Zhang H, Su L, Müller S, Tighiouart M, Xu Z, Zhang X, Shin H J C, Hunt J, Sun S-Y, Shin D M, Chen Z G
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Br J Cancer. 2008 Nov 18;99(10):1684-94. doi: 10.1038/sj.bjc.6604735. Epub 2008 Oct 28.
Caveolin-1 (Cav-1) plays an important role in modulating cellular signalling, but its role in metastasis is not well defined. A significant reduction in Cav-1 levels was detected in lymph node metastases as compared with primary tumour of head and neck squamous cell carcinoma (HNSCC) specimens (P<0.0001), confirming the downregulation of Cav-1 observed in a highly metastatic M4 cell lines derived from our orthotopic xenograft model. To investigate the function of Cav-1 in metastasis of HNSCC, we compared stable clones of M4 cells carrying human cav-1 cDNA (CavS) with cells expressing an empty vector (EV) in vitro and in the orthotopic xenograft model. Overexpression of Cav-1 suppressed growth of the CavS tumours compared with the EV tumours. The incidence of lung metastases was significantly lower in animals carrying CavS tumours than those with EV tumours (P=0.03). In vitro, CavS cells displayed reduced cell growth, invasion, and increased anoikis compared with EV cells. In CavS cells, Cav-1 formed complex with integrin beta1 and Src. Further application of integrin beta1 neutralising antibody or Src inhibitor PP2 to EV cells illustrated similar phenotypes as CavS cells, suggesting that Cav-1 may play an inhibitory role in tumorigenesis and lung metastasis through regulating integrin beta1- and Src-mediated cell-cell and cell-matrix interactions.
小窝蛋白-1（Cav-1）在调节细胞信号传导中起重要作用，但其在转移中的作用尚不清楚。与头颈部鳞状细胞癌（HNSCC）标本的原发性肿瘤相比，在淋巴结转移中检测到Cav-1水平显著降低（P<0.0001），这证实了在我们原位异种移植模型衍生的高转移性M4细胞系中观察到的Cav-1下调。为了研究Cav-1在HNSCC转移中的功能，我们在体外和原位异种移植模型中比较了携带人cav-1 cDNA的M4细胞稳定克隆（CavS）与表达空载体（EV）的细胞。与EV肿瘤相比，Cav-1的过表达抑制了CavS肿瘤的生长。携带CavS肿瘤的动物肺转移发生率显著低于携带EV肿瘤的动物（P=0.03）。在体外，与EV细胞相比，CavS细胞的细胞生长、侵袭减少，失巢凋亡增加。在CavS细胞中，Cav-1与整合素β1和Src形成复合物。将整合素β1中和抗体或Src抑制剂PP2进一步应用于EV细胞，表现出与CavS细胞相似的表型，表明Cav-1可能通过调节整合素β1和Src介导的细胞-细胞和细胞-基质相互作用在肿瘤发生和肺转移中发挥抑制作用。
