Regulatory mechanisms for transforming growth factor β as an autocrine inhibitor in human hepatocellular carcinoma: Implications for roles of Smads in its growth

Matsuzaki, Koichi; Date, Masataka; Furukawa, Fukiko; Tahashi, Yoshiya; Matsushita, Makoto; Sugano, Yasushi; Yamashiki, Noriyo; Nakagawa, Taiichi; Seki, Toshihito; Nishizawa, Mikio; Fujisawa, Jun–ichi; Inoue, Katsumi

doi:10.1053/jhep.2000.9145

Cited by 46 publications

(45 citation statements)

References 38 publications

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“…This postulated mode of action is in agreement with data published previously. 7,39,44 The reduction of preneoplastic foci by endogenous TGF-␤ 1 early in the carcinogenesis process would likewise protect against tumor formation.…”

Section: Discussionmentioning

confidence: 99%

“…Once phosphorylated, Smads-2/3 form a complex with Smad-4 and translocate to the nucleus, where they positively or negatively regulate transcription of TGF-␤ target genes through cooperative interactions with DNA, transcription factors, coactivators, and corepresors. 6,7 TGF-␤ 1 is an important physiological mediator for apoptosis in both normal and neoplastic liver. 8 There are several lines of evidence: TGF-␤1 1 induces apoptosis in primary hepatocyte cultures derived from both adult and fetal rat liver 9 -11 ; intravenous administration of TGF-␤ 1 induces apoptosis in both normal and regressing liver 9,12 and also in hepatocytes from preneoplastic foci.…”

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confidence: 99%

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Interferon α-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic transforming growth factor β1

et al. 2004

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In previous work we showed that interferon alfa-2b (IFN-␣2b) increases apoptosis on rat hepatic preneoplastic foci. The aim of this study was to determine if transforming growth factor ␤ 1 (TGF-␤ 1 ) was involved in the programmed cell death on the foci. Animals were divided into 6 groups: subjected to a 2-phase model (diethylnitrosamine plus 2-acetylaminofluorene) of preneoplasia development (group 1); treated with IFN-␣2b during the 2 phases (group 2); treated with IFN-␣2b during initiation with diethylnitrosamine (group 3); treated with IFN-␣2b during 2-acetylaminofluorene administration (group 4); subjected only to an initiation stage (group 5); and treated with IFN-␣2b during the initiation period (group 6). Serum TGF-␤ 1 levels were increased in IFN-␣2b-treated rats. Immunohistochemical studies showed that IFN-␣2b significantly increased the quantity of TGF-␤ 1 -positive hepatocytes in groups 2 to 4. Phosphorylated-Smads-2/3 (p-Smads-2/3) proteins in liver nuclear extracts were significantly elevated. To determine the source of TGF-␤ 1 , isolated hepatocytes, Kupffer cells, and peritoneal macrophages from animals in groups 1 and 5 were cultured with or without IFN-␣2b. IFN-␣2b stimulus induced several-fold increases of TGF-␤ 1 secretion from hepatocytes. Neither Kupffer cells nor peritoneal macrophages secreted detectable TGF-␤ 1 levels when they were treated with IFN-␣2b. IFN-␣2b-stimulated cultured hepatocytes from preneoplastic livers showed enhanced apoptosis, measured by fluorescence microscopy and caspase-3 activity. They presented higher nuclear accumulation of p-Smads-2/3, indicating increased TGF-␤ 1 signaling. When anti-TGF-␤ 1 was added to the culture media, TGF-␤ 1 activation and apoptosis induced by IFN-␣2b were blocked. In conclusion, IFN-␣2b-induced production of TGF-␤ 1 by hepatocytes from preneoplastic liver is involved in the apoptotic elimination of altered hepatic foci. (HEPATOLOGY 2004;40:394 -402.)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Interferon α-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic transforming growth factor β1

et al. 2004

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“…This well known cytokine increases in many tumors, including HCC. 39 It is not increased, however, in HCC vs. NL or AT, thus its increase in HPBL vs. HCC is of true functional significance. There is no other previous association of TGFb1 with HPBL.…”

Section: Biologic Significance Of Genes Differentially Expressed Betwmentioning

confidence: 93%

Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas†

et al. 2006

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H epatocellular carcinomas (HCC) and hepatoblastomas of childhood (HPBL) are two types of liver cancer with high mortality and morbidity and international prevalence. There have been several recent studies of patterns of gene expression and molecular classification of HCC. [1][2][3][4] The studies demonstrated that HCC can be clustered in subgroups of gene expression patterns that have different prognostic and clinical behavior. Other recent studies also examined similarities between HCC precursor lesions (low and high grade liver nodules) and demonstrated significant similarities but also differences between HCC and precursor lesions. 5 In this study, we also focused on gene expression of HCC and HPBL, but from a different perspective than previous studies. We utilized a set of tissues from normal liver (NL), HCC, HPBL and tumor adjacent (AT) tissues and determined gene expression patterns not as a ratio of tumor vs. normal, but rather as absolute separate values for each unique tissue. This allowed standard but stringent statistical analysis not feasible when gene expression is only viewed as a fold change over normal tissues. Identification of gene expression patterns of liver tumors from this perspective allows identification of the main differences between the tumor subtypes and the adjacent nontumor (but often cirrhotic) liver; it also offers the potential of defining new therapeutic and diagnostic modalities. Our findings include some genes already shown to increase in HCC, thus validating our overall approach. Our results also revealed many other genes, not so far involved with biology of liver tumors. In addition, we carried a whole genome analysis of 27 HCC and determined chromosomal loci with genetic abnormalities common to most of the HCC. Materials and MethodsSee Supplemental information at the HEPATOLOGY

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“…DNA synthesis was measured by incorporation of 1 Ci/ml [ 3 H] thymidine (Amersham Pharmacia Biotech) into 5% trichloroacetic acid-precipitable material after a 4-hour pulse as described previously. 23 Statistical Analysis. All P values were based on twotailed statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma

et al. 2007

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Many patients with chronic hepatitis caused by hepatitis C virus (HCV) infection develop liver fibrosis with high risk for hepatocellular carcinoma (HCC), but the mechanism underling this process is unclear. Conversely, transforming growth factor beta (TGF-␤) activates not only TGF-␤ type I receptor (T␤RI) but also c-Jun N-terminal kinase (JNK), which convert the mediator Smad3 into two distinctive phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). Whereas the T␤RI/pSmad3C pathway suppresses epithelial cell growth by upregulating p21 WAF1 transcription, JNK/pSmad3L-mediated signaling promotes extracellular matrix deposition, partly, by upregulating plasminogen activator inhibitor 1 (PAI-1). We studied the domain-specific Smad3 phosphorylation in biopsy specimens representing chronic hepatitis, cirrhosis, or HCC from 100 patients chronically infected with HCV, and correlated Smad3 phosphorylation with clinical course. As HCV-infected livers progressed from chronic hepatitis through cirrhosis to HCC, hepatocytic pSmad3L/PAI-1 increased with fibrotic stage and necroinflammatory grade, and pSmad3C/p21 WAF1 decreased.

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Regulatory mechanisms for transforming growth factor β as an autocrine inhibitor in human hepatocellular carcinoma: Implications for roles of Smads in its growth

Cited by 46 publications

References 38 publications

Interferon α-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic transforming growth factor β1

Interferon α-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic transforming growth factor β1

Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas†

Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma

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