Sulfatase 2 up‐regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma†

Abstract

In contrast to the tumor suppressor effect of SULF1, SULF2 has an oncogenic effect in HCC mediated in part through up-regulation of FGF signaling and GPC3 expression.

Dynamic expression patterns of 6‐O endosulfatases during zebrafish development suggest a subfunctionalisation event for sulf2

“…It is possible, therefore, that tumour growth in cancer cells overexpressing SULF2 is potentiated by tumour angiogenesis. In hepatocellular and breast carcinomas, however, overexpression of SULF1 inhibits tumour growth/angiogenesis partially by inhibiting FGF, HGF, and VEGF stimulation of tumour cell growth and metastasis (Lai et al, 2004b(Lai et al, , 2008 and correlates with the low levels of FGF/HS/FGFR2 signal complexes formed in SULF1-expressing cells in vitro (Lai et al, 2006;Narita et al, 2006). Clearly, in pathological conditions sulfatases can have both proand anti-angiogenic roles depending on the context of the perturbed signalling environment.…”

Functional Consequences of the Subdomain Organization of the Sulfs

“…The phenotypes in single and double null mice include abnormalities in general growth, muscle innervation, muscle regeneration, skeletal tissue, and lung development. The Sulfs have been extensively investigated in cancer with some studies consistent with tumor suppression activity (15,21,22) and others with a pro-oncogenic role (23)(24)(25).As is the case for the prototypic QSulf-1 (8), HSulf-1 and HSulf-2 consist of four domains from the N to C terminus: a signal peptide, a catalytic domain of 374 amino acids, a basic hydrophilic domain of 346/366 amino acids, and a C-terminal domain of 109/127 amino acids (7,8). In the 17-member sulfatase family (26), the Sulfs share the most extensive sequence homology with lysosomal glucosamine-6-sulfatase in the catalytic and C-terminal domains, although the centrally inserted hydrophilic domain is absent from this enzyme and other sulfatases.…”

“…The phenotypes in single and double null mice include abnormalities in general growth, muscle innervation, muscle regeneration, skeletal tissue, and lung development. The Sulfs have been extensively investigated in cancer with some studies consistent with tumor suppression activity (15,21,22) and others with a pro-oncogenic role (23)(24)(25).…”

Novel Therapeutic Targets for Hepatocellular Carcinoma Treatment

“…Upregulation of SULF2 is observed in 57% HCC tissues and 73% HCC cell lines. Level of SULF2 is positively correlated with a more aggressive tumor phenotype and poorer patient survival (Lai et al, 2008). Ectopic expression of SULF2 promoted cell proliferation and migration in various HCC cell lines, and enhanced tumor growth in vivo.…”

“…The tumorigenic effect of SULF2 is partially brought by the induction of the aforementioned pro-cancerous glypican-3 expression. It was found that SULF2 enhanced the binding of FGF2 to the cancer cell and activated FGF signaling in a glypican-3 dependent manner (Lai et al, 2008). In addition, SULF2 increased cell surface glypican-3 and Wnt3a level in HCC, leading to the increase of glypican-3-dependent Wnt/ -catenin signaling .…”