H Long Terminal Repeat-Associating 2 (HHLA2) is a Biomarker of Advanced Stage Hepatocellular Carcinoma and Promotes Tumor Cell Development In Vitro.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:33990536", "kind": "science-record", "revision": 9, "content_hash": "sha256:29feefe9d339fb02f00ad70610fb476105e0e19f380cebdb43b2919cbd773294", "created_at": "2026-11-01T15:41:35Z", "updated_at": "2026-11-01T22:46:42Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "H Long Terminal Repeat-Associating 2 (HHLA2) is a Biomarker of Advanced Stage Hepatocellular Carcinoma and Promotes Tumor Cell Development In Vitro.", "doi": "10.12659/MSM.930215", "pmid": "33990536", "authors": ["Min Luo", "Yao Xiong", "Yan Lin", "Rong Liang", "Yongqiang Li", "Lianying Ge"], "journal": "Medical science monitor : international medical journal of experimental and clinical research", "year": 2021, "abstract": "BACKGROUND Several risk factors contribute to the inflammation promoting hepatocellular carcinoma (HCC) development, but the underlying mechanisms are unknown. Human endogenous retrovirus H long terminal repeat-associating 2 (HHLA2), a B7 family member, is highly expressed in various malignant tumor tissues and is related to tumor progression and metastasis. MATERIAL AND METHODS Bioinformatics analysis was used to analyze the gene expression chip GSE33006 of HCC tissue in the GEO database, draw a heat map of differentially expressed genes, and analyze the GO pathway of gene function annotation. Then, we compared HCC tissues with para-carcinoma liver tissues from 55 patients for expression patterns and associations with HHLA2. Effects of HHLA2 knockdown were examined in the human HCC cell line HepG2 to explore effects of HHLA2 on HepG2 cells. RESULTS A significantly higher expression of HHLA2 at the mRNA and protein levels was detected in HCC tissues than in para-carcinoma liver tissues, which was similar to HHLA2 expression in the GSE33006 data. A higher expression of HHLA2 protein was associated with advanced cancer stage, tumor differentiation, and invasion of adjacent structures. In vitro knockdown of HHLA2 expression significantly increased HepG2 cell adhesion, promoted cell apoptosis, induced cell cycle arrest in the G1/S phase, and inhibited cell proliferation, migration, and invasion. CONCLUSIONS Our data indicated there was a higher expression of HHLA2 in HCC tissues than in para-carcinoma liver tissues, and HHLA2 plays a major role in the development and progression of HCC. Owing to its higher expression, HHLA2 is a potential prognostic biomarker for HCC.", "claims": [{"id": "claim-method", "statement": "Differences between groups were assessed using the t test or Mann-Whitney U test, based on data distribution. One-way analysis of variance (ANOVA) was used when more than 2 groups were compared.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33990536", "locator": "sections[12] \"Statistical analysis\" paragraph 2", "quote": "Differences between groups were assessed using the t test or Mann-Whitney U test, based on data distribution. One-way analysis of variance (ANOVA) was used when more than 2 groups were compared."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Data on 3 HCC samples and 3 para-carcinoma samples were retrieved from the human HCC transcriptional chip GSE33006 in the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo) [10].", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33990536", "locator": "sections[3] \"Data Source\" paragraph 2", "quote": "Data on 3 HCC samples and 3 para-carcinoma samples were retrieved from the human HCC transcriptional chip GSE33006 in the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo) [10]."}], "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:33990536"], "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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"sha256:24196556ca454d313459ac6c7ae0daae5e3492f728c45c38016e421bd38e6ca9", "bytes": 27117, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.12659/MSM.930215", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8132585", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE33006", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE33006", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE33006", "version": null, "note": "Data on 3 HCC samples and 3 para-carcinoma samples were retrieved from the human HCC transcriptional chip GSE33006 in the Gene Expression 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Effects of HHLA2 knockdown were examined in the human HCC cell line Hep", "nd invasion of adjacent structures. In vitro knockdown of HHLA2 expression significantly increased"], "order_basis": "paper_text_order:857", "id": "assay:1"}, {"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": ["own were examined in the human HCC cell line HepG2 to explore effects of HHLA2 on HepG2 cells.", "ll line HepG2 to explore effects of HHLA2 on HepG2 cells. RESULTS A significantly higher expres", "of HHLA2 expression significantly increased HepG2 cell adhesion, promoted cell apoptosis, indu"], "order_basis": "paper_text_order:908", "id": "assay:2"}, {"role": "data_generation", "definition_id": "apoptosis_assay", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.69, "evidence": ["increased HepG2 cell adhesion, promoted cell apoptosis, induced cell cycle arrest in the G1/S phase"], "order_basis": "paper_text_order:1404", "id": "assay:3"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["es and para-carcinoma tissues by qRT-PCR and western blot analysis. Eleven normal liver tissues were u", "(both *** P<0.001). (B) Respective cases by western blot showing HHLA2 protein levels in paired sampl"], "order_basis": "paper_text_order:3819", "id": "assay:4"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Differences between groups were assessed using the t test or Mann-Whitney U test, based on data distribution. One-way analysis of variance (ANOVA) was used when more than 2 groups were compared."], "order_basis": "consumes_earlier_output", "id": "assay:5"}]}