{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T14:50:16Z","timestamp":1785336616893,"version":"3.55.0"},"reference-count":81,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70113491"],"award-info":[{"award-number":["70113491"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["HA 7860\/1-2"],"award-info":[{"award-number":["HA 7860\/1-2"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["70113491"],"award-info":[{"award-number":["70113491"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HA 7860\/1-2"],"award-info":[{"award-number":["HA 7860\/1-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Primary liver cancer is the third leading cause of cancer-related death worldwide. An increasing body of evidence suggests that the Hippo tumor suppressor pathway plays a critical role in restricting cell proliferation and determining cell fate during physiological and pathological processes in the liver. Merlin (Moesin-Ezrin-Radixin-like protein) encoded by the NF2 (neurofibromatosis type 2) gene is an upstream regulator of the Hippo signaling pathway. Targeting of Merlin to the plasma membrane seems to be crucial for its major tumor-suppressive functions; this is facilitated by interactions with membrane-associated proteins, including CD44 (cluster of differentiation 44). Mutations within the CD44-binding domain of Merlin have been reported in many human cancers. This study evaluated the relative contribution of CD44- and Merlin-dependent processes to the development and progression of liver tumors. To this end, mice with a liver-specific deletion of the Nf2 gene were crossed with Cd44-knockout mice and subjected to extensive histological, biochemical and molecular analyses. In addition, cells were isolated from mutant livers and analyzed by in vitro assays. Deletion of Nf2 in the liver led to substantial liver enlargement and generation of hepatocellular carcinomas (HCCs), intrahepatic cholangiocarcinomas (iCCAs), as well as mixed hepatocellular cholangiocarcinomas. Whilst deletion of Cd44 had no influence on liver size or primary liver tumor development, it significantly inhibited metastasis formation in Nf2-mutant mice. CD44 upregulates expression of integrin \u03b22 and promotes transendothelial migration of liver cancer cells, which may facilitate metastatic spreading. Overall, our results suggest that CD44 may be a promising target for intervening with metastatic spreading of liver cancer.<\/jats:p>","DOI":"10.3390\/cells12091257","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T01:28:28Z","timestamp":1682558908000},"page":"1257","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Deletion of Cd44 Inhibits Metastasis Formation of Liver Cancer in Nf2-Mutant Mice"],"prefix":"10.3390","volume":"12","author":[{"given":"Monserrat","family":"Gerardo-Ram\u00edrez","sequence":"first","affiliation":[{"name":"Department of Medicine I, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5453-0854","authenticated-orcid":false,"given":"Vanessa","family":"Giam","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9199-8990","authenticated-orcid":false,"given":"Marco","family":"Groth","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Morrison","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), 07745 Jena, Germany"},{"name":"Faculty of Biological Sciences, Friedrich-Schiller University, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9477-4036","authenticated-orcid":false,"given":"Helen L.","family":"May-Simera","sequence":"additional","affiliation":[{"name":"Cilia Cell Biology, Institute of Molecular Physiology, Johannes Gutenberg University, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3991-5721","authenticated-orcid":false,"given":"Markus P.","family":"Radsak","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8314-2682","authenticated-orcid":false,"given":"Jens U.","family":"Marquardt","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University Medical Center Schleswig-Holstein, Campus L\u00fcbeck, 23558 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1967-0621","authenticated-orcid":false,"given":"Peter R.","family":"Galle","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Herrlich","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4857-1561","authenticated-orcid":false,"given":"Beate K.","family":"Straub","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6074-6961","authenticated-orcid":false,"given":"Monika","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA A Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/s41419-020-2509-x","article-title":"Oncogenic driver genes and tumor microenvironment determine the type of liver cancer","volume":"11","author":"Wang","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1002\/ueg2.12286","article-title":"New concepts in the treatment of hepatocellular carcinoma","volume":"10","author":"Sidali","year":"2022","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_4","unstructured":"Gelband, H., Jha, P., Sankaranarayanan, R., and Horton, S. (2015). Cancer: Disease Control Priorities, The International Bank for Reconstruction and Development\/The World Bank. [3rd ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.devcel.2010.06.015","article-title":"The Merlin\/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals","volume":"19","author":"Zhang","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1101\/gad.1938710","article-title":"Nf2\/Merlin controls progenitor homeostasis and tumorigenesis in the