title: PI3K/Akt/mTOR signaling & its regulator tumour suppressor genesPTEN&LKB1in human uterine leiomyomas.
abstract: OBJECTIVE
  Despite their high occurrence and associated significant level of morbidity manifesting as spectrum of clinical symptoms, the pathogenesis of uterine leiomyomas (ULs) remains unclear. We investigated expression profile of tumour suppressor genes PTEN (phosphatase and tensin homolog deleted on chromosome ten) and LKB1 (liver kinase B1), and key signaling components of P13K (phosphatidylinositol 3-kinase)/Akt (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in leiomyomas and adjacent normal myometrium in women of reproductive age, to explore the possibility of targeting this pathway for future therapeutic implications.
  
  
  METHODS
  Real time PCR (qPCR) was used to quantify relative gene expression levels of PTEN, Akt1, Akt2, mTOR, LKB1 and VEGFA (vascular endothelial growth factor A) in leiomyoma as compared to adjacent normal myometrium. Immunohistochemistry was subsequently performed to analyze expression of PTEN, phospho-Akt, phospho-mTOR, phospho-S6, LKB1 and VEGFA in leiomyoma and adjacent normal myometrium.
  
  
  RESULTS
  Significant upregulation of PTEN (2.52 fold; P=0.03) and LKB1 (3.93 fold; P0.01), and downregulation of VEGFA (2.95 fold; P=0.01) genes were observed in leiomyoma as compared to normal myometrium. Transcript levels of Akt1, Akt2 and mTOR did not vary significantly between leiomyoma and myometrium. An increased immunoexpression of PTEN (P=0.015) and LKB1 (P<0.001) and decreased expression of VEGFA (P=0.01) was observed in leiomyoma as compared to myometrium. Immunostaining for activated (phosphorylated) Akt, mTOR and S6 was absent or low in majority of leiomyoma and myometrium.
  
  
  CONCLUSIONS
  Upregulation of PTEN and LKB1 in concert with negative or low levels of activated Akt, mTOR and S6 indicates that PI3K/Akt/mTOR pathway may not play a significant role in pathogenesis of leiomyoma.
authors.affiliation: Post-Graduate Department of Pathology, King George's Medical University, Lucknow, India.
authors.forename: Annu
authors.initials: A
authors.lastname: Makker
authors.affiliation: Post-Graduate Department of Pathology, King George's Medical University, Lucknow, India.
authors.forename: Madhu Mati
authors.initials: MM
authors.lastname: Goel
authors.affiliation: Department of Biochemistry, King George's Medical University, Lucknow, India.
authors.forename: Abbas Ali
authors.initials: AA
authors.lastname: Mahdi
authors.affiliation: Post-Graduate Department of Pathology, King George's Medical University, Lucknow, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Bhatia
authors.affiliation: Department of Obstetrics & Gynecology, King George's Medical University, Lucknow, India.
authors.forename: Vinita
authors.initials: V
authors.lastname: Das
authors.affiliation: Department of Obstetrics & Gynecology, King George's Medical University, Lucknow, India.
authors.forename: Anjoo
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Department of Obstetrics & Gynecology, King George's Medical University, Lucknow, India.
authors.forename: Amita
authors.initials: A
authors.lastname: Pandey
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000328:Adult; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007889:Leiomyoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D009363:Neoplasm Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human; C546842:MTOR protein, human; C109790:STK11 protein, human; C494929:PTEN protein, human