In this study, 2388 DEGs (including 1574 up-regulated genes and 814 down-regulated genes) between the LUAD samples and normal samples in the training set were identified. For the 150 metabolism-associated DEGs, 17 GO_BP functional terms and 20 KEGG pathways (such as PPAR signaling pathway) were enriched. Based on the optimal gene combination involving eight genes (CYP17A1, ASPG, DUOX1, CIDEC, TH, B4GALNT1, APOA2, and GCKR), the PS model was constructed. Combined with pathologic stage and PS model status, the nomogram survival model was established.
Through mediating the p(38)/β-catenin/PPARγ pathway, transforming growth factor β (TGFβ) enhances the invasion, migration, and epithelial mesenchymal transition of NSCL CH460 cells (25, 26). Therefore, the PPAR signaling pathway might function in the pathogenesis of LUAD. The silver nanobiocomposite of ASPG has lower cytotoxicity against lung cancer cells, and thus it can be applied as an promising anticancer agent for treating the tumor (27). DUOX1 affect epithelial homeostasis and innate airway host defense, and its silencing accelerates epithelial-to-mesenchymal transition in lung epithelial cancer and may be related to invasive and metastatic lung cancer (28, 29). DUOX1 expression is inhibited by epigenetic mechanisms in lung cancer, which may be implicated in the diagnosis and therapy of the tumor (30). Thus, ASPG and DUOX1 might be implicated in the prognosis of LUAD patients.
CIDEC, a member of the cell death-inducing DNA fragmentation factor-like effector family, could promote lipid droplet formation in adipocytes and mediate adipocyte apoptosis(31). It was reported that the CIDE family regulated lipid metabolism and played an important role in the development of metabolic disorders such as obesity(32), insulin resistance(33) and hepatic steatosis(34)Ming Yu et al.According to HPA database, CIDEC was a characteristic gene in lung cancer and other cancers. A four-gene signature (involving CIDEC; dickkopf WNT signaling pathway inhibitor 1, DKK1; ubiquitin specific peptidase 4, USP4; and ZFP3 zinc finger protein, ZFP3) is an independent prognostic marker, which can be used to predict the outcomes of LUAD patients (35). Through CIDEC/extracellular regulated MAP kinase (ERK)/p38 pathway, ADP ribosylation factor like GTPase 14 (ARL14) is involved in the mechanisms of LUAD and can be novel prognostic marker and therapeutic target of the disease (36). B3GALNT1 and tubulointerstitial nephritis antigen-like 1 (TINAGL1) are found to be key genes mediating the metastasis of NSCLC, which are candidate target genes for the treatment of the disease (37, 38). A model involving six biomarkers (including APOA2) and age has high sensitivity and specificity, which is effective for the diagnosis of the patients with lung cancer (39). These suggested that CIDEC, B4GALNT1, and APOA2 might also be correlated with the prognosis of LUAD patients.
Although the roles of CYP17A1, TH, and GCKR in LUAD have not been studied, they have influences on other tumors. For example, CYP17A1 and CYP19A1 are important for estrogen biosynthesis, and their expression may contribute to improving the accuracy of diagnosis and selecting the proper treatment for invasive ductal breast cancer (40).Recently,one research reported that CYP17A1 significantly distinguished between non-smoking and smoking-associated adenocarcinomas.(41)The CT and CC genotypes of TH have higher frequencies in gastric cancer patients compared with the controls, therefore, they are correlated with a significantly higher risk of the tumor (42). The rs780093 and rs780094 polymorphisms in GCKR have significant correlations with OS and progression-free survival, and thus GCKR polymorphisms may be independent prognostic marker in metastatic gastric cancer patients receiving EOF chemotherapy (43). Therefore, CYP17A1, TH, and GCKR might play roles in the prognosis of LUAD patients.
This study constructed a PS model based on metabolism-associated genes and a nomogram survival model combined with multiple bioinformatics methods. However, no experiments were conducted to validate these findings. Therefore, these results still needed to be confirmed by experimental studies.
In conclusion, 2388 DEGs between the LUAD and normal samples were obtained. Besides, the PPAR signaling pathway might affect the pathogenesis of LUAD. Furthermore, the PS model (involving CYP17A1, ASPG, DUOX1, CIDEC, TH, B4GALNT1, APOA2, and GCKR) and the nomogram survival model might be effective for the prognostic prediction of LUAD patients.