Cohen-Dvashi Hadas, Ben-Chetrit Nir, Russell Roslin, Carvalho Silvia, Lauriola Mattia, Nisani Sophia, Mancini Maicol, Nataraj Nishanth, Kedmi Merav, Roth Lee, Köstler Wolfgang, Zeisel Amit, Yitzhaky Assif, Zylberg Jacques, Tarcic Gabi, Eilam Raya, Wigelman Yoav, Will Rainer, Lavi Sara, Porat Ziv, Wiemann Stefan, Ricardo Sara, Schmitt Fernando, Caldas Carlos, Yarden Yosef
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
Cancer Research UK Cambridge Research Institute Li Ka Shing Centre, Cambridge, UK.
EMBO Mol Med. 2015 Mar;7(3):299-314. doi: 10.15252/emmm.201404134.
Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we identify Navigator-3 (NAV3), a gene frequently mutated or deleted in human tumors, as a regulator of epithelial migration and invasion. Following induction by growth factors, NAV3 localizes to the plus ends of microtubules and enhances their polarized growth. Accordingly, NAV3 depletion trimmed microtubule growth, prolonged growth factor signaling, prevented apoptosis and enhanced random cell migration. Mathematical modeling suggested that NAV3-depleted cells acquire an advantage in terms of the way they explore their environment. In animal models, silencing NAV3 increased metastasis, whereas ectopic expression of the wild-type form, unlike expression of two, relatively unstable oncogenic mutants from human tumors, inhibited metastasis. Congruently, analyses of > 2,500 breast and lung cancer patients associated low NAV3 with shorter survival. We propose that NAV3 inhibits breast cancer progression by regulating microtubule dynamics, biasing directionally persistent rather than random migration, and inhibiting locomotion of initiated cells.
原发性肿瘤细胞的播散取决于其迁移和侵袭特性。在此，我们鉴定出导航蛋白3（NAV3），一种在人类肿瘤中经常发生突变或缺失的基因，作为上皮细胞迁移和侵袭的调节因子。在生长因子诱导后，NAV3定位于微管的正端并增强其极化生长。因此，NAV3缺失会缩短微管生长、延长生长因子信号传导、防止细胞凋亡并增强随机细胞迁移。数学模型表明，NAV3缺失的细胞在探索环境的方式上具有优势。在动物模型中，沉默NAV3会增加转移，而野生型形式的异位表达，与来自人类肿瘤的两个相对不稳定的致癌突变体的表达不同，会抑制转移。同样，对2500多名乳腺癌和肺癌患者的分析表明，低NAV3水平与较短的生存期相关。我们认为，NAV3通过调节微管动力学、偏向定向持续而非随机迁移以及抑制起始细胞的运动来抑制乳腺癌进展。
