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

Abstract

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.

SULF1/SULF2 reactivation during liver damage and tumour growth

“…The normal 4-5 month fetal livers in contrast only expressed the full length ( Figure 1) and no shorter variants (not shown). These variants vary in their cell signalling activities as described in our earlier study (Gill et al 2012;Gill et al 2014). The relative proportions of full length (SULF1A & SULF2A) and shorter variants (SULF1B & SULF2B) of both SULF1 and SULF2 also varied amongst these samples (Figure 2).…”

“…A proportion (15-25%) of the HCC samples, however, did not express either of these two enzymes (Figure 2). The composition of both SULF1 and SULF2 variants also varied in HCC samples with some samples expressing mainly full length catalytically active SULF1 or SULF2 while others expressing only the shorter variants without the catalytically active exon 6 (Figure 2) (Gill et al 2012). The normal 4-5 month fetal livers in contrast only expressed the full length ( Figure 1) and no shorter variants (not shown).…”

“…Our earlier RT PCR analysis of human fetal and adult normal canine liver and some immunocytochemical analysis of some tumours demonstrated the increased expression of Sulf1/Sulf2 in a number of canine and some human tumours since normal adult liver unlike the fetal liver did not express detectable levels of Sulf1 or Sulf2 (Gill et al 2012). In the present study, we undertook further analysis of both Sulf1 and Sulf2 in a larger number of normal adult (n=28), fetal (n=12) and HCC (n=105) human liver samples and 4 liver cell lines.…”

“…Changes in Sulf1/Sulf2 expression in normal and pathological tissues could thus indicate their cell signalling activity in such tissues. The role of Sulf1/Sulf2 in HCC growth, however, is not clear due to some conflicting reports of Sulf1/Sulf2 upregulation (Bret et al 2011;Gill et al 2011;Gill et al 2012;Gill et al 2014;Nawroth et al 2007; LemjabbarAlaoui et al ; Rosen and Lemjabbar-Alaoui 2010) as well as the downregulation of such enzymes in HCC (Lai et al 2008a;Lai et al 2006;Xu G et al 2014). This therefore raises the question as to whether Sulf1 or Sulf2 enzymes are preferentially expressed in normal adult or fetal liver or tumour tissues.…”

“…This therefore raises the question as to whether Sulf1 or Sulf2 enzymes are preferentially expressed in normal adult or fetal liver or tumour tissues. This study was undertaken to determine if it is the normal or the tumour tissues that express high levels of Sulf1 or Sulf2 since a number of studies have reported the upregulation of Sulf1 and Sulf2 enzymes in tumours (Kroy DC et al 2010;Gill et al 2012;Gill et al 2014;Bret et al 2011;Nawroth et al 2007) while others have reported the down-regulation of these enzymes in tumour tissues (Lai et al 2006;Lai et al 2008b;Xu G et al 2014) compared with normal tissues thus implying that Sulfs and particularly Sulf1 is a tumour suppressor rather than a tumour growth enhancer. Since HCC develops over a long time period and is often preceded by additional steps such as hepatitis and cirrhosis, this analysis also included some other liver samples likely to activate cell signalling in response to liver damage-induced regeneration.…”