Defects in cytochrome c oxidase expression induce a metabolic shift to glycolysis and carcinogenesis.

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Using whole genome microarray expression analysis we show that genetic silencing of the CcO subunit Cox4i1 in mouse C2C12 myoblasts resulted in metabolic shift to glycolysis, activated a retrograde stress signaling, and induced carcinogenesis. In the knockdown cells, the expression of Cox4i1 was less than 5% of the control and the expression of the irreversible glycolytic enzymes (Hk1, Pfkm and Pkm) increased two folds, facilitating metabolic shift to glycolysis. The expression of Ca (2+) sensitive Calcineurin (Ppp3ca) and the expression of PI3-kinase (Pik3r4 and Pik3cb) increased by two folds. This Ca (2+)/Calcineurin/PI3K retrograde stress signaling induced the up-regulation of many nuclear genes involved in tumor progression. Overall, we found 1047 genes with 2-folds expression change (with p-value less than 0.01) between the knockdown and the control, among which were 35 up-regulated genes in pathways in cancer (enrichment p-value less than 10(- 5)). Functional analysis revealed that the up-regulated genes in pathways in cancer were dominated by genes in signal transduction, regulation of transcription and PI3K signaling pathway. These results suggest that a defect in CcO complex initiates a retrograde signaling which can induce tumor progression. Physiological studies of these cells and esophageal tumors from human patients support these results. GEO accession number = GSE68525.", "claims": [{"id": "claim-method", "statement": "Fold changes are presented as the mean ± s.e.m. (standard error of the mean) and p-values were determined by one-tailed Welch's t-test, which is used to test the hypothesis that two populations have equal means and is more reliable than Student's t-test when the samples from two populations have unequal variances and unequal sample sizes [3].", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26697345", "locator": "sections[7] \"Statistical analysis\" paragraph 2", "quote": "Fold changes are presented as the mean ± s.e.m. 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Using whole genome microarray expression analysis we show that genetic sil", "ed cDNA was fragmented and labeled using the Affymetrix GeneChip WT Terminal Labeling kit (PN: 90067", "(3.25 μg) was hybridized for 17 h at 45°C to Affymetrix GeneChip Mouse Gene 2.0ST Arrays (PN: 902118", "versus p-value for the full probeset of the Affymetrix GeneChip Mouse Gene 2.0ST Arrays. Out of 41,"], "order_basis": "paper_text_order:302", "id": "assay:1"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["netic silencing of the CcO subunit Cox4i1 in mouse C2C12 myoblasts resulted in metabolic shift", "ized for 17 h at 45°C to Affymetrix GeneChip Mouse Gene 2.0ST Arrays (PN: 902118). Statistical", "the full probeset of the Affymetrix GeneChip Mouse Gene 2.0ST Arrays. Out of 41,345 probes, 604"], "order_basis": "paper_text_order:393", "id": "assay:2"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["ignaling, and induced carcinogenesis. In the knockdown cells, the expression of Cox4i1 was less tha", "ge (with p-value less than 0.01) between the knockdown and the control, among which were 35 up-regu"], "order_basis": "paper_text_order:534", "id": "assay:3"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["welch_t"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Fold changes are presented as the mean ± s.e.m. 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