{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:01:55Z","timestamp":1791644515944,"version":"4.3.4"},"reference-count":52,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T00:00:00Z","timestamp":1706572800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Intrahepatic cholangiocarcinoma (ICC) is a high\u2010grade malignant digestive system tumor with an insidious onset and unfavorable prognosis. Liensinine, a small molecule derived from plants, has been proven to have significant tumor suppressor activity in other cancers. However, there are no reports on whether liensinine can inhibit the proliferation or metastasis of ICC. This study aimed to explore the tumor\u2010suppressive activity of liensinine in ICC and its underlying mechanisms. The phenotypic changes in ICC cells were monitored in vitro using cell function tests. Western blot and immunofluorescence analyses verified the efficacy of liensinine. Tumor\u2010bearing nude mice were used to explore the effect of liensinine on tumors and its toxicity and side effects in vivo. Liensinine suppressed ICC cell proliferation and arrested the cell cycle at the G1 phase. The epithelial\u2010mesenchymal transition (EMT) of ICC cells was also inhibited, thereby restraining their invasion and migration of tumor cells. In addition, this study found that the potential mechanism of liensinine inhibiting EMT may be via suppression of the TGF\u2010\u03b21\/P\u2010smad3 signaling pathway through hypoxia\u2010inducible factor 1 alpha (HIF\u20101a). In vivo experiments showed that liensinine inhibited the growth of Hucc\u2010T1 transplanted tumors in nude mice. Liensinine restrained the proliferation of ICC cells and suppressed EMT in ICC via the HIF\u20101a\u2010mediated TGF\u2010\u03b21\/P\u2010smad3 signaling pathway.<\/jats:p>","DOI":"10.1002\/mc.23687","type":"journal-article","created":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T14:14:35Z","timestamp":1706624075000},"page":"772-784","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Liensinine inhibits progression of intrahepatic cholangiocarcinoma by regulating TGF\u2010\u03b21 \/P\u2010smad3 signaling through HIF\u20101a"],"prefix":"10.1002","volume":"63","author":[{"given":"Xuewen","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment of Severe Hepato\u2010Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenming","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment of Severe Hepato\u2010Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozai","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment of Severe Hepato\u2010Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment of Severe Hepato\u2010Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rizhao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment of Severe Hepato\u2010Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment of Severe Hepato\u2010Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment of Severe Hepato\u2010Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengping","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment of Severe Hepato\u2010Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiandong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment of Severe Hepato\u2010Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment of Severe Hepato\u2010Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Hepatobiliary Pancreatic Tumor Bioengineering Cross International Joint Laboratory of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiacheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment of Severe Hepato\u2010Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31200"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2011.131"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.01.021"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00153-7"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61903-0"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.10.009"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI159839"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4413"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2020.12.020"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2021.145796"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2018.12.001"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-020-00632-3"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11912-019-0752-z"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11655-018-2562-9"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/jpp\/rgaa006"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1142\/S0192415X19500356"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2021.02.017"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.5732"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.c12-00820"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2020.113566"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1056970"},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2022\/8245614","article-title":"Liensinine inhibits osteosarcoma growth by ROS\u2010Mediated suppression of the JAK2\/STAT3 signaling pathway","volume":"2022","author":"Jia F","year":"2022","journal-title":"Oxid Med Cell Longevity"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/abbs\/gmz041"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8FO01137K"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2015.05.007"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V82.12.3610.3610"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.111044"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-019-0309-8"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408398.2015.1077195"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21759"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30157-1"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2020.1838484"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1030-2"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules21070965"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13061236"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24061131"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-021-02188-y"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-015-1864-y"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222212389"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.10.013"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21249739"},{"key":"e_1_2_10_43_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2022\/1533779","article-title":"Liensinine inhibits cell growth and blocks autophagic flux in Nonsmall\u2010Cell lung cancer","volume":"2022","author":"Chang M","year":"2022","journal-title":"J Oncol"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.3892\/or.2016.5187"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.31557\/APJCP.2023.24.2.551"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcla.23986"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.06.004"},{"issue":"1","key":"e_1_2_10_48_1","first-page":"215","article-title":"Hypoxia\u2010induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia\u2010inducible factor 1\u03b1 activation","volume":"53","author":"Yang X","year":"2018","journal-title":"Int J Oncol"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.42416"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-022-04360-9"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27731"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095-3941.2020.0568"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21051605"}],"container-title":["Molecular Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.23687","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T13:19:42Z","timestamp":1710422382000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mc.23687"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,30]]},"references-count":52,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1002\/mc.23687"],"URL":"https:\/\/doi.org\/10.1002\/mc.23687","archive":["Portico"],"relation":{},"ISSN":["0899-1987","1098-2744"],"issn-type":[{"value":"0899-1987","type":"print"},{"value":"1098-2744","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,30]]},"assertion":[{"value":"2023-07-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}