title: Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition.
abstract: Previously, we reported that hypoxia was able to induce invasion and metastasis in gastric cancer and that hypoxia-inducible factor-1 (HIF-1) is a key factor involved in this tumor type. Krüppel-like factor 8 (KLF8) as a transcriptional repressor has been suggested as a promoter of tumor metastasis in breast cancer and an inducer of the epithelial‑mesenchymal transition (EMT). KLF8 is also highly expressed in gastric cancer tissues, contributing to poor prognosis. However, the association between KLF8 and HIF-1 in regulating the progression of human gastric cancer in hypoxia is unclear. In the present study, we found that KLF8 was overexpressed in gastric cancer metastatic tissues and cells. Additionally, KLF8 siRNA significantly inhibited SGC7901 cell invasion and migration compared with SGC7901, SGC7901/Scr-si cells. Hypoxia is thus able to induce KLF8 expression and EMT in SGC7901 cells. However, following the examination of changes in cell morphology and epithelial and mesenchymal markers, it was found that KLF8 siRNA and HIF-1 siRNA strongly reversed EMT in cells undergoing hypoxia. Furthermore, hypoxia-induced KLF8 overexpression was attenuated by HIF-1 siRNA. Experiments using luciferase promoter constructs resulted in a marked increase in the activity of cells exposed to hypoxia and decreased activity in cells co-transfected with HIF-1 siRNA. The chromatin immunoprecipitation assay revealed proximal HRE at -133 is the main HIF-1 binding site in the KLF8 promoter. In conclusion, the results demonstrated that KLF8 is actively enhanced by hypoxia and is a novel HIF-1 target. KLF8 is a novel EMT regulating transcription factor that involved in the progression of gastric cancer. The specific anti-EMT drugs in combination with anti-hypoxia are new promising cancer therapies.
authors.affiliation: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
authors.forename: Yafang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
authors.forename: Yongan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Pang
authors.affiliation: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
authors.forename: Pei
authors.initials: P
authors.lastname: Qian
authors.affiliation: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
authors.forename: Helong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000556:secondary; D000818:Animals; D001665:Binding Sites; D015687:Cell Hypoxia; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D051741:Kruppel-Like Transcription Factors; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C507402:KLF8 protein, human; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins