{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T07:21:58Z","timestamp":1789456918642,"version":"build-2803163510"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2019,11,6]],"date-time":"2019-11-06T00:00:00Z","timestamp":1572998400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,11,6]],"date-time":"2019-11-06T00:00:00Z","timestamp":1572998400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Aristolochic acid (AA) exposure has been statistically associated with human liver cancers. However, direct evidence of AA exposure\u2013induced liver cancer is absent. This study aims to establish a direct causal relationship between AA exposure and liver cancers based on a mouse model and then explores the AA\u2010mediated genomic alterations that could be implicated in human cancers with AA\u2010associated mutational signature.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      We subjected mice, including phosphatase and tensin homolog (\n                      <jats:italic toggle=\"yes\">Pten<\/jats:italic>\n                      )\u2010deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and CCl\n                      <jats:sub>4<\/jats:sub>\n                      . Significantly, AAI exposure induced mouse liver cancers, including hepatocellular carcinoma (HCC) and combined HCC and intrahepatic cholangiocarcinoma, in a dose\u2010dependent manner. Moreover, AAI exposure also enhanced tumorigenesis in these CCl\n                      <jats:sub>4<\/jats:sub>\n                      \u2010treated or\n                      <jats:italic toggle=\"yes\">Pten<\/jats:italic>\n                      \u2010deficient mice. AAI led to DNA damage and AAI\u2010DNA adduct that could initiate liver cancers through characteristic adenine\u2010to\u2010thymine transversions, as indicated by comprehensive genomic analysis, which revealed recurrent mutations in Harvey rat sarcoma virus oncogene. Interestingly, an AA\u2010associated mutational signature was mainly implicated in human liver cancers, especially from China. Moreover, we detected the AAI\u2010DNA adduct in 25.8% (16\/62) of paratumor liver tissues from randomly selected Chinese patients with HCC. Furthermore, based on phylogenetic analysis, the characteristic mutations were found in the initiating malignant clones in the AA\u2010implicated mouse and human liver cancers where the mutations of tumor protein p53 and Janus kinase 1 were prone to be significantly enriched in the AA\u2010affected human tumors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides evidence for AA\u2010induced liver cancer with the featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA\u2010associated human cancers, especially liver cancers.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.30863","type":"journal-article","created":{"date-parts":[[2019,7,20]],"date-time":"2019-07-20T04:10:16Z","timestamp":1563595816000},"page":"929-942","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":82,"title":["The Mutational Features of Aristolochic Acid\u2013Induced Mouse and Human Liver Cancers"],"prefix":"10.1097","volume":"71","author":[{"given":"Zhao\u2010Ning","family":"Lu","sequence":"first","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Luo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010Nan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Shi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze\u2010Guang","family":"Han","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine,Shanghai Jiao Tong University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,11,6]]},"reference":[{"key":"hep30863-bib-0001-20250501","first-page":"569325","article-title":"Chinese herbs containing aristolochic acid associated with renal failure and urothelial carcinoma: a review from epidemiologic observations to causal 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