{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:57:50Z","timestamp":1792504670915,"version":"4.5.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T00:00:00Z","timestamp":1687564800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T00:00:00Z","timestamp":1687564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81872340"],"award-info":[{"award-number":["81872340"]}],"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":["82072626"],"award-info":[{"award-number":["82072626"]}],"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":["81902431"],"award-info":[{"award-number":["81902431"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005953","name":"Society of Hong Kong Scholars","doi-asserted-by":"publisher","award":["XJ2020012"],"award-info":[{"award-number":["XJ2020012"]}],"id":[{"id":"10.13039\/501100005953","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005953","name":"Society of Hong Kong Scholars","doi-asserted-by":"publisher","award":["2020-036"],"award-info":[{"award-number":["2020-036"]}],"id":[{"id":"10.13039\/501100005953","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010722","name":"Harbin Medical University","doi-asserted-by":"publisher","award":["HMUMIF-22008"],"award-info":[{"award-number":["HMUMIF-22008"]}],"id":[{"id":"10.13039\/100010722","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Hepatol Int"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Endocytosis is a fundamental process for internalizing small extracellular vesicles (sEVs). The present study aimed to elucidate the role of clathrin light chain A (CLTA) in sEV uptake in hepatocellular carcinoma (HCC).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Materials and methods<\/jats:title>\n                <jats:p>CLTA expression was analyzed by bioinformatics, quantitative PCR and immunohistochemistry. The clinical relevance of CLTA was analyzed by Fisher\u2019s exact test, Kaplan\u2013Meier analysis, and multivariate cox regression model. The functions of CLTA in sEV uptake and cancerous properties were examined by PKH67-sEV uptake, MTT, colony formation, and transwell assays. Mass spectrometry was used to identify the downstream effectors of CLTA. CLTA inhibitor, Pitstop 2, was tested in a mouse model of patient-derived xenografts (PDXs).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>CLTA expression was higher in tumor tissues than in non-tumorous liver tissues and progressively increased from the early to late tumor stage. CLTA overexpression was associated with larger tumor size and poor prognosis in HCC. Cellular CLTA contributed to the sEV uptake, resulting in enhanced cancerous properties. Mechanistically, CLTA increases capping actin protein gelsolin-like (CAPG) expression to facilitate sEV uptake, thereby promoting the proliferation, motility, and invasiveness of HCC cells. What\u2019s more, the CLTA inhibitor Pitstop 2 alone or in combination with sorafenib attenuated tumor growth in mice implanted with PDXs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The study reveals the role of CLTA in sEV uptake to promote HCC progression. Inhibition of CLTA and its mediated pathway illuminate a new therapeutic strategy for HCC patients.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s12072-023-10562-5","type":"journal-article","created":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T12:16:58Z","timestamp":1687609018000},"page":"1490-1499","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Clathrin light chain A facilitates small extracellular vesicle uptake to promote hepatocellular carcinoma progression"],"prefix":"10.1007","volume":"17","author":[{"given":"Yi","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiu Ling","family":"Fung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander Hin Ning","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene Oi-Lin","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melody Y. M.