title: Genetic and Methylation-Induced Loss of miR-181a2/181b2 within chr9q33.3 Facilitates Tumor Growth of Cervical Cancer through the PIK3R3/Akt/FoxO Signaling Pathway.
abstract: OBJECTIVE
  Loss of Chr9q31-33 is one of the most common chromosome imbalances of cervical cancer, but the underlying mechanism has not been well documented.
  
  
  METHODS
  The loss of heterozygosity (LOH) status of Chr9q31-33 was investigated utilizing 26 microsatellite markers. We detected the expression of miR-181a2/181b2 by qRT-PCR analysis of cervical cancer cell lines and 100 paired tumor samples and corresponding adjacent non-tumor tissues. Kaplan-Meier and Cox proportional hazard regression analyses were performed to identify the prognostic value of miR-181a2/181b2. Regulation of expression was analyzed by methylation-specific PCR. The tumor-suppressing effects of miR-181a2/181b2 were determined in vitro and in vivo The target gene and signaling pathway that mediated the function of miR-181a2/181b2 were also identified.
  
  
  RESULTS
  Chr9q33.3 was identified as one of the most deleted regions in cervical cancer. Underexpression of miR-181a2/181b2 was detected in 46% of cervical cancer and was induced by the LOH of chr9q33.3 and promoter hypermethylation. Attenuated miR-181a2/181b2 expression predicted a poor prognostic phenotype and advanced clinical stage of cervical cancer. miR-181a2/181b2 prominently dampened cell-cycle progression, suppressed cell growth, and promoted apoptosis of tumor cells in vitro They also effectively impeded tumor formation and growth in vivo miR-181a2/181b2 exert the tumor suppressor ability by depressing the direct target PIK3R3 (p55γ) and consequently modulating the PIK3R3/Akt/FoxO signaling pathway.
  
  
  CONCLUSIONS
  We demonstrated a cause-and-effect event beginning from loss of chr9q33.3, a frequent event in cervical cancer, to the underexpression of miR-181a2/181b2, leading to the elevated activation of the PI3K pathway. Clin Cancer Res; 23(2); 575-86. ©2016 AACR.
authors: Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, China.
authors: Qian
authors: Q
authors: Mei
authors: Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, China.
authors: Xiang
authors: X
authors: Li
authors: Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing, China.
authors: Kang
authors: K
authors: Zhang
authors: Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, China.
authors: Zhiqiang
authors: Z
authors: Wu
authors: Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, China.
authors: Xiaolei
authors: X
authors: Li
authors: Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing, China.
authors: Yuanguang
authors: Y
authors: Meng
authors: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China.
authors: Mingzhou
authors: M
authors: Guo
authors: Case Comprehensive Cancer Centre, Case Western Reserve University, Cleveland, Ohio.
authors: Guangbin
authors: G
authors: Luo
authors: Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, China.
authors: Xiaobing
authors: X
authors: Fu
authors: Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, China. hanwdrsw69@yahoo.com.
authors: Weidong
authors: W
authors: Han
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D051058:Oncogene Protein v-akt / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; C523442:PIK3R3 protein, human; D051058:Oncogene Protein v-akt