title: TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKT pathway and is associated with poor prognosis in lung cancer.
abstract: We integrated four gene expression profile data sets, namely two different pair-matched stage I lung adenocarcinoma data sets, secondary metastatic tumors vs benign tumors and lung tumor metastasizes to the brain, and we identified one kinase, T-LAK Cell-Originated Protein Kinase (TOPK), as a putative gene that promotes metastasis. To delineate the role of TOPK in lung cancer, we showed that overexpression of TOPK, but not a catalytically inactive form of TOPK, can enhance the migration and invasion of lung fibroblasts or cells with low TOPK expression. In addition, TOPK-induced cell migration was shown to be a PI3K/AKT-dependent event. TOPK concurrently promoted AKT phosphorylation at Ser(473) and decreased the phosphatase and tensin homolog (PTEN) levels, whereas TOPK knockdown had the reverse effects. LY294002, a PI3K inhibitor, did not inhibit the TOPK-induced decrease in PTEN, and co-expression of PTEN significantly reduced TOPK-induced AKT phosphorylation in a dose-dependent manner; these results indicate that the TOPK-mediated PTEN decrease has an upstream role in regulating PI3K/AKT-stimulated migration. Using immunohistochemical analysis of lung cancer tissue samples, we showed that a high TOPK expression level correlates strongly with reduced overall and disease-free survivals. Moreover, an inverse correlation between TOPK and PTEN expression was present and is consistent with the biochemical findings. Finally, a combination of high TOPK and low PTEN expression was inversely correlated with overall and disease-free survivals, independent of other pathologic staging factors. Our results suggest that TOPK is a potential therapeutic target in lung cancer that promotes cell migration by modulating a PI3K/PTEN/AKT-dependent signaling pathway; they also suggest that high TOPK expression, either alone or in combination with a low level of PTEN, may serve as a prognostic marker for lung cancer.
authors: Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City, Taiwan.
authors: M-C
authors: MC
authors: Shih
authors: J-Y
authors: JY
authors: Chen
authors: Y-C
authors: YC
authors: Wu
authors: Y-H
authors: YH
authors: Jan
authors: B-M
authors: BM
authors: Yang
authors: P-J
authors: PJ
authors: Lu
authors: H-C
authors: HC
authors: Cheng
authors: M-S
authors: MS
authors: Huang
authors: C-J
authors: CJ
authors: Yang
authors: M
authors: M
authors: Hsiao
authors: J-M
authors: JM
authors: Lai
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D000368:Aged; D045744:Cell Line, Tumor; D002465:Cell Movement; D018572:Disease-Free Survival; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000401:mortality* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human