Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis.
Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis.
复制标题
DOI：
10.1038/onc.2009.365
复制
发表时间：
2010-02-04
期刊：
影响因子：
8
通讯作者：
Rosen, S. D.
中科院分区：
文献类型：
--
作者：
Lemjabbar-Alaoui, H.;van Zante, A.;Singer, M. S.;Xue, Q.;Wang, Y-Q;Tsay, D.;He, B.;Jablons, D. M.;Rosen, S. D.
硫酸乙酰肝素蛋白聚糖（HSPG）结合多种生长因子/形态发生素并调节其信号传导。HS链内葡糖胺的6-O-硫酸化（6S）对于许多这些配体相互作用至关重要。Sulf-1和Sulf-2是细胞外中性pH硫酸酯酶，通过从完整HS链中去除6S，为HSPG功能的调节提供了一种新的合成后机制。因此，硫可以调节几种信号传导途径，包括促进Wnt信号传导。我们发现SULF 2转录和Sulf-2蛋白在人肺腺癌和鳞状细胞癌中诱导，这两种主要类型的非小细胞肺癌（NSCLC）。我们证实了广泛的Sulf-2蛋白表达在10/10的人肺鳞癌手术标本的肿瘤细胞。我们研究了五个Sulf-2+ NSCLC细胞系，其中两个是由支气管上皮细胞的烟草烟雾转化。在这些细胞系中，shRNA介导的Sulf-2敲低导致其细胞表面6S增加，同时在体外逆转了其转化的表型，消除了自分泌Wnt信号传导，并强烈减弱了裸小鼠中异种移植瘤的形成。相反，在非恶性支气管上皮细胞中强制Sulf-2表达产生部分转化的表型。我们的研究结果支持Sulf-2在肺癌中的重要作用，肺癌是主要的癌症杀手。
Heparan sulfate proteoglycans (HSPGs) bind to multiple growth factors/morphogens and regulate their signaling. 6-O-sulfation (6S) of glucosamine within HS-chains is critical for many of these ligand interactions. Sulf-1 and Sulf-2, which are extracellular neutral-pH sulfatases, provide a novel post-synthetic mechanism for regulation of HSPG function by removing 6S from intact HS-chains. The Sulfs can thereby modulate several signaling pathways, including the promotion of Wnt signaling. We found induction of SULF2 transcripts and Sulf-2 protein in human lung adenocarcinoma and squamous cell carcinoma, the two major classes of non-small cell lung cancers (NSCLC). We confirmed widespread Sulf-2 protein expression in tumor cells of 10/10 surgical specimens of human lung squamous carcinomas. We studied five Sulf-2+ NSCLC cell lines, including two which were derived by cigarette-smoke transformation of bronchial epithelial cells. shRNA-mediated Sulf-2 knockdown in these lines caused an increase in 6S on their cell surface and in parallel reversed their transformed phenotype in vitro, eliminated autocrine Wnt signaling, and strongly blunted xenograft tumor formation in nude mice. Conversely, forced Sulf-2 expression in non-malignant bronchial epithelial cells produced a partially transformed phenotype. Our findings support an essential role for Sulf-2 in lung cancer, the leading cancer killer.
登录
查看更多内容
影响因子：
7.8
作者：
Ai, Xingbin;Do, Anh-Tri;Lozynska, Olga;Kusche-Gullberg, Marion;Lindahl, Ulf;Emerson, Charles P Jr
通讯作者：
Emerson, Charles P Jr
影响因子：
4.8
作者：
Dai, YM;Yang, Y;Sanderson, RD
通讯作者：
Sanderson, RD
影响因子：
8.4
作者：
Huang, Cheng-Long;Liu, Dage;Ueno, Masaki
通讯作者：
Ueno, Masaki
影响因子：
4.8
作者：
Brickman, YG;Ford, MD;Turnbull, JE
通讯作者：
Turnbull, JE
DOI：
10.1186/bcr1604
发表时间：
2006
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Grigoriadis A;Mackay A;Reis-Filho JS;Steele D;Iseli C;Stevenson BJ;Jongeneel CV;Valgeirsson H;Fenwick K;Iravani M;Leao M;Simpson AJ;Strausberg RL;Jat PS;Ashworth A;Neville AM;O'Hare MJ
通讯作者：
O'Hare MJ