Abstract
BackgroundThe sulfation pattern of heparan sulfate chains influences signaling events mediated by heparan sulfate proteoglycans located on cell surface. SULF1 and SULF2 are two endosulfatases able to cleave specific 6-O sulfate groups within the heparan chains. Their action can modulate signaling processes, many of which with key relevance for cancer development and expansion. SULF1 has been associated with tumor suppressor effects in various models of cancer, whereas SULF2 dysregulation was in relation with protumorigenic actions. However, other observations argue for contradictory effects of these sulfatases in cancer, suggesting the complexity of their action in the tumor microenvironment.MethodsWe compared the expression of the genes encoding SULF1, SULF2 and heparan sulfate proteoglycans in a large panel of cancer samples to their normal tissue counterparts using publicly available gene expression data, including the data obtained from two cohorts of newly-diagnosed multiple myeloma patients, the Oncomine Cancer Microarray database, the Amazonia data base and the ITTACA database. We also analysed prognosis data in relation with these databases.ResultsWe demonstrated that SULF2 expression in primary multiple myeloma cells was associated with a poor prognosis in two independent large cohorts of patients. It remained an independent predictor when considered together with conventional multiple myeloma prognosis factors. Besides, we observed an over-representation of SULF2 gene expression in skin cancer, colorectal carcinoma, testicular teratoma and liver cancer compared to their normal tissue counterpart. We found that SULF2 was significantly over-expressed in high grade uveal melanoma compared to low grade and in patients presenting colorectal carcinoma compared to benign colon adenoma.We observed that, in addition to previous observations, SULF1 gene expression was increased in T prolymphocytic leukemia, acute myeloid leukemia and in renal carcinoma compared to corresponding normal tissues. Furthermore, we found that high SULF1 expression was associated with a poor prognosis in lung adenocarcinoma.Finally, SULF1 and SULF2 were simultaneously overexpressed in 6 cancer types: brain, breast, head and neck, renal, skin and testicular cancers.ConclusionsSULF1 and SULF2 are overexpressed in various human cancer types and can be associated to progression and prognosis. Targeting SULF1 and/or SULF2 could be interesting strategies to develop novel cancer therapies.
Highlights
The sulfation pattern of heparan sulfate chains influences signaling events mediated by heparan sulfate proteoglycans located on cell surface
Tumor suppressor functions of sulfatase 1 (SULF1) Expression of SULF1 mRNA can be detected in several normal human tissues, as observed by MorimotoTomita et al [2] in a panel of 24 tissue types, the highest levels being found in testes, stomach, skeletal muscle, lung, and kidney
Considering that Heparan sulfate proteoglycans (HSPGs) sulfation pattern drives in part cell communication molecule binding [15,16,17], a loss of SULF1 expression is expected to disrupt the effects of these cell communication molecules during malignancies
Summary
The sulfation pattern of heparan sulfate chains influences signaling events mediated by heparan sulfate proteoglycans located on cell surface. SULF1 and SULF2 are two endosulfatases able to cleave specific 6-O sulfate groups within the heparan chains. Their action can modulate signaling processes, many of which with key relevance for cancer development and expansion. SULF1 has been associated with tumor suppressor effects in various models of cancer, whereas SULF2 dysregulation was in relation with protumorigenic actions. Other observations argue for contradictory effects of these sulfatases in cancer, suggesting the complexity of their action in the tumor microenvironment. Heparan sulfate proteoglycans (HSPGs) are negativelycharged proteins located at a high cell density on various cell types or released into the extracellular matrix. SULF1-deficient mice did not present any abnormal phenotype whereas SULF2-knock-out mice displayed a small but significant reduction in litter size and body weight, and a hydrocephalus at birth resulting in a life span shorter than 2 weeks [4]
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