Quantitative proteomic analysis reveals sophisticated metabolic alteration and identifies FMNL1 as a diagnostic and prognostic marker in clear cell renal cell carcinoma

ABSTRACT: Purpose: In this study, we have undertaken the whole proteomic analysis and got a better understanding of biological processes involved in the development and progression of ccRCC. We hope promising biomarkers can be uncovered to facilitate early diagnosis, predict the prognosis and progression, more importantly, to be applied as potential therapeutic targets. Experimental design: Fresh frozen tissue samples were surgically resected from patients with local or locally advanced ccRCC. Trypsin digested proteins were analyzed using TMT-based LC-MS/MS proteomic approach, followed by bioinformatic analysis. A potential prognostic marker FMNL1, annotated with actin cytoskeleton assembly and cell migration, was chosen to be validated in TCGA_KIRC datasets(n=597), further validation sets(n=20) and expanded validation sets(n=97). Results: A total of 657 differentially expressed proteins were identified and quantified between ccRCC and adjacent normal tissues (p-value<0.05, FC>2 or<1/2), of which 186 proteins were up-regulated and 471 proteins were down-regulated. Bioinformatic analysis showed enriched metabolic biological processes and pathways including oxidative phosphorylation, valine, leucine and isoleucine degeneration, propanoate metabolism, fatty-acid degeneration, TCA cycle, glycolysis/gluconeogenesis, etc. Univariate and multivariate analysis defined FMNL1 as an independent negative prognostic marker in the TCGA datasets. High expression of FMNL1 correlated significantly with tumor stage, T stage, lymph node metastasis(P<0.05), and distant metastasis(P<0.05) both in the TCGA-KIRC datasets and expanded validation sets. And KM survival curve illustrated that patients with high FMNL1 protein level had shorter OS time in the expanded validation sets (p=0.0273) Conclusion and clinical relevance: The proteomic results uncovered sophisticated metabolic reprogramming of ccRCC and indicated that the upregulation of rate-limiting enzymes in glycolysis and mitochondrial impairment may be the cause of metabolic reprogramming in ccRCC. Moreover, FMNL1 has been identified as a diagnostic and prognostic marker, and may be implicated in the progression of ccRCC.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: 桂 马  

LAB HEAD: Gui Ma

PROVIDER: PXD022919 | Pride | 2022-02-16

REPOSITORIES: Pride