PMID- 22359598
OWN - NLM
STAT- MEDLINE
DCOM- 20120803
LR  - 20220330
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 2
DP  - 2012
TI  - ER stress negatively modulates the expression of the miR-199a/214 cluster to 
      regulates tumor survival and progression in human hepatocellular cancer.
PG  - e31518
LID - 10.1371/journal.pone.0031518 [doi]
LID - e31518
AB  - BACKGROUND: Recent studies have emphasized causative links between microRNAs 
      (miRNAs) deregulation and tumor development. In hepatocellular carcinoma (HCC), 
      more and more miRNAs were identified as diagnostic and prognostic cancer 
      biomarkers, as well as additional therapeutic tools. This study aimed to 
      investigate the functional significance and regulatory mechanism of the 
      miR-199a2/214 cluster in HCC progression. METHODS AND FINDINGS: In this study, we 
      showed that miR-214, as well as miR-199a-3p and miR-199a-5p levels were 
      significantly reduced in the majority of examined 23 HCC tissues and HepG2 and 
      SMMC-7721 cell lines, compared with their nontumor counterparts. To further 
      explore the role of miR-214 in hepatocarcinogenesis, we disclosed that the ER 
      stress-induced pro-survival factor XBP-1 is a target of miR-214 by using western 
      blot assay and luciferase reporter assay. Re-expression of miR-214 in HCC cell 
      lines (HepG2 and SMMC-7721) inhibited proliferation and induced apoptosis. 
      Furthermore, ectopic expression of miR-214 dramatically suppressed the ability of 
      HCC cells to form colonies in vitro and to develop tumors in a subcutaneous 
      xenotransplantation model of the BALB/c athymic nude mice. Moreover, 
      reintroduction of XBP-1s attenuated miR-214-mediated suppression of HCC cells 
      proliferation, colony and tumor formation. To further understand the mechanism of 
      the miR-199a/214 cluster down-expression in HCC, we found that thapsigargin (TG) 
      and tunicamycin (TM) or hypoxia-induced unfolded protein response (UPR) 
      suppresses the expression of the miR-199a/214 cluster in HCC cells. By promoter 
      analysis of the miR-199a2/214 gene, we conjectured NFkappaB as a potential negative 
      regulator. We further found that UPR and LPS-induced NFkappaB activation suppressed 
      miR-199a2/214 transcription, and this suppression was reversed by NFkappaB inhibition 
      in HCC cells. CONCLUSIONS: Our study suggest that modulation of miR-214 levels 
      may provide a new therapeutic approach for cancer treatment and revealed that UPR 
      may offer a new explanation for why the miR-199a/214 cluster were down-regulated 
      in the progression in HCC.
FAU - Duan, Quanlu
AU  - Duan Q
AD  - Department of Internal Medicine and Gene Therapy Center, Huazhong University of 
      Science and Technology, Wuhan, People's Republic of China.
FAU - Wang, Xingxu
AU  - Wang X
FAU - Gong, Wei
AU  - Gong W
FAU - Ni, Li
AU  - Ni L
FAU - Chen, Chen
AU  - Chen C
FAU - He, Xingxing
AU  - He X
FAU - Chen, Fuqiong
AU  - Chen F
FAU - Yang, Lei
AU  - Yang L
FAU - Wang, Peihua
AU  - Wang P
FAU - Wang, Dao Wen
AU  - Wang DW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120216
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (MIRN214 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (NF-kappa B)
RN  - 0 (Regulatory Factor X Transcription Factors)
RN  - 0 (Transcription Factors)
RN  - 0 (X-Box Binding Protein 1)
RN  - 0 (XBP1 protein, human)
RN  - 0 (Xbp1 protein, mouse)
RN  - 0 (mirn199 microRNA, human)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Carcinoma, Hepatocellular/*pathology
MH  - DNA-Binding Proteins
MH  - Disease Progression
MH  - Down-Regulation/genetics/physiology
MH  - Endoplasmic Reticulum/*pathology
MH  - Humans
MH  - Mice
MH  - MicroRNAs/*genetics/physiology
MH  - NF-kappa B/metabolism
MH  - Regulatory Factor X Transcription Factors
MH  - Stress, Physiological
MH  - Transcription Factors
MH  - Transplantation, Heterologous
MH  - *Unfolded Protein Response
MH  - X-Box Binding Protein 1
PMC - PMC3281082
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/02/24 06:00
MHDA- 2012/08/04 06:00
PMCR- 2012/02/16
CRDT- 2012/02/24 06:00
PHST- 2011/09/16 00:00 [received]
PHST- 2012/01/09 00:00 [accepted]
PHST- 2012/02/24 06:00 [entrez]
PHST- 2012/02/24 06:00 [pubmed]
PHST- 2012/08/04 06:00 [medline]
PHST- 2012/02/16 00:00 [pmc-release]
AID - PONE-D-11-18270 [pii]
AID - 10.1371/journal.pone.0031518 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(2):e31518. doi: 10.1371/journal.pone.0031518. Epub 2012 Feb 16.