Methylmalonic acid promotes colorectal cancer progression via activation of Wnt/β-catenin pathway mediated epithelial–mesenchymal transition

Abstract

Background It has been manifested in several studies that age-related metabolic reprogramming is associated with tumor progression, in particular, colorectal cancer (CRC). Here we investigated the role of upregulated metabolites of the aged serum, including methylmalonic acid (MMA), phosphoenolpyruvate (PEP), and quinolinate (QA), in CRC. Methods Functional assays including CCK-8, EdU, colony formation and transwell experiments were used to ascertain which upregulated metabolite of elderly serum was related to tumor progression. RNA-seq analysis was conducted to explore the potential mechanisms of MMA-induced CRC progression. Subcutaneous tumorigenesis and metastatic tumor models were constructed to verify the function of MMA in vivo. Results Among three consistently increased metabolites of the aged sera, MMA was responsible for tumorigenesis and metastasis in CRC, according to functional assays. The promotion of Epithelial–mesenchymal transition (EMT) was observed in CRC cells treated with MMA, on the basis of protein expression of EMT markers. Moreover, combined with transcriptome sequencing, Wnt/β-catenin signaling pathway was activated in CRC cells treated with MMA, which was verified by western blot and qPCR experiments. Furthermore, animal assays demonstrated the pro-proliferation and promotion of metastasis role of MMA in vivo. Conclusion We have identified that age-dependent upregulation of MMA in serum promoted the progression of CRC via Wnt/β-catenin signaling pathway mediated EMT. These collective findings provide valuable insights into the vital role of age-related metabolic reprogramming in CRC progression and propose a potential therapeutic target for elderly CRC.

WNT/β-catenin regulatory roles on PD-(L)1 and immunotherapy responses

“…The frequency of β-catenin + tumor cells and programmed death-ligand 1 (PD-L1) + immune cells can be regarded as an indicator of CRC progression [ 9 ]. WNT/β-catenin activity promotes CRC progression through induction of epithelial-mesenchymal transition (EMT) [ 10 ]. Expression of Frizzled-10 (Fzd-10) receptor and further β-catenin activation promote cancer stem cell (CSC) expansion and predicts weak prognosis in HCC [ 11 ].…”

Physiological Methylmalonic Acid Contributes to Cell Growth via Mitochondrial Dysfunction in Colorectal Cancer Cell Spheroids

“…Recently, it was found that the blood level of MMA increases with aging and that it also promotes lung cancer metastasis (Gomes et al 2020) (Gomes et al 2022) (Li et al 2022). However, with the exception of a few reports, it is not well known how MMA affects cancers other than lung cancer (Hu et al 2023) (Zhang et al 2024).…”