PMID- 20081105
OWN - NLM
STAT- MEDLINE
DCOM- 20100426
LR  - 20240317
IS  - 1944-9917 (Electronic)
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 24
IP  - 2
DP  - 2010 Feb
TI  - A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer.
PG  - 447-63
LID - 10.1210/me.2009-0295 [doi]
AB  - MicroRNAs (miRNAs) are small noncoding RNAs that direct gene regulation through 
      translational repression and degradation of complementary mRNA. Although miRNAs 
      have been implicated as oncogenes and tumor suppressors in a variety of human 
      cancers, functional roles for individual miRNAs have not been described in clear 
      cell ovarian carcinoma, an aggressive and chemoresistant subtype of ovarian 
      cancer. We performed deep sequencing to comprehensively profile miRNA expression 
      in 10 human clear cell ovarian cancer cell lines compared with normal ovarian 
      surface epithelial cultures and discovered 54 miRNAs that were aberrantly 
      expressed. Because of the critical roles of the phosphatidylinositol 
      3-kinase/v-akt murine thymoma viral oncogene homolog 1/mammalian target of 
      rapamycin (mTOR) pathway in clear cell ovarian cancer, we focused on mir-100, a 
      putative tumor suppressor that was the most down-regulated miRNA in our cancer 
      cell lines, and its up-regulated target, FRAP1/mTOR. Overexpression of mir-100 
      inhibited mTOR signaling and enhanced sensitivity to the rapamycin analog RAD001 
      (everolimus), confirming the key relationship between mir-100 and the mTOR 
      pathway. Furthermore, overexpression of the putative tumor suppressor mir-22 
      repressed the EVI1 oncogene, which is known to suppress apoptosis by stimulating 
      phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1 
      signaling. In addition to these specific effects, reversing the expression of 
      mir-22 and the putative oncogene mir-182 had widespread effects on target and 
      nontarget gene populations that ultimately caused a global shift in the cancer 
      gene signature toward a more normal state. Our experiments have revealed strong 
      candidate miRNAs and their target genes that may contribute to the pathogenesis 
      of clear cell ovarian cancer, thereby highlighting alternative therapeutic 
      strategies for the treatment of this deadly cancer.
FAU - Nagaraja, Ankur K
AU  - Nagaraja AK
AD  - Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
FAU - Creighton, Chad J
AU  - Creighton CJ
FAU - Yu, Zhifeng
AU  - Yu Z
FAU - Zhu, Huifeng
AU  - Zhu H
FAU - Gunaratne, Preethi H
AU  - Gunaratne PH
FAU - Reid, Jeffrey G
AU  - Reid JG
FAU - Olokpa, Emuejevoke
AU  - Olokpa E
FAU - Itamochi, Hiroaki
AU  - Itamochi H
FAU - Ueno, Naoto T
AU  - Ueno NT
FAU - Hawkins, Shannon M
AU  - Hawkins SM
FAU - Anderson, Matthew L
AU  - Anderson ML
FAU - Matzuk, Martin M
AU  - Matzuk MM
LA  - eng
GR  - T32 GM008307/GM/NIGMS NIH HHS/United States
GR  - K12 HD001426/HD/NICHD NIH HHS/United States
GR  - R01CA60651/CA/NCI NIH HHS/United States
GR  - K12HD01426-02/HD/NICHD NIH HHS/United States
GR  - T32GM008307/GM/NIGMS NIH HHS/United States
GR  - P30CA125123/CA/NCI NIH HHS/United States
GR  - U54 HG003273/HG/NHGRI NIH HHS/United States
GR  - R01 CA060651/CA/NCI NIH HHS/United States
GR  - P30 CA125123/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100115
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (MIRN100 microRNA, human)
RN  - 0 (MIRN22 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn182 microRNA, human)
RN  - 0 (RNA, Messenger)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenocarcinoma, Clear Cell/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Computational Biology
MH  - Dose-Response Relationship, Drug
MH  - Epithelial Cells/drug effects/metabolism
MH  - Everolimus
MH  - Female
MH  - Gene Expression Profiling
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/antagonists & 
      inhibitors/*genetics/metabolism
MH  - MicroRNAs/antagonists & inhibitors/chemistry/genetics/*metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - Ovarian Neoplasms/genetics/*metabolism
MH  - Ovary/cytology/*drug effects
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/*genetics/metabolism
MH  - RNA, Messenger/chemistry
MH  - Sequence Analysis, RNA
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases
PMC - PMC2817607
EDAT- 2010/01/19 06:00
MHDA- 2010/04/27 06:00
PMCR- 2011/02/01
CRDT- 2010/01/19 06:00
PHST- 2010/01/19 06:00 [entrez]
PHST- 2010/01/19 06:00 [pubmed]
PHST- 2010/04/27 06:00 [medline]
PHST- 2011/02/01 00:00 [pmc-release]
AID - me.2009-0295 [pii]
AID - 4594 [pii]
AID - 10.1210/me.2009-0295 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2010 Feb;24(2):447-63. doi: 10.1210/me.2009-0295. Epub 2010 Jan 
      15.