Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma
Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma
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DOI：
10.1002/hep.22202
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发表时间：
2008-04-01
期刊：
影响因子：
13.5
通讯作者：
Roberts, Lewis R.
中科院分区：
文献类型：
--
作者：
Lai, Jin-Ping;Sandhu, Dalbir S.;Roberts, Lewis R.
已经表明，肝素降解endosulfatase，硫酸酯酶1（SULF 1），作为肝脏肿瘤抑制剂的功能，但相关的硫酸酯酶，硫酸酯酶2（SULF 2），在肝癌发生中的作用仍有待阐明。我们研究了SULF 2对肝肿瘤发生的影响。SULF 2在139例肝细胞癌（HCC）中的79例（57%）和11例HCC细胞系中的8例（73%）中表达增加。SULF 2的强制表达增加了HCC细胞的生长和迁移，而使用靶向SULF 2的短发夹RNA敲低SULF 2则在体外废除了HCC细胞的增殖和迁移。由于SULF 1和SULF 2与硫酸乙酰肝素蛋白聚糖（HSPG）和HSPG磷脂酰肌醇蛋白聚糖3（GPC 3）在HCC中上调，我们研究了SULF 2对GPC 3表达的影响以及SULF 2与GPC 3的相关性。SULF 2介导的细胞生长与成纤维细胞生长因子2（FGF 2）的结合增加、细胞外信号调节激酶和AKT的磷酸化以及GPC3的表达相关。GPC3的敲低减弱了表达SULF 2的HCC细胞中的FGF 2结合。SULF 2对GPC3的上调和肿瘤生长的影响在裸鼠异种移植物中得到证实。此外，在切除的HCC组织中SULF 2表达增加的HCC患者预后更差，术后复发率更高。结论：与SULF 1的肿瘤抑制作用相反，SULF 2在HCC中具有致癌作用，部分通过上调FGF信号传导和GPC3表达介导。
It has been shown that the heparin-degrading endosulfatase, sulfatase 1 (SULF1), functions as a liver tumor suppressor, but the role of the related sulfatase, sulfatase 2 (SULF2), in liver carcinogenesis remains to be elucidated. We investigated the effect of SULF2 on liver tumorigenesis. Expression of SULF2 was increased in 79 (57%) of 139 hepatocellular carcinomas (HCCs) and 8 (73%) of 11 HCC cell lines. Forced expression of SULF2 increased HCC cell growth and migration, whereas knockdown of SULF2 using short hairpin RNA targeting SULF2 abrogated HCC cell proliferation and migration in vitro. Because SULF1 and SULF2 desulfate heparan sulfate proteoglycans (HSPGs) and the HSPG glypican 3 (GPC3) is up-regulated in HCC, we investigated the effects of SULF2 on GPC3 expression and the association of SULF2 with GPC3. SULF2-mediated cell growth was associated with increased binding of fibroblast growth factor 2 (FGF2), phosphorylation of extracellular signal-regulated kinase and AKT, and expression of GPC3. Knockdown of GPC3 attenuated FGF2 binding in SULF2-expressing H CC cells. The effects of SULF2 on up-regulation of GPC3 and tumor growth were confirmed in nude mouse xenografts. Moreover, HCC patients with increased SULF2 expression in resected HCC tissues had a worse prognosis and a higher rate of recurrence after surgery. Conclusion: 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.