Tsukuba Research Institute, Novartis Pharma, KK, Tsukuba-shi, Ibaraki, Japan.
Cancer Biol Ther. 2009 Jul;8(13):1292-9. doi: 10.4161/cbt.8.13.8884.
Focal adhesion kinase (FAK) is shown to be frequently correlated with malignancy of the tumor and poor prognosis of the diseases.Because FAK resides immediately downstream of the interaction of cell surface adhesion molecules and extracellular matricies, it is considered to be critical to regulate several cellular processes including growth, differentiation, adhesion, motility and apoptosis. However, the studies on the role of FAK related to cell proliferation have been limited even in vitro. Here, in order to validate the role of FAK in in vivo tumor formation and proliferation, we employed direct intratumoral injection of short hairpin RNA (shRNA) targeting FAK with cationic liposome. Using shRNAs targeting FAK selected from the constructed shRNA library for FAK and by optimization of in vivo delivery conditions, we demonstrated different patterns of the association of FAK inhibition with in vivo tumor formation/proliferation inhibition in two models, PC3M heterotopic xenograft and 4T1 orthotopic syngraft models. These observations indicated that the roles of FAK in tumorigenesis are different among the tumor species. In addition, we showed that ERK is the critical MAP kinase in the signaling pathway down stream of FAK in in vivo proliferation of 4T1 tumor cells.
黏着斑激酶（FAK）常与肿瘤的恶性程度和疾病的不良预后相关。因为 FAK 位于细胞表面黏附分子与细胞外基质相互作用的下游，所以它被认为是调节多种细胞过程（包括生长、分化、黏附、迁移和凋亡）的关键。然而，即使在体外，FAK 与细胞增殖相关的作用研究也很有限。为了验证 FAK 在体内肿瘤形成和增殖中的作用，我们采用阳离子脂质体直接向肿瘤内注射靶向 FAK 的短发夹 RNA（shRNA）。我们使用从针对 FAK 的构建 shRNA 文库中选择的靶向 FAK 的 shRNAs，并通过优化体内递送条件，在 PC3M 异位异种移植和 4T1 原位同基因移植模型中，展示了 FAK 抑制与体内肿瘤形成/增殖抑制之间的不同关联模式。这些观察结果表明，FAK 在肿瘤发生中的作用在不同肿瘤类型之间存在差异。此外，我们还表明 ERK 是 FAK 在 4T1 肿瘤细胞体内增殖过程中信号通路下游的关键 MAP 激酶。
