Synthesis of intracellular aliphatic polycations, involved in hepatocancerogenesis is regulated by hepatotrophic factor ALR

Small molecules like aliphatic polycations, named polyamines, were proven to be essential for hepatic growth and regeneration. Additionally, different stages of liver regeneration are regulated by a variety of factors such as the liver growth associated protein ALR, augmenter of liver regeneration. Also, increased ALR levels were detected for various types of acute liver disease, and in addition, we could find increased expression of ALR in livers from patients with cirrhosis, hepatocellular and cholangiocellular carcinoma [1]. On the other hand polyamines are known to contribute to carcinogenesis and tumour progression by increased levels due to over-expression of ornithine decarboxylase (ODC) [2], the rate limiting key enzyme of polyamine metabolism and further, to be correlated with the degree of malignancy in hepatocellular carcinomas [3]. Therefore, using primary human hepatocytes in vitro we investigated the effect of ALR on the biosynthesis of intracellular polyamines. We demonstrated by HPLC analysis that recombinant ALR enhanced intracellular hepatic levels of putrescine, spermidine and spermine within 9–12h after treatment. The activation of polyamine biosynthesis was dose dependent with putrescine showing the strongest increases. Additionally, ALR treatment induced mRNA expression of ornithine decarboxylase and S-adenosylmethionin decarboxylase, both key enzymes of polyamine biosynthesis. Further, ALR induced c-myc mRNA expression, a regulator of ODC expression and therefore we assume that ALR exerts its augmenting effects on liver regeneration as well as a putative role of ALR in hepatocellular carcinoma through stimulation of signalling pathways leading an activated polyamine metabolism regulated by increased c-myc as well as ODC and AdoMetDC mRNA expression.

Literatur: [1] W.E. Thasler, T. Schlott, P. Thelen, C. Hellerbrand, F. Bataille, M. Lichtenauer, H.J. Schlitt, K.W. Jauch, T.S. Weiss, Expression of augmenter of liver regeneration (ALR) in human liver cirrhosis and carcinoma, Histopathology 47 (2005) 57-66. [2] T. Thomas, T.J. Thomas, Polyamine metabolism and cancer, J Cell Mol. Med. 7 (2003) 113-126. [3] S. Kubo, A. Tamori, S. Nishiguchi, T. Omura, H. Kinoshita, K. Hirohashi, T. Kuroki, S. Otani, Relationship of polyamine metabolism to degree of malignancy of human hepatocellular carcinoma, Oncol. Rep. 5 (1998) 1385-1388.

growth factors - liver regeneration - polyamines - proliferation - signal transduction