FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2760562495> ?p ?o ?g. }

• W2760562495 endingPage "2725" @default.
• W2760562495 startingPage "2711" @default.
• W2760562495 abstract "Activation of the phosphoinositide 3-kinase–AKT, Yes-associated protein (YAP), and MYC pathways is involved in human liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). However, the nature of the interactions among these pathways has remained poorly understood. Herein, we demonstrate the coordination of these pathways during the formation of mouse liver tumors induced by hepatocyte-specific somatic integration of myristoylated AKT, mutant YAP, Myc, or their combinations. Although the introduction of YAP or Myc alone was inefficient in inducing tumors, these proteins accelerated tumorigenesis induced by AKT. The generated tumors demonstrated various histological features: low-grade HCC by AKT/Myc, CC by AKT/YAP, and high-grade HCC by AKT/Myc/YAP. CC induced by AKT/YAP was associated with activation of the Notch pathway. Interestingly, the combination of Myc and YAP generated tumors composed of hepatoblast/stem-like cells expressing mRNA for Afp, Dlk1, Nanog, and Sox2 and occasionally forming immature ducts. Finally, immunohistochemical analysis revealed that human HCC and CC were predominantly associated with phosphorylation of S6 and glycogen synthase kinase-3β, respectively, and >60% of CC cases were positive for both phosphorylated glycogen synthase kinase--3β and YAP. Our study suggests that hepatocyte-derived tumors demonstrate a wide spectrum of tumor phenotypes, including HCC, CC, and hepatoblastoma-like, through the combinatory effects of the oncogenic pathways and that the state of the phosphoinositide 3-kinase–AKT pathway is a key determinant of differentiation. Activation of the phosphoinositide 3-kinase–AKT, Yes-associated protein (YAP), and MYC pathways is involved in human liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). However, the nature of the interactions among these pathways has remained poorly understood. Herein, we demonstrate the coordination of these pathways during the formation of mouse liver tumors induced by hepatocyte-specific somatic integration of myristoylated AKT, mutant YAP, Myc, or their combinations. Although the introduction of YAP or Myc alone was inefficient in inducing tumors, these proteins accelerated tumorigenesis induced by AKT. The generated tumors demonstrated various histological features: low-grade HCC by AKT/Myc, CC by AKT/YAP, and high-grade HCC by AKT/Myc/YAP. CC induced by AKT/YAP was associated with activation of the Notch pathway. Interestingly, the combination of Myc and YAP generated tumors composed of hepatoblast/stem-like cells expressing mRNA for Afp, Dlk1, Nanog, and Sox2 and occasionally forming immature ducts. Finally, immunohistochemical analysis revealed that human HCC and CC were predominantly associated with phosphorylation of S6 and glycogen synthase kinase-3β, respectively, and >60% of CC cases were positive for both phosphorylated glycogen synthase kinase--3β and YAP. Our study suggests that hepatocyte-derived tumors demonstrate a wide spectrum of tumor phenotypes, including HCC, CC, and hepatoblastoma-like, through the combinatory effects of the oncogenic pathways and that the state of the phosphoinositide 3-kinase–AKT pathway is a key determinant of differentiation. As the third leading cause of cancer death in the world, primary liver cancer is refractory to various treatment modalities. This finding may be partly explained by its wide genetic variations, as reflected by diverse phenotypes and histological types.1Zucman-Rossi J. Villanueva A. Nault J.C. Llovet J.M. Genetic landscape and biomarkers of hepatocellular carcinoma.Gastroenterology. 2015; 149: 1226-1239.e4Abstract Full Text Full Text PDF PubMed Scopus (765) Google Scholar Although hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CC) are prototypical epithelial liver cancers, there are many intermediate variants [combined hepatocellular cholangiocarcinoma (cHCC-CC)] and tumors reminiscent of immature (fetal) liver [hepatoblastoma (HB)]. On morphological and immunohistochemical grounds, it has been hypothesized that HCC and CC are derived from hepatocytes and bile ducts/ductules (cholangiocytes), respectively. Some cHCC-CC subtypes and a fraction of HCCs have been regarded as tumors of immature bipotential cells or liver stem/progenitor cells with hepatoblastic features, which have been postulated to present in the adult liver.2Komuta M. Spee B. Vander Borght S. De Vos R. Verslype C. Aerts R. Yano H. Suzuki T. Matsuda M. Fujii H. Desmet V.J. Kojiro M. Roskams T. Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin.Hepatology. 2008; 47: 1544-1556Crossref PubMed Scopus (290) Google Scholar, 3Lee J.S. Heo J. Libbrecht L. Chu I.S. Kaposi-Novak P. Calvisi D.F. Mikaelyan A. Roberts L.R. Demetris A.J. Sun Z. Nevens F. Roskams T. Thorgeirsson S.S. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells.Nat Med. 2006; 12: 410-416Crossref PubMed Scopus (790) Google Scholar However, the cells of origin and the mechanisms of phenotypic determination of primary liver cancer have remained obscure. Mouse hepatocarcinogenesis models using diethylnitrosamine or chronic liver injuries (eg, carbon tetrachloride and thioacetamide) to induce liver tumors apparently exhibit hepatocytic differentiation (hepatocellular adenoma or HCC) with reactivation of a variety of fetal/neonatal liver genes.4Chen X. Yamamoto M. Fujii K. Nagahama Y. Ooshio T. Xin B. Okada Y. Furukawa H. Nishikawa Y. Differential reactivation of fetal/neonatal genes in mouse liver tumors induced in cirrhotic and non-cirrhotic conditions.Cancer Sci. 2015; 106: 972-981Crossref PubMed Scopus (31) Google Scholar Various transgenic models of HCC have been generated through liver-specific overexpression of oncogenes, such as Myc, Tgfa, E2F1, Ccnd1, and HRASG12V, or genes that encode viral proteins, such as HbsAg, HBX, and SV40 T-Ag.5Lee J.S. Grisham J.W. Thorgeirsson S.S. Comparative functional genomics for identifying models of human cancer.Carcinogenesis. 2005; 26: 1013-1020Crossref PubMed Scopus (47) Google Scholar In addition, various types of HCC have been induced in mice lacking Mdr2, Lkb1, or AOX genes.6Mauad T.H. van Nieuwkerk C.M. Dingemans K.P. Smit J.J. Schinkel A.H. Notenboom R.G. van den Bergh Weerman M.A. Verkruisen R.P. Groen A.K. Oude Elferink R.P. van der Valk M.A. Borst P. Offerhaus G.J. Mice with homozygous disruption of the mdr2 P-glycoprotein gene: a novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis.Am J Pathol. 1994; 145: 1237-1245PubMed Google Scholar However, Myc overexpression also leads to tumors with mixed hepatocytic and cholangiocytic phenotypes7Shachaf C.M. Kopelman A.M. Arvanitis C. Karlsson A. Beer S. Mandl S. Bachmann M.H. Borowsky A.D. Ruebner B. Cardiff R.D. Yang Q. Bishop J.M. Contag C.H. Felsher D.W. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.Nature. 2004; 431: 1112-1117Crossref PubMed Scopus (727) Google Scholar and cancer stem cell–like features.8Chow E.K. Fan L.L. Chen X. Bishop J.M. Oncogene-specific formation of chemoresistant murine hepatic cancer stem cells.Hepatology. 2012; 56: 1331-1341Crossref PubMed Scopus (72) Google Scholar Furthermore, the liver-specific knockout of phosphatase of tensin homolog, which activates the phosphoinositide 3-kinase (PI3K)–AKT pathway, induces both HCC and CC.9Horie Y. Suzuki A. Kataoka E. Sasaki T. Hamada K. Sasaki J. Mizuno K. Hasegawa G. Kishimoto H. Iizuka M. Naito M. Enomoto K. Watanabe S. Mak T.W. Nakano T. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.J Clin Invest. 2004; 113: 1774-1783Crossref PubMed Scopus (543) Google Scholar, 10Kenerson H.L. Yeh M.M. Kazami M. Jiang X. Riehle K.J. McIntyre R.L. Park J.O. Kwon S. Campbell J.S. Yeung R.S. Akt and mTORC1 have different roles during liver tumorigenesis in mice.Gastroenterology. 2013; 144: 1055-1065Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Similarly, the activation of the Yes-associated protein (YAP) pathway by knockout of upstream negative regulators induces HCC, CC, and cHCC-CC.11Dong J. Feldmann G. Huang J. Wu S. Zhang N. Comerford S.A. Gayyed M.F. Anders R.A. Maitra A. Pan D. Elucidation of a universal size-control mechanism in Drosophila and mammals.Cell. 2007; 130: 1120-1133Abstract Full Text Full Text PDF PubMed Scopus (1769) Google Scholar, 12Lu L. Li Y. Kim S.M. Bossuyt W. Liu P. Qiu Q. Wang Y. Halder G. Finegold M.J. Lee J.S. Johnson R.L. