Comprehensive analysis of the competing endogenous circRNA-lncRNA-miRNA-mRNA network and identification of a novel potential biomarker for hepatocellular carcinoma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34049287", "kind": "science-record", "revision": 7, "content_hash": "sha256:5094ed7dd349153f41ba5b62f45e6c331a308c7626568606522d26e7c69e47b6", "created_at": "2026-11-01T15:41:37Z", "updated_at": "2026-11-01T21:25:26Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Comprehensive analysis of the competing endogenous circRNA-lncRNA-miRNA-mRNA network and identification of a novel potential biomarker for hepatocellular carcinoma.", "doi": "10.18632/aging.203056", "pmid": "34049287", "authors": ["Lu Zhang", "Haisu Tao", "Jiang Li", "Erlei Zhang", "Huifang Liang", "Bixiang Zhang"], "journal": "Aging", "year": 2021, "abstract": "BACKGROUND: The competing endogenous RNAs (ceRNAs) hypothesis has received increasing attention as a novel explanation for tumorigenesis and cancer progression. However, there is still a lack of comprehensive analysis of the circular RNA (circRNA)-long non-coding RNA (lncRNA)-miRNA-mRNA ceRNA network in hepatocellular carcinoma (HCC).\nMETHODS: RNA sequencing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were employed to identify Differentially Expressed mRNAs (DEmRNAs), DElncRNAs, and DEcircRNAs between HCC and normal tissues. Candidates were identified to construct networks through a comprehensive bioinformatics strategy. A prognostic mRNA signature was established based on data from TCGA database and validated using data from the GEO database. Then, the HCC prognostic circRNA-lncRNA-miRNA-mRNA ceRNA network was established. Finally, the expression and function of an unexplored hub gene, deoxythymidylate kinase (DTYMK), was explored through data mining. The results were examined using clinical samples and in vitro experiments.\nRESULTS: We constructed a prognostic signature with seven target mRNAs by univariate, lasso and multivariate Cox regression analyses, which yielded 1, 3 and 5-year AUC values of 0.797, 0.733 and 0.721, respectively, indicating its sensitivity and specificity in the prognosis of HCC. Moreover, the prognostic signature could be validated in GSE14520. The prognostic ceRNA network of 21 circRNAs, 15 lncRNAs, 5 miRNAs, and 7 mRNAs was established according to the targeting relationship between 7 hub mRNAs and other RNAs. Our experiment results indicated that the depletion of DTYMK inhibited liver cancer cell proliferation and invasion.\nCONCLUSIONS: The network revealed in this study may help comprehensively elucidate the ceRNA mechanisms driving HCC, and provide novel candidate biomarkers for evaluating the prognosis of HCC.", "claims": [{"id": "claim-method", "statement": "In order to determine the relationship between the patients' mRNA expression and OS, univariate Cox proportional hazard regression analysis, the lasso penalty Cox analysis and multiple Cox regression analysis were carried out, and a prognostic model was constructed.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34049287", "locator": "sections[5] \"Prognostic model construction\" paragraph 2", "quote": "In order to determine the relationship between the patients' mRNA expression and OS, univariate Cox proportional hazard regression analysis, the lasso penalty Cox analysis and multiple Cox regression analysis were carried out, and a prognostic model was constructed."}], "state": "complete"}, {"id": "claim-data-access", "statement": "We downloaded RNA-seq profiles of HCC patients from TCGA database.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34049287", "locator": "sections[3] \"Data retrieval and processing\" paragraph 2", "quote": "We downloaded RNA-seq profiles of HCC patients from TCGA database."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "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:34049287"], "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. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE138178"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE138178"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:34049287", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.18632/aging.203056", "sha256": 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METHODS: RNA sequencing data from The Cancer Genome Atlas (TCGA) and"], "order_basis": "paper_text_order:467", "id": "assay:1"}, {"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": ["METHODS Sample collection, cell culture, and transfection The 47 pairs of HCC tissues and paracancer n", "io (Guangzhou, China). 97H and G2 cells were transfected with siDTYMK or siNC by using Lipofectamine", ") at 37° C in 5% CO2. Small interfering RNA (siRNA) and the corresponding negative control (siN"], "order_basis": "paper_text_order:2093", "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": ["r Type Culture Collection (CCTCC, China) and cultured in DMEM (Gibico, USA) supplemented with 10% fet", "ittee of Tongji Hospital. MHCC-97H [97H] and HepG2 [G2] were purchased from China Center for Ty"], "order_basis": "paper_text_order:2325", "id": "assay:3"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["TYMK protein level in HPA, we found that the immunohistochemical staining of HCC tissue was also higher than", "MK in the HCCDB database. (B) Representative immunohistochemistry (IHC) images from the HPA with the DTYMK ant", "se. (B) Representative immunohistochemistry (IHC) images from the HPA with the DTYMK antibody"], "order_basis": "paper_text_order:3047", "id": "assay:4"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["cox_ph"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["In order to determine the relationship between the patients' mRNA expression and OS, univariate Cox proportional hazard regression analysis, the lasso penalty Cox analysis and multiple Cox regression analysis were carried out, and a prognostic model was constructed."], "order_basis": "consumes_earlier_output", "id": "assay:5"}]}