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Cancers 2018, 10(6), 183; https://doi.org/10.3390/cancers10060183

Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis

Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan
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Received: 30 April 2018 / Revised: 19 May 2018 / Accepted: 1 June 2018 / Published: 5 June 2018
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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Abstract

Chronic viral hepatitis is a global public health problem, with approximately 570 million persons chronically infected. Hepatitis B and C viruses increase the risk of morbidity and mortality from liver cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic complications that develop. Hepatitis virus infection induces transforming growth factor (TGF)-β, which influences microenvironments within the infected liver. TGF-β promotes liver fibrosis by up-regulating extracellular matrix production by hepatic stellate cells. TGF-β is also up-regulated in patients with HCC, in whom it contributes importantly to bringing about a favorable microenvironment for tumor growth. Thus, TGF-β is thought to be a major factor regulating liver fibrosis and carcinogenesis. Since TGF-β carries out regulatory signaling by influencing the phosphorylation of Smads, we have generated several kinds of phospho-specific antibodies to Smad2/3. Using these, we have identified three types of phospohorylated forms: COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C), linker phosphorylated Smad2/3 (pSmad2L and pSmad3L), and dually phosphorylated Smad3 (pSmad2L/C and pSmad3L/C). TGF-β-mediated pSmad2/3C signaling terminates cell proliferation; on the other hand, cytokine-induced pSmad3L signaling accelerates cell proliferation and promotes fibrogenesis. This review addresses TGF-β/Smad signal transduction in chronic liver injuries and carcinogenic processes. We also discuss the reversibility of Smad signaling after antiviral therapy. View Full-Text
Keywords: transforming growth factor (TGF)-β; Smad; hepatic stellate cells (HSC); myofibroblasts (MFB); liver fibrocarcinogenesis transforming growth factor (TGF)-β; Smad; hepatic stellate cells (HSC); myofibroblasts (MFB); liver fibrocarcinogenesis
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Yoshida, K.; Matsuzaki, K.; Murata, M.; Yamaguchi, T.; Suwa, K.; Okazaki, K. Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis. Cancers 2018, 10, 183.

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