{"id":4079,"date":"2018-10-18T14:20:17","date_gmt":"2018-10-18T05:20:17","guid":{"rendered":"http:\/\/www.med.osaka-u.ac.jp\/eng\/?page_id=4079"},"modified":"2022-08-08T11:40:06","modified_gmt":"2022-08-08T02:40:06","slug":"kodama20181018","status":"publish","type":"page","link":"https:\/\/www.med.osaka-u.ac.jp\/eng\/activities\/results\/2018year\/kodama20181018","title":{"rendered":"KODAMA Takahiro, TAKEHARA Tetsuo\u226aGastroenterology and Hepatology\u226b <span>Sleeping Beauty Helps Identify Genes Involved in a Fatty Liver-associated liver cancer<\/span>"},"content":{"rendered":"<ul class=\"linkBar clearfix\">\n<li><a href=\"http:\/\/www.med.osaka-u.ac.jp\/activities\/results\/2018year\/kodama20181012\">Text in Japanese<\/a><\/li>\n<\/ul>\n<p>2018-10-12<\/p>\n<p>Researchers from Osaka University have used a gene screening technique called Sleeping Beauty mutagenesis to identify genes potentially responsible for a fatty liver-associated liver cancer<\/p>\n<p class=\"figure\"><img loading=\"lazy\" decoding=\"async\" class=\"alignleft size-medium wp-image-4089\" src=\"http:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2018\/10\/af45086930c1e90e5f0170422f340607-400x171.png\" alt=\"\" width=\"400\" height=\"171\" srcset=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2018\/10\/af45086930c1e90e5f0170422f340607-400x171.png 400w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2018\/10\/af45086930c1e90e5f0170422f340607.png 664w\" sizes=\"(max-width: 400px) 100vw, 400px\" \/><a href=\"http:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2018\/10\/af45086930c1e90e5f0170422f340607.png\"> <span class=\"caption\">Fig.1: Genome-wide cancer gene discovery by Sleeping Beauty transposon mutagenesis (credit: Osaka University) <\/span> <span class=\"click\">Click to enlarge<\/span><\/a><\/p>\n<p>&nbsp;<\/p>\n<p>With an estimated twenty-thousand protein-coding genes in the human genome, pinpointing a specific gene or pathway responsible for a particular disease can be like finding a needle in the proverbial haystack. This has certainly been the case for hepatocellular carcinoma (HCC), with studies identifying more than ten thousand mutations in the cancer genomes of HCC patients, making it extremely difficult to develop targeted therapies.<\/p>\n<p>In addition to being the second most lethal form of cancer worldwide, increasing numbers of people are diagnosed with HCC each year. A major emerging risk factor for this type of liver cancer, particularly in Western countries, is non-alcoholic fatty liver disease (NAFLD), characterized by excess fat storage in the liver. Linked to a high-fat diet and type 2 diabetes, damage caused to the liver by NAFLD is likened to that seen in cases of serious alcohol abuse.<\/p>\n<p>Given the lack of treatment options and poor prognosis for HCC patients, research teams led by Osaka University set out to identify genes driving the development of NAFLD-HCC. \u201cWe used a new technology to comprehensively search for oncogenes in individual animals by large-scale screening of genes and signal transduction pathways that contribute to the development of liver cancer associated with fatty liver disease\u201d explains Tetsuo Takehara, co-author of a recent study published in Proceedings of the National Academy of Sciences of the United States of America.<\/p>\n<p>This new technology involves small, mobile DNA sequences\u2014charmingly named Sleeping Beauty transposons\u2014that were randomly integrated into the genome in two separate mouse models of NAFLD. Transposon insertion disrupts genes normally involved in tumor suppression or activates nearby oncogenes, allowing researchers to identify potential HCC-causing genes by accelerated or excessive liver tumor development in affected mice.<\/p>\n<p>\u201cAmongst hundreds of candidate genes, we discovered that Sav1, a component of the Hippo pathway, was the most frequently mutated gene in both Sleeping Beauty screens\u201d says leading author Takahiro Kodama. Interestingly, Sav1 and the Hippo pathway are involved in the regulation of organ size. If this pathway is disrupted, liver progenitor cells replicate uncontrollably, leading to tumor formation.