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• W1982153609 abstract "We have previously shown in transgenic mice that transforming growth factor (TGF)-α dramatically enhances c-myc-induced hepatocarcinogenesis by promoting proliferation and survival of hepatocellular carcinoma (HCC) cells. As transgenic livers display increased levels of mature TGF-β1 from the early stages of hepatocarcinogenesis, we have now assessed whether impairment of TGF-β1 signaling contributes to the deregulation of cell cycle progression and apoptosis observed during this process. Focal preneoplastic lesions lacking expression of TGF-β receptor type II (TβRII) were detected in c-myc/TGF-α but not in c-myc livers. In c-myc/TGF-α mice, 40% (2/5) of adenomas and 90% (27/30) of HCCs showed down-regulation of TβRII expression in comparison with 11% (2/18) of adenomas and 47% (14/30) of HCCs in c-myc mice. Down-regulation of the TGF-β1-inducible p15INK4B mRNA and reduced apoptotic rates in TβRII-negative HCCs further indicated the disruption of TGF-β1 signaling. Furthermore, both TβRII-negative and -positive c-myc TGF-α HCCs, but not c-myc HCCs, were characterized by decreased levels of the cell cycle inhibitor p27. These results suggest 1) an inverse correlation of decreased p27 expression with the particularly strong expression of TGF-α in these lesions, consistent with the capacity of TGF-α signaling to post-transcriptionally regulate p27, and 2) the presence of alternative, downstream defects of TGF-β1 signaling in c-myc/TGF-α HCCs that may impair the growth-inhibitory response to TGF-β1. Thus, the accelerated neoplastic development in c-myc/TGF-α mice is associated with an early and frequent occurrence of TβRII-negative lesions and with reduced levels of p27 in HCC cells, indicating that disruption of TGF-β1 responsiveness may play a crucial role in the enhancement of c-myc-induced hepatocarcinogenesis by TGF-α. We have previously shown in transgenic mice that transforming growth factor (TGF)-α dramatically enhances c-myc-induced hepatocarcinogenesis by promoting proliferation and survival of hepatocellular carcinoma (HCC) cells. As transgenic livers display increased levels of mature TGF-β1 from the early stages of hepatocarcinogenesis, we have now assessed whether impairment of TGF-β1 signaling contributes to the deregulation of cell cycle progression and apoptosis observed during this process. Focal preneoplastic lesions lacking expression of TGF-β receptor type II (TβRII) were detected in c-myc/TGF-α but not in c-myc livers. In c-myc/TGF-α mice, 40% (2/5) of adenomas and 90% (27/30) of HCCs showed down-regulation of TβRII expression in comparison with 11% (2/18) of adenomas and 47% (14/30) of HCCs in c-myc mice. Down-regulation of the TGF-β1-inducible p15INK4B mRNA and reduced apoptotic rates in TβRII-negative HCCs further indicated the disruption of TGF-β1 signaling. Furthermore, both TβRII-negative and -positive c-myc TGF-α HCCs, but not c-myc HCCs, were characterized by decreased levels of the cell cycle inhibitor p27. These results suggest 1) an inverse correlation of decreased p27 expression with the particularly strong expression of TGF-α in these lesions, consistent with the capacity of TGF-α signaling to post-transcriptionally regulate p27, and 2) the presence of alternative, downstream defects of TGF-β1 signaling in c-myc/TGF-α HCCs that may impair the growth-inhibitory response to TGF-β1. Thus, the accelerated neoplastic development in c-myc/TGF-α mice is associated with an early and frequent occurrence of TβRII-negative lesions and with reduced levels of p27 in HCC cells, indicating that disruption of TGF-β1 responsiveness may play a crucial role in the enhancement of c-myc-induced hepatocarcinogenesis by TGF-α. The frequent co-expression of transforming growth factor (TGF)-α and c-myc in human hepatocellular carcinoma (HCC)1Grisham JW Interspecies comparison of liver carcinogenesis: implications for cancer risk assessment.Carcinogenesis. 