Single-cell transcriptomic sequencing data reveal aberrant DNA methylation in SMAD3 promoter region in tumor-associated fibroblasts affecting molecular mechanism of radiosensitivity in non-small cell lung cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:38493128", "kind": "science-record", "revision": 4, "content_hash": "sha256:e40153cd691272deec9233ea0da64710761c8681c122798bc0ad3dd95ef35811", "created_at": "2026-11-01T19:20:26Z", "updated_at": "2026-11-01T22:11:27Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Single-cell transcriptomic sequencing data reveal aberrant DNA methylation in SMAD3 promoter region in tumor-associated fibroblasts affecting molecular mechanism of radiosensitivity in non-small cell lung cancer.", "doi": "10.1186/s12967-024-05057-2", "pmid": "38493128", "authors": ["Fushi Han", "Shuzhen Chen", "Kangwei Zhang", "Kunming Zhang", "Meng Wang", "Peijun Wang"], "journal": "Journal of translational medicine", "year": 2024, "abstract": "OBJECTIVE: Non-small cell lung cancer (NSCLC) often exhibits resistance to radiotherapy, posing significant treatment challenges. This study investigates the role of SMAD3 in NSCLC, focusing on its potential in influencing radiosensitivity via the ITGA6/PI3K/Akt pathway.\nMETHODS: The study utilized gene expression data from the GEO database to identify differentially expressed genes related to radiotherapy resistance in NSCLC. Using the GSE37745 dataset, prognostic genes were identified through Cox regression and survival analysis. Functional roles of target genes were explored using Gene Set Enrichment Analysis (GSEA) and co-expression analyses. Gene promoter methylation levels were assessed using databases like UALCAN, DNMIVD, and UCSC Xena, while the TISCH database provided insights into the correlation between target genes and CAFs. Experiments included RT-qPCR, Western blot, and immunohistochemistry on NSCLC patient samples, in vitro studies on isolated CAFs cells, and in vivo nude mouse tumor models.\nRESULTS: Fifteen key genes associated with radiotherapy resistance in NSCLC cells were identified. SMAD3 was recognized as an independent prognostic factor for NSCLC, linked to poor patient outcomes. High expression of SMAD3 was correlated with low DNA methylation in its promoter region and was enriched in CAFs. In vitro and in vivo experiments confirmed that SMAD3 promotes radiotherapy resistance by activating the ITGA6/PI3K/Akt signaling pathway.\nCONCLUSION: High expression of SMAD3 in NSCLC tissues, cells, and CAFs is closely associated with poor prognosis and increased radiotherapy resistance. SMAD3 is likely to enhance radiotherapy resistance in NSCLC cells by activating the ITGA6/PI3K/Akt signaling pathway.", "claims": [{"id": "claim-method", "statement": "Following this, both univariate and multivariate Cox regression analyses were executed to ascertain independent prognostic factors for NSCLC.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38493128", "locator": "sections[5] \"Cox regression analysis and construction of nomogram\" paragraph 2", "quote": "Following this, both univariate and multivariate Cox regression analyses were executed to ascertain independent prognostic factors for NSCLC."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The datasets generated and/or analysed during the current study are available in the manuscript and supplementary materials.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38493128", "locator": "sections[41] \"notes\" paragraph 1", "quote": "The datasets generated and/or analysed during the current study are available in the manuscript and supplementary materials."}], "state": "complete"}, {"id": "claim-target-result", "statement": "SMAD3 is likely to enhance radiotherapy resistance in NSCLC cells by activating the ITGA6/PI3K/Akt signaling pathway.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:38493128", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "SMAD3 is likely to enhance radiotherapy resistance in NSCLC cells by activating the ITGA6/PI3K/Akt signaling pathway."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "SMAD3 is likely to enhance radiotherapy resistance in NSCLC cells by activating the ITGA6/PI3K/Akt signaling pathway.", "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:38493128"], "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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Experiments included RT-qPCR, Western blot, and immunohistochemistry on N", "rget genes and CAFs. Experiments included RT-qPCR, Western blot, and immunohistochemistry on N", "LC, representing a high-risk gene (Fig. 2A). RT-qPCR data confirmed that the expression of the ab", "ples of NSCLC patients (n = 120) measured by RT-qPCR. * p < 0.05. C Correlation between SMAD3 exp"], "order_basis": "paper_text_order:1039", "id": "assay:1"}, {"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": ["enes and CAFs. 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D Immunohistochemistry of SMAD3 protein in normal lung tissues and"], "order_basis": "paper_text_order:1065", "id": "assay:3"}, {"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": ["in vitro studies on isolated CAFs cells, and in vivo nude mouse tumor models. RESULTS: Fifteen ke", "egion and was enriched in CAFs. In vitro and in vivo experiments confirmed that SMAD3 promotes ra", "ies on isolated CAFs cells, and in vivo nude mouse tumor models. 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