Lai Jin-Ping, Chien Jeremy, Strome Scott E, Staub Julie, Montoya Damian P, Greene Eddie L, Smith David I, Roberts Lewis R, Shridhar Viji
Division of Gastroenterology and Hepatology, Mayo Clinic Cancer Center, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Oncogene. 2004 Feb 19;23(7):1439-47. doi: 10.1038/sj.onc.1207258.
Recently, we cloned a novel sulfatase domain-containing downregulated gene, HSulf-1, which modulates heparin-binding growth factor signaling in ovarian cancer. Based on the pilot data showing the loss of HSulf-1 in head and neck squamous cell carcinoma cell lines (SCCHN), we sought to employ SCCHN as a model to define the role of HSulf-1 in the molecular regulation of tumorigenicity. Three SCCHN lines (012SCC, WMMSCC, and 015SCC) had no detectable HSulf-1 mRNA. Clonal lines of HSulf-1-expressing 012SCC attenuated the activation of ERK/mitogen-activated protein kinase (MAPK) signaling mediated by fibroblast growth factor (FGF-2) and both ERK/MAPK and Akt signaling mediated by hepatocyte growth factor (HGF). Consistent with this downregulation, phosphorylation of HGF receptor, c-Met, which is frequently overexpressed in SCCHN, was also attenuated in HSulf-1 clonal 012SCC cell lines. HGF markedly enhanced the motility and migration of vector-transfected cells in a transwell invasion chamber. However, HGF-mediated motility and invasion was attenuated in HSulf-1 clonal 012SCC cell lines. In addition, transfected cells displayed significant growth inhibition concomitant with a decrease in mitogenicity, as measured by thymidine incorporation and increased sensitivity to staurosporine- and cisplatin-induced apoptosis. These data suggest that HSulf-1 normally functions as a negative regulator in cell growth and loss of HSulf-1 in SCCHN potentiates growth factor signaling, enhances motility, invasiveness and inhibits stress-induced apoptosis, with a resulting increase in tumorigenicity.
最近，我们克隆了一个新的含硫酸酯酶结构域的下调基因HSulf-1，它可调节卵巢癌中肝素结合生长因子信号传导。基于在头颈部鳞状细胞癌细胞系（SCCHN）中显示HSulf-1缺失的初步数据，我们试图采用SCCHN作为模型来确定HSulf-1在肿瘤发生分子调控中的作用。三个SCCHN细胞系（012SCC、WMMSCC和015SCC）未检测到HSulf-1 mRNA。表达HSulf-1的012SCC克隆系减弱了由成纤维细胞生长因子（FGF-2）介导的ERK/丝裂原活化蛋白激酶（MAPK）信号传导以及由肝细胞生长因子（HGF）介导的ERK/MAPK和Akt信号传导。与这种下调一致，在SCCHN中经常过度表达的HGF受体c-Met的磷酸化在HSulf-1克隆的012SCC细胞系中也减弱。HGF显著增强了载体转染细胞在transwell侵袭小室中的运动性和迁移能力。然而，HGF介导的运动性和侵袭在HSulf-1克隆的012SCC细胞系中减弱。此外，转染细胞显示出明显的生长抑制，同时有丝分裂原性降低，这通过胸苷掺入来衡量，并且对星形孢菌素和顺铂诱导的凋亡敏感性增加。这些数据表明，HSulf-1通常作为细胞生长的负调节因子发挥作用，SCCHN中HSulf-1的缺失增强了生长因子信号传导，增强了运动性、侵袭性并抑制了应激诱导的凋亡，从而导致肿瘤发生增加。