1997; 18: 59-81Crossref PubMed Scopus (102) Google Scholar strongly suggests an important role for these genes in malignant growth of the liver. Consistent with this notion, we have demonstrated in transgenic mouse models that sustained c-myc overexpression results in persistent proliferation of hepatocytes and increased occurrence of HCC development2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar, 3Santoni-Rugiu E Preisegger KH Kiss A Audolfsson T Shiota G Schmidt EV Thorgeirsson SS Inhibition of neoplastic development in the liver by hepatocyte growth factor in a transgenic mouse model.Proc Natl Acad Sci USA. 1996; 93: 9577-9582Crossref PubMed Scopus (113) Google Scholar and that co-expression of TGF-α dramatically enhances c-myc-induced hepatocarcinogenesis.2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar, 4Murakami H Sanderson N Nagy P Marino P Merlino GT Thorgeirsson SS Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor α in hepatic oncogenesis.Cancer Res. 1993; 53: 1719-1723PubMed Google Scholar We have further shown that this synergistic effect is largely due to 1) an unrestrained cell cycle progression of neoplastic hepatocytes via disruption of the cyclin D-pRb-E2F pathway5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google Scholar and 2) a TGF-α-dependent inhibition of apoptosis in cancer cells in the transgenic livers.2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar, 5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google Scholar In contrast, the mitotic activity of peritumorous dysplastic hepatocytes drastically declines, and many of them ultimately apoptose, predominantly as a result of progressive up-regulation of mature TGF-β1.2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar, 5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google Scholar Thus, overexpression of mature TGF-β1, a potent growth inhibitor and apoptosis inducer for hepatocytes,6Fausto N Laird AD Webber EM Role of growth factors and cytokines in hepatic regeneration.FASEB J. 1995; 9: 1527-1536Crossref PubMed Scopus (569) Google Scholar, 7Schulte-Hermann R Grausl-Krapp B Bursch W Apoptosis and hepatocarcinogenesis.in: Jirtle RL Liver Regeneration and Carcinogenesis: Cellular and Molecular Mechanisms. Academic Press, New York1995: 141-178Crossref Google Scholar may also provide a selective milieu in which (pre)neoplastic cells with reduced sensitivity to this cytokine will progress more rapidly toward a malignant phenotype. Consistent with this idea, constitutive expression of active TGF-β1 transgene in mouse liver predisposed to both spontaneous and chemically induced hepatocarcinogenesis.8Factor VM Kao C-Y Santoni-Rugiu E Woitach JT Jensen MR Thorgeirsson SS Constitutive expression of mature transforming growth factor β1 in the liver accelerates hepatocarcinogenesis in transgenic mice.Cancer Res. 1997; 57: 2089-2095PubMed Google Scholar Furthermore, co-expression of c-myc and mature TGF-β1 in the liver accelerates hepatocarcinogenesis that is associated with reduced TGF-β receptor type II (TβRII) expression.8Factor VM Kao C-Y Santoni-Rugiu E Woitach JT Jensen MR Thorgeirsson SS Constitutive expression of mature transforming growth factor β1 in the liver accelerates hepatocarcinogenesis in transgenic mice.Cancer Res. 1997; 57: 2089-2095PubMed Google Scholar These observations suggest that decreased responsiveness to TGF-β1 and c-myc up-regulation contribute to HCC progression.The data summarized above provide indirect evidence for a progressive loss of sensitivity to TGF-β1 during hepatocarcinogenesis in c-myc and c-myc/TGF-α mice. In epithelial cells, including hepatocytes, TGF-β1 inhibition of cell cycle progression is due to transcriptional down-regulation of proliferation-associated genes9Alexandrow MG Moses HL Transforming growth factor β and cell cycle regulation.Cancer Res. 1995; 55: 1452-1457PubMed Google Scholar, 10Sugiyama A Nagaki M Shidoji Y Moriwaki H Muto Y Regulation of cell cycle-related genes in rat hepatocytes by transforming growth factor β1.Biochem Biophys Res Commun. 1997; 238: 539-543Crossref PubMed Scopus (32) Google Scholar and to inhibition of cyclin-dependent kinase (CDK) activities by induction/regulation of the CDK inhibitors (CDKIs) p15, p27, and p21.10Sugiyama A Nagaki M Shidoji Y Moriwaki H Muto Y Regulation of cell cycle-related genes in rat hepatocytes by transforming growth factor β1.Biochem Biophys Res Commun. 