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Ming","family":"Che","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Ping","family":"Yun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfu","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5637-121X","authenticated-orcid":false,"given":"Judy Wai Ping","family":"Yam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,6,24]]},"reference":[{"key":"10562_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","volume":"71","author":"RL Siegel","year":"2021","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7\u201333","journal-title":"CA Cancer J Clin"},{"issue":"6","key":"10562_CR2","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394\u2013424","journal-title":"CA Cancer J Clin"},{"key":"10562_CR3","doi-asserted-by":"publisher","first-page":"m3544","DOI":"10.1136\/bmj.m3544","volume":"371","author":"JD Yang","year":"2020","unstructured":"Yang JD, Heimbach JK. New advances in the diagnosis and management of hepatocellular carcinoma. BMJ. 2020;371:m3544","journal-title":"BMJ"},{"key":"10562_CR4","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/nrm.2017.125","volume":"19","author":"G van Niel","year":"2018","unstructured":"van Niel G, D\u2019Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213\u2013228","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"3","key":"10562_CR5","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1007\/s10571-016-0366-z","volume":"36","author":"ER Abels","year":"2016","unstructured":"Abels ER, Breakefield XO. Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell Mol Neurobiol. 2016;36(3):301\u2013312","journal-title":"Cell Mol Neurobiol"},{"issue":"6","key":"10562_CR6","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1016\/j.ccell.2016.10.009","volume":"30","author":"A Becker","year":"2016","unstructured":"Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell. 2016;30(6):836\u2013848","journal-title":"Cancer Cell"},{"key":"10562_CR7","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.jconrel.2017.09.019","volume":"266","author":"H Costa Verdera","year":"2017","unstructured":"Costa Verdera H, Gitz-Francois JJ, Schiffelers RM, Vader P. Cellular uptake of extracellular vesicles is mediated by clathrin-independent endocytosis and macropinocytosis. J Control Release. 2017;266:100\u2013108","journal-title":"J Control Release"},{"key":"10562_CR8","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-3-030-94004-1_1","volume":"98","author":"R Mishra","year":"2022","unstructured":"Mishra R, Gupta Y, Ghaley G, Bhowmick NA. Functional diversity of macropinocytosis. Subcell Biochem. 2022;98:3\u201314","journal-title":"Subcell Biochem"},{"key":"10562_CR9","doi-asserted-by":"publisher","first-page":"24641","DOI":"10.3402\/jev.v3.24641","volume":"3","author":"LA Mulcahy","year":"2014","unstructured":"Mulcahy LA, Pink RC, Carter DR. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014;3:24641","journal-title":"J Extracell Vesicles"},{"key":"10562_CR10","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1146\/annurev.biochem.78.081307.110540","volume":"78","author":"GJ Doherty","year":"2009","unstructured":"Doherty GJ, McMahon HT. Mechanisms of endocytosis. Annu Rev Biochem. 2009;78:857\u2013902","journal-title":"Annu Rev Biochem"},{"issue":"5","key":"10562_CR11","doi-asserted-by":"publisher","first-page":"2364","DOI":"10.7150\/thno.47996","volume":"11","author":"C Tu","year":"2021","unstructured":"Tu C, Du Z, Zhang H, Feng Y, Qi Y, Zheng Y, et al. Endocytic pathway inhibition attenuates extracellular vesicle-induced reduction of chemosensitivity to bortezomib in multiple myeloma cells. Theranostics. 2021;11(5):2364\u20132380","journal-title":"Theranostics"},{"key":"10562_CR12","doi-asserted-by":"publisher","first-page":"4974","DOI":"10.1038\/s41467-019-12855-6","volume":"10","author":"M Biancospino","year":"2019","unstructured":"Biancospino M, Buel GR, Nino CA, Maspero E, di Perrotolo RS, Raimondi A, et al. Clathrin light chain A drives selective myosin VI recruitment to clathrin-coated pits under membrane tension. Nat Commun. 