{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T04:14:45Z","timestamp":1786248885624,"version":"build-2736575974"},"reference-count":48,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2020,3,2]],"date-time":"2020-03-02T00:00:00Z","timestamp":1583107200000},"content-version":"unspecified","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81702767"],"award-info":[{"award-number":["81702767"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81801066"],"award-info":[{"award-number":["81801066"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Funds from the Renmin Hospital, Hubei University of Medicine","award":["Yong Li, 03328"],"award-info":[{"award-number":["Yong Li, 03328"]}]},{"name":"Funds from the Wuhan University","award":["2042019kf0206"],"award-info":[{"award-number":["2042019kf0206"]}]},{"name":"National Basic Research Program of China (973program\uff09","award":["2015CB932600"],"award-info":[{"award-number":["2015CB932600"]}]},{"name":"Hubei Provincial Natural Science Foundation of China","award":["2018CFC874"],"award-info":[{"award-number":["2018CFC874"]}]},{"DOI":"10.13039\/501100011930","name":"Beijing Medical and Health Foundation","doi-asserted-by":"publisher","award":["YWJKJJHKYJJ-B17241-Q1"],"award-info":[{"award-number":["YWJKJJHKYJJ-B17241-Q1"]}],"id":[{"id":"10.13039\/501100011930","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,2,5]]},"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Interferon-\u03b1 (IFN-\u03b1) plays a pivotal role in host antitumor immunity, and the evasion of IFN-\u03b1 signaling pathway can lead to IFN-\u03b1 resistance during the treatment of cancer. Although the interplay between IFN-\u03b1 and tumor cells has been extensively investigated in differentiated tumor cells, much less attention has been directed to tumor-repopulating cells (TRCs).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Three-dimentional soft fibrin matrix was used to select and grow highly malignant and tumorigenic melanoma TRCs. The regulation of integrin \u03b23 (ITGB3)-c-SRC-STAT signaling pathway in melanoma TRCs was investigated both in vitro and in vivo. The relevant mRNA and protein expression levels were analyzed by qRT-PCR and western blot analysis. Immunoprecipitation and chromatin immunoprecipitation (ChIP) followed by qPCR (ChIP-qPCR) assays were performed to detect protein-protein and protein-DNA interactions. The clinical impacts of retinoic acid inducible gene-I (RIG-I) were assessed in melanoma datasets obtained from The Cancer Genome Atlas and Gene Expression Omnibus profiles.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>IFN-\u03b1-induced apoptosis was decreased in melanoma TRCs. Compared with conventional flask-cultured cells, IFN-\u03b1-mediated STAT1 activation was diminished in melanoma TRCs. Decreased expression of RIG-I in melanoma TRCs led to diminished activation of STAT1 via enhancing the interaction between Src homology region 2 domain-containing phosphatase-1 and STAT1. In addition, low expression levels of RIG-I correlated with poor prognosis in patients with melanoma. STAT3 was highly phosphorylated in TRCs and knockdown of STAT3 reversed the downregulation of RIG-I in TRCs. Knockdown of STAT3 resulted in STAT1 activation and increased expression of the pro-apoptosis genes in IFN-\u03b1-treated TRCs. Combined treatment of STAT3 inhibitor and IFN-\u03b1 increased the apoptosis rate of TRCs. Disruption of ITGB3\/c-SRC\/STAT3 signaling pathway significantly elevated the efficiency of IFN-\u03b1-induced apoptosis of TRCs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In melanoma TRCs, ITGB3-c-SRC-STAT3 pathway caused RIG-I repression and then affect STAT1 activation to cause resistance to IFN-\u03b1-induced apoptosis. RIG-I is a prognostic marker in patients with melanoma. Combination of STAT3 inhibitor and IFN-\u03b1 could enhance the efficacy of melanoma treatment. Our findings may provide a new concept of combinatorial treatment for future immunotherapy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2019-000111","type":"journal-article","created":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T05:36:03Z","timestamp":1583732163000},"page":"e000111","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["Downregulation of RIG-I mediated by ITGB3\/c-SRC\/STAT3 signaling confers resistance to interferon-\u03b1-induced apoptosis in tumor-repopulating cells of melanoma"],"prefix":"10.1136","volume":"8","author":[{"given":"Yong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingqiu","family":"Song","sequence":"additional","affiliation":[{"name":"Cancer Center