Chakraborty Goutam, Rangaswami Hema, Jain Shalini, Kundu Gopal C
National Center for Cell Science, Pune 411 007, India.
J Biol Chem. 2006 Apr 21;281(16):11322-31. doi: 10.1074/jbc.M512546200. Epub 2006 Feb 10.
Hypoxia is a key parameter that controls tumor angiogenesis and malignant progression by regulating the expression of several oncogenic molecules. The nonreceptor protein-tyrosine kinases Syk and Lck play crucial roles in the signaling mechanism of various cellular processes. The enhanced expression of Syk in normal breast tissue but not in malignant breast carcinoma has prompted us to investigate its potential role in mammary carcinogenesis. Accordingly, we hypothesized that hypoxia/reoxygenation (H/R) may play an important role in regulating Syk activation, and Lck may be involved in this process. In this study, we have demonstrated that H/R differentially regulates Syk phosphorylation and its subsequent interaction and cross-talk with Lck in MCF-7 cells. Moreover, Syk and Lck play differential roles in regulating Sp1 activation and expressions of melanoma cell adhesion molecule (MelCAM), urokinase-type plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF) in response to H/R. Overexpression of wild type Syk inhibited the H/R-induced uPA, MMP-9, and VEGF expression but up-regulated MelCAM expression. Our data also indicated that MelCAM acts as a tumor suppressor by negatively regulating H/R-induced uPA secretion and MMP-9 activation. The mice xenograft study showed the cross-talk between Syk and Lck regulated H/R-induced breast tumor progression and further correlated with the expressions of MelCAM, uPA, MMP-9, and VEGF. Human clinical specimen analysis supported the in vitro and in vivo findings. To our knowledge, this is first report that the cross-talk between Syk and Lck regulates H/R-induced breast cancer progression and further suggests that Syk may act as potential therapeutic target for the treatment of breast cancer.
缺氧是一个关键参数，通过调节多种致癌分子的表达来控制肿瘤血管生成和恶性进展。非受体蛋白酪氨酸激酶Syk和Lck在各种细胞过程的信号传导机制中发挥关键作用。Syk在正常乳腺组织中表达增强，而在恶性乳腺癌中不表达，这促使我们研究其在乳腺癌发生中的潜在作用。因此，我们假设缺氧/复氧（H/R）可能在调节Syk激活中起重要作用，并且Lck可能参与这一过程。在本研究中，我们证明了H/R在MCF-7细胞中差异调节Syk磷酸化及其随后与Lck的相互作用和串扰。此外，Syk和Lck在响应H/R时，在调节Sp1激活以及黑色素瘤细胞粘附分子（MelCAM）、尿激酶型纤溶酶原激活剂（uPA）、基质金属蛋白酶-9（MMP-9）和血管内皮生长因子（VEGF）的表达中发挥不同作用。野生型Syk的过表达抑制了H/R诱导uPA、MMP-9和VEGF的表达，但上调了MelCAM的表达。我们的数据还表明，MelCAM通过负调节H/R诱导的uPA分泌和MMP-9激活而作为一种肿瘤抑制因子发挥作用。小鼠异种移植研究表明，Syk和Lck之间的串扰调节了H/R诱导的乳腺肿瘤进展，并进一步与MelCAM、uPA、MMP-9和VEGF的表达相关。人类临床标本分析支持了体外和体内研究结果。据我们所知，这是首次报道Syk和Lck之间的串扰调节H/R诱导的乳腺癌进展，并进一步表明Syk可能作为治疗乳腺癌的潜在治疗靶点。
