying hub genes to construct specific multigene prognostic signatures that could enhance the prediction of clinical outcomes in PC. In this study, we analyzed transcriptome data related to PC from clinical plasma samples alongside public databases. Using WGCNA on the merged datasets GSE62452 and GSE71989, we identified significant gene modules associated with PC. Furthermore, KEGG pathway and GO enrichment analyses of the genes in the identified modules revealed their involvement in ECM–receptor interaction processes and the PI3K-Akt signaling pathway.
After overlapping the DEGs of our clinical microarray dataset and the significant modules, we obtained 8 genes that were highly expressed in patients with PC. Then, through LASSO regression, we identified 5 genes: FERMT1, S100A14, KCNN4, PKM, and ITGA3. The validation dataset GSE16515 confirmed the elevated expression of these 5 hub genes in tumors, suggesting their potential diagnostic utility for PC.
Several studies have sought to combine key gene expressions with clinical parameters to develop models that aid in predicting patient prognosis. Survival analyses of the TCGA database revealed that higher expression of these genes was related to a poor survival rate. Moreover, according to the multivariate model, the expression of FERMT1, S100A14, and ITGA3 was an independent risk factor for poor prognosis. In this study, we examined the correlations between the expression of prognosis-related genes and clinicopathological characteristics. The results indicated that lymph node metastasis was an independent prognostic factor in PC patients.
Our findings contribute further evidence for the importance of the key molecules currently under investigation for PC. Based on our data, several studies have reported associations between these hub genes and the progression of PC to a certain extent. Metastasis is the main cause of cancer-associated death. Activation of the epithelial–mesenchymal transition (EMT)-associated program is regarded as a central driver of tumorigenesis to metastasis (Krebs et al. 2017, Bhutia et al. 2020). Currently, the role of EMT in KRAS-driven PC development has been intensively studied (Bhutia et al. 2020, Wang et al. 2015, Paul et al. 2023). Previous studies have indicated that S100A14 and ITGA3 may be important determinants of EMT in PC. Most S100 proteins are considered EMT facilitators or EMT markers in carcinoma cells (Al-Ismaeel et al. 2019, Ou et al. 2021). The depletion of S100A14 strongly increased cell invasion (Low et al. 2023). Consistent with the EMT and mesenchymal–epithelial transition states, ITGA3 (Liu et al. 2021)was reported to upregulate the expression of ZIP4 in a PC cell line through the ZEB1/YAP1-ITGA3 signaling axis to promote EMT plasticity. Fermitin family member 1 (FERMT1) is associated with immune cell infiltration, and its N6-methyladenosine modification might be a marker of the treatment response to PC chemotherapy (Wu et al. 2023). In addition, studies have demonstrated that FERMT1 functions as a methylation-driven gene and participates in PC oncogenesis (Deng et al. 2021, Nie et al. 2023).
Potassium calcium-activated channel subfamily N member 4 (KCNN4) is a type of intermediate conductance calcium-activated potassium channel, and numerous studies have demonstrated that KCNN4 closely relates to the invasion and metastasis in many types of tumors (Li et al. 2020, Xu et al. 2021, Ibrahim et al. 2021)]. KCNN4 has been shown to induce Ca2+ entry, which leads to the activation of nuclear factor kappa B signaling and contributes to PDAC growth and metastasis. Mo et al. (Mo et al. 2022) illustrated that KCNN4 promotes PDAC cell proliferation, migration, and invasion through the Ca2+/MET/AKT axis and identified KCNN4 as a potential therapeutic target in PDAC. As a new potential therapeutic target, the splicing of pyruvate kinase (PKM) is correlated with drug resistance in PC patients (Calabretta et al. 2016).
Numerous studies have affirmed the significance of hub genes in the landscape of PC. When considered alongside our previous analyses, data suggest that the differential expression of FERMT1, S100A14, KCNN4, PKM, and ITGA3 in tumor and normal tissues might be related to the underlying mechanisms of PC, which must be further explored.
However, this study also has several limitations. The results of this study are mainly based on a microarray of our clinical samples and bioinformatics analysis without in vitro or in vivo experimental validation. Further gene expression validation could strengthen our conclusions, and the genes involved require further evaluation at the protein level. In addition, functional and molecular experiments are needed to investigate the underlying mechanism involved. Therefore, future work will involve further elucidation and multi-center verification of the gene signature with larger clinical sample sizes.