title: Direct regulation of FOXK1 by C-jun promotes proliferation, invasion and metastasis in gastric cancer cells.
abstract: Forkhead box (FOX) K1 is a member of the FOX transcription factor superfamily. High FOXK1 expression is associated with several cancers. However, whether FOXK1 expression contributes to gastric cancer (GC) development and progression remains unknown. We analyzed the FOXK1 promoter using the Promo software and found several binding sequence transcription factors, including c-jun. However, the molecular mechanism by which FOXK1 affects the c-jun-mediated malignant phenotype is poorly understood. Here, we found that FOXK1 protein expression was higher in 8/10 (80.0%) fresh cancer tissues compared with that in adjacent normal tissues. FOXK1 overexpression enhanced the proliferation, migration and invasion of GC cells. Moreover, FOXK1 expression was stimulated by transforming growth factor-β1 (TGF-β1). FOXK1 acted as a potential epithelial-to-mesenchymal transition (EMT) inducer by stimulating vimentin expression and inducing the loss of E-cadherin in stable FOXK1-transfected cells. The results of promoter reporter and chromatin immunoprecipitation assays demonstrated that c-jun directly binds to and activates the human FOXK1 gene promoter. A positive correlation was observed between the expression patterns of FOXK1 and c-jun in GC cells and tissue. FOXK1 and c-jun expression were correlated with tumor progression and represented significant predictors of overall survival in GC patients. However, the siRNA-mediated repression of c-jun in FOXK1-overexpressing cells reversed EMT, as well as the proliferative and metastatic phenotypes. In vivo, c-jun promoted FOXK1-mediated proliferation and metastasis via orthotopic implantation. The evidence presented here suggests that FOXK1-directed regulation by c-jun promote the development and progression of human GC.
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, China.|Department of Gastroenterology, Guangzhou Nansha Central Hospital, Guangzhou 511457, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Wu
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Ruyi
authors.initials: R
authors.lastname: Xie
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Mengnan
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Qingzhen
authors.initials: Q
authors.lastname: Nan
authors.affiliation: Department of Rheumatism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Side
authors.initials: S
authors.lastname: Liu
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jide
authors.initials: J
authors.lastname: Wang
mesh_terms: D001483:Base Sequence; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: C495879:FOXK1 protein, human; D051858:Forkhead Transcription Factors; D016755:Proto-Oncogene Proteins c-jun; D053773:Transforming Growth Factor beta1