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver.Proc Natl Acad Sci U S A. 2010; 107: 1437-1442Crossref PubMed Scopus (564) Google Scholar, 13Nishio M. Sugimachi K. Goto H. Wang J. Morikawa T. Miyachi Y. Takano Y. Hikasa H. Itoh T. Suzuki S.O. Kurihara H. Aishima S. Leask A. Sasaki T. Nakano T. Nishina H. Nishikawa Y. Sekido Y. Nakao K. Shin-Ya K. Mimori K. Suzuki A. Dysregulated YAP1/TAZ and TGF-beta signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice.Proc Natl Acad Sci U S A. 2016; 113: E71-E80Crossref PubMed Scopus (126) Google Scholar Finally, the deregulated enhanced green fluorescent signaling induced by liver-specific deletion of Nf2/Merlin generates both HCC and CC.14Benhamouche S. Curto M. Saotome I. Gladden A.B. Liu C.H. Giovannini M. McClatchey A.I. Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver.Genes Dev. 2010; 24: 1718-1730Crossref PubMed Scopus (214) Google Scholar The broad phenotypic spectrum of primary epithelial liver cancers might be explained by the variable cells of origin: hepatocytes, cholangiocytes, hepatoblasts, and liver stem/progenitor cells. Recent lineage tracing experiments in mice have demonstrated that HCC is derived from mature hepatocytes rather than from liver stem/progenitor cells.15Mu X. Espanol-Suner R. Mederacke I. Affo S. Manco R. Sempoux C. Lemaigre F.P. Adili A. Yuan D. Weber A. Unger K. Heikenwalder M. Leclercq I.A. Schwabe R.F. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment.J Clin Invest. 2015; 125: 3891-3903Crossref PubMed Scopus (139) Google Scholar The presence of CC of intrahepatic bile duct origin has been proved experimentally by bile duct–specific activation of the PI3K-AKT pathway and YAP16Yamada D. Rizvi S. Razumilava N. Bronk S.F. Davila J.I. Champion M.D. Borad M.J. Bezerra J.A. Chen X. Gores G.J. IL-33 facilitates oncogene-induced cholangiocarcinoma in mice by an interleukin-6-sensitive mechanism.Hepatology. 2015; 61: 1627-1642Crossref PubMed Scopus (97) Google Scholar or KRAS.17Ikenoue T. Terakado Y. Nakagawa H. Hikiba Y. Fujii T. Matsubara D. Noguchi R. Zhu C. Yamamoto K. Kudo Y. Asaoka Y. Yamaguchi K. Ijichi H. Tateishi K. Fukushima N. Maeda S. Koike K. Furukawa Y. A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion.Sci Rep. 2016; 6: 23899Crossref PubMed Scopus (52) Google Scholar However, given that both hepatocytes and intrahepatic bile ductal/ductular cells originate from hepatoblasts during development18Shiojiri N. The origin of intrahepatic bile duct cells in the mouse.J Embryol Exp Morphol. 1984; 79: 25-39PubMed Google Scholar and that several lines of evidence have demonstrated that mature hepatocytes retain phenotypic plasticity to differentiate into cholangiocytes in vitro and in vivo,19Nishikawa Y. Doi Y. Watanabe H. Tokairin T. Omori Y. Su M. Yoshioka T. Enomoto K. Transdifferentiation of mature rat hepatocytes into bile duct-like cells in vitro.Am J Pathol. 2005; 166: 1077-1088Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 20Michalopoulos G.K. Barua L. Bowen W.C. Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury.Hepatology. 2005; 41: 535-544Crossref PubMed Scopus (245) Google Scholar, 21Yanger K. Zong Y. Maggs L.R. Shapira S.N. Maddipati R. Aiello N.M. Thung S.N. Wells R.G. Greenbaum L.E. Stanger B.Z. Robust cellular reprogramming occurs spontaneously during liver regeneration.Genes Dev. 2013; 27: 719-724Crossref PubMed Scopus (335) Google Scholar, 22Nagahama Y. Sone M. Chen X. Okada Y. Yamamoto M. Xin B. Matsuo Y. Komatsu M. Suzuki A. Enomoto K. Nishikawa Y. Contributions of hepatocytes and bile ductular cells in ductular reactions and remodeling of the biliary system after chronic liver injury.Am J Pathol. 2014; 184: 3001-3012Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar it is also possible that phenotypes of primary liver cancers might be determined by the combination of transdifferentiation and possibly dedifferentiation. This might be induced by genetic and cellular alterations occurring during tumorigenesis. Furthermore, it has been shown that CC can be induced from mature hepatocytes when the PI3K-AKT pathway is activated together with the Notch or YAP pathway.23Fan B. Malato Y. Calvisi D.F. Naqvi S. Razumilava N. Ribback S. Gores G.J. Dombrowski F. Evert M. Chen X. Willenbring H. Cholangiocarcinomas can originate from hepatocytes in mice.J Clin Invest. 