{"doi":"10.1186/s13046-021-02085-4","title":"Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway","abstract":"<jats:title>Abstract</jats:title><jats:sec>\n                <jats:title>Background</jats:title>\n                <jats:p>Recurrent hepatocellular carcinoma (HCC) shows strong resistance to sorafenib, and the tumor-repopulating cells (TRCs) with cancer stem cell-like properties are considered a driver for its high recurrent rate and drug resistance.</jats:p>\n              </jats:sec><jats:sec>\n                <jats:title>Methods</jats:title>\n                <jats:p>Suppression of TRCs may thus be an effective therapeutic strategy for treating this fatal disease. We evaluated the pharmacology and mechanism of sulfarotene, a new type of synthetic retinoid, on the cancer stem cell-like properties of HCC TRCs, and assessed its preclinical efficacy in models of HCC patient-derived xenografts (PDXs).</jats:p>\n              </jats:sec><jats:sec>\n                <jats:title>Results</jats:title>\n                <jats:p>Sulfarotene selectively inhibited the growth of HCC TRCs in vitro and significantly deterred TRC-mediated tumor formation and lung metastasis in vivo without apparent toxicity, with an IC<jats:sub>50</jats:sub> superior to that of acyclic retinoid and sorafenib, to which the recurrent HCC exhibits significant resistance at advanced stage. Sulfarotene promoted the expression and activation of RARα, which down-regulated SOS2, a key signal mediator associated with RAS activation and signal transduction involved in multiple downstream pathways. Moreover, sulfarotene selectively inhibited tumorigenesis of HCC PDXs with high expression for SOS2.</jats:p>\n              </jats:sec><jats:sec>\n                <jats:title>Conclusions</jats:title>\n                <jats:p>Our study identified sulfarotene as a selective inhibitor for the TRCs of HCC, which targets a novel RARα-SOS2-RAS signal nexus, shedding light on a new, promising strategy of target therapy for advanced liver cancer.</jats:p>\n              </jats:sec>","journal":"Journal of Experimental &amp; Clinical Cancer Research","year":2021,"id":27599,"datarank":0.7282607087855701,"base_score":2.995732273553991,"endowment":2.995732273553991,"self_citation_contribution":0.4493598410330987,"citation_network_contribution":0.27890086775247147,"self_endowment_contribution":0.4493598410330987,"citer_contribution":0.27890086775247147,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":2,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":6,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":156831,"name":"Wenxing Qin","orcid":null,"position":1,"is_corresponding":false},{"id":41797,"name":"Yao Zhang","orcid":"0000-0003-3853-3550","position":2,"is_corresponding":false},{"id":156834,"name":"Yongde Luo","orcid":null,"position":3,"is_corresponding":false},{"id":156836,"name":"Bing Niu","orcid":null,"position":4,"is_corresponding":false},{"id":156837,"name":"Quanlin An","orcid":null,"position":5,"is_corresponding":false},{"id":156838,"name":"Biwei Yang","orcid":null,"position":6,"is_corresponding":false},{"id":156839,"name":"Keqing Shi","orcid":null,"position":7,"is_corresponding":false},{"id":156840,"name":"Zhijie Yu","orcid":null,"position":8,"is_corresponding":false},{"id":156841,"name":"Junwei Chen","orcid":"0000-0002-5785-0984","position":9,"is_corresponding":false},{"id":16135,"name":"Xin Cao","orcid":"0000-0001-5789-7582","position":10,"is_corresponding":false},{"id":156842,"name":"Jinglin Xia","orcid":"0000-0003-1566-3934","position":11,"is_corresponding":false},{"id":156829,"name":"Feng Qi","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":6,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34479623","pmcid":"PMC8418008","openalex_id":"https://openalex.org/W34479623","authors":[],"funders":[{"funder_name":"national natural science foundation of china","grant_id":"81772590","title":null},{"funder_name":"national natural science foundation of china","grant_id":"81572395","title":null},{"funder_name":"natural science foundation of shanghai","grant_id":"20ZR1410400","title":null},{"funder_name":"the open funding of key laboratory of diagnosis and treatment of severe hepato-pancreatic diseases of zhejiang province","grant_id":"2018E10008","title":null},{"funder_name":"interdisziplinäres zentrum für klinische forschung, universitätsklinikum würzburg","grant_id":"JCTD-2019-07","title":null}],"total_grants":5,"fwci":0.0,"citation_percentile":0.00140351,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://jeccr.biomedcentral.com/counter/pdf/10.1186/s13046-021-02085-4","host_type":"GOLD"},{"url":"https://jeccr.biomedcentral.com/counter/pdf/10.1186/s13046-021-02085-4","host_type":"publisher"},{"url":"https://link.springer.com/content/pdf/10.1186/s13046-021-02085-4.pdf","host_type":"publisher"},{"url":"https://link.springer.com/article/10.1186/s13046-021-02085-4/fulltext.html","host_type":"publisher"},{"url":"https://www.ncbi.nlm.nih.gov/pubmed/54411","host_type":"journal"},{"url":"http://www.hebrewbooks.org/54411","host_type":"repository"},{"url":"https://doaj.org/article/b3a503565fdd489584f52d12cff78b3c","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8418008","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8418008","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8418008?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Medical and Biological Sciences","Occupational Health and Safety Research","Quality and Safety in Healthcare","Medicine"],"mesh_terms":["Cell Line, Tumor","Animals","Humans","Mice","Carcinoma, Hepatocellular","Liver Neoplasms","Retinoids","Son of Sevenless Proteins","Antineoplastic Agents","Signal Transduction","Drug Resistance, Neoplasm","Sorafenib"],"keywords":["Graphics","Service (business)","Computer science","Visual arts","Multimedia","Computer graphics (images)","Business","Art","Marketing","Hepatocellular carcinoma","Retinoid","Sos2","Tumor-repopulating Cells","Sulfarotene"],"sdg_mappings":[],"linked_datasets":[{"doi":"10.6084/m9.figshare.16569904.v1","title":"Additional file 1 of Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.16569904","title":"Additional file 1 of Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.16569913.v1","title":"Additional file 3 of Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.16569910.v1","title":"Additional file 2 of Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.16569910","title":"Additional file 2 of Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.16569913","title":"Additional file 3 of Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway","publisher":"figshare","resource_type":"Dataset"}],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-08T18:39:19.997977Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}