title: Deregulation of miR-100, miR-99a and miR-199b in tissues and plasma coexists with increased expression of mTOR kinase in endometrioid endometrial carcinoma.
abstract: BACKGROUND
  Alterations of mTOR gene expression have been implicated in the pathogenesis of endometrioid endometrial cancer however only few studies explored the cause of increased mTOR activation in this malignancy. miRNAs are small, noncoding RNAs, which were proven to regulated gene expression at the posttranscriptional level. The study aimed to explore deregulation of miRNAs targeting mTOR kinase (miR-99a, miR-100 and miR-199b) as a possible cause of its altered expression in EEC tissues. In addition expression of the three miRNAs was investigated in plasma of EEC patients and was assessed in terms of diagnostic and prognostic utility.
  
  
  METHODS
  We investigated expression of mTOR kinase transcripts in 46 fresh tissue samples. Expression of miR-99a, miR-100 and miR-199b was investigated in the same group of fresh samples, and in additional 58 FFPE sections as well as in 48 plasma samples using qPCR. Relative quantification was performed using experimentally validated endogenous controls.
  
  
  RESULTS
  mTOR kinase expression was increased in EEC tissues and was accompanied by decreased expression of all three miRNAs. Down-regulation of the investigated miRNAs was discovered in plasma of EEC patients and miRNA signatures classified EEC tissues (miR-99a/miR-100/miR-199b) and plasma (miR-99a/miR-199b) samples with higher accuracy in comparison to single miRNAs. We also revealed that miR-100 was an independent prognostic marker of overall survival.
  
  
  CONCLUSIONS
  We conclude that increased expression of mTOR kinase coexists with down-regulation of its targeting miRNAs, which could suggest a new mechanism of mTOR pathway alterations in EEC. In addition, our findings implicate that miRNA signatures can be considered promising biomarkers for early detection and prognosis of endometrioid endometrial carcinoma.
authors.affiliation: Laboratory of Biostructure, Chair and Department of Human Anatomy, Medical University of Lublin, Jaczewskiego 4, Lublin, Poland. anna.torres@wp.pl
authors.forename: Anna
authors.initials: A
authors.lastname: Torres
authors.forename: Kamil
authors.initials: K
authors.lastname: Torres
authors.forename: Anna
authors.initials: A
authors.lastname: Pesci
authors.forename: Marcello
authors.initials: M
authors.lastname: Ceccaroni
authors.forename: Tomasz
authors.initials: T
authors.lastname: Paszkowski
authors.forename: Paola
authors.initials: P
authors.lastname: Cassandrini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zamboni
authors.forename: Ryszard
authors.initials: R
authors.lastname: Maciejewski
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D018269:Carcinoma, Endometrioid / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D012372:ROC Curve; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human