2012; 122: 2911-2915Crossref PubMed Scopus (333) Google Scholar, 24Li X. Tao J. Cigliano A. Sini M. Calderaro J. Azoulay D. Wang C. Liu Y. Jiang L. Evert K. Demartis M.I. Ribback S. Utpatel K. Dombrowski F. Evert M. Calvisi D.F. Chen X. Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver.Oncotarget. 2015; 6: 10102-10115Crossref PubMed Scopus (46) Google Scholar Thus, liver tumors derived from mature hepatocytes demonstrate a wide spectrum of phenotypes from HCC to CC, possibly encompassing cHCC-CC and HB. In this study, we explored the interactions of the PI3K-AKT, YAP, and Myc pathways in hepatocytic tumorigenesis and phenotypic determination, using a combination of Sleeping Beauty (SB) transposon-mediated oncogene integration and hydrodynamic tail vein injection (HTVi) in mice. Herein, we demonstrate that the activation of the PI3K-AKT pathway alone in hepatocytes induces HCC with bile ductular transdifferentiation and that the simultaneous activation of the Myc or YAP pathway with the PI3K-AKT pathway promotes hepatocarcinogenesis with unidirectional differentiation, thus resulting in HCC and CC, respectively. Furthermore, unless the PI3K-AKT pathway is active, coactivation of the Myc and YAP pathways generates dedifferentiated liver tumors reminiscent of HB composed of hepatoblast-like cells with a high nuclear/cytoplasmic ratio. C57BL/6J mice were purchased from Charles River Laboratories Japan (Yokohama, Japan). The mice were euthanized under deep anesthesia, and the livers were removed for further examination. The protocols used for animal experimentation were approved by the Animal Research Committee, Asahikawa Medical University (Asahikawa, Japan). All animal experiments adhered to the criteria outlined in the Guide for the Care and Use of Laboratory Animals.25Committee for the Update of the Guide for the Care and Use of Laboratory Animals; National Research CouncilGuide for the Care and Use of Laboratory Animals.Eighth Edition. National Academies Press, Washington, DC2011Crossref Google Scholar An SB13 transposase-expressing vector [pT2/C-Luc/PGKSB13; Addgene plasmid #20207 deposited by Dr. John Ohlfest (University of Minnesota)], a myristoylated AKT-hemagglutinin (HA)-expressing transposon cassette vector [pT3-EF1α-myrAKT-HA; Addgene plasmid #31789 deposited by Dr. Xin Chen (University of California, San Francisco)], and a mutant YAP-expressing transposon cassette vector (pT3-EF1α-FLAG-YAPS127A; Addgene plasmid #46049 deposited by Dr. Xin Chen) were obtained from Addgene (Cambridge, MA). cDNA fragments of Notch1 intracellular domain (N1ICD), Notch2 intracellular domain (N2ICD), and enhanced green fluorescent protein were amplified from p3xFlag-N1ICD [Addgene plasmid #20183 deposited by Dr. Raphael Kopan (University of Cincinnati), Addgene], p3xFlag-N2ICD [Addgene plasmid #20184 deposited by Dr. Raphael Kopan (University of Cincinnati); Addgene], and pCMV–enhanced green fluorescent protein (Takara Bio, Kusatsu, Japan), respectively. A full-length Myc fragment was amplified from the cDNA of diethylnitrosamine-induced mouse liver tumors. These cDNA fragments were cloned into the pT3-EF1α plasmid with the Gateway system (ThermoFisher Scientific, Waltham, MA). LoxP sites were removed from pT3-EF1α-myrAKT-HA and pT3-EF1α-FLAG-YAPS127A using the GENEART Site-Directed Mutagenesis System (ThermoFisher Scientific) (pT3-myrAkt-ΔΔLoxP and pT3-YAPS127A-ΔΔLoxP, respectively). All plasmids were amplified and purified using the EndoFree Plasmid Maxi kit (Qiagen, Hilden, Germany)." @default.
• W2760562495 created "2017-10-06" @default.
• W2760562495 creator A5008171524 @default.
• W2760562495 creator A5027558518 @default.
• W2760562495 creator A5036810926 @default.
• W2760562495 creator A5040916685 @default.
• W2760562495 creator A5041369305 @default.
• W2760562495 creator A5042205540 @default.
• W2760562495 creator A5045329864 @default.
• W2760562495 creator A5046317415 @default.
• W2760562495 creator A5048586536 @default.
• W2760562495 creator A5061160958 @default.
• W2760562495 creator A5068363630 @default.
• W2760562495 creator A5084302861 @default.
