PMID- 24599125
OWN - NLM
STAT- MEDLINE
DCOM- 20140706
LR  - 20201222
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 74
IP  - 9
DP  - 2014 May 1
TI  - Hypoxia-inducible factor-1 promotes pancreatic ductal adenocarcinoma invasion and 
      metastasis by activating transcription of the actin-bundling protein fascin.
PG  - 2455-64
LID - 10.1158/0008-5472.CAN-13-3009 [doi]
AB  - Because of the early onset of local invasion and distant metastasis, pancreatic 
      ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a 
      5-year survival rate of less than 5%. In this study, we investigated the role of 
      fascin, a prometastasis actin-bundling protein, in PDAC progression, invasion, 
      and the molecular mechanisms underlying fascin overexpression in PDAC. Our data 
      showed that the expression levels of fascin were higher in cancer tissues than in 
      normal tissues, and fascin overexpression correlated with the PDAC 
      differentiation and prognosis. Fascin overexpression promoted PDAC cell migration 
      and invasion by elevating matrix metalloproteinase-2 (MMP-2) expression. Fascin 
      regulated MMP-2 expression through protein kinase C and extracellular 
      signal-regulated kinase. Importantly, our data showed that hypoxia induced fascin 
      overexpression in PDAC cells by promoting the binding of hypoxia-inducible 
      factor-1 (HIF-1) to a hypoxia response element on the fascin promoter and 
      transactivating fascin mRNA transcription. Intriguingly, HIF-1alpha expression levels 
      in PDAC patient specimens significantly correlated with fascin expression. 
      Moreover, immunohistochemistry staining of consecutive sections demonstrated 
      colocalization between HIF-1alpha and fascin in PDAC specimens, suggesting that 
      hypoxia and HIF-1alpha were responsible for fascin overexpression in PDAC. When 
      ectopically expressed, fascin was able to rescue PDAC cell invasion after HIF-1alpha 
      knockdown. Our results demonstrated that fascin is a direct target gene of HIF-1. 
      Our data suggested that the hypoxic tumor microenvironment in PDAC might promote 
      invasion and metastasis by inducing fascin overexpression, and fascin might be 
      targeted to block PDAC progression.
CI  - (c)2014 AACR.
FAU - Zhao, Xiao
AU  - Zhao X
AD  - Authors' Affiliations: Department of Pancreatic Carcinoma, Tianjin Medical 
      University Cancer Institute and Hospital, National Clinical Research Center for 
      Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; and 
      Department of Tumor Biology and Comprehensive Melanoma Research Center, H. Lee 
      Moffitt Cancer Center and Research Institute, Tampa, Florida.
FAU - Gao, Song
AU  - Gao S
FAU - Ren, He
AU  - Ren H
FAU - Sun, Wei
AU  - Sun W
FAU - Zhang, Huan
AU  - Zhang H
FAU - Sun, Jianwei
AU  - Sun J
FAU - Yang, Shengyu
AU  - Yang S
FAU - Hao, Jihui
AU  - Hao J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140305
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Carrier Proteins)
RN  - 0 (FSCN1 protein, human)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Microfilament Proteins)
RN  - EC 3.4.24.24 (MMP2 protein, human)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
SB  - IM
MH  - Aged
MH  - Binding Sites
MH  - Carcinoma, Pancreatic Ductal/*metabolism/mortality/secondary
MH  - Carrier Proteins/*genetics/metabolism
MH  - Cell Line, Tumor
MH  - Female
MH  - Gene Expression
MH  - Gene Expression Regulation, Neoplastic
MH  - HEK293 Cells
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*physiology
MH  - Kaplan-Meier Estimate
MH  - Male
MH  - Matrix Metalloproteinase 2/genetics/metabolism
MH  - Microfilament Proteins/*genetics/metabolism
MH  - Middle Aged
MH  - Neoplasm Invasiveness
MH  - Pancreatic Neoplasms/*metabolism/mortality/pathology
MH  - Promoter Regions, Genetic
MH  - Response Elements
MH  - *Transcriptional Activation
EDAT- 2014/03/07 06:00
MHDA- 2014/07/07 06:00
CRDT- 2014/03/07 06:00
PHST- 2014/03/07 06:00 [entrez]
PHST- 2014/03/07 06:00 [pubmed]
PHST- 2014/07/07 06:00 [medline]
AID - 0008-5472.CAN-13-3009 [pii]
AID - 10.1158/0008-5472.CAN-13-3009 [doi]
PST - ppublish
SO  - Cancer Res. 2014 May 1;74(9):2455-64. doi: 10.1158/0008-5472.CAN-13-3009. Epub 
      2014 Mar 5.