title: Effects of the HIF-1α and NF-κB loop on epithelial-mesenchymal transition and chemoresistance induced by hypoxia in pancreatic cancer cells.
abstract: Hypoxia is a microenvironmental factor which plays a critical role in tumor development and chemoresistance. Epithelial-to-mesenchymal transition (EMT) induced by hypoxia is one of the critical causes of treatment failure and chemoresistance in different types of human cancers. Stabilization of the hypoxia-inducible factor-1α (HIF-1α) transcription complex, caused by intratumoral hypoxia, promotes tumor progression and chemoresistance. Previous evidence suggests that hypoxia can also activate nuclear factor-κB (NF-κB), a known mediator of EMT, which is accompanied by reduced expression of epithelial marker E-cadherin and enhanced expression of the mesenchymal markers Vimentin and N-cadherin as well as overexpression of various transcription factors of EMT, such as Snail and Twist. Based on this evidence, the present study aimed to investigate whether downregulation of the p65 subunit of NF-κB or HIF-1α by small interfering RNA (siRNA) may reverse the EMT phenotype and inhibit the proliferation and induce the apoptosis of pancreatic cancer cell lines (PANC-1, BxPC3) under hypoxic conditions in vitro and enhance the efficacy of gemcitabine in the treatment of pancreatic cancer. These results provide molecular evidence showing that the activation of the HIF-1α and NF-κB loop is mechanistically linked with the chemoresistance phenotype (EMT phenotype) of pancreatic cancer cells under hypoxic conditions, suggesting that the inactivation of HIF-1α and NF-κB signaling by novel strategies may be a potential targeted therapeutic approach for overcoming EMT and chemoresistance induced by hypoxia.
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, P.R. China.
authors.forename: Zhuo-Xin
authors.initials: ZX
authors.lastname: Cheng
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, P.R. China.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, P.R. China.
authors.forename: Wei-Xin
authors.initials: WX
authors.lastname: Liu
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, P.R. China.
authors.forename: Wei-Bin
authors.initials: WB
authors.lastname: Xia
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, P.R. China.
authors.forename: Ying-Hai
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, P.R. China.
authors.forename: Yi-Kun
authors.initials: YK
authors.lastname: Qu
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, P.R. China.
authors.forename: Lin-Qi
authors.initials: LQ
authors.lastname: Guo
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, P.R. China.
authors.forename: Long
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Microbiology, Harbin Medical University, Nangang, Harbin 150081, P.R. China.
authors.forename: Zhao-Hua
authors.initials: ZH
authors.lastname: Zhong
mesh_terms: D000111:Acetylcysteine; D017209:Apoptosis; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D000111:Acetylcysteine