title: let-7b/g silencing activates AKT signaling to promote gastric carcinogenesis.
abstract: BACKGROUND
  Aberrant AKT activation contributes to gastric cancer cell survival and chemotherapy resistance, however its regulation is poorly understood. microRNAs have been established to be important regulators in gastric carcinogenesis. Here, we showed the functional role and putative target of let-7b and let-7g (let-7b/g) in gastric carcinogenesis.
  
  
  METHODS
  The expression of let-7b/g in gastric cancer cell lines and primary tumors were evaluated by miRNA qRT-PCR. The putative target gene of let-7b/g was explored by TargetScan followed by further validation. Functional analyses including MTT proliferation, monolayer colony formation, cell invasion assays and in vivo study were performed in both ectopic expression and knockdown approaches.
  
  
  RESULTS
  let-7b/g was found down-regulated in gastric cancer and its downregulation was associated with poor survival and correlated with lymph node metastasis. let-7b/g inhibited AKT2 expression by directly binding to its 3'UTR, reduced p-AKT (S473) activation and suppressed expression of the downstream effector pS6. AKT2 mRNA expression showed negative correlation with the expression of let-7b/g in primary tumors. Short interfering RNA (siRNA) mediated knockdown of AKT2 phenocopied the tumor-suppressive effects of let-7b/g. Moreover, AKT2 re-expression partly abrogated the growth-inhibitory effect of let-7b/g.
  
  
  CONCLUSIONS
  In conclusion, our findings reveal decreased let-7b/g contributes to aberrant AKT activation in gastric tumorigenesis and provide a potential therapeutic strategy for gastric cancer.
authors.forename: Wei
authors.initials: W
authors.lastname: Kang
authors.forename: Joanna H M
authors.initials: JH
authors.lastname: Tong
authors.forename: Raymond W M
authors.initials: RW
authors.lastname: Lung
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Dong
authors.forename: Weiqin
authors.initials: W
authors.lastname: Yang
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.forename: Kin Mang
authors.initials: KM
authors.lastname: Lau
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Alfred Sl
authors.initials: AS
authors.lastname: Cheng
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China. kfto@cuhk.edu.hk.
authors.forename: Ka Fai
authors.initials: KF
authors.lastname: To
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D034741:RNA, Small Interfering; C487931:mirnlet7 microRNA, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt