PMID- 17600126
OWN - NLM
STAT- MEDLINE
DCOM- 20070913
LR  - 20181113
IS  - 0002-9440 (Print)
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 171
IP  - 2
DP  - 2007 Aug
TI  - Hypoxia-inducible factor-1 facilitates cervical cancer progression in human 
      papillomavirus type 16 transgenic mice.
PG  - 667-81
AB  - Advanced cervical cancer remains a vexing clinical challenge despite screening 
      programs. Many of these cancers are hypoxic, and expression of the alpha subunit 
      of the major regulator of the hypoxic cellular response, the transcription factor 
      hypoxia-inducible factor-1 (HIF-1), is correlated with poor prognosis. Here, we 
      tested a functional role for HIF-1alpha in pathogenesis of cervical cancer in 
      estrogen-treated transgenic mice. Double-transgenic (DTG) mice developed locally 
      invasive cervical cancers 70 times larger than K14-HPV16 mice. In vivo 
      bromodeoxyuridine incorporation was elevated in DTG cancers without a significant 
      increase in apoptosis. HIF-1alpha gain of function did not up-regulate canonical 
      HIF-1 targets in premalignant DTG cervices, in contrast to elevation of these 
      targets in K14-HIF-1alpha transgenic cervices. The DTG transcriptional signature 
      included up-regulation of mRNAs encoding cytokines and chemokines, immune 
      signaling molecules, extracellular proteases, and cell motility factors, as well 
      as reduced expression of cell adhesion and epithelial differentiation genes. 
      Importantly, a set of gene markers derived from the DTG transcriptome predicted 
      cervical cancer progression in patients. This study suggests a novel paradigm for 
      HIF-1 function evident in multistage carcinogenesis as opposed to established 
      malignancies, including interaction with viral oncogenes to induce multiple 
      genomic networks in premalignancy that fosters the development of advanced 
      cervical cancer.
FAU - Lu, Zhi Hong
AU  - Lu ZH
AD  - Division of Urologic Surgery, Washington University School of Medicine, St. 
      Louis, Missouri, USA. luz@wudosis.wustl.edu
FAU - Wright, Jason D
AU  - Wright JD
FAU - Belt, Brian
AU  - Belt B
FAU - Cardiff, Robert D
AU  - Cardiff RD
FAU - Arbeit, Jeffrey M
AU  - Arbeit JM
LA  - eng
GR  - T32 CA009621/CA/NCI NIH HHS/United States
GR  - R01-90722/PHS HHS/United States
GR  - T32CA 009621-17/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20070628
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (BNip3 protein, mouse)
RN  - 0 (Estrogens)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Keratin-14)
RN  - 0 (Membrane Proteins)
RN  - 0 (Mitochondrial Proteins)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Animals
MH  - Apoptosis/genetics/physiology
MH  - Caspase 3/genetics/metabolism
MH  - Cervix Uteri/metabolism/pathology
MH  - Cluster Analysis
MH  - Disease Progression
MH  - Estrogens/administration & dosage
MH  - Female
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Human papillomavirus 16/*genetics/physiology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*genetics/physiology
MH  - Immunohistochemistry
MH  - Keratin-14/genetics/physiology
MH  - Membrane Proteins/genetics/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Mitochondrial Proteins/genetics/metabolism
MH  - Mutation
MH  - Oligonucleotide Array Sequence Analysis/methods
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Transcription, Genetic
MH  - Uterine Cervical Neoplasms/genetics/metabolism/*pathology
PMC - PMC1934541
EDAT- 2007/06/30 09:00
MHDA- 2007/09/14 09:00
PMCR- 2008/02/01
CRDT- 2007/06/30 09:00
PHST- 2007/06/30 09:00 [pubmed]
PHST- 2007/09/14 09:00 [medline]
PHST- 2007/06/30 09:00 [entrez]
PHST- 2008/02/01 00:00 [pmc-release]
AID - S0002-9440(10)61999-2 [pii]
AID - 10.2353/ajpath.2007.061138 [doi]
PST - ppublish
SO  - Am J Pathol. 2007 Aug;171(2):667-81. doi: 10.2353/ajpath.2007.061138. Epub 2007 
      Jun 28.