Chatterji Tanushree, Varkaris Andreas S, Parikh Nila U, Song Jian H, Cheng Chien-Jui, Schweppe Rebecca E, Alexander Stephanie, Davis John W, Troncoso Patricia, Friedl Peter, Kuang Jian, Lin Sue-Hwa, Gallick Gary E
Department of Genitourinary Medical Oncology, The David Koch Center for Applied Research in Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Programs in Cancer Biology and Cancer Metastasis, The University of Texas Graduate School of Biomedical Sciences at Houston, TX, USA.
Oncotarget. 2015 Apr 30;6(12):10175-94. doi: 10.18632/oncotarget.3391.
To study the role of FAK signaling complexes in promoting metastatic properties of prostate cancer (PCa) cells, we selected stable, highly migratory variants, termed PC3 Mig-3 and DU145 Mig-3, from two well-characterized PCa cell lines, PC3 and DU145. These variants were not only increased migration and invasion in vitro, but were also more metastatic to lymph nodes following intraprostatic injection into nude mice. Both PC3 Mig-3 and DU145 Mig-3 were specifically increased in phosphorylation of FAK Y861. We therefore examined potential alterations in Src family kinases responsible for FAK phosphorylation and determined only Yes expression was increased. Overexpression of Yes in PC3 parental cells and src-/-fyn-/-yes-/- fibroblasts selectively increased FAK Y861 phosphorylation, and increased migration. Knockdown of Yes in PC3 Mig-3 cells decreased migration and decreased lymph node metastasis following orthotopic implantation of into nude mice. In human specimens, Yes expression was increased in lymph node metastases relative to paired primary tumors from the same patient, and increased pFAK Y861 expression in lymph node metastases correlated with poor prognosis. These results demonstrate a unique role for Yes in phosphorylation of FAK and in promoting PCa metastasis. Therefore, phosphorylated FAK Y861 and increased Yes expression may be predictive markers for PCa metastasis.
为了研究黏着斑激酶（FAK）信号复合物在促进前列腺癌细胞（PCa）转移特性中的作用，我们从两种特征明确的PCa细胞系PC3和DU145中筛选出稳定的、高迁移性的变体，称为PC3 Mig-3和DU145 Mig-3。这些变体不仅在体外具有增强的迁移和侵袭能力，而且在前列腺内注射到裸鼠体内后，对淋巴结的转移能力也更强。PC3 Mig-3和DU145 Mig-3中FAK Y861的磷酸化水平均特异性升高。因此，我们检测了负责FAK磷酸化的Src家族激酶的潜在变化，结果发现只有Yes的表达增加。在PC3亲本细胞和成纤维细胞src-/-fyn-/-yes-/-中过表达Yes可选择性增加FAK Y861的磷酸化水平，并增强细胞迁移能力。在PC3 Mig-3细胞中敲低Yes可降低细胞迁移能力，并减少原位植入裸鼠后的淋巴结转移。在人类标本中，与同一患者配对的原发性肿瘤相比，淋巴结转移灶中Yes的表达增加，且淋巴结转移灶中pFAK Y861表达增加与预后不良相关。这些结果表明Yes在FAK磷酸化和促进PCa转移中具有独特作用。因此，磷酸化的FAK Y861和增加的Yes表达可能是PCa转移的预测标志物。
