Combination of RUNX1 inhibitor and gemcitabine mitigates chemo-resistance in pancreatic ductal adenocarcinoma by modulating BiP/PERK/eIF2α-axis-mediated endoplasmic reticulum stress.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:37697370", "kind": "science-record", "revision": 5, "content_hash": "sha256:b7e66ad4ec116a0a7bef30787fc573dce237494d262b52c4b963628d710a8e3b", "created_at": "2026-11-01T19:02:30Z", "updated_at": "2026-11-01T22:52:41Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Combination of RUNX1 inhibitor and gemcitabine mitigates chemo-resistance in pancreatic ductal adenocarcinoma by modulating BiP/PERK/eIF2α-axis-mediated endoplasmic reticulum stress.", "doi": "10.1186/s13046-023-02814-x", "pmid": "37697370", "authors": ["Chunhua She", "Chao Wu", "Weihua Guo", "Yongjie Xie", "Shouyi Li", "Weishuai Liu", "Chao Xu", "Hui Li", "Pei Cao", "Yanfang Yang", "Xiuchao Wang", "Antao Chang", "Yukuan Feng", "Jihui Hao"], "journal": "Journal of experimental & clinical cancer research : CR", "year": 2023, "abstract": "BACKGROUND: Gemcitabine (GEM)-based chemotherapy is the first-line option for pancreatic ductal adenocarcinoma (PDAC). However, the development of drug resistance limits its efficacy, and the specific mechanisms remain largely unknown. RUNX1, a key transcription factor in hematopoiesis, also involved in the malignant progression of PDAC, but was unclear in the chemoresistance of PDAC.\nMETHODS: Comparative analysis was performed to screen GEM-resistance related genes using our single-cell RNA sequencing(scRNA-seq) data and two public RNA-sequencing datasets (GSE223463, GSE183795) for PDAC. The expression of RUNX1 in PDAC tissues was detected by qRT-PCR, immunohistochemistry (IHC) and western blot. The clinical significance of RUNX1 in PDAC was determined by single-or multivariate analysis and survival analysis. We constructed the stably expressing cell lines with shRUNX1 and RUNX1, and successfully established GEM-resistant cell line. The role of RUNX1 in GEM resistance was determined by CCK8 assay, plate colony formation assay and apoptosis analysis in vitro and in vivo. To explore the mechanism, we performed bioinformatic analysis using the scRNA-seq data to screen for the endoplasm reticulum (ER) stress signaling that was indispensable for RUNX1 in GEM resistance. We observed the cell morphology in ER stress by transmission electron microscopy and validated RUNX1 in gemcitabine resistance depended on the BiP/PERK/eIF2α pathway by in vitro and in vivo oncogenic experiments, using ER stress inhibitor(4-PBA) and PERK inhibitor (GSK2606414). The correlation between RUNX1 and BiP expression was assessed using the scRNA-seq data and TCGA dataset, and validated by RT-PCR, immunostaining and western blot. The mechanism of RUNX1 regulation of BiP was confirmed by ChIP-PCR and dual luciferase assay. Finally, the effect of RUNX1 inhibitor on PDAC was conducted in vivo mouse models, including subcutaneous xenograft and patient-derived xenograft (PDX) mouse models.\nRESULTS: RUNX1 was aberrant high expressed in PDAC and closely associated with GEM resistance. Silencing of RUNX1 could attenuate resistance in GEM-resistant cell line, and its inhibitor Ro5-3335 displayed an enhanced effect in inhibiting tumor growth, combined with GEM treatment, in PDX mouse models and GEM-resistant xenografts. In detail, forced expression of RUNX1 in PDAC cells suppressed apoptosis induced by GEM exposure, which was reversed by the ER stress inhibitor 4-PBA and PERK phosphorylation inhibitor GSK2606414. RUNX1 modulation of ER stress signaling mediated GEM resistance was supported by the analysis of scRNA-seq data. Consistently, silencing of RUNX1 strongly inhibited the GEM-induced activation of BiP and PERK/eIF2α signaling, one of the major pathways involved in ER stress. It was identified that RUNX1 directly bound to the promoter region of BiP, a primary ER stress sensor, and stimulated BiP expression to enhance the reserve capacity for cell adaptation, which in turn facilitated GEM resistance in PDAC cells.\nCONCLUSIONS: This study identifies RUNX1 as a predictive biomarker for response to GEM-based chemotherapy. RUNX1 inhibition may represent an effective strategy for overcoming GEM resistance in PDAC cells.", "claims": [{"id": "claim-method", "statement": "Survival was analyzed using Kaplan–Meier and log-rank tests. Single-or multivariate analyses and the COX model were used to evaluate the hazard of variance related to survival.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:37697370", "locator": "sections[19] \"Statistical analysis\" paragraph 2", "quote": "Survival was analyzed using Kaplan–Meier and log-rank tests. Single-or multivariate analyses and the COX model were used to evaluate the hazard of variance related to survival."}], "state": "complete"}, {"id": "claim-data-access", "statement": "HRA000433 (14 patients with PDAC) was downloaded from The Genome Sequence Archive for Human (GSA-Human). CRA001160 (24 patients with PDAC and 11 control pancreatic tissues) was obtained from the Genome Sequence Archive under project PRJCA001063.TCGA RNA-seq data of PDAC tissues were downloaded from the Genomic Data Commons (GDC) portal, and clinical data were obtained from the TCGA Data Portal.