1997; 238: 539-543Crossref PubMed Scopus (32) Google Scholar, 11Hannon GJ Beach D p15INK4b is a potential effector of cell cycle arrest mediated by TGF-β.Nature. 1994; 371: 257-261Crossref PubMed Scopus (1882) Google Scholar, 12Polyak K Kato JY Solomon MJ Sherr CJ Massagué J Roberts JM Koff A p27Kipl, a cyclin-Cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest.Genes Dev. 1994; 8: 9-22Crossref PubMed Scopus (1824) Google Scholar, 13Polyak K Lee M Erdjument-Bromage H Koff A Roberts JM Tempst P Massagué J Cloning of p27Kipl, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.Cell. 1994; 78: 59-66Abstract Full Text PDF PubMed Scopus (2048) Google Scholar, 14Slingerland JM Hengst L Pan CH Alexander D Stampfer MR Reed SI A novel inhibitor of cyclin-Cdk activity detected in transforming growth factor β-arrested epithelial cells.Mol Cell Biol. 1994; 14: 3683-3694Crossref PubMed Google Scholar, 15Reynisdottir I Polyak K Iavarone A Massagué J Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-β.Genes Dev. 1995; 9: 1831-1845Crossref PubMed Scopus (888) Google Scholar These mechanisms contribute to maintaining the retinoblastoma protein (pRb) in hypophosphorylated form, a process critical for the growth-suppressive function of TGF-β1.16Laiho M DeCaprio JA Ludlow JW Livingston DM Massagué J Growth inhibition by TGF-β linked to suppression of retinoblastoma protein phosphorylation.Cell. 1990; 62: 175-185Abstract Full Text PDF PubMed Scopus (676) Google Scholar However, pRb was hyperphosphorylated in c-myc and c-myc/TGF-α HCCs.5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google Scholar In addition, many of the genes transcriptionally inhibited by TGF-β1, such as endogenous c-myc,9Alexandrow MG Moses HL Transforming growth factor β and cell cycle regulation.Cancer Res. 1995; 55: 1452-1457PubMed Google Scholar TGF-α,17Mulder KM Zhong Q Choi HG Humphrey LE Brattain MG Inhibitory effects of transforming growth factor β1 on mitogenic response, transforming growth factor α, and c-myc in quiescent, well-differentiated colon carcinoma cells.Cancer Res. 1990; 50: 7581-7586PubMed Google Scholar cyclins D1 and A,9Alexandrow MG Moses HL Transforming growth factor β and cell cycle regulation.Cancer Res. 1995; 55: 1452-1457PubMed Google Scholar, 10Sugiyama A Nagaki M Shidoji Y Moriwaki H Muto Y Regulation of cell cycle-related genes in rat hepatocytes by transforming growth factor β1.Biochem Biophys Res Commun. 1997; 238: 539-543Crossref PubMed Scopus (32) Google Scholar, 18Ko TC Sheng HM Reisman D Thompson EA Beauchamp RD Transforming growth factor β1 inhibits cyclin D1 expression in intestinal epithelial cells.Oncogene. 1995; 10: 177-184PubMed Google Scholar and E2F-1 and -219Schwarz JK Bassing CH Kovesdi I Datto MB Blazing M Gorge S Wang XF Nevins JR Expression of the E2F1 transcription factor overcomes type β transforming growth factor-mediated growth suppression.Proc Natl Acad Sci USA. 1995; 92: 483-487Crossref PubMed Scopus (152) Google Scholar were induced,2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar, 5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google Scholar indicating that the increased levels of TGF-β12Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar were unable to block proliferation in the transformed cells. This interpretation is consistent with the observations that deregulated expression of c-myc, cyclin D1, or E2F is able to overcome TGF-β1-mediated growth inhibition.9Alexandrow MG Moses HL Transforming growth factor β and cell cycle regulation.Cancer Res. 1995; 55: 1452-1457PubMed Google Scholar, 19Schwarz JK Bassing CH Kovesdi I Datto MB Blazing M Gorge S Wang XF Nevins JR Expression of the E2F1 transcription factor overcomes type β transforming growth factor-mediated growth suppression.Proc Natl Acad Sci USA. 1995; 92: 483-487Crossref PubMed Scopus (152) Google Scholar, 20Okamoto A Jiang W Kim S-J Spillare EA Stoner GD Weinstein IB Harris CC Overexpression of human cyclin D1 reduces the transforming growth factor β (TGF-β) type II receptor and growth inhibition by TGF-β1 in an immortalized human esophageal epithelial cell line.Proc Natl Acad Sci USA. 1994; 91: 11576-11580Crossref PubMed Scopus (84) Google ScholarGiven the presence of increased levels of mature TGF-β1 from the early stages of hepatocarcinogenesis