HSulf‐1 inhibits cell proliferation and invasion in human gastric cancer

Abstract

The HSulf-1 gene encodes an extracellular 6-O-endosulfatase and regulates the sulfation status of heparan sulfate proteoglycans (HSPG). We have demonstrated that promoter hypermethylation is correlated with the HSulf-1 silencing in gastric cancer. To investigate the functional importance of HSulf-1 silencing in gastric cancer, we restored HSulf-1 expression in the gastric cancer cell line MKN28, which lacks endogenous HSulf-1. Following restoration of expression, HSulf-1 inhibited cell proliferation, motility, and invasion in vitro, as well as significantly suppressing the MKN28 xenograft model (P < 0.05). No noticeable changes in proliferation and motility were observed following restoration of HSulf-1 in another gastric cancer cell line, namely AGS cells. Interestingly, in MKN28 cells, which have been reported to be dependent on extracellular Wnt signaling, we found that HSulf-1 inhibited the transcriptional activity of the Wnt ⁄ b-catenin pathway and downregulated its targeted genes. Conversely, in AGS cells, in the constitutive Wnt ⁄ b-catenin pathway is active, HSulf-1 had no effect on the activity of the Wnt ⁄ b-catenin pathway. Furthermore, transfection of Wnt3a cDNA or b-catenin shRNA resulted in rescue or enhancement, respectively, of the effects of HSulf-1 in MKN28 cells. Furthermore, HSPG epitope analysis confirmed that HSulf-1 affected the structure of heparan sulfate on the cell surface. Together, the results of the present study suggest that extracellular HSulf-1 may function as a negative regulator of proliferation and invasion in gastric cancer by suppressing Wnt ⁄ b-catenin signaling at the cell surface. (Cancer Sci 2011; 102: 1815-1821 G astric cancer is the second most common cause of cancerrelated deaths worldwide.(1,2) Understanding the mechanisms involved in gastric tumorigenesis and metastasis is important for the development of new effective therapeutic agents.The HSulf-1 gene, characterized as Human ortholog of Qsulf-1, can hydrolyze the sulfate ester bonds of heparan sulfate proteoglycans (HSPG), leading to removal of the sulfate at the 6-O position of glucosamine. (3,4) It is believed that changes in the sulfation status of HSPG can affect their interactions with signaling molecules and therefore modulate signal transduction. (3,(5)(6)(7)(8)

A 4-gene panel as a marker at chromosome 8q in Asian gastric cancer patients

“…Then SULF1 modifies HSPG, and this leads to changes in HSPG-related signal transduction pathways. Deregulation of SULF1 may have a significant impact on cell growth and carcinogenesis [24][25][26]. Although its silencing with promoter hypermethylation has been reported in breast and gastric cancers [25], SULF1 was overexpressed in various human cancer types [27], including GC [28,29].…”

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

“…Several other tumor suppressor genes that function through modulating Wnt/b-catenin signaling were found silenced in gastric cancer, such as members of the sFRP and Dkk gene families. CpG methylation-depending silencing of sFRP1, sFRP2, sFRP4, sFRP5, HSulf-1, WIF-1, RUNX3 as well as, Dkk-1, Dkk-2 and Dkk-3 has been frequently observed among gastric cancer cells lines and primary specimens [59,96,108,144,147,148] . In addition, Yu et al [148] showed by multivariate analysis that Dkk-3 methylation was associated significantly and independently with poor disease survival in gastric cancer, but not in colorectal cancer.…”

“…These molecular changes seem to be required to drive early carcinogenesis events in the stomach, a hypothesis that is supported by studies showing that GSK3b phosphorylation and inactivation is associated with cancer progression in gastric cancer [105] . Different studies have shown downregulation-in occasion by unspecified mechanisms-of various negative regulators of the Wnt/b-catenin signaling involved in proliferation and invasion in gastric cancer, including sFRP, Sox7, Sox10, Sox17, HSulf-1, RACK1, ZNRF3 and OSR1 [78,[106][107][108][109][110][111][112][113] . Some Wnt-target genes, such as Dkk-1, Axin, Nemo kinase, etc., have shown to cause inhibition of Wnt signaling itself [114,115] .…”

Sulfatase 1 mediates the inhibitory effect of angiotensin II type 2 receptor inhibitor on angiotensin II-induced hypertensive mediator expression and proliferation in vascular smooth muscle cells from spontaneously hypertensive rats

“…In general, Sulf1 has been known to inhibit cancer cell proliferation [29,30]. Moreover, Sulf1 expression has been established to be down-regulated in ovarian, breast, and hepatocellular cancers [10,11,29]. Dysregulated Sulf1 activity has also been shown to be associated with increased VSMCs proliferation [15].…”

“…Taken together, these results suggest that the maintenance of AT2 R expression via Sulf1 on the AT2 R pathway plays an important role in the inhibition of AT2 R inhibitor on Ang II-induced hypertensive mediator expression and cell proliferation in SHR VSMCs. In general, Sulf1 has been known to inhibit cancer cell proliferation [29,30]. Moreover, Sulf1 expression has been established to be down-regulated in ovarian, breast, and hepatocellular cancers [10,11,29].…”