2019;10:4974","journal-title":"Nat Commun"},{"key":"10562_CR13","doi-asserted-by":"publisher","first-page":"23527","DOI":"10.1073\/pnas.2003662117","volume":"117","author":"L Redlingshofer","year":"2020","unstructured":"Redlingshofer L, McLeod F, Chen Y, Camus MD, Burden JJ, Palomer E, et al. Clathrin light chain diversity regulates membrane deformation in vitro and synaptic vesicle formation in vivo. Proc Natl Acad Sci USA. 2020;117:23527\u201323538","journal-title":"Proc Natl Acad Sci USA"},{"issue":"10","key":"10562_CR14","doi-asserted-by":"publisher","first-page":"jcs224030","DOI":"10.1242\/jcs.224030","volume":"132","author":"OM Tsygankova","year":"2019","unstructured":"Tsygankova OM, Keen JH. A unique role for clathrin light chain A in cell spreading and migration. J Cell Sci. 2019;132(10):jcs224030","journal-title":"J Cell Sci"},{"key":"10562_CR15","doi-asserted-by":"publisher","first-page":"22258","DOI":"10.1074\/jbc.M114.588046","volume":"289","author":"T Tian","year":"2014","unstructured":"Tian T, Zhu Y-L, Zhou Y-Y, Liang G-F, Wang Y-Y, Hu F-H, et al. Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J Biol Chem. 2014;289:22258\u201322267","journal-title":"J Biol Chem"},{"key":"10562_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2022.151267","volume":"101","author":"M Skruzny","year":"2022","unstructured":"Skruzny M. The endocytic protein machinery as an actin-driven membrane-remodeling machine. Eur J Cell Biol. 2022;101: 151267","journal-title":"Eur J Cell Biol"},{"key":"10562_CR17","doi-asserted-by":"publisher","first-page":"2614","DOI":"10.1007\/s00018-004-4225-6","volume":"61","author":"P Silacci","year":"2004","unstructured":"Silacci P, Mazzolai L, Gauci C, Stergiopulos N, Yin HL, Hayoz D. Gelsolin superfamily proteins: key regulators of cellular functions. Cell Mol Life Sci. 2004;61:2614\u20132623","journal-title":"Cell Mol Life Sci"},{"key":"10562_CR18","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.jsb.2016.07.009","volume":"196","author":"M Lampe","year":"2016","unstructured":"Lampe M, Vassilopoulos S, Merrifield C. Clathrin coated pits, plaques and adhesion. J Struct Biol. 2016;196:48\u201356","journal-title":"J Struct Biol"},{"key":"10562_CR19","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.jconrel.2010.01.036","volume":"145","author":"G Sahay","year":"2010","unstructured":"Sahay G, Alakhova DY, Kabanov AV. Endocytosis of nanomedicines. J Control Release. 2010;145:182\u2013195","journal-title":"J Control Release"},{"key":"10562_CR20","first-page":"9719671","volume":"2022","author":"S Jiang","year":"2022","unstructured":"Jiang S, Yang Y, Zhang Y, Ye Q, Song J, Zheng M, et al. Overexpression of CAPG is associated with poor prognosis and immunosuppressive cell infiltration in ovarian cancer. Dis Mark. 2022;2022:9719671","journal-title":"Dis Mark"},{"key":"10562_CR21","first-page":"186","volume":"18","author":"S Bahrami","year":"2020","unstructured":"Bahrami S, Gheysarzadeh A, Sotoudeh M, Bandehpour M, Khabazian R, Zali H, et al. The association between gelsolin-like actin-capping protein (CapG) overexpression and bladder cancer prognosis. Urol J. 2020;18:186\u2013193","journal-title":"Urol J"},{"key":"10562_CR22","first-page":"8623937","volume":"2018","author":"TJ Tsai","year":"2018","unstructured":"Tsai TJ, Lim YP, Chao WY, Chen CC, Chen YJ, Lin CY, et al. Capping actin protein overexpression in human colorectal carcinoma and its contributed tumor migration. Anal Cell Pathol (Amst). 2018;2018:8623937","journal-title":"Anal Cell Pathol (Amst)"},{"key":"10562_CR23","first-page":"1011","volume":"39","author":"DP Yun","year":"2018","unstructured":"Yun DP, Wang YQ, Meng DL, Ji YY, Chen JX, Chen HY, et al. Actin-capping protein CapG is associated with prognosis, proliferation and metastasis in human glioma. Oncol Rep. 2018;39:1011\u20131022","journal-title":"Oncol Rep"},{"key":"10562_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2019.152683","volume":"215","author":"Z Lang","year":"2019","unstructured":"Lang Z, Chen Y, Zhu H, Sun Y, Zhang H, Huang J, et al. Prognostic and clinicopathological significance of CapG in various cancers: evidence from a meta-analysis. Pathol Res Pract. 2019;215: 152683","journal-title":"Pathol Res Pract"},{"key":"10562_CR25","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1002\/cm.21117","volume":"70","author":"S Nag","year":"2013","unstructured":"Nag S, Larsson M, Robinson RC, Burtnick LD. Gelsolin: the tail of a molecular gymnast. Cytoskeleton (Hoboken). 