title: Activation of NF-kappaB is a novel target of KRAS-induced endometrial carcinogenesis.
abstract: OBJECTIVE
  Although the KRAS mutation is one of critical genetic alterations in endometrial carcinogenesis, the downstream targets are not known.
  
  
  METHODS
  In this study, we investigated the molecular targets of KRAS signals, using tumorigenic cells with oncogenic KRAS mutation established from telomerase reverse transcriptase (TERT)-immortalized endometrial epithelial cells.
  
  
  RESULTS
  We first confirmed that the RAF-ERK pathway, but not the PI3K-Akt pathway, was activated in KRAS tumorigenic cells. However, the introduction of constitutively active MAP/ERK kinase into immortalized cells to mimic RAF-ERK activation failed to obtain tumorigenic phenotypes, indicating the existence of other carcinogenic pathways triggered by KRAS. Recent evidence suggestive of linkage with KRAS signals prompted us to examine the involvement of NF-κB in endometrial carcinogenesis. We found that the DNA-binding activity of NF-κB was markedly elevated in KRAS tumorigenic cells compared with TERT-immortalized cells. Furthermore, the ability of NF-κB to activate the target gene promoters significantly increased in KRAS tumorigenic cells. Introduction of a mutant IκB that is resistant to degradation and thereby enhances the inhibitory effect on NF-κB largely abrogated the transformed phenotypes of KRAS tumorigenic cells. Thus, oncogenic KRAS signals contributed to the tumorigenic phenotypes of endometrial cells by activating the transcription function of NF-κB.
  
  
  CONCLUSIONS
  These findings clearly show that NF-κB activation is a novel target of oncogenic KRAS in endometrial carcinogenesis, implying the potential utility of NF-κB inhibitors for endometrial cancer chemoprevention, especially with KRAS mutation.
authors.affiliation: Department of Obstetrics and Gynecology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Mizumoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Kyo
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takakura
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Maida
authors.forename: Noriko
authors.initials: N
authors.lastname: Mori
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Bono
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Masaki
authors.initials: M
authors.lastname: Inoue
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D019098:Telomerase / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D019098:Telomerase