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

Abstract

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 was chosen to be validated in TCGA_KIRC datasets (n=525 and 72), further validation sets (n=10 and 10) and expanded validation sets (n=81 and 16). The effects of FMNL1 on proliferation, migration and invasion were determined by colony formation, wound healing, and transwell assays in 786-O and Caki-1 cells in vitro study. 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. 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 and distant metastasis (P<0.05) both in the TCGA-KIRC datasets and expanded validation sets. Kaplan-Meier survival curve illustrated that the patients with high FMNL1 protein level had shorter OS time in the expanded validation sets (p=0.0273). In vitro experiments presented the functional effects of FMNL1 knockdown on the inhibition of proliferation, migration and invasion in cancer cell lines. 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 promising prognostic marker, and knockdown of FMNL1 could inhibit ccRCC cell proliferation, migration and invasion, which might be used as a new effective therapeutic strategy to inhibit the progression of ccRCC.

A novel prognostic signature contributes to precision treatment in colon adenocarcinoma with KRAS mutation

“…FMNL1 encodes a formin-related protein that is implicated in morphogenesis, cytokinesis and cell polarity. FMNL1 has been reported to act as a prognostic factor in multiple tumors (Chen et al, 2018;Higa et al, 2019;Ma et al, 2021); however, the role of FMNL1 in colon cancer has not been investigated yet. Our findings provided new clues for the crucial role of FMNL1 as a potential target for KRAS-mutant colon cancer.…”

Systematic Characterization of Expression Patterns and Immunocorrelations of Formin-Like Genes in Breast Cancer

“…FMNL1 expression was shown to be upregulated in a variety of cancers, and this upregulation aided cell invasiveness. FMNL1 could intensify the aggressiveness of tumor cells intensify the aggressiveness of tumor cells through a variety of ways, in addition to facilitating cytoskeletal remodeling [ 23 ]. FMNL1 increased cell aggressiveness in nasopharyngeal cancer by epigenetically upregulating MTA1.…”

“…In the current study, we discovered that high FMNL1 expression predicted a better prognosis in HCC. Previous studies have linked high FMNL1 expression to a poor prognosis in a variety of cancers, including clear cell renal cell carcinoma [ 23 ], gastric cancer [ 9 ], and glioblastoma [ 28 ]. FMNL1 was found to promote T cell and macrophage migration in the previous studies [ 29 , 30 ].…”

Fatty acid metabolism-related lncRNAs are potential biomarkers for survival prediction in clear cell renal cell carcinoma

“…[12][13][14][15][16][17][18] Notably, the TCGA analysis of ccRCC revealed that metabolic changes play a crucial role in the evolution of ccRCC. [14,19,20] A study and its subsequent analysis revealed a correlation between poorer survival of ccRCC patients and the increased expression of genes related to the pentose phosphate pathway and fatty acid synthesis pathway, as well as the decreased expression of genes related to the TCA cycle. [21] The significance of FA metabolism in cancer cell functioning, as well as the Warburg effect (perturbed glucose metabolism) and altered amino acid metabolism (specifically glutamine metabolism), is gaining recognition.…”