Linked Life Data

20513003

Source:http://linkedlifedata.com/resource/pubmed/id/20513003

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2010-5-31
pubmed:abstractText
Hypoxia-inducible factors (HIFs) provoke adaptation to hypoxic stress occurring in rapidly growing tumor tissues. Therefore, overexpression of HIF-1 or HIF-2 is a common feature in hepatocellular carcinoma but their specific function is still controversially discussed. To analyze HIF function in hypoxia-induced cell death we created a stable knockdown of HIF-1alpha and HIF-2alpha in HepG2 cells and generated tumor spheroids as an in vitro hepatocellular carcinoma model. Knockdown of HIF-1alpha enhanced expression of HIF-2alpha and vice versa. Unexpectedly, knockdown of HIF-1alpha or HIF-2alpha increased cell viability as well as spheroid size and decreased caspase-3 activity. Antiapoptotic Bcl-X(L) expression increased in both knockdown spheroids, whereas proapoptotic Bax was only reduced in HIF-1alpha-knockdown cells. Furthermore, an HIF-2alpha-knockdown significantly increased Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) expression in an HIF-1alpha-dependent manner. Concomitantly, electron microscopy revealed a substantial increase in autophagosomal structures in HIF-2alpha-knockdown spheroids and mito-/lysotracker costaining confirmed lysosomal activity of these autophagosomes. Blocking autophagosome maturation using