Talin1 promotes tumor invasion and metastasis via focal adhesion signaling and anoikis resistance.
Talin1 promotes tumor invasion and metastasis via focal adhesion signaling and anoikis resistance.
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DOI：
10.1158/0008-5472.can-09-2833
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发表时间：
2010-03-01
期刊：
影响因子：
11.2
通讯作者：
Kyprianou N
中科院分区：
文献类型：
--
作者：
Sakamoto S;McCann RO;Dhir R;Kyprianou N
Talin1是一种焦点黏附复合体蛋白，调节整合素与细胞外基质(ECM)的相互作用。本研究探讨了talin1在前列腺癌的体内外转移过程中的意义。Talin1过表达通过激活生存信号和赋予对失巢凋亡的抵抗力来增强前列腺癌细胞的黏附、迁移和侵袭。ShRNA介导的talin1缺失在体外显着抑制前列腺癌细胞的迁移和跨内皮细胞侵袭，在体内显着抑制前列腺癌的转移。Talin1通过粘着斑激酶(FAK)和Src等粘着斑蛋白的磷酸化和AKT的下游激活来调节细胞存活信号。靶向AKT激活可显著降低talin1介导的前列腺癌细胞侵袭力。此外，talin1免疫反应与TRAMP小鼠模型中前列腺癌的进展直接相关。Talin1在人前列腺标本中的分布显示，与原发前列腺癌相比，转移性组织中胞浆Talin1的表达显著增加(P<；0.0001)。这些发现表明：(A)干扰talin1信号/粘着斑相互作用在靶向转移性前列腺癌方面的治疗意义，以及(B)talin1作为肿瘤进展到转移的标志物的潜在价值。
Talin1 is a focal adhesion complex protein that regulates integrin interactions with the extracellular matrix (ECM). This study investigated the significance of talin1 in prostate cancer progression to metastasis in vitro and in vivo. Talin1 overexpression enhanced prostate cancer cell adhesion, migration and invasion by activating survival signals and conferring resistance to anoikis. ShRNA-mediated talin1 loss led to a significant suppression of prostate cancer cell migration and transendothelial invasion in vitro and a significant inhibition of prostate cancer metastasis in vivo. Talin1 regulated cell survival signals via phosphorylation of focal adhesion complex proteins such as focal adhesion kinase (FAK) and Src, and downstream activation of AKT. Targeting AKT activation led to a significant reduction of talin1-mediated prostate cancer cell invasion. Furthermore, talin1 immunoreactivity directly correlated with prostate tumor progression to metastasis in the TRAMP mouse model. Talin1 profiling in human prostate specimens revealed a significantly higher expression of cytoplasmic talin1 in metastatic tissue compared to primary prostate tumors (P<0.0001). These findings suggest: (a) a therapeutic significance of disrupting talin1 signaling/focal adhesion interactions in targeting metastatic prostate cancer and (b) a potential value for talin1 as a marker of tumor progression to metastasis.