Activin and follistatin in liver biology and hepatocellular carcinoma

Last updated: 01 August 2008

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Activins and inhibins represent a subgroup of cytokines within the transforming growth factor (TGF) beta superfamily of growth and differentiation factors. They are dimers of two beta subunits (Activins) or of one alpha and one beta subunit (Inhibins) linked by a disulphide bond. While there is only one gene coding for the inhibin alpha subunit, four different beta subunit genes exist in humans termed activin beta A, beta B, beta C, and beta E. Activin A, the dimer of two beta A subunits is widely expressed throughout the body and has multiple functions in development, tissue homeostasis and inflammation. It exerts its function via transmembrane receptor serine/threonine kinases and intracellular smad and MAPK signalling cascades. Activin activity is controlled by follistatin a secreted monomeric protein which binds activin A with high affinity and blocks its interaction with activin receptors. In the liver, activin A is a potent inducer of hepatocyte apoptosis and was shown to play an important role in the regulation of cell number and tissue architecture. There is increasing evidence that deregulation of the balance between activin A and follistatin expression contributes to hepatic failure, chronic inflammation, cirrhosis, and hepatocellular carcinoma (HCC). Increased production of activin A has been suggested to be a contributing factor to impaired liver regeneration in patients with acute liver failure, whereas elevated follistatin, found in rodent models of hepatocarcinogenesis and in serum and tumour tissue of patients with HCC, may block activin–mediated growth control of tumour cells. A recent report demonstrated that mice deficient for the E3 ubiquitin ligase parkin develop hepatic tumours, which is mediated in part through up-regulation of follistatin. An attempt to use follistatin as serum biomarker for HCC development in patients with non-alcoholic and alcoholic fatty liver disease failed, however, due to the presence of high follistatin levels not only in patients with HCC but also in patients with cirrhosis but no HCC. Little is known so far about the role of inhibins and activins other than activin A for hepatic physiology and pathology, despite the intriguing fact that from all organs of the body the liver contains the highest transcript levels of both beta C and beta E.
  • C. Rodgarkia-Dara, S. Vejda, N. Erlach, A. Losert, W. Berger, W. Bursch, R. Schulte-Hermann and M. Grusch The activin axis in liver biology and disease, Mutation Research Reviews 613 (2006) 123-137 (Link->)
  • A. Deli, E. Kreidl, S. Santifaller, B. Trotter, K. Seir, W. Berger, R. Schulte-Hermann, C. Rodgarkia-Dara and M. Grusch Activins and activin antagonists in hepatocellular carcinoma, World J Gastroenterol 14 (2008) 1699-1709. (Link->)
  • M. Grusch, C. Rodgarkia-Dara, W. Bursch and R. Schulte-Hermann Activins and the liver, in: S. Jakowlew (Ed.), Transforming Growth Factor-Beta in Cancer Therapy, Volume I, Humana press, Totowa, NJ, 2008, pp. 483-508.
  • Grusch M, Drucker C, Peter-Vörösmarty B, Erlach N, Lackner A, Losert A, Macheiner D, Schneider WJ, Hermann M, Groome NP, Parzefall W, Berger W, Grasl-Kraupp B, Schulte-Hermann R.Deregulation of the activin/follistatin system in hepatocarcinogenesis. J Hepatol. 45 (2006) 45673-80. (Link->)
  • Fujiwara M, Marusawa H, Wang HQ, Iwai A, Ikeuchi K, Imai Y, Kataoka A, Nukina N, Takahashi R, Chiba T. Parkin as a tumor suppressor gene for hepatocellular carcinoma. Oncogene (2008) doi: 10.1038/onc.2008.199. (Link->)
  • Beale G, Chattopadhyay D, Gray J, Stewart S, Hudson M, Day C, Trerotoli P, Giannelli G, Manas D, Reeves H. AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non- alcoholic and alcoholic fatty liver disease. BMC Cancer 8 (2008) 200 doi: 10.1186/1471-2407-8-200 (Link->)

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Updated 09 Dec 2008

1. Intracrine signalling of activin A in hepatocytes upregulates connective tissue growth factor (CTGF/CCN2) expression
(2008) Gressner, O.A. | Lahme, B. | Siluschek, M. | Rehbein, K. | Weiskirchen, R. | Gressner, A.M.
Liver International pp.1207-1216 Cited 0 times.

 
2. Muscle myostatin signalling is enhanced in experimental cancer cachexia
(2008) Costelli, P. | Muscaritoli, M. | Bonetto, A. | Penna, F. | Reffo, P. | Bossola, M. | Bonelli, G. | Doglietto, G.B. | Baccino, F.M. | Fanelli, F.R.
European Journal of Clinical Investigation pp.531-538 Cited 0 times.

 
3. Activins and activin antagonists in hepatocellular carcinoma
(2008) Deli, A. | Kreidl, E. | Santifaller, S. | Trotter, B. | Seir, K. | Berger, W. | Schulte-Hermann, R. | Rodgarkia-Dara, C. | Grusch, M.
World Journal of Gastroenterology pp.1699-1709 Cited 1 times.

more >
provided by Scirus
Updated 09 Dec 2008

1. Deregulation of the activin/follistatin system in hepatocarcinogenesis
Nov 2006
Background/Aims: Activins A and E negatively regulate hepatic cell number by inhibiting cell replication and inducing apoptosis. Follistatin and follistatin-like 3 bind activins and antagonise their biological activities. Aim of our study...
[http://www.sciencedirect.com/science?_ob=GatewayUR...]

 
2. Deregulation of the activin/follistatin system in hepatocarcinogenesis.
Nov 2006
BACKGROUND/AIMS: Activins A and E negatively regulate hepatic cell number by inhibiting cell replication and inducing apoptosis. Follistatin and follistatin-like 3 bind activins and antagonise their biological activities....
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=...]

 
3. The activin axis in liver biology and disease.
Nov 2006
Activins are a closely related subgroup within the TGFbeta superfamily of growth and differentiation factors. They consist of two disulfide-linked beta subunits. Four mammalian activin beta subunits termed beta( A), beta(B),...
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=...]