in mice co-expressing c-myc and TGF-α transgenes,2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar we have investigated whether impairment of TGF-β1-mediated growth-suppressive pathways may constitute a part of the multistage process of hepatocarcinogenesis in this transgenic model.5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google ScholarMaterials and MethodsTransgenic Mice and Tissue PreparationGeneration of the Alb-c-myc (c-myc) single-transgenic and Alb-c-myc/MT-TGF-α (c-myc/TGF-α) double-transgenic mice, transgene expression pattern, and pathological changes were as reported before.2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar, 4Murakami H Sanderson N Nagy P Marino P Merlino GT Thorgeirsson SS Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor α in hepatic oncogenesis.Cancer Res. 1993; 53: 1719-1723PubMed Google Scholar In the current study, only male mice were investigated due to a more rapid neoplastic development culminating in appearance of HCC after a latency of 4 months in c-myc/TGF-α mice and of more than 12 months in c-myc mice.2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar No tumors were observed in age-matched (C57BL/6J × CBA/J) × CD1 wild-type (wt) mice used as controls. Nontumorous liver lobes, individual tumors ≥5 mm, and separately microdissected peritumorous tissues were snap-frozen in liquid nitrogen and stored at −80°C until further use. Animal housing and care were in accordance with NIH guidelines.Northern Blot AnalysisTen micrograms of poly(A)+ RNA isolated from nontumorous, tumorous, and corresponding peritumorous tissues, was electrophoresed and blotted as described previously.2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar, 5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google Scholar Blots were probed with 32P-labeled cDNA probes, including a 1.3-kb fragment of mouse p15INK4B,21Quelle DE Ashum RA Hannon GJ Rehberger PA Trono D Richter KH Walker C Beach D Sherr CJ Serrano M Cloning and characterization of murine p16INK4A and p15INK4B genes.Oncogene. 1995; 11: 635-645PubMed Google Scholar kindly provided by Dr. C.J. Sherr (St. Jude Children's Research Hospital, Memphis, TN), and a PCR-generated 0.35-kb fragment of mouse ribosomal protein L7 (rpL7) used to normalize RNA expression levels. The latter were visualized and quantified by PhosphorImager scanning and ImageQuant software (Molecular Dynamics, Sunnyvale, CA) as described.5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google Scholar Differences (mean ± SE) were analyzed by unpaired t-test and considered significant when the two-tailed P value was <0.05.Western Blot AnalysisThis was performed essentially as reported before.5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google Scholar Briefly, 0.3 g of non-neoplastic, neoplastic, and corresponding perineoplastic liver samples were homogenized in ice-cold lysis buffer containing 30 mmol/L Tris, pH 7.5, 150 mmol/L NaCl, 1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% SDS, 10% glycerol, 5 mmol/L EDTA, 1 mmol/L Na3 VO4, 20 mmol/L inorganic pyrophosphate, 1 mmol/L phenylmethylsulfonyl fluoride, 10 μg/ml aprotinin, and 10 μg/ml leupeptin. After an incubation of 15 minutes on ice, homogenates were sonicated three times for 10 seconds each and centrifuged to eliminate insoluble debris. Protein concentrations in the clarified supernatants were measured with Bio-Rad protein assay kit (Bio-Rad, Hercules, CA), 100 μg of total lysate proteins solubilized in boiling Laemmli buffer containing β-mercaptoethanol were separated by 12% SDS-polyacrylamide gel electrophoresis, transferred to nitrocellulose membranes, and reacted with 1 μg/ml rabbit polyclonal anti-p27 antibody (Ab N-20; Santa Cruz Biotechnology, Santa Cruz, CA). The specificity of the reaction was tested by preincubating the primary Ab with the corresponding p27 control peptide (1:20 w/w; Santa Cruz). Equal loading conditions were confirmed by staining the membranes with Ponceau-S.ImmunohistochemistryImmunohistochemistry (IHC) was performed on formalin-fixed, paraffin-embedded 5-μm sections from non-neoplastic liver lobes, from livers containing foci and benign tumors, and from 30 c-myc and 30 c-myc/TGF-α HCCs and their corresponding