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:37697370", "locator": "sections[36] \"notes\" paragraph 1", "quote": "HRA000433 (14 patients with PDAC) was downloaded from The Genome Sequence Archive for Human (GSA-Human). CRA001160 (24 patients with PDAC and 11 control pancreatic tissues) was obtained from the Genome Sequence Archive under project PRJCA001063.TCGA RNA-seq data of PDAC tissues were downloaded from the Genomic Data Commons (GDC) portal, and clinical data were obtained from the TCGA Data Portal."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Survival analysis revealed that higher RUNX1 expression predicted shorter survival, which was consistent with the TCGA data (Fig. 1H).", "kind": "quantitative", "target": {"value": 0.01, "unit": "p-value", "tolerance": null, "source": "Subsequently, univariate and multivariate analyses were conducted using the Cox proportional hazards model, which demonstrated that high RUNX1 expression was a significant independent risk factor in the prognosis of PDAC patients (p < 0.01) (Table 2)."}, "evidence": [{"asset": "source:pmid:37697370", "locator": "sections[21] \"Aberrant RUNX1 expression indicates poor survival in PDAC\" paragraph 3", "quote": "Survival analysis revealed that higher RUNX1 expression predicted shorter survival, which was consistent with the TCGA data (Fig. 1H)."}, {"asset": "source:pmid:37697370", "locator": "sections[21] \"Aberrant RUNX1 expression indicates poor survival in PDAC\" paragraph 3", "quote": "Subsequently, univariate and multivariate analyses were conducted using the Cox proportional hazards model, which demonstrated that high RUNX1 expression was a significant independent risk factor in the prognosis of PDAC patients (p < 0.01) (Table 2)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Survival analysis revealed that higher RUNX1 expression predicted shorter survival, which was consistent with the TCGA data (Fig. 1H).", "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:37697370"], "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:GSE183795"], "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:GSE183795"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:37697370", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1186/s13046-023-02814-x", "sha256": "sha256:17f22d8c2165c1e30fc2db098fd732fc51db31da334742d7cb69110df9030319", "bytes": 74418, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1186/s13046-023-02814-x", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC10494371", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE183795", "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=GSE183795", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE183795", "version": null, "note": "HRA000433 (14 patients with PDAC) was downloaded from The Genome Sequence Archive for Human (GSA-Human). 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Th", "sistance related genes using our single-cell RNA sequencing(scRNA-seq) data and two public RNA-sequencin"], "order_basis": "paper_text_order:631", "id": "assay:2"}, {"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": ["NX1 in PDAC tissues was detected by qRT-PCR, immunohistochemistry (IHC) and western blot. The clinical signifi", "s detected by qRT-PCR, immunohistochemistry (IHC) and western blot. The clinical significance", "31–36-8, MedChemExpress). Tissue samples and immunohistochemistry (IHC) assay Tumor tissues were obtained from", "s). Tissue samples and immunohistochemistry (IHC) assay Tumor tissues were obtained from pati"], "order_basis": "paper_text_order:799", "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": ["CCK8 assay, plate colony formation assay and apoptosis analysis in vitro and in vivo. To explore th", "expression of RUNX1 in PDAC cells suppressed apoptosis induced by GEM exposure, which was reversed", "of RUNX1 in GEM resistance was determined by CCK8 assay, plate colony formation assay and apop", "with antibodies of RUNX1, BiP, p-eIF2α, and caspase 3 using a DAB substrate kit (Maixin Biotech,"], "order_basis": "paper_text_order:1140", "id": "assay:4"}, {"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": ["on assay and apoptosis analysis in vitro and in vivo. To explore the mechanism, we performed bioi", "n the BiP/PERK/eIF2α pathway by in vitro and in vivo oncogenic experiments, using ER stress inhib", "ect of RUNX1 inhibitor on PDAC was conducted in vivo mouse models, including subcutaneous xenogra", "UNX1 inhibitor on PDAC was conducted in vivo mouse models, including subcutaneous xenograft and"], "order_basis": "paper_text_order:1217", "id": "assay:5"}, {"role": "data_generation", "definition_id": "clinical_cohort", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["models, including subcutaneous xenograft and patient-derived xenograft (PDX) mouse models. RESULTS: RUNX1", "re and at the end of the experiment. For the patient-derived xenograft (PDX) animal model, samples were r", "(IHC) assay Tumor tissues were obtained from patients who underwent radical surgery between December 2"], "order_basis": "paper_text_order:2081", "id": "assay:6"}, {"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": ["(ATCC). SW1990, BxPC3, and L3.7–2 cells were cultured in Roswell Park Memorial Institute Medium (RPMI", "lin/streptomycin (P/S). MIA-PaCa2 cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) su"], "order_basis": "paper_text_order:3701", "id": "assay:7"}, {"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": ["Survival was analyzed using Kaplan–Meier and log-rank tests. Single-or multivariate analyses and the COX model were used to evaluate the hazard of variance related to survival."], "order_basis": "consumes_earlier_output", "id": "assay:8"}]}