of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pindong","family":"Li","sequence":"additional","affiliation":[{"name":"Cancer Center of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haizhou","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China"},{"name":"Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongjie","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuandong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YunYan","family":"Tai","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianhe","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longchao","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiufang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanbin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"},{"name":"Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0958-5506","authenticated-orcid":false,"given":"Jing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China"},{"name":"Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengjun","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"},{"name":"Institute of Cancer Research, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2020,3,8]]},"reference":[{"key":"2025100307465554000_8.1.e000111.1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1961"},{"key":"2025100307465554000_8.1.e000111.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.14"},{"key":"2025100307465554000_8.1.e000111.3","doi-asserted-by":"publisher","DOI":"10.1038\/nri1604"},{"key":"2025100307465554000_8.1.e000111.4","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/s41573-018-0011-2","article-title":"Interferons \u03b1 and \u03b2 in cancer: therapeutic opportunities from new insights","volume":"18","author":"Borden","year":"2019","journal-title":"Nat Rev Drug Discov"},{"key":"2025100307465554000_8.1.e000111.5","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.37.5394"},{"key":"2025100307465554000_8.1.e000111.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1004095"},{"key":"2025100307465554000_8.1.e000111.7","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1996.420"},{"key":"2025100307465554000_8.1.e000111.8","doi-asserted-by":"crossref","unstructured":"Arimoto K-I , Miyauchi S , Stoner SA , et al . Negative regulation of type I IFN signaling. J Leukoc Biol 2018. doi:10.1002\/JLB.2MIR0817-342R. [Epub ahead of print: 22 Jan 2018].","DOI":"10.1002\/JLB.2MIR0817-342R"},{"key":"2025100307465554000_8.1.e000111.9","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29004"},{"key":"2025100307465554000_8.1.e000111.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.01.004"},{"key":"2025100307465554000_8.1.e000111.11","doi-asserted-by":"publisher","DOI":"10.1038\/sj.thj.6200004"},{"key":"2025100307465554000_8.1.e000111.12","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/icb.2013.41","article-title":"Modulation of antitumour immune responses by intratumoural Stat1 expression","volume":"91","author":"Messina","year":"2013","journal-title":"Immunol Cell Biol"},{"key":"2025100307465554000_8.1.e000111.13","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13045-019-0722-9","article-title":"Differential roles of STAT1 and STAT2 in the sensitivity of JAK2V617F- vs. BCR-ABL-positive cells to interferon alpha","volume":"12","author":"Schubert","year":"2019","journal-title":"J Hematol Oncol"},{"key":"2025100307465554000_8.1.e000111.14","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrclinonc.2017.166","article-title":"Tumour heterogeneity and resistance to cancer therapies","volume":"15","author":"Dagogo-Jack","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"2025100307465554000_8.1.e000111.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.02.005"},{"key":"2025100307465554000_8.1.e000111.16","doi-asserted-by":"publisher","DOI":"10.1038\/nmat3361"},{"key":"2025100307465554000_8.1.e000111.17","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-2615"},{"key":"2025100307465554000_8.1.e000111.18","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41419-019-1309-7","article-title":"Soft fibrin matrix downregulates DAB2IP to promote Nanog-dependent growth of colon tumor-repopulating cells","volume":"10","author":"Zhang","year":"2019","journal-title":"Cell Death Dis"},{"key":"2025100307465554000_8.1.e000111.19","doi-asserted-by":"publisher","DOI":"10.1038\/nature07567"},{"key":"2025100307465554000_8.1.e000111.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.10.033"},{"key":"2025100307465554000_8.1.e000111.21","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms15207","article-title":"Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-\u03b3-induced immunologic dormancy of tumor-repopulating cells","volume":"8","author":"Liu","year":"2017","journal-title":"Nat Commun"},{"key":"2025100307465554000_8.1.e000111.