adjacent tissues. Immunostainings for TβRII and I using Abs against the cytoplasmic kinase domain of either receptor (L-21 and V-22, respectively; Santa Cruz) have been reported previously.3Santoni-Rugiu E Preisegger KH Kiss A Audolfsson T Shiota G Schmidt EV Thorgeirsson SS Inhibition of neoplastic development in the liver by hepatocyte growth factor in a transgenic mouse model.Proc Natl Acad Sci USA. 1996; 93: 9577-9582Crossref PubMed Scopus (113) Google Scholar, 8Factor VM Kao C-Y Santoni-Rugiu E Woitach JT Jensen MR Thorgeirsson SS Constitutive expression of mature transforming growth factor β1 in the liver accelerates hepatocarcinogenesis in transgenic mice.Cancer Res. 1997; 57: 2089-2095PubMed Google Scholar Immunoreactivity was revealed with the Vectastain ABC Elite kit followed by Vector VIP peroxidase substrate (Vector Laboratories, Burlingame, CA), a reddish chromogen. Sections were then lightly counterstained with hematoxylin. In each run, sections reacted with primary Abs preadsorbed to corresponding immunogen peptides (Santa Cruz) showed no evidence of staining, thereby verifying the reaction specificity. Twenty random fields/section were examined with a ×200 magnification by two pathologists and immunostainings arbitrarily scored as follows: −, when absent; +, when <5% of cells in the section were positive; ++, when 5% to 50% of cells were positive; +++, when >50% were stained.ResultsOverexpression of TGF-β1 and Down-Regulation of TβRs during Hepatocarcinogenesis in c-myc and c-myc/TGF-α Transgenic MiceOur previous in situ hybridization and IHC studies showed that hepatocarcinogenesis in c-myc and c-myc/TGF-α mice is characterized by strong autocrine up-regulation of mature TGF-β1 associated with growth inhibition and apoptosis of dysplastic hepatocytes.2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar, 5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google ScholarTo address the possibility that these conditions may favor the selection of cells unresponsive to TGF-β1, we analyzed the expression of the transmembrane TβRII during hepatocarcinogenesis in the two transgenic lines. Upon ligand binding, the serine-threonine kinase TβRII recruits and phosphorylates TβRI, which consequently becomes active and propagates TGF-β1 signals to downstream effectors.22Heldin CH Miyazona K ten Dijke P TGFβ signaling from cell membrane to nucleus through SMAD proteins.Nature. 1997; 390: 465-471Crossref PubMed Scopus (3316) Google Scholar, 23Massagué J TGF-β signal transduction.Annu Rev Biochem. 1998; 67: 753-791Crossref PubMed Scopus (3963) Google Scholar To study the expression pattern of TβRs we employed an immunohistochemical procedure previously used in other transgenic mouse hepatocarcinogenesis models.3Santoni-Rugiu E Preisegger KH Kiss A Audolfsson T Shiota G Schmidt EV Thorgeirsson SS Inhibition of neoplastic development in the liver by hepatocyte growth factor in a transgenic mouse model.Proc Natl Acad Sci USA. 1996; 93: 9577-9582Crossref PubMed Scopus (113) Google Scholar, 8Factor VM Kao C-Y Santoni-Rugiu E Woitach JT Jensen MR Thorgeirsson SS Constitutive expression of mature transforming growth factor β1 in the liver accelerates hepatocarcinogenesis in transgenic mice.Cancer Res. 1997; 57: 2089-2095PubMed Google Scholar Nontumorous and peritumorous transgenic tissues showed a more intense, albeit nonuniform, TβRII immunostaining than age-matched wt livers (data not shown). However, in c-myc/TGF-α livers not yet populated by frank tumors, we observed small focal lesions with decreased expression of TβRII (Figure 1A). These early TβRII-negative cell clusters consisted of cells, apparently diploid, smaller than dysplastic hepatocytes and with a basophilic or basophilic-clear cell phenotype2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar and represented only a subset (15/80, 19%) of the preneoplastic foci analyzed in the double-transgenic livers. Interestingly, these foci were characterized by a much lower apoptotic activity and increased mitosis when compared with TβRII-positive foci, which were composed of large, polymorphic, eosinophilic cells.2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar, 5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google