TG-interacting factor-induced superoxide production from NADPH oxidase contributes to the migration/invasion of urothelial carcinoma.
Urothelial carcinoma (UC) of the bladder is the fourth most common cancer and the ninth leading cause of death from cancer among men in the United States. However, higher recurrence, resistance to therapy, and poor diagnostic/prognostic biomarkers of UC prompt us to identify novel targets to improve the clinical applications. TG-interacting factor (TGIF), a transcriptional corepressor to modulate the TGF-β signaling, is associated with various types of human cancer. In the present study, we found that cellular migration activity, reactive oxygen species production, AKT(S473) phosphorylation, TGIF, and p67(phox) expression were higher in invasive T24 cells than in noninvasive RT4 cells. In addition, overexpression of TGIF in RT4 cells enhanced cellular migration/invasion ability; it involved NADPH oxidase 2 (Nox2)/p67(phox) complex activation, reactive oxygen species production, and AKT(S473) phosphorylation. In contrast, the migration/invasion ability of T24 cells was suppressed by the knockdown of TGIF or p67(phox), respectively. Overexpression of AKT1 could increase cellular superoxide production and invasion. Moreover, by using the PI3K/AKT inhibitor wortmannin or shRNA of AKT1, the TGIF-induced Nox activation and superoxide production were significantly inhibited. Accordingly, we suggest that PI3K/AKT signaling mediates TGIF-induced Nox2/p67(phox) complex activation and the resultant superoxide production which reinforces the PI3K/AKT signaling to promote the cellular migration/invasion ability of UC.
Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. huanghs@mail.ncku.edu.tw
Huei-Sheng
HS
Huang
Zi-Miao
ZM
Liu
Pei-Chi
PC
Chen
Hong-Yu
HY
Tseng
Bi-Wen
BW
Yeh
D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; C097504:TGIF1 protein, human; C079789:neutrophil cytosol factor 67K; D013481:Superoxides; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2