Mammalian Sulf1 RNA alternative splicing and its significance to tumour growth regulation.

SULF1/SULF2 enzymes regulate the activities of several growth factors by selective hydrolysis of 6-O-sulphates of heparan sulphate proteoglycan co-receptors, the sulfation of which is essential for signal transduction of some ligand/receptor interactions but not others. This study demonstrates the existence of SULF1 variants with a wide spectrum of splicing patterns in mammalian tumours. The levels and relative proportions of SULF1/SULF2 splice variants markedly vary in different tumours with a potential to regulate cell growth differentially. Although mammalian Sulf1 compared with Sulf2 gene generates a much larger number of splice variants, both enzymes follow generally similar distribution and signalling association trends in hepatocellular carcinomas.

Sulf2 gene is alternatively spliced in mammalian developing and tumour tissues with functional implications.

SULF2 enzyme regulates the activities of a number of signalling pathways that in many tissues are up-regulated during development and disease. As we recently showed for avian Sulf1, the present study demonstrates that mammalian Sulf2 gene can also generate functionally distinct splice variants that would regulate normal development and tumour growth differentially. It is thus important to distinguish SULF1/SULF2 isoforms in mammalian tissues to understand their functional and clinical relevance to disease. This study demonstrates that unlike normal adult lung with little or no SULF2 expression, this enzyme is expressed at high levels in most lung tumours showing differential cellular distribution of full length and shorter SULF2 variants in such tumours. Furthermore, we show that the short SULF2 splice variants are associated with those signalling pathways that are inhibited by full length SULF1/SULF2 variants and therefore could promote growth in such lung tumours.