Scholar, 8Factor VM Kao C-Y Santoni-Rugiu E Woitach JT Jensen MR Thorgeirsson SS Constitutive expression of mature transforming growth factor β1 in the liver accelerates hepatocarcinogenesis in transgenic mice.Cancer Res. 1997; 57: 2089-2095PubMed Google Scholar In addition, in c-myc/TGF-α mice, two of five (40%) hepatocellular adenomas (HCAs) examined, both of basophilic phenotype, showed reduced TβRII expression. The extremely rapid HCC development in the double-transgenic mice2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar prevented us from staining a more informative number of benign tumors. Importantly, however, the vast majority (27/30, 90%) of c-myc/TGF-α HCCs displayed down-regulation of TβRII expression as compared with adjacent parenchyma (Figure 1, B–D; Table 1), implying the possibility of a selection and expansion of TβRII-negative cells during tumor progression. We did not detect TβRII-negative preneoplastic cell clusters in c-myc livers. Decreased TβRII immunoreactivity was observed in 11% (2/19) of c-myc HCAs and in 47% (14/30) of c-myc HCCs (Table 1), indicating that loss of TβRII during neoplastic development in c-myc transgenic livers is a slower and less frequent event. Notably, a significant number of HCCs in c-myc/TGF-α but not in c-myc mice, exhibited down-regulation of both TβRII and TβRI immunostaining (Table 1), consistent with c-myc/TGF-α HCCs being biologically more aggressive than c-myc HCCs.2Santoni-Rugiu E Nagy P Jensen MR Factor VM Thorgeirsson SS Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α.Am J Pathol. 1996; 149: 407-428PubMed Google Scholar Indeed, all of the TβRI-negative HCCs were poorly differentiated and highly invasive lesions composed of anaplastic cells and neovascular structures that totally replaced the hepatic parenchyma and infiltrated adjacent organs. Also remarkable was that HCCs with loss of TβRs were particularly rich in mitotic figures (Figure 1D)and, according to our previous observations,5Santoni-Rugiu E Jensen MR Thorgeirsson SS Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor α.Cancer Res. 1998; 58: 123-134PubMed Google Scholar were characterized by apoptotic rates ∼10-fold lower than those in TβRII-positive HCCs. In keeping with this, TβRII-negative HCCs were bigger than their TβRII-positive counterparts (average size 2.2 × 1.9 ± 0.6 × 0.8 cm versus 1.3 × 1 ± 0.2 × 0.3 cm) and appeared more vascularized due to sinousoid dilation, proliferation of neocapillaries, and presence of unaccompanied arteries. These data support the notion that escape from TGF-β1 inhibitory effects may represent a major growth advantage for transformed cells in the transgenic livers.Table 1Differential Expression of TGF-β1, TβRI, and TβRII in Peritumorous Tissues (PT), Preneoplastic Foci, HCAs and HCCs of c-myc and c-myc/TGF-α Transgenic Mice As Assessed by Immunohistochemical Stainingc-mycc-myc/TGF-αStaining (pattern)PTFoci (n = 92)HCA (n = 19)HCC (n = 30)PTFoci (n = 80)HCA (n = 5)HCC (n = 30)TGF-β1 (cytoplasmic)++/++++++++++++++++++++/+++TβRI (cytoplasmic)*Significant difference between c-myc and c-myc/TGF-α HCAs or HCCs (P < 0.0001).+++++++++2 (7%)+†Intensity of immunostaining in the remaining samples was comparable with that in PT.+++++++++10 (33%)−/+†Intensity of immunostaining in the remaining samples was comparable with that in PT.TβRII (cytoplasmic)*Significant difference between c-myc and c-myc/TGF-α HCAs or HCCs (P < 0.0001).++++++2 (11%)+†Intensity of immunostaining in the remaining samples was comparable with that in PT.14 (47%)−/+†Intensity of immunostaining in the remaining samples was comparable with that in PT.+++15 (19%)−/+†Intensity of immun" @default.
• W1982153609 created "2016-06-24" @default.
• W1982153609 creator A5029953314 @default.
• W1982153609 creator A5033396141 @default.
• W1982153609 creator A5062476875 @default.
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• W1982153609 date "1999-06-01" @default.
• W1982153609 modified "2023-09-25" @default.
• W1982153609 title "Acceleration of c-myc-Induced Hepatocarcinogenesis by Co-Expression of Transforming Growth Factor (TGF)-α in Transgenic Mice Is Associated with TGF-β1 Signaling Disruption" @default.
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