{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:59:47Z","timestamp":1791241187635,"version":"4.1.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":304,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"name":"National 973 Key Basic Research Program of China","award":["2013CB910504"],"award-info":[{"award-number":["2013CB910504"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,11]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Hepatoblastoma (HB) is the most common primary liver tumor in children. Mutations in the \u03b2-catenin gene that lead to constitutive activation of the Wnt pathway have been detected in a large proportion of HB tumors. To identify novel mutations in HB, we performed whole-exome sequencing of six paired HB tumors and their corresponding lymphocytes. This identified 24 somatic nonsynonymous mutations in 21 genes, many of which were novel, including three novel mutations targeting the<\/jats:bold>\n                                 <jats:bold>\n                                    CTNNB1\n                                 <\/jats:bold>\n                                 <jats:bold>(G512V) and<\/jats:bold>\n                                 <jats:bold>\n                                    CAPRIN2\n                                 <\/jats:bold>\n                                 <jats:bold>(R968H\/S969C) genes in the Wnt pathway, and genes previously shown to be involved in the ubiquitin ligase complex (<\/jats:bold>\n                                 <jats:bold>\n                                    SPOP\n                                 <\/jats:bold>\n                                 <jats:bold>,<\/jats:bold>\n                                 <jats:bold>\n                                    KLHL22\n                                 <\/jats:bold>\n                                 <jats:bold>,<\/jats:bold>\n                                 <jats:bold>\n                                    TRPC4AP\n                                 <\/jats:bold>\n                                 <jats:bold>, and<\/jats:bold>\n                                 <jats:bold>\n                                    RNF169\n                                 <\/jats:bold>\n                                 <jats:bold>). Functionally, both the<\/jats:bold>\n                                 <jats:bold>\n                                    CTNNB1\n                                 <\/jats:bold>\n                                 <jats:bold>(G512V) and<\/jats:bold>\n                                 <jats:bold>\n                                    CAPRIN2\n                                 <\/jats:bold>\n                                 <jats:bold>(R968H\/S969C) were observed to be gain-of-functional mutations, and the<\/jats:bold>\n                                 <jats:bold>\n                                    CAPRIN2\n                                 <\/jats:bold>\n                                 <jats:bold>(R968H\/S969C) was also shown to activate the Wnt pathway in HB cells. These findings suggested the activation of the Wnt pathway in HB, which was confirmed by immunohistochemical staining of the \u03b2-catenin in 42 HB tumors. We further used short hairpin RNA (shRNA)-mediated interference to assess the effect of 21 mutated genes on HB cell survival. The results suggested that one novel oncogene (<\/jats:bold>\n                                 <jats:bold>\n                                    CAPRIN2\n                                 <\/jats:bold>\n                                 <jats:bold>) and three tumor suppressors (<\/jats:bold>\n                                 <jats:bold>\n                                    SPOP\n                                 <\/jats:bold>\n                                 <jats:bold>,<\/jats:bold>\n                                 <jats:bold>\n                                    OR5I1\n                                 <\/jats:bold>\n                                 <jats:bold>, and<\/jats:bold>\n                                 <jats:bold>\n                                    CDC20B\n                                 <\/jats:bold>\n                                 <jats:bold>) influence HB cell growth. Moreover, we found that<\/jats:bold>\n                                 <jats:bold>\n                                    SPOP\n                                 <\/jats:bold>\n                                 <jats:bold>S119N is a loss-of-function mutation in HB cells. We finally demonstrated that one of the mechanisms by which<\/jats:bold>\n                                 <jats:bold>\n                                    SPOP\n                                 <\/jats:bold>\n                                 <jats:bold>inhibits HB cell proliferation is through regulating CDKN2B expression.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion\n                                 <\/jats:bold>\n                                 <jats:bold>: These results extend the landscape of genetic alterations in HB and highlight the dysregulation of Wnt and ubiquitin pathways in HB tumorigenesis. (Hepatology 2014;;60:1686\u20131696)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.27243","type":"journal-article","created":{"date-parts":[[2014,6,9]],"date-time":"2014-06-09T16:35:58Z","timestamp":1402331758000},"page":"1686-1696","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":110,"title":["Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase 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