• W2760562495 date "2017-12-01" @default.
• W2760562495 modified "2023-10-15" @default.
• W2760562495 title "Oncogenic Determination of a Broad Spectrum of Phenotypes of Hepatocyte-Derived Mouse Liver Tumors" @default.
• W2760562495 cites W1492511624 @default.
• W2760562495 cites W1601583906 @default.
• W2760562495 cites W1916446105 @default.
• W2760562495 cites W1939393508 @default.
• W2760562495 cites W1955705095 @default.
• W2760562495 cites W1970509520 @default.
• W2760562495 cites W1974532695 @default.
• W2760562495 cites W1975960651 @default.
• W2760562495 cites W1978681263 @default.
• W2760562495 cites W1984927780 @default.
• W2760562495 cites W1986657600 @default.
• W2760562495 cites W1990847702 @default.
• W2760562495 cites W2008208404 @default.
• W2760562495 cites W2008781245 @default.
• W2760562495 cites W2017842650 @default.
• W2760562495 cites W2023471348 @default.
• W2760562495 cites W2028593002 @default.
• W2760562495 cites W2054657650 @default.
• W2760562495 cites W2055254495 @default.
• W2760562495 cites W2060323466 @default.
• W2760562495 cites W2060782406 @default.
• W2760562495 cites W2062351247 @default.
• W2760562495 cites W2072348418 @default.
• W2760562495 cites W2074510758 @default.
• W2760562495 cites W2074648434 @default.
• W2760562495 cites W2084074847 @default.
• W2760562495 cites W2087106096 @default.
• W2760562495 cites W2091734645 @default.
• W2760562495 cites W2092743512 @default.
• W2760562495 cites W2105042695 @default.
• W2760562495 cites W2117310576 @default.
• W2760562495 cites W2124471593 @default.
• W2760562495 cites W2125156743 @default.
• W2760562495 cites W2132886417 @default.
• W2760562495 cites W2141595533 @default.
• W2760562495 cites W2141956267 @default.
• W2760562495 cites W2158378236 @default.
• W2760562495 cites W2159516932 @default.
• W2760562495 cites W2165802669 @default.
• W2760562495 cites W2168229235 @default.
• W2760562495 cites W2172179525 @default.
• W2760562495 cites W2172697812 @default.
• W2760562495 cites W2195648176 @default.
• W2760562495 cites W2225462341 @default.
• W2760562495 cites W2333177725 @default.
• W2760562495 cites W2520593853 @default.
• W2760562495 cites W2574853867 @default.
• W2760562495 cites W2613973112 @default.
• W2760562495 cites W4244649699 @default.
• W2760562495 doi "https://doi.org/10.1016/j.ajpath.2017.07.022" @default.
• W2760562495 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28964793" @default.
• W2760562495 hasPublicationYear "2017" @default.
• W2760562495 type Work @default.
• W2760562495 sameAs 2760562495 @default.
• W2760562495 citedByCount "31" @default.
• W2760562495 countsByYear W27605624952018 @default.
• W2760562495 countsByYear W27605624952019 @default.
• W2760562495 countsByYear W27605624952020 @default.
• W2760562495 countsByYear W27605624952021 @default.
• W2760562495 countsByYear W27605624952022 @default.
• W2760562495 countsByYear W27605624952023 @default.
• W2760562495 crossrefType "journal-article" @default.
• W2760562495 hasAuthorship W2760562495A5008171524 @default.
• W2760562495 hasAuthorship W2760562495A5027558518 @default.
• W2760562495 hasAuthorship W2760562495A5036810926 @default.
• W2760562495 hasAuthorship W2760562495A5040916685 @default.
• W2760562495 hasAuthorship W2760562495A5041369305 @default.
• W2760562495 hasAuthorship W2760562495A5042205540 @default.
• W2760562495 hasAuthorship W2760562495A5045329864 @default.
• W2760562495 hasAuthorship W2760562495A5046317415 @default.
• W2760562495 hasAuthorship W2760562495A5048586536 @default.
• W2760562495 hasAuthorship W2760562495A5061160958 @default.
• W2760562495 hasAuthorship W2760562495A5068363630 @default.
• W2760562495 hasAuthorship W2760562495A5084302861 @default.
• W2760562495 hasBestOaLocation W27605624951 @default.
• W2760562495 hasConcept C104317684 @default.
• W2760562495 hasConcept C127716648 @default.
• W2760562495 hasConcept C142724271 @default.
• W2760562495 hasConcept C185592680 @default.
• W2760562495 hasConcept C202751555 @default.
• W2760562495 hasConcept C21951064 @default.

• next