2013;70:360\u2013384","journal-title":"Cytoskeleton (Hoboken)"},{"key":"10562_CR26","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1083\/jcb.200101113","volume":"154","author":"W Witke","year":"2001","unstructured":"Witke W, Li W, Kwiatkowski DJ, Southwick FS. Comparisons of CapG and gelsolin-null macrophages: demonstration of a unique role for CapG in receptor-mediated ruffling, phagocytosis, and vesicle rocketing. J Cell Biol. 2001;154:775\u2013784","journal-title":"J Cell Biol"},{"key":"10562_CR27","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s12935-022-02469-2","volume":"22","author":"J Lu","year":"2022","unstructured":"Lu J, Chen Y, Zhang X, Guo J, Xu K, Li L. A novel prognostic model based on single-cell RNA sequencing data for hepatocellular carcinoma. Cancer Cell Int. 2022;22:38","journal-title":"Cancer Cell Int"},{"issue":"4","key":"10562_CR28","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1056\/NEJMoa0708857","volume":"359","author":"JM Llovet","year":"2008","unstructured":"Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378\u2013390","journal-title":"N Engl J Med"},{"key":"10562_CR29","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/j.bbcan.2017.10.002","volume":"1868","author":"L Niu","year":"2017","unstructured":"Niu L, Liu L, Yang S, Ren J, Lai PBS, Chen GG. New insights into sorafenib resistance in hepatocellular carcinoma: responsible mechanisms and promising strategies. Biochim Biophys Acta Rev Cancer. 2017;1868:564\u2013570","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"10562_CR30","doi-asserted-by":"publisher","first-page":"175628482110169","DOI":"10.1177\/17562848211016959","volume":"14","author":"A Granito","year":"2021","unstructured":"Granito A, Forgione A, Marinelli S, Renzulli M, Ielasi L, Sansone V, et al. Experience with regorafenib in the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol. 2021;14:17562848211016960","journal-title":"Therap Adv Gastroenterol"},{"issue":"3","key":"10562_CR31","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1080\/14737140.2023.2181162","volume":"23","author":"B Stefanini","year":"2023","unstructured":"Stefanini B, Ielasi L, Chen R, Abbati C, Tonnini M, Tovoli F, et al. TKIs in combination with immunotherapy for hepatocellular carcinoma. Expert Rev Anticancer Ther. 2023;23(3):279\u2013291","journal-title":"Expert Rev Anticancer Ther"}],"container-title":["Hepatology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12072-023-10562-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12072-023-10562-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12072-023-10562-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T05:36:52Z","timestamp":1700545012000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12072-023-10562-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,24]]},"references-count":31,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["10562"],"URL":"https:\/\/doi.org\/10.1007\/s12072-023-10562-5","relation":{},"ISSN":["1936-0533","1936-0541"],"issn-type":[{"value":"1936-0533","type":"print"},{"value":"1936-0541","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,24]]},"assertion":[{"value":"7 March 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Yi Xu, Yue Yao, Liang Yu, Hiu Ling Fung, Alexander Hin Ning Tang, Irene Oi-Lin Ng, Melody YM Wong, Chi-Ming Che, Jing Ping Yun, Yunfu Cui, Judy Wai Ping Yam have declared that there is no conflict of interest exists.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was authorized by the Institutional Review Board of The University of Hong Kong\/Hospital Authority Hong Kong West Cluster (HKU\/HA HKW IRB) and Sun Yat-sen University Cancer Centre. Informed consent was obtained from each participant. All study procedures involving human specimens were handled according to the relevant ethical regulations. All animal research and works were performed under the research protocols CULATR 5714-21 and 5925-21 and were followed rigorously in accordance with the Animals (Control of Experiments) Ordinance (Hong Kong) and the Institute\u2019s guidance from the Centre for Comparative Medical Research (CCMR), Li Ka Shing Faculty of Medicine, The University of Hong Kong. All mice were obtained and kept in a designated pathogen-free environment in CCMR block.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}