MYB proto-oncogene like 2 promotes hepatocellular carcinoma growth and glycolysis via binding to the Optic atrophy 3 promoter and activating its expression.

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The current study explored the expression of OPA3 in hepatocellular carcinoma (HCC), its association with the prognosis and its involvement in HCC cell proliferation and aerobic glycolysis. In addition, the transcription factors that activate its expression were screened and validated. Gene expression data in normal liver and liver cancer were acquired from the Genotype-Tissue Expression Project (GTEx) and The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (TCGA-LIHC). Chromatin immunoprecipitation-seq data (GSM1010876) in Cistrome Data Browser was used for searching transcriptional factors binding to the OPA3 promoter. HCC cell lines HLF and JHH2 were used for in-vitro and in-vivo studies. Results showed that OPA3 is significantly upregulated in HCC and associated with unfavorable prognosis. OPA3 knockdown impaired HCC cell growth in vitro and in vivo. Besides, it decreased glucose uptake, lactate production, intracellular ATP levels, and extracellular acidification rate (ECAR) of HLF and JHH2 cells. MYB Proto-Oncogene Like 2 (MYBL2) can bind to the promoter of OPA3 and enhance its transcription. MYBL2 knockdown decreased aerobic glycolysis in HCC cells. OPA3 overexpression reversed these alterations. In conclusion, this study revealed a novel MYBL2-OPA3 axis that enhances HCC cell proliferation and aerobic glycolysis.", "claims": [{"id": "claim-method", "statement": "Youden Index [19] for death detection (the gene expression point with the maximum value of area under the curve) was identified in receiver operating characteristic (ROC) analysis. This index was applied as the cutoff for patient separation in Kaplan-Meier (K-M) survival analysis.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35176941", "locator": "sections[3] \"Bioinformatic analysis\" paragraph 2", "quote": "Youden Index [19] for death detection (the gene expression point with the maximum value of area under the curve) was identified in receiver operating characteristic (ROC) analysis. This index was applied as the cutoff for patient separation in Kaplan-Meier (K-M) survival analysis."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The data and material used to support the findings of this study are available from the corresponding author upon request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35176941", "locator": "sections[23] \"Data availability\" paragraph 2", "quote": "The data and material used to support the findings of this study are available from the corresponding author upon request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "This study revealed a novel MYBL2-OPA3 axis that enhances HCC cell proliferation and aerobic glycolysis.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:35176941", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "In conclusion, this study revealed a novel MYBL2-OPA3 axis that enhances HCC cell proliferation and aerobic glycolysis."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "This study revealed a novel MYBL2-OPA3 axis that enhances HCC cell proliferation and aerobic glycolysis.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:35176941"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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OPA3 knockdown impaired HCC cell growth in vitro and in viv", "of OPA3 and enhance its transcription. MYBL2 knockdown decreased aerobic glycolysis in HCC cells. O", ". Each shRNA or overexpression vector was co-transfected into 293 T cells with the packaging plasmids", "the envelope plasmid pMD2.G, using FuGENE 6 transfection reagent (Promega, Madison, WI, USA). HLF and"], "order_basis": "paper_text_order:1016", "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": 0.77, "evidence": ["ckdown impaired HCC cell growth in vitro and in vivo. Besides, it decreased glucose uptake, lacta"], "order_basis": "paper_text_order:1063", "id": "assay:2"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["ing, China). Another two HCC lines, Huh1 and HepG2 were obtained from the American Type Culture", "C cell lines, including Huh1, HLF, JHH2, and HepG2. One-way ANOVA with post-hoc Dunnett’s multi"], "order_basis": "paper_text_order:1786", "id": "assay:3"}, {"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["tors regulating OPA3 transcription. Based on RNA-seq data extracted from TCGA and GTEx, we checke"], "order_basis": "paper_text_order:3688", "id": "assay:4"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["ion by qRT-PCR (a) and protein expression by Western blotting (b) in normal liver parenchyma cells (CP-H04"], "order_basis": "paper_text_order:4683", "id": "assay:5"}, {"role": "data_generation", "definition_id": "apoptosis_assay", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["d by setting shNC as the control group. E-F. 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With IHC data retrieved from the HPA database, we con", "growth curves (l and p) and IHC staining of Ki-67 (m and q) of xenograft tumors derived from H"], "order_basis": "paper_text_order:5801", "id": "assay:7"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["survival_km"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Youden Index [19] for death detection (the gene expression point with the maximum value of area under the curve) was identified in receiver operating characteristic (ROC) analysis. This index was applied as the cutoff for patient separation in Kaplan-Meier (K-M) survival analysis."], "order_basis": "consumes_earlier_output", "id": "assay:8"}]}