Taniuchi Keisuke, Furihata Mutsuo, Naganuma Seiji, Dabanaka Ken, Hanazaki Kazuhiro, Saibara Toshiji
Department of Endoscopic Diagnostics and Therapeutics, Kochi Medical School, Kochi University, Nankoku, Japan.
Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Nankoku, Japan.
Cancer Sci. 2016 Oct;107(10):1430-1442. doi: 10.1111/cas.13018. Epub 2016 Sep 2.
The cell-adhesion glycoprotein PODXL is associated with an aggressive tumor phenotype in several forms of cancer. Here, we report that high PODXL expression was an independent predictor of worse overall survival of pancreatic cancer patients, and that PODXL promoted pancreatic cancer cell motility and invasion by physically binding to the cytoskeletal protein gelsolin. Suppression of PODXL or gelsolin decreased membrane protrusions with abundant peripheral actin structures, and in turn inhibited cell motility and invasion. Transfection of a PODXL-rescue construct renewed the expression of gelsolin bound to peripheral actin structures in cell protrusions, and abrogated the decreased cell protrusions caused by the knockdown of PODXL. Furthermore, transfection of a PODXL-rescue construct into pancreatic cancer cells in which both PODXL and gelsolin were suppressed failed to increase the formation of the protrusions. Thus, PODXL enhances motility and invasiveness through an increase in gelsolin-actin interactions in cell protrusions.
细胞黏附糖蛋白PODXL与多种癌症的侵袭性肿瘤表型相关。在此，我们报告高PODXL表达是胰腺癌患者总体生存较差的独立预测因素，并且PODXL通过与细胞骨架蛋白凝溶胶蛋白物理结合来促进胰腺癌细胞的运动和侵袭。抑制PODXL或凝溶胶蛋白会减少具有丰富外周肌动蛋白结构的膜突起，进而抑制细胞运动和侵袭。转染PODXL拯救构建体可恢复与细胞突起中外周肌动蛋白结构结合的凝溶胶蛋白的表达，并消除因PODXL敲低导致的细胞突起减少。此外，将PODXL拯救构建体转染到PODXL和凝溶胶蛋白均被抑制的胰腺癌细胞中，未能增加突起的形成。因此，PODXL通过增加细胞突起中凝溶胶蛋白-肌动蛋白的相互作用来增强运动性和侵袭性。
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