<\/p>\n<p>The researchers noted significant liver damage and accumulation of proteins involved in tumor formation in NAFLD mice with a deletion of the Sav1 gene, suggesting they had found their \u201cneedle\u201d. \u201cAlthough we knew that deletion of Sav1 leads to liver enlargement and the development of liver tumors, these new findings provide a key link between dysregulation of the Hippo pathway and the development of HCC in NAFLD\u201d says Kodama. \u201cKnowing this, we can potentially develop new liver cancer treatments targeting the Hippo pathway.\u201d<\/p>\n<p class=\"figure\"><img loading=\"lazy\" decoding=\"async\" class=\"alignleft size-medium wp-image-4090\" src=\"http:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2018\/10\/dcc8172ef808fcaadae790621446a59c-400x198.png\" alt=\"\" width=\"400\" height=\"198\" srcset=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2018\/10\/dcc8172ef808fcaadae790621446a59c-400x198.png 400w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2018\/10\/dcc8172ef808fcaadae790621446a59c.png 623w\" sizes=\"(max-width: 400px) 100vw, 400px\" \/><a href=\"http:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2018\/10\/dcc8172ef808fcaadae790621446a59c.png\">\u00a0<span class=\"caption\">Fig.2: Sav1 gene plays an important protective role in development and progression of fatty liver-associated hepatocellular carcinoma. (credit: Osaka University) <\/span> <span class=\"click\">Click to enlarge<\/span><\/a><\/p>\n<p>The article, \u201cMolecular profiling of non-alcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis\u201d, was published in Proceedings of the National Academy of Sciences of the United States of America at DOI: https:\/\/doi.org\/10.1073\/pnas.1808968115.<\/p>\n<p><strong>Article<\/strong>: Molecular profiling of non-alcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis<br \/><strong>Journal<\/strong>: Proceedings of the National Academy of Sciences of the United States of America<br \/><strong>DOI<\/strong>: https:\/\/doi.org\/10.1073\/pnas.1808968115<br \/><strong>Authors<\/strong>: Takahiro Kodama, Jing Yi, Justin Newberg, Jean Tien, Hao Wu, Milton Finegold, Michiko Kodama, Zhubo Wei, Takeshi Tamura, Tetsuo Takehara, Randy Johnson, Nancy Jenkins, Neal Copeland <br \/>Funding: Japan Society for the Promotion of Science (JSPS), Japan Agency for Medical Research and Development (AMED), Astellas Foundation for Research on Metabolic Disorders, Yasuda Medical Foundation<\/p>\n<p><strong>Summary<\/strong><br \/>Hepatocellular carcinoma, a deadly form of liver cancer, is increasingly being linked to non-alcoholic fatty liver disease; however, the underlying genetic mechanism of disease progression had remained unknown. Using a Sleeping Beauty mutagenesis screen, Osaka University researchers found that Sav1 and downstream components of the Hippo signaling pathway are drivers of the development of liver cancer associated with fatty liver disease. These findings pave the way for liver cancer treatments targeting the Hippo pathway.<\/p>\n<p><strong>Primary Keyword<\/strong>: Medicine\/Health<br \/><strong>Additional Keywords<\/strong>: Cancer, Liver, Diet\/Body Weight <br \/><strong>Categories<\/strong>: Life Sciences, Medical<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Text in Japanese 2018-10-12 Researchers from Osaka University have used a gene screening technique called Slee [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":4089,"parent":3238,"menu_order":117,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"_links":{"self":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/4079"}],"collection":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/comments?post=4079"}],"version-history":[{"count":13,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/4079\/revisions"}],"predecessor-version":[{"id":7442,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/4079\/revisions\/7442"}],"up":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/3238"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/media\/4089"}],"wp:attachment":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/media?parent=4079"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}