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.11.011"},{"key":"2025100307465554000_8.1.e000111.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2013.08.007"},{"key":"2025100307465554000_8.1.e000111.24","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-2509"},{"key":"2025100307465554000_8.1.e000111.25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905139106"},{"key":"2025100307465554000_8.1.e000111.26","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx247"},{"key":"2025100307465554000_8.1.e000111.27","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2407-14-970","article-title":"PROGgeneV2: enhancements on the existing database","volume":"14","author":"Goswami","year":"2014","journal-title":"BMC Cancer"},{"key":"2025100307465554000_8.1.e000111.28","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1172\/JCI96329","article-title":"STAT3\/p53 pathway activation disrupts IFN-\u03b2\u2013induced dormancy in tumor-repopulating cells","volume":"128","author":"Liu","year":"2018","journal-title":"J Clin Invest"},{"key":"2025100307465554000_8.1.e000111.29","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3818"},{"key":"2025100307465554000_8.1.e000111.30","doi-asserted-by":"publisher","DOI":"10.1126\/science.7541555"},{"key":"2025100307465554000_8.1.e000111.31","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1549407"},{"key":"2025100307465554000_8.1.e000111.32","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2748"},{"key":"2025100307465554000_8.1.e000111.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2336149100"},{"key":"2025100307465554000_8.1.e000111.34","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042617-053309"},{"key":"2025100307465554000_8.1.e000111.35","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1007\/s13238-017-0431-5","article-title":"Rig-I: a multifunctional protein beyond a pattern recognition receptor","volume":"9","author":"Xu","year":"2018","journal-title":"Protein Cell"},{"key":"2025100307465554000_8.1.e000111.36","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511797200"},{"key":"2025100307465554000_8.1.e000111.37","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406413200"},{"key":"2025100307465554000_8.1.e000111.38","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1004128"},{"key":"2025100307465554000_8.1.e000111.39","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.redox.2018.10.024","article-title":"Enhanced mitochondrial pyruvate transport elicits a robust ROS production to sensitize the antitumor efficacy of interferon-\u03b3 in colon cancer","volume":"20","author":"Tai","year":"2019","journal-title":"Redox Biol"},{"key":"2025100307465554000_8.1.e000111.40","doi-asserted-by":"publisher","DOI":"10.1038\/nri3845"},{"key":"2025100307465554000_8.1.e000111.41","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/BF00046905","article-title":"Fibrin as a component of the tumor stroma: origins and biological significance","volume":"2","author":"Dvorak","year":"1983","journal-title":"Cancer And Metastasis Review"},{"key":"2025100307465554000_8.1.e000111.42","doi-asserted-by":"crossref","first-page":"3302","DOI":"10.1182\/blood.V96.10.3302","article-title":"Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells","volume":"96","author":"Palumbo","year":"2000","journal-title":"Blood"},{"key":"2025100307465554000_8.1.e000111.43","first-page":"11","article-title":"Fibrinogen and tumor cell metastasis","volume":"31","author":"Palumbo","year":"2001","journal-title":"Haemostasis"},{"key":"2025100307465554000_8.1.e000111.44","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-3233(05)70008-5"},{"key":"2025100307465554000_8.1.e000111.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2014.12.006"},{"key":"2025100307465554000_8.1.e000111.46","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2953"},{"key":"2025100307465554000_8.1.e000111.47","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-2663"},{"key":"2025100307465554000_8.1.e000111.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2006.08.011"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2019-000111","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T14:47:07Z","timestamp":1759502827000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2019-000111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,3,8]]},"published-print":{"date-parts":[[2020,3]]}},"alternative-id":["10.1136\/jitc-2019-000111"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2019-000111","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3]]}}}