{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T06:48:06Z","timestamp":1778222886254,"version":"3.51.4"},"reference-count":50,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,8,14]],"date-time":"2020-08-14T00:00:00Z","timestamp":1597363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hepatocellular carcinoma (HCC) is highly resistant to anticancer therapy and novel therapeutic strategies are needed. Chronotherapy may become a promising approach because it may improve the efficacy of antimitotic radiation and chemotherapy by considering timing of treatment. To date little is known about time\u2010of\u2010day dependent changes of proliferation and DNA damage in HCC. Using transgenic c\u2010myc\/transforming growth factor (TGF\u03b1) mice as HCC animal model, we immunohistochemically demonstrated Ki67 as marker for proliferation and \u03b3\u2010H2AX as marker for DNA damage in HCC and surrounding healthy liver (HL). Core clock genes (<jats:italic>Per1<\/jats:italic>, <jats:italic>Per2<\/jats:italic>, <jats:italic>Cry1<\/jats:italic>, <jats:italic>Cry2<\/jats:italic>, <jats:italic>Bmal 1<\/jats:italic>, <jats:italic>Rev\u2010erb\u03b1<\/jats:italic> and <jats:italic>Clock<\/jats:italic>) were examined by qPCR. Data were obtained from samples collected ex vivo at four different time points and from organotypic slice cultures (OSC). Significant differences were found between HCC and HL. In HCC, the number of Ki67 immunoreactive cells showed two peaks (ex vivo: ZT06 middle of day and ZT18 middle of night; OSC: CT04 and CT16). In ex vivo samples, the number of \u03b3\u2010H2AX positive cells in HCC peaked at ZT18 (middle of the night), while in OSC their number remained high during subjective day and night. In both HCC and HL, clock gene expression showed a time\u2010of\u2010day dependent expression ex vivo but no changes in OSC. The expression of <jats:italic>Per2<\/jats:italic> and <jats:italic>Cry1<\/jats:italic> was significantly lower in HCC than in HL. Our data support the concept of chronotherapy of HCC. OSC may become useful to test novel cancer therapies.<\/jats:p>","DOI":"10.1002\/ijc.33228","type":"journal-article","created":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T12:24:04Z","timestamp":1595507044000},"page":"226-237","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Time\u2010dependent changes in proliferation, <scp>DNA<\/scp> damage and clock gene expression in hepatocellular carcinoma and healthy liver of a transgenic mouse model"],"prefix":"10.1002","volume":"148","author":[{"given":"Soha A.","family":"Hassan","sequence":"first","affiliation":[{"name":"Institute of Anatomy II, Medical Faculty Heinrich\u2010Heine\u2010University  D\u00fcsseldorf Germany"},{"name":"Zoology Department, Faculty of Science Suez University  Suez Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Schmithals","sequence":"additional","affiliation":[{"name":"Department of Medicine 1 University Hospital Frankfurt  Frankfurt Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maike","family":"von Harten","sequence":"additional","affiliation":[{"name":"Department of Medicine 1 University Hospital Frankfurt  Frankfurt Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albrecht","family":"Piiper","sequence":"additional","affiliation":[{"name":"Department of Medicine 1 University Hospital Frankfurt  Frankfurt Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5051-0303","authenticated-orcid":false,"given":"Horst\u2010Werner","family":"Korf","sequence":"additional","affiliation":[{"name":"Institute of Anatomy I, Medical Faculty Heinrich\u2010Heine\u2010University  D\u00fcsseldorf Germany"},{"name":"Institute of Anatomy II, Goethe University  Frankfurt Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"von Gall","sequence":"additional","affiliation":[{"name":"Institute of Anatomy II, Medical Faculty Heinrich\u2010Heine\u2010University  D\u00fcsseldorf Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,8,14]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"IARC. 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