Deregulation of the activin/follistatin system in hepatocarcinogenesis

Grusch, Michael; Drucker, Claudia; Peter-Vörösmarty, Barbara; Erlach, Natascha; Lackner, Andreas; Losert, Annemarie; Macheiner, Doris; Schneider, Wolfgang J.; Hermann, Marcela; Groome, Nigel P.; Parzefall, Wolfram; Berger, Walter; Grasl‐Kraupp, Bettina; Schulte‐Hermann, Rolf

doi:10.1016/j.jhep.2006.06.014

Cited by 65 publications

(73 citation statements)

References 49 publications

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“…Together these findings suggest an involvement of activin A not only in fibrosis but also in lipid accumulation. A study from our group in contrast, has found reduced expression of activin beta A transcripts in tumor tissue from chemicallyinduced rat liver tumors [59] . In addition to a pro-apoptotic and a pro-fibrotic effect, activin A has also been linked to hepatic neoangiogenesis via stimulation of VEGF expression in human hepatoma cells [60] .…”

Section: Dysfunctionmentioning

confidence: 68%

“…In mouse and rat models of chemically induced liver tumors, we found follistatin expression to be upregulated in about 60% of tumor tissue samples [59,126] . Moreover, we demonstrated that administration of follistatin stimulated DNA synthesis in preneoplastic rat hepatocytes in an ex vivo system, whereas hepatoma cell lines were unresponsive to exogenous follistatin possibly due to autocrine production of follistatin or other activin antagonists [59,[126][127][128] .…”

Section: Follistatinmentioning

confidence: 90%

“…Moreover, we demonstrated that administration of follistatin stimulated DNA synthesis in preneoplastic rat hepatocytes in an ex vivo system, whereas hepatoma cell lines were unresponsive to exogenous follistatin possibly due to autocrine production of follistatin or other activin antagonists [59,[126][127][128] . Knock-out mice for parkin, an E3 ubiquitin ligase implicated in Parkinson's disease and frequently deleted in HCC and hepatoma cell lines [129] , develop liver tumors in a follistatin upregulationdependent fashion [130] .…”

Section: Follistatinmentioning

confidence: 99%

“…Knock-out mice for parkin, an E3 ubiquitin ligase implicated in Parkinson's disease and frequently deleted in HCC and hepatoma cell lines [129] , develop liver tumors in a follistatin upregulationdependent fashion [130] . In human HCC elevated follistatin levels were found in the tumor tissue and the circulation of patients [53,59,131] . However, follistatin had no benefit as surveillance biomarker for HCC development in patients with alcoholic and non-alcoholic liver disease (ALD and NAFLD) due to the already elevated levels in the underlying liver pathologies [131] .…”

Section: Follistatinmentioning

confidence: 99%

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Activins and follistatins: Emerging roles in liver physiology and cancer

Kreidl

Öztürk²,

Metzner³

et al. 2009

WJH

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Activins are secreted proteins belonging to the TGF-β family of signaling molecules. Activin signals are crucial for differentiation and regulation of cell proliferation and apoptosis in multiple tissues. Signal transduction by activins relies mainly on the Smad pathway, although the importance of crosstalk with additional pathways is increasingly being recognized. Activin signals are kept in balance by antagonists at multiple levels of the signaling cascade. Among these, follistatin and FLRG, two members of the emerging family of follistatin-like proteins, can bind secreted activins with high affinity, thereby blocking their access to cell surface-anchored activin receptors. In the liver, activin A is a major negative regulator of hepatocyte proliferation and can induce apoptosis. The functions of other activins expressed by hepatocytes have yet to be more clearly defined. Deregulated expression of activins and follistatin has been implicated in hepatic diseases including inflammation, fibrosis, liver failure and primary cancer. In particular, increased follistatin levels have been found in the circulation and in the tumor tissue of patients suffering from hepatocellular carcinoma as well as in animal models of liver cancer. It has been argued that up-regulation of follistatin protects neoplastic hepatocytes from activin-mediated growth inhibition and apoptosis. The use of follistatin as biomarker for liver tumor development is impeded, however, due to the presence of elevated follistatin levels already during preceding stages of liver disease. The current article summarizes our evolving understanding of the multi-faceted activities of activins and follistatins in liver physiology and cancer.

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Section: Dysfunctionmentioning

confidence: 68%

Section: Follistatinmentioning

confidence: 90%

Section: Follistatinmentioning

confidence: 99%

Section: Follistatinmentioning

confidence: 99%

See 2 more Smart Citations

Activins and follistatins: Emerging roles in liver physiology and cancer

Kreidl

Öztürk²,

Metzner³

et al. 2009

WJH

View full text Add to dashboard Cite

show abstract

“…Disease FSTL3 expression levels were increased in hepatocytes in chemical hepatocarcinogenesis models in the rat but decreased in hepatocellular carcinoma (HCC) in humans (Grusch et al, 2006).…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%