liver","volume":"24","author":"Benhamouche","year":"2010","journal-title":"Genes Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"E1312","DOI":"10.1073\/pnas.1110428108","article-title":"Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance","volume":"108","author":"Zhou","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1073\/pnas.0911409107","article-title":"Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression","volume":"107","author":"Song","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1073\/pnas.0911427107","article-title":"Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver","volume":"107","author":"Lu","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1101\/gad.264234.115","article-title":"Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP","volume":"29","author":"Chen","year":"2015","journal-title":"Genes Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1002\/hep.28768","article-title":"Large tumor suppressor homologs 1 and 2 regulate mouse liver progenitor cell proliferation and maturation through antagonism of the coactivators YAP and TAZ","volume":"64","author":"Yi","year":"2016","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E71","DOI":"10.1073\/pnas.1517188113","article-title":"Dysregulated YAP1\/TAZ and TGF-\u03b2 signaling mediate hepatocarcinogenesis in Mob1a\/1b-deficient mice","volume":"113","author":"Nishio","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8248","DOI":"10.1073\/pnas.0912203107","article-title":"The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis","volume":"107","author":"Lee","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.cell.2006.05.030","article-title":"Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach","volume":"125","author":"Zender","year":"2006","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1016\/j.cell.2007.07.019","article-title":"Elucidation of a universal size-control mechanism in Drosophila and mammals","volume":"130","author":"Dong","year":"2007","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1016\/j.cub.2007.10.039","article-title":"YAP1 increases organ size and expands undifferentiated progenitor cells","volume":"17","author":"Camargo","year":"2007","journal-title":"Curr. Biol. CB"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"937957","DOI":"10.3389\/fonc.2022.937957","article-title":"Advances in prognostic and therapeutic targets for hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The hippo signaling pathway","volume":"12","author":"Mranda","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1101\/gad.1602907","article-title":"Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control","volume":"21","author":"Zhao","year":"2007","journal-title":"Genes Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4576","DOI":"10.1002\/cncr.24495","article-title":"Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma","volume":"115","author":"Xu","year":"2009","journal-title":"Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/onc.2015.125","article-title":"Role of Merlin\/NF2 inactivation in tumor biology","volume":"35","author":"Petrilli","year":"2016","journal-title":"Oncogene"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1002\/hep.24450","article-title":"c-Met represents a potential therapeutic target for personalized treatment in hepatocellular carcinoma","volume":"54","author":"You","year":"2011","journal-title":"Hepatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8457","DOI":"10.1038\/ncomms9457","article-title":"A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma","volume":"6","author":"Luo","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/sj.bjc.6604002","article-title":"Nf2\/Merlin: A coordinator of receptor signalling and intercellular contact","volume":"98","author":"Curto","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Sato, T., and Sekido, Y. (2018). NF2\/Merlin Inactivation and Potential Therapeutic Targets in Mesothelioma. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19040988"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1016\/j.febslet.2014.04.001","article-title":"Molecular insights into NF2\/Merlin tumor suppressor function","volume":"588","author":"Cooper","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/humu.20393","article-title":"Mutational spectrum of the NF2 gene: A meta-analysis of 12 years of research and diagnostic laboratory findings","volume":"28","author":"Ahronowitz","year":"2007","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1101\/gad.189601","article-title":"The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44","volume":"15","author":"Morrison","year":"2001","journal-title":"Genes Dev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1038\/sj.onc.1209849","article-title":"Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin","volume":"26","author":"Bai","year":"2007","journal-title":"Oncogene"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1158\/1541-7786.MCR-15-0020-T","article-title":"Tumor Suppressor NF2 Blocks Cellular Migration by Inhibiting Ectodomain Cleavage of CD44","volume":"13","author":"Hartmann","year":"2015","journal-title":"Mol. Cancer Res. MCR"},{"key":"ref_30","first-page":"154","article-title":"CD44 Acts as a Signaling Platform Controlling Tumor Progression and Metastasis","volume":"6","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fcell.2017.00018","article-title":"CD44: A Multifunctional Cell Surface Adhesion Receptor Is a Regulator of Progression and Metastasis of Cancer Cells","volume":"5","author":"Senbanjo","year":"2017","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12935-016-0325-2","article-title":"Prognostic value of CD44 expression in patients with hepatocellular carcinoma: Meta-analysis","volume":"16","author":"Luo","year":"2016","journal-title":"Cancer Cell Int."},{"key":"ref_33","first-page":"5701","article-title":"CD44 Expression Is a Prognostic Factor in Patients with Intrahepatic Cholangiocarcinoma After Surgical Resection","volume":"37","author":"Morine","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_34","first-page":"95","article-title":"Aberrant expression of CD44 in bile duct cancer correlates with poor prognosis","volume":"13","author":"Kunlabut","year":"2012","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9","DOI":"10.4174\/astr.2015.89.1.9","article-title":"CD44 expression in patients with combined hepatocellular cholangiocarcinoma","volume":"89","author":"Kim","year":"2015","journal-title":"Ann. Surg. Treat. