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We used a mouse model of intrahepatic cholangiocarcinoma (CCA), constructed by transposon\u2010mediated somatic gene integration of\n                    <jats:italic>AKT<\/jats:italic>\n                    and\n                    <jats:italic>YAP<\/jats:italic>\n                    into hepatocytes, to investigate the effects of additional integration of\n                    <jats:italic>Myc<\/jats:italic>\n                    or\n                    <jats:italic>Mycn<\/jats:italic>\n                    . Both\n                    <jats:italic>Myc<\/jats:italic>\n                    and\n                    <jats:italic>Mycn<\/jats:italic>\n                    induced a poorly differentiated hepatocellular carcinoma (HCC) component, resulting in the formation of combined hepatocellular\u2010cholangiocarcinoma (cHCC\u2010CCA). Interestingly, the ratio of HCC to CCA components differed significantly;\n                    <jats:italic>AKT\/YAP\/Mycn<\/jats:italic>\n                    (AYN) tumors exhibited a lower proportion of CCA components than\n                    <jats:italic>AKT\/YAP\/Myc<\/jats:italic>\n                    (AYM) tumors. To explore the underlying mechanisms, we analyzed the expression levels of genes involved in liver differentiation. We found that AYN tumors, at both the mRNA and protein levels, exhibited lower expression of HNF1B, a transcription factor that is highly expressed in human CCA but not in HCC. When\n                    <jats:italic>Hnf1b<\/jats:italic>\n                    was co\u2010introduced with AYN, the percentage of the CCA area increased significantly. Furthermore, these tumors exhibited increased expression of TEAD proteins, which interact with YAP to initiate transcription. Notably, treatment with a YAP\u2010TEAD inhibitor suppressed\n                    <jats:italic>AKT\/YAP\/Mycn\/Hnf1b<\/jats:italic>\n                    tumor growth. These findings indicate that\n                    <jats:italic>Myc<\/jats:italic>\n                    and\n                    <jats:italic>Mycn<\/jats:italic>\n                    play distinct roles in the phenotypic determination of primary liver tumors and suggest that their differential effects on\n                    <jats:italic>Hnf1b<\/jats:italic>\n                    expression and subsequent TEAD activation may be a key regulatory mechanism.\n                  <\/jats:p>","DOI":"10.1111\/cas.70233","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T10:41:41Z","timestamp":1763980901000},"page":"536-547","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Difference of\n                    <scp>MYC<\/scp>\n                    and\n                    <scp>MYCN<\/scp>\n                    in Combined Hepatocellular\u2013Cholangiocarcinoma: Regulation of Differentiation by\n                    <scp>HNF1B<\/scp>"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1760-5252","authenticated-orcid":false,"given":"Masanori","family":"Goto","sequence":"first","affiliation":[{"name":"Division of Tumor Pathology, Department of Pathology Asahikawa Medical University School of Medicine  Asahikawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Tumor Pathology, School of Health Sciences Kumamoto University  Kumamoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Division of Tumor Pathology, Department of Pathology Asahikawa Medical University School of Medicine  Asahikawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumiko","family":"Fujii","sequence":"additional","affiliation":[{"name":"Division of Tumor Pathology, Department of Pathology Asahikawa Medical University School of Medicine  Asahikawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kumi","family":"Takasawa","sequence":"additional","affiliation":[{"name":"Division of Tumor Pathology, Department of Pathology Asahikawa Medical University School of Medicine  Asahikawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Kamikokura","sequence":"additional","affiliation":[{"name":"Division of Tumor Pathology, Department of Pathology Asahikawa Medical University School of Medicine  Asahikawa Japan"},{"name":"Department of Diagnostic Pathology Asahikawa Medical University Hospital  Asahikawa 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