Multi-omics profiles refine L-dopa decarboxylase (DDC) as a reliable biomarker for prognosis and immune microenvironment of clear cell renal cell carcinoma

Abstract

BackgroundIncreasing evidence indicates that L-dopa decarboxylase (DDC), which mediates aberrant amino acid metabolism, is significantly associated with tumor progression. However, the impacts of DDC are not elucidated clearly in clear cell renal cell carcinoma (ccRCC). This study aimed to evaluate DDC prognostic value and potential mechanisms for ccRCC patients.MethodsTranscriptomic and proteomic expressions of and clinical data including 532 patients with ccRCC (The Cancer Genome Atlas RNA-seq data), 226 ccRCC samples (Gene Expression Omnibus), 101 ccRCC patients from the E-MTAB-1980 cohort, and 232 patients with ccRCC with proteogenomic data (Fudan University Shanghai Cancer Center) were downloaded and analyzed to investigate the prognostic implications of DDC expression. Cox regression analyses were implemented to explore the effect of DDC expression on the prognosis of pan-cancer. The "limma" package identified the differentially expressed genes (DEGs) between high DDC subgroups and low DDC groups. Functional enrichments were performed based DEGs between DDC subgroups. The differences of immune cell infiltrations and immune checkpoint genes between DDC subgroups were analyzed to identify potential influence on immune microenvironment.ResultsWe found significantly decreased DDC expression in ccRCC tissues compared with normal tissues from multiple independent cohorts based on multi-omics data. We also found that DDC expression was correlated with tumor grades and stages.The following findings revealed that lower DDC expression levels significantly correlated with shorter overall survival (P <0.001) of patients with ccRCC. Moreover, we found that DDC expression significantly correlated with an immunosuppressive tumor microenvironment, higher intra-tumoral heterogeneity, elevated expression of immune checkpoint CD274, and possibly mediated malignant behaviors of ccRCC cells via the PI3k/Akt signaling pathway.ConclusionThe present study is the first to our knowledge to indicate that decreased DDC expression is significantly associated with poor survival and an immune-suppressive tumor microenvironment in ccRCC. These findings suggest that DDC could serve as a biomarker for guiding molecular diagnosis and facilitating the development of novel individual therapeutic strategies for patients with advanced ccRCC.

Construction and validation of risk model of EMT‐related prognostic genes for kidney renal clear cell carcinoma

“…A recent study reported that upregulated IL20RB is confirmed as a novel prognostic and therapeutic biomarker in KIRC, which is consistent with our results 28 . It was also reported that downregulated DDC is significantly associated with poor survival and an immune‐suppressive TME in KIRC 29 . Another study confirmed that decreased TEK expression had a poor prognosis for patients with KIRC 30 .…”

“…28 It was also reported that downregulated DDC is significantly associated with poor survival and an immune-suppressive TME in KIRC. 29 Another study confirmed that decreased TEK expression had a poor prognosis for patients with KIRC. 30 We evaluated their prognostic value using a risk score and found that the low-risk group had a significantly better prognosis than the high-risk group.…”