Long non-coding RNA NORAD/miR-224-3p/MTDH axis contributes to CDDP resistance of esophageal squamous cell carcinoma by promoting nuclear accumulation of β-catenin.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34893064", "kind": "science-record", "revision": 5, "content_hash": "sha256:d3bc37fdd05d2f2a936a3bfd7fec140c85b64cfe726d10cc6480b01d230a6168", "created_at": "2026-11-01T17:36:36Z", "updated_at": "2026-11-01T22:48:02Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Long non-coding RNA NORAD/miR-224-3p/MTDH axis contributes to CDDP resistance of esophageal squamous cell carcinoma by promoting nuclear accumulation of β-catenin.", "doi": "10.1186/s12943-021-01455-y", "pmid": "34893064", "authors": ["Yunlong Jia", "Cong Tian", "Hongyan Wang", "Fan Yu", "Wei Lv", "Yuqing Duan", "Zishuo Cheng", "Xuexiao Wang", "Yu Wang", "Tianxu Liu", "Jiali Wang", "Lihua Liu"], "journal": "Molecular cancer", "year": 2021, "abstract": "BACKGROUND: Cis-diamminedichloro-platinum (CDDP)-based chemotherapy regimens are the most predominant treatment strategies for patients with esophageal squamous cell carcinoma (ESCC). Dysregulated long non-coding RNAs (lncRNAs) contribute to CDDP resistance, which results in treatment failure in ESCC patients. However, the majority of lncRNAs involved in CDDP resistance in ESCC remain to be elucidated.\nMETHODS: The public Gene Expression Omnibus (GEO) dataset GSE45670 was analysed to reveal potential lncRNAs involved in CDDP resistance of ESCC. Candidate upregulated lncRNAs were detected in ESCC specimens by qRT-PCR to identify crucial lncRNAs. Non-coding RNA activated by DNA damage (NORAD) was selected for further study. Kaplan-Meier analysis and a COX proportional regression model were performed to analyse the potential of NORAD for predicting prognosis of ESCC patients. The role of NORAD in CDDP resistance were determined by conducting gain and loss-of-function experiments in vitro. Fluorescence in situ hybridization (FISH) was performed to determine the subcellular location of NORAD in ESCC cells. A public GEO dataset and bioinformatic algorithms were used to predict the microRNAs (miRNAs) that might be latently sponged by NORAD. qRT-PCR was conducted to verify the expression of candidate miRNAs. Luciferase reporter and Argonaute-2 (Ago2)-RNA immunoprecipitation (RIP) assays were conducted to evaluate the interaction between NORAD and candidate miRNAs. A miRNA rescue experiment was performed to authenticate the NORAD regulatory axis and its effects on CDDP resistance in ESCC cells. Western blotting was conducted to confirm the precise downstream signalling pathway of NORAD. A xenograft mouse model was established to reveal the effect of NORAD on CDDP resistance in vivo.\nRESULTS: The expression of NORAD was higher in CDDP-resistant ESCC tissues and cells than in CDDP-sensitive tissues and cells. NORAD expression was negatively correlated with the postoperative prognosis of ESCC patients who underwent CDDP-based chemotherapy. NORAD knockdown partially arrested CDDP resistance of ESCC cells. FISH showed that NORAD was located in the cytoplasm in ESCC cells. Furthermore, overlapping results from bioinformatic algorithms analyses and qRT-PCR showed that NORAD could sponge miR-224-3p in ESCC cells. Ago2-RIP demonstrated that NORAD and miR-224-3p occupied the same Ago2 to form an RNA-induced silencing complex (RISC) and subsequently regulated the expression of metadherin (MTDH) in ESCC cells. The NORAD/miR-224-3p/MTDH axis promoted CDDP resistance and progression in ESCC cells by promoting nuclear accumulation of β-catenin in vitro and in vivo.\nCONCLUSIONS: NORAD upregulates MTDH to promote CDDP resistance and progression in ESCC by sponging miR-224-3p. Our results highlight the potential of NORAD as a therapeutic target in ESCC patients receiving CDDP-based chemotherapy.", "claims": [{"id": "claim-method", "statement": "Survival analysis was carried out using the log-rank test in association with Kaplan-Meier analysis and the Cox proportional hazards model.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34893064", "locator": "sections[21] \"Statistical analysis\" paragraph 2", "quote": "Survival analysis was carried out using the log-rank test in association with Kaplan-Meier analysis and the Cox proportional hazards model."}], "state": "complete"}, {"id": "claim-data-access", "statement": "All data and materials in our study are available upon reasonable request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34893064", "locator": "sections[36] \"Availability of data and materials\" paragraph 2", "quote": "All data and materials in our study are available upon reasonable request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "NORAD promotes CDDP resistance and progression in ESCC by sponging miR-224-3p, thereby upregulating MTDH and promoting nuclear accumulation of β-catenin.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:34893064", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "NORAD upregulates MTDH to promote CDDP resistance and progression in ESCC by sponging miR-224-3p."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "NORAD promotes CDDP resistance and progression in ESCC by sponging miR-224-3p, thereby upregulating MTDH and promoting nuclear accumulation of β-catenin.", "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:34893064"], "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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Western blotting was conducted to confirm the precise downstr", "ion of MTDH in TE1/CDDP-R cells, detected by western blotting. g NORAD knockdown decreases the nuclear exp"], "order_basis": "paper_text_order:1732", "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": ["eam signalling pathway of NORAD. A xenograft mouse model was established to reveal the effect of NORA", "eveal the effect of NORAD on CDDP resistance in vivo. RESULTS: The expression of NORAD was higher", "clear accumulation of β-catenin in vitro and in vivo. CONCLUSIONS: NORAD upregulates MTDH to prom", "eam signalling pathway of NORAD. A xenograft mouse model was established to reveal the effect o"], "order_basis": "paper_text_order:1838", "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": ["who underwent CDDP-based chemotherapy. NORAD knockdown partially arrested CDDP resistance of ESCC c", "and MTDH-3′-UTR-Mut#4 in TE1/CDDP-R cells co-transfected with miR-224-3p mimic. e The effects of miR-", "n the expression of MTDH in TE1/CDDP-R cells transfected with MTDH-3′-UTR-WT, MTDH-3′-UTR-Mut#1, MTDH", "tes to CDDP resistance of TE1 cells. a NORAD knockdown increases the sensitivity of TE1/CDDP-R cell"], "order_basis": "paper_text_order:2189", "id": "assay:3"}, {"role": "data_generation", "definition_id": "apoptosis_assay", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["e NORAD knockdown increases the CDDP-induced apoptosis rate of TE1/CDDP-R cells, and overexpression", "pression of NORAD decreases the CDDP-induced apoptosis rate of TE1 cells, detected by FCM. f NORAD", "f NORAD/miR-224-3p/MTDH axis on CDDP induced apoptosis of TE1/CDDP-R and TE1 cells. c NORAD knockdo", "ity of TE1/CDDP-R cells to CDDP, detected by CCK-8. b Overexpression of NORAD decreases the sen"], "order_basis": "paper_text_order:7230", "id": "assay:4"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["ion of MTDH in TE1/CDDP-R cells, detected by immunofluorescence. In all cases, error bars denote SD of tripl"], "order_basis": "paper_text_order:10545", "id": "assay:5"}, {"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": ["Survival analysis was carried out using the log-rank test in association with Kaplan-Meier analysis and the Cox proportional hazards model."], "order_basis": "consumes_earlier_output", "id": "assay:6"}]}