{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:49:18Z","timestamp":1776919758749,"version":"3.51.2"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","license":[{"start":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T00:00:00Z","timestamp":1567468800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:p>Each year, more than 25,000 people succumb to liver cancer in the United States, and this neoplasm represents the second cause of cancer\u2010related death globally. R\u2010spondins (RSPOs) are secreted regulators of Wnt signaling that function in development and promote tissue stem cell renewal. In cancer, RSPOs 2 and 3 are oncogenes first identified by insertional mutagenesis screens in tumors induced by mouse mammary tumor virus and by transposon mutagenesis in the colonic epithelium of rodents. <jats:italic toggle=\"yes\">RSPO2<\/jats:italic> has been reported to be activated by chromosomal rearrangements in colorectal cancer and overexpressed in a subset of hepatocellular carcinoma. Using human liver tumor gene expression data, we first discovered that a subset of liver cancers were characterized by high levels of <jats:italic toggle=\"yes\">RSPO2<\/jats:italic> in contrast to low levels in adjacent nontumor tissue. To determine if RSPOs are capable of inducing liver tumors, we used an <jats:italic toggle=\"yes\">in vivo<\/jats:italic> model from which we found that overexpression of <jats:italic toggle=\"yes\">RSPO2<\/jats:italic> in the liver promoted Wnt signaling, hepatomegaly, and enhanced liver tumor formation when combined with loss of transformation\u2010related protein 53 (<jats:italic toggle=\"yes\">Trp53<\/jats:italic>). Moreover, the Hippo\/yes\u2010associated protein (Yap) pathway has been implicated in many human cancers, influencing cell survival. Histologic and gene expression studies showed activation of Wnt\/\u03b2\u2010catenin and Hippo\/Yap pathways following <jats:italic toggle=\"yes\">RSPO2<\/jats:italic> overexpression. We demonstrate that knockdown of <jats:italic toggle=\"yes\">Yap1<\/jats:italic> leads to reduced tumor penetrance following <jats:italic toggle=\"yes\">RSPO2<\/jats:italic> overexpression in the context of loss of <jats:italic toggle=\"yes\">Trp53. Conclusion: RSPO2<\/jats:italic> overexpression leads to tumor formation in the mouse liver in a Hippo\/Yap\u2010dependent manner. Overall, our results suggest a role for Yap in the initiation and progression of liver tumors and uncover a novel pathway activated in RSPO2\u2010induced malignancies. We show that RSPO2 promotes liver tumor formation <jats:italic toggle=\"yes\">in vivo<\/jats:italic> and <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and that RSPO2's oncogenic activity requires Hippo\/Yap activation in hepatocytes. Both RSPO2 and YAP1 are suggested to represent novel druggable targets in Wnt\u2010driven tumors of the liver.<\/jats:p>","DOI":"10.1002\/hep4.1422","type":"journal-article","created":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T19:35:46Z","timestamp":1567539346000},"page":"1496-1509","source":"Crossref","is-referenced-by-count":23,"title":["R\u2010spondin 2 Drives Liver Tumor Development in a Yes\u2010Associated Protein\u2010Dependent Manner"],"prefix":"10.1097","volume":"3","author":[{"given":"Caitlin B.","family":"Conboy","sequence":"first","affiliation":[{"name":"Masonic Cancer Center,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Germ\u00e1n L.","family":"V\u00e9lez\u2010Reyes","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara R.","family":"Tschida","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsiangyu","family":"Hu","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Koes","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryant","family":"Keller","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Alsinet","sequence":"additional","affiliation":[{"name":"Liver Cancer Translational Research Laboratory,Liver Unit, L'Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer\u2010Hospital Clinic of Barcelona,University of Barcelona,Barcelona,Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Cornell\u00e0","sequence":"additional","affiliation":[{"name":"Liver Cancer Translational Research Laboratory,Liver Unit, L'Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer\u2010Hospital Clinic of Barcelona,University of Barcelona,Barcelona,Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roser","family":"Pinyol","sequence":"additional","affiliation":[{"name":"Liver Cancer Translational Research Laboratory,Liver Unit, L'Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer\u2010Hospital Clinic of Barcelona,University of Barcelona,Barcelona,Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan E.","family":"Abrahante","sequence":"additional","affiliation":[{"name":"University of Minnesota Informatics Institute,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nuri A.","family":"Temiz","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael A.","family":"Linden","sequence":"additional","affiliation":[{"name":"Comparative Pathology Shared Resource,University of Minnesota,St. Paul,MN"},{"name":"Department of Medicine,Division of Hematology, Oncology, and Transplantation,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khalid","family":"Amin","sequence":"additional","affiliation":[{"name":"Comparative Pathology Shared Resource,University of Minnesota,St. Paul,MN"},{"name":"Department of Medicine,Division of Hematology, Oncology, and Transplantation,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy P.","family":"Kuka","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent W.","family":"Keng","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center,University of Minnesota,Minneapolis,MN"},{"name":"Department of Applied Biology and Chemical Technology,Hong Kong Polytechnic University,Kowloon,Hong Kong"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josep M.","family":"Llovet","sequence":"additional","affiliation":[{"name":"Liver Cancer Translational Research Laboratory,Liver Unit, L'Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer\u2010Hospital Clinic of Barcelona,University of Barcelona,Barcelona,Spain"},{"name":"Mount Sinai Liver Cancer Program,Division of Liver Diseases,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York,NY"},{"name":"Catalan Institution for Research and Advanced Studies,Barcelona,Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy K.","family":"Starr","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Women's Health,University of Minnesota,Minneapolis,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Largaespada","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center,University of Minnesota,Minneapolis,MN"},{"name":"Department of Pediatrics,University of 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