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Mitochondrial matrix protein C14orf159 attenuates colorectal cancer metastasis through suppression of Wnt/β-catenin signaling

ABSTRACT: Despite the progression in understanding the molecular events in colorectal tumorigenesis, the mechanisms underlying metastasis remain unclear. Recently, altered metabolism including mitochondrial function of cancer cells has emerged as an important factor which regulates metastatic capability of cancer. Here, we show that mitochondrial matrix protein C14orf159 attenuates colorectal cancer metastasis by suppressing Wnt/β-catenin signaling. We demonstrated that C14orf159 maintained mitochondrial membrane potential of human colorectal cancer cells and was involved in amino acids and glutathione metabolism. In human colorectal cancer specimens, expression of C14orf159 was decreased in the tumor invasive fronts and metastatic lesions. C14orf159 attenuated the capability of migration, invasion and spheroid growth in colorectal cancer cells in vitro and colorectal tumor growth and metastasis in vivo. Mechanistically, C14orf159 reduced expression of the genes involved in colorectal cancer metastasis including WNT and MMP family partly by maintaining mitochondrial membrane potential. These findings provide a new link between mitochondrial membrane potential and Wnt/β-catenin signaling, and uncover the novel function of the mitochondrial matrix protein C14orf159 as a suppressor in colorectal cancer metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167947 | GEO | 2021/11/02

REPOSITORIES: GEO

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Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.

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Mitochondrial matrix protein C14orf159 attenuates colorectal cancer metastasis through suppression of Wnt/β-catenin signaling

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