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1007\/s12253-014-9745-2","article-title":"Clinicopathologic significance of Sox2, CD44 and CD44v6 expression in intrahepatic cholangiocarcinoma","volume":"20","author":"Gu","year":"2014","journal-title":"Pathol. Oncol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrm1004","article-title":"CD44: From adhesion molecules to signalling regulators","volume":"4","author":"Ponta","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3074","DOI":"10.1101\/gad.242602","article-title":"CD44 is required for two consecutive steps in HGF\/c-Met signaling","volume":"16","author":"Chen","year":"2002","journal-title":"Genes Dev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6105","DOI":"10.1158\/0008-5472.CAN-05-0207","article-title":"A five-amino-acid peptide blocks Met- and Ron-dependent cell migration","volume":"65","author":"Matzke","year":"2005","journal-title":"Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"44754","DOI":"10.1074\/jbc.M206872200","article-title":"Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an A\u03b2-like peptide","volume":"277","author":"Lammich","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1101\/gad.14.13.1617","article-title":"Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2","volume":"14","author":"Giovannini","year":"2000","journal-title":"Genes Dev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.ccell.2018.05.003","article-title":"Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling","volume":"33","author":"Dhar","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2564","DOI":"10.1002\/ijc.33144","article-title":"Cluster of differentiation 44 promotes osteosarcoma progression in mice lacking the tumor suppressor Merlin","volume":"147","author":"Ma","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/nature07517","article-title":"Accurate whole human genome sequencing using reversible terminator chemistry","volume":"456","author":"Bentley","year":"2008","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e36","DOI":"10.1093\/nar\/30.9.e36","article-title":"Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR","volume":"30","author":"Pfaffl","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<151::AID-GENE17>3.0.CO;2-E","article-title":"Hepatocyte-specific expression of Cre recombinase","volume":"26","author":"Kellendonk","year":"2000","journal-title":"Genesis"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<149::AID-GENE16>3.0.CO;2-V","article-title":"DNA excision in liver by an albumin-Cre transgene occurs progressively with age","volume":"26","author":"Postic","year":"2000","journal-title":"Genesis"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1182\/blood.V90.6.2217","article-title":"CD44 regulates hematopoietic progenitor distribution, granuloma formation, and tumorigenicity","volume":"90","author":"Schmits","year":"1997","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4917","DOI":"10.4049\/jimmunol.163.9.4917","article-title":"CD44-deficient mice develop normally with changes in subpopulations and recirculation of lymphocyte subsets","volume":"163","author":"Protin","year":"1999","journal-title":"J. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.dld.2015.05.011","article-title":"Yes-associated protein in the liver: Regulation of hepatic development, repair, cell fate determination and tumorigenesis","volume":"47","author":"Nguyen","year":"2015","journal-title":"Dig Liver Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1038\/nprot.2006.339","article-title":"Clonogenic assay of cells in vitro","volume":"1","author":"Franken","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"306879","DOI":"10.1155\/2012\/306879","article-title":"Anoikis resistance: An essential prerequisite for tumor metastasis","volume":"2012","author":"Kim","year":"2012","journal-title":"Int. J. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1172\/JCI8692","article-title":"The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhesion","volume":"105","author":"Siegelman","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.yexcr.2004.10.015","article-title":"CD44 cross-linking induces integrin-mediated adhesion and transendothelial migration in breast cancer cell line by up-regulation of LFA-1 (\u03b1L\u03b22) and VLA-4 (\u03b14\u03b21)","volume":"304","author":"Wang","year":"2005","journal-title":"Exp. Cell Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1091\/mbc.e11-02-0134","article-title":"c-Met recruits ICAM-1 as a coreceptor to compensate for the loss of CD44 in Cd44 null mice","volume":"22","author":"Olaku","year":"2011","journal-title":"Mol. Biol. Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/978-1-59745-471-1_23","article-title":"Influence of genetic background on genetically engineered mouse phenotypes","volume":"530","author":"Doetschman","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_57","first-page":"217","article-title":"Influence of genetic background on knockout mouse phenotypes","volume":"158","author":"Sanford","year":"2001","journal-title":"Methods Mol. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3389\/fcell.2020.00055","article-title":"The Function of the HGF\/c-Met Axis in Hepatocellular Carcinoma","volume":"8","author":"Wang","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1016\/j.cell.2014.03.060","article-title":"Hippo pathway activity influences liver cell fate","volume":"157","author":"Yimlamai","year":"2014","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"471","DOI":"10.2174\/138920310791824011","article-title":"Merlin, a \u201cmagic\u201d linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival","volume":"11","author":"Stamenkovic","year":"2010","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3655","DOI":"10.1158\/0008-5472.CAN-07-2940","article-title":"Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min\/+) mice attenuates intestinal tumorigenesis","volume":"68","author":"Zeilstra","year":"2008","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/mc.22961","article-title":"cd44 deletion suppresses atypia in the precancerous mouse testis","volume":"58","author":"Li","year":"2019","journal-title":"Mol. Carcinog."