{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:59:32Z","timestamp":1791241172032,"version":"4.1.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2403,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,2]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Recent evidence has indicated that Hedgehog (Hh) signaling significantly contributes to liver development and regeneration and that activation of the pathway may contribute to growth of hepatocellular carcinoma (HCC) in adults. However, the role of Hh signaling in pediatric liver tumors remains to be elucidated. In this study, we show that Hh signaling is activated in hepatoblastoma (HB), the most common liver tumor in childhood, with most occurrences before the age of 3 years. The Hh target genes\n                      <jats:italic toggle=\"yes\">glioma-associated oncogene homolog 1<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">GLI1<\/jats:italic>\n                      ) and\n                      <jats:italic toggle=\"yes\">Patched<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">PTCH1<\/jats:italic>\n                      ) showed increased transcript levels in 65% and 30% of HB samples, respectively, compared with normal liver tissues. Most interestingly, the gene encoding the hedgehog interacting protein (\n                      <jats:italic toggle=\"yes\">HHIP<\/jats:italic>\n                      ) is transcriptionally silenced by cytosine-phospho-guanosine (CpG) island promoter hypermethylation in 26% of HB cases and treatment with the DNA-demethylating agent 5-aza-2\u2032-deoxycytidine partially restored\n                      <jats:italic toggle=\"yes\">HHIP<\/jats:italic>\n                      expression. Blocking Hh signaling with the antagonist cyclopamine had a strong inhibitory effect on cell proliferation of HB cell lines with an activated pathway. We further demonstrate that this decrease in cell viability is caused by a massive induction of apoptosis, as shown by morphological changes and phosphatidylserine membrane asymmetry. In cyclopamine-exposed HB cells, caspase 3 and poly(adenosine diphosphate-ribose) polymerase proteins were specifically activated by their proteolytic cleavage.\n                      <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                      This study demonstrates, for the first time, the frequent occurrence of\n                      <jats:italic toggle=\"yes\">GLI1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">PTCH1<\/jats:italic>\n                      overexpression and\n                      <jats:italic toggle=\"yes\">HHIP<\/jats:italic>\n                      promoter methylation in early childhood HB, thus indicating a key role for Hh signaling activation in the malignant transformation of embryonal liver cells. (Hepatology 2009;49:482\u2013490.)\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.22649","type":"journal-article","created":{"date-parts":[[2008,9,22]],"date-time":"2008-09-22T14:33:17Z","timestamp":1222093997000},"page":"482-490","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":90,"title":["Blocking the hedgehog pathway inhibits hepatoblastoma growth 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