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Intestinal Lachnospiraceae bacterium-derived Propionate Inhibits the Progression of Clear Cell Renal Cell Carcinoma

ABSTRACT: Gut microbiota has been reported to be associated with the development of various diseases, however, its interaction with clear cell renal cell carcinoma (ccRCC) remains unknown. To investigate the potential relationship between gut microbiota alteration and ccRCC development, we analyze feces from healthy volunteers and ccRCC patients. We realize that ccRCC patients have a lower abundance of Lachnospiraceae bacterium (L. bacterium). Further experiments reveale that L. bacterium and its metabolites propionate exerte the antitumor effects. Mechanistically, L. bacterium-derived propionate inhibit tumor cell proliferation and migration by down-regulating the expression of HOXD10 and its downstream IFITM1 and then activating JAK1-STAT1/2 pathway. Furthermore, we designe a biofilm coated-L. bacterium as a potential probiotic to improve oral delivery and therapeutic efficacy. Finally, the expanded validation cohort confirme that measuring and targeting L. bacterium and its associated pathways will provide valuable insights into clinical management and improve the prognosis of patients with ccRCC.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse phase

PROVIDER: MTBLS12539 | MetaboLights | 2025-06-13

REPOSITORIES: MetaboLights

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Project description: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.

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Intestinal Lachnospiraceae bacterium-derived Propionate Inhibits the Progression of Clear Cell Renal Cell Carcinoma

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