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.devcel.2016.09.027","article-title":"Rac1-Mediated DNA Damage and Inflammation Promote Nf2 Tumorigenesis but Also Limit Cell-Cycle Progression","volume":"39","author":"Shi","year":"2016","journal-title":"Dev. Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"ra77","DOI":"10.1126\/scisignal.2004060","article-title":"The p130 isoform of angiomotin is required for Yap-mediated hepatic epithelial cell proliferation and tumorigenesis","volume":"6","author":"Yi","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.oraloncology.2012.11.009","article-title":"CD44 interacts with EGFR and promotes head and neck squamous cell carcinoma initiation and progression","volume":"49","author":"Perez","year":"2013","journal-title":"Oral Oncol."},{"key":"ref_66","first-page":"1783","article-title":"CD44 inhibition attenuates EGFR signaling and enhances cisplatin sensitivity in human EGFR wild-type non-small-cell lung cancer cells","volume":"45","author":"Yin","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1038\/s41388-017-0030-1","article-title":"Differential recruitment of CD44 isoforms by ErbB ligands reveals an involvement of CD44 in breast cancer","volume":"37","author":"Morath","year":"2018","journal-title":"Oncogene"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1083\/jcb.148.6.1159","article-title":"Hyaluronic acid (HA) binding to CD44 activates Rac1 and induces lamellipodia outgrowth","volume":"148","author":"Oliferenko","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4541","DOI":"10.1074\/jbc.M307356200","article-title":"Engagement of CD44 promotes Rac activation and CD44 cleavage during tumor cell migration","volume":"279","author":"Murai","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1158\/0008-5472.CAN-09-2505","article-title":"CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma","volume":"70","author":"Xu","year":"2010","journal-title":"Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2951","DOI":"10.18632\/oncotarget.3095","article-title":"Adhesion glycoprotein CD44 functions as an upstream regulator of a network connecting ERK, AKT and Hippo-YAP pathways in cancer progression","volume":"6","author":"Yu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s40164-021-00247-w","article-title":"CD44 promotes hepatocellular carcinoma progression via upregulation of YAP","volume":"10","author":"Zhang","year":"2021","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.biopha.2018.03.042","article-title":"Standard CD44 modulates YAP1 through a positive feedback loop in hepatocellular carcinoma","volume":"103","author":"Fan","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.devcel.2019.04.018","article-title":"High-Molecular-Weight Hyaluronan Is a Hippo Pathway Ligand Directing Cell Density-Dependent Growth Inhibition via PAR1b","volume":"49","author":"Ooki","year":"2019","journal-title":"Dev. Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1101\/gad.12.7.1058","article-title":"A splice variant of CD44 expressed in the apical ectodermal ridge presents fibroblast growth factors to limb mesenchyme and is required for limb outgrowth","volume":"12","author":"Sherman","year":"1998","journal-title":"Genes Dev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1101\/gad.11.8.996","article-title":"Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation","volume":"11","author":"Kaya","year":"1997","journal-title":"Genes Dev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"8797","DOI":"10.1128\/MCB.01355-07","article-title":"Haploinsufficiency of c-Met in cd44\u2212\/\u2212 mice identifies a collaboration of CD44 and c-Met in vivo","volume":"27","author":"Matzke","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_78","first-page":"4427","article-title":"CD44 stimulation induces integrin-mediated adhesion of colon cancer cell lines to endothelial cells by up-regulation of integrins and c-Met and activation of integrins","volume":"59","author":"Fujisaki","year":"1999","journal-title":"Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Zen, K., Liu, D.Q., Guo, Y.L., Wang, C., Shan, J., Fang, M., Zhang, C.Y., and Liu, Y. (2008). CD44v4 is a major E-selectin ligand that mediates breast cancer cell transendothelial migration. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001826"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1096\/fj.201600398rrr","article-title":"Dynamic contributions of P- and E-selectins to \u03b22-integrin-induced neutrophil transmigration","volume":"31","author":"Gong","year":"2017","journal-title":"FASEB J."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.4049\/jimmunol.1800188","article-title":"Ligation of the CD44 Glycoform HCELL on Culture-Expanded Human Monocyte-Derived Dendritic Cells Programs Transendothelial Migration","volume":"201","author":"Videira","year":"2018","journal-title":"J. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/9\/1257\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:23:31Z","timestamp":1760124211000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/9\/1257"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,26]]},"references-count":81,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["cells12091257"],"URL":"https:\/\/doi.org\/10.3390\/cells12091257","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,26]]}}}