Hsu Y.-H.Lin W.-L.Hou Y.-T.YEONG-SHIAU PUCHIA-TUNG SHUNCHI-LING CHENWu Y.-Y.Chen J.-Y.Chen T.-H.TZUU-SHUH JOU2021-02-022021-02-0220100002-9440https://www.scopus.com/inward/record.uri?eid=2-s2.0-77953228383&doi=10.2353%2fajpath.2010.090539&partnerID=40&md5=8393cfb7b4faf7a855cdc560e4c49fc7https://scholars.lib.ntu.edu.tw/handle/123456789/544444Podocalyxin was initially identified in glomerular podocytes to critically maintain the structural and functional integrity of the glomerular ultrafiltrative apparatus. Lately, it has emerged as a malignant marker in tumors arising from a variety of tissue origins. By immunohistochemistry, we identified that 9.6% of renal cell carcinoma patients overexpress this protein. This subset of patients had significantly shorter disease-specific and overall survivals, and, importantly, we established podocalyxin overexpression as an independent prognostic factor for latent distant metastasis with multivariate analysis. Podocalyxin down-regulation by small interfering RNA led to defective migration in model renal tubular cells, which was corrected by re-expression of podocalyxin. The activity of the small GTPase Rac1, a well-characterized modulator of cell migration, was diminished by podocalyxin knock-down. Conversely, podocalyxin overexpression in human embryonic kidney cells up-regulated Rac1 activity, which depended on a complex formed by podocalyxin, ERMbinding phosphoprotein 50, ezrin, and ARHGEF7, a Rac1 activator. Therefore, podocalyxin can serve as a biomarker to identify renal cell carcinoma patients with higher metastatic potential for more aggressive intervention at earlier clinical stages. Copyright ? American Society for Investigative Pathology.[SDGs]SDG3arhgef7; enzyme activator; ezrin; guanine nucleotide exchange factor; phosphoprotein; podocalyxin; Rac1 protein; small interfering RNA; tumor marker; unclassified drug; cytoskeleton protein; ezrin; multiprotein complex; phosphoprotein; podocalyxin; Rac1 protein; Rho guanine nucleotide exchange factor; sialoglycoprotein; sodium proton exchange protein; sodium-hydrogen exchanger regulatory factor; adult; animal cell; animal cell culture; article; cancer staging; cell aggregation; cell migration; cell strain; cell strain HEK293; clinical assessment; computer aided design; distant metastasis; down regulation; enzyme activity; female; genetic transfection; histopathology; human; human cell; human cell culture; immunohistochemistry; kidney carcinoma; kidney tubule cell; male; metastasis potential; multivariate analysis; nonhuman; overall survival; plasmid; podocyte; priority journal; prognosis; protein expression; protein purification; reverse transcription polymerase chain reaction; wound healing; aged; animal; cell adhesion; cell line; cell motion; dog; enzyme activation; gene silencing; genetics; Kaplan Meier method; kidney carcinoma; metabolism; metastasis; middle aged; pathology; physiology; Adult; Aged; Animals; Carcinoma, Renal Cell; Cell Adhesion; Cell Line; Cell Movement; Cytoskeletal Proteins; Dogs; Enzyme Activation; Female; Gene Knockdown Techniques; Guanine Nucleotide Exchange Factors; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multiprotein Complexes; Neoplasm Metastasis; Phosphoproteins; rac1 GTP-Binding Protein; Rho Guanine Nucleotide Exchange Factors; Sialoglycoproteins; Sodium-Hydrogen Antiporterjournal article10.2353/ajpath.2010.090539203954462-s2.0-77953228383