Abstract：
Attachment of circulating tumor cells to the endothelial cells (ECs) lining blood vessels is a critical step in cancer metastatic colonization, which leads to metastatic outgrowth. Breast and prostate cancers are common malignancies in women and men, respectively. Here, we observe that β1-integrin is required for human prostate and breast cancer cell adhesion to ECs under shear-stress conditions in vitro and to lung blood vessel ECs in vivo. We identify IQGAP1 and neural Wiskott-Aldrich syndrome protein (NWASP) as regulators of β1-integrin transcription and protein expression in prostate and breast cancer cells. IQGAP1 and NWASP depletion in cancer cells decreases adhesion to ECs in vitro and retention in the lung vasculature and metastatic lung nodule formation in vivo. Mechanistically, NWASP and IQGAP1 act downstream of Cdc42 to increase β1-integrin expression both via extracellular signal-regulated kinase (ERK)/focal adhesion kinase signaling at the protein level and by myocardin-related transcription factor/serum response factor (SRF) transcriptionally. Our results identify IQGAP1 and NWASP as potential therapeutic targets to reduce early metastatic dissemination.
摘要：
循环肿瘤细胞与血管内皮细胞（ECs）的连接是癌症转移定植的关键步骤，导致转移性生长。乳腺癌和前列腺癌是女性和男性常见的恶性肿瘤，分别。这里,我们观察到β1-整合素是人前列腺癌和乳腺癌细胞在体外剪切应力条件下粘附到EC和在体内粘附到肺血管EC所必需的。我们将IQGAP1和神经Wiskott-Aldrich综合征蛋白（NWASP）鉴定为前列腺癌和乳腺癌细胞中β1整合素转录和蛋白表达的调节剂。癌细胞中的IQGAP1和NWASP消耗减少了体外对EC的粘附，并在体内保留在肺脉管系统和转移性肺结节形成中。机械上,NWASP和IQGAP1作用于Cdc42的下游，通过蛋白质水平的细胞外信号调节激酶（ERK）/粘着斑激酶信号传导以及通过与心肌素相关的转录因子/血清反应因子（SRF）转录增加β1-整联蛋白的表达。我们的结果确定IQGAP1和NWASP是减少早期转移扩散的潜在治疗靶点。
