PMID- 24637915
OWN - NLM
STAT- MEDLINE
DCOM- 20141111
LR  - 20220311
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 3
DP  - 2014
TI  - MiR-99a antitumor activity in human breast cancer cells through targeting of mTOR 
      expression.
PG  - e92099
LID - 10.1371/journal.pone.0092099 [doi]
LID - e92099
AB  - MicroRNAs (miRNAs) play an important role in human tumorigenesis as oncogenes or 
      tumor suppressors. miR-99a has been reported as a tumor suppressor gene in 
      various cancers in humans. However, only limited information about the function 
      of miR-99a in human breast cancers is available. Here we investigated the 
      expression of miR-99a in breast cancer tissue specimens and its antitumor 
      activity in breast cancer cells. We initially identified that the expression of 
      miR-99a was significantly reduced in four breast cancer cell lines. More 
      importantly, we found downregulation of miR-99a in breast cancer specimens from 
      ten different patients. We then analyzed the mechanism of miR-99a in inhibiting 
      tumorigenesis. Cell-based assays that showed overexpression of miR-99a not only 
      reduced breast cancer cell viability by inducing accumulation of cells at sub-G1 
      phase and cell apoptosis, but also inhibited tumorigenicity in vivo. As a 
      critical miR-99a target, we have shown that the function of mammalian target of 
      rapamycin (mTOR) was greatly inhibited by miR-99a-based Luciferase report assay; 
      overexpression of miR-99a reduced the expression of mTOR and its downstream 
      phosphorylated proteins (p-4E-BP1 and p-S6K1). Similar to restoring miR-99a 
      expression, mTOR downregulation suppressed cell viability and increased cell 
      apoptosis, whereas restoration of mTOR expression significantly reversed the 
      inhibitory effects of miR-99a on the mTOR/p-4E-BP1/p-S6K1 signal pathway and the 
      miR-99a antitumor activity. In clinical specimens and cell lines, mTOR was 
      commonly overexpressed and its protein levels were statistically inversely 
      correlated with miR-99a expression. Taken together, these results have 
      demonstrated that miR-99a antitumor activity is achieved by targeting the 
      mTOR/p-4E-BP1/p-S6K1 pathway in human breast cancer cells. This study suggests a 
      potential therapeutic strategy to effectively control breast cancer development.
FAU - Hu, Yu
AU  - Hu Y
AD  - Department of Breast Surgery, Xiangya Hospital, Central South University, 
      Changsha, China.
FAU - Zhu, Qin
AU  - Zhu Q
AD  - Department of General Surgery, Xiangya Hospital, Central South University, 
      Changsha, China.
FAU - Tang, Lili
AU  - Tang L
AD  - Department of Breast Surgery, Xiangya Hospital, Central South University, 
      Changsha, China.
LA  - eng
PT  - Journal Article
DEP - 20140317
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (MIRN99 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Phosphoproteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Antineoplastic Agents/*metabolism
MH  - Apoptosis/genetics
MH  - Base Sequence
MH  - Breast Neoplasms/*genetics/*pathology
MH  - Cell Cycle Proteins
MH  - Cell Line, Tumor
MH  - Cell Survival/genetics
MH  - Down-Regulation
MH  - Female
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Mice
MH  - MicroRNAs/genetics/*metabolism
MH  - Molecular Sequence Data
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction/genetics
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*genetics/metabolism
MH  - Up-Regulation/genetics
MH  - Xenograft Model Antitumor Assays
PMC - PMC3956864
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/03/19 06:00
MHDA- 2014/11/12 06:00
PMCR- 2014/03/17
CRDT- 2014/03/19 06:00
PHST- 2013/08/26 00:00 [received]
PHST- 2014/02/19 00:00 [accepted]
PHST- 2014/03/19 06:00 [entrez]
PHST- 2014/03/19 06:00 [pubmed]
PHST- 2014/11/12 06:00 [medline]
PHST- 2014/03/17 00:00 [pmc-release]
AID - PONE-D-13-35150 [pii]
AID - 10.1371/journal.pone.0092099 [doi]
PST - epublish
SO  - PLoS One. 2014 Mar 17;9(3):e92099. doi: 10.1371/journal.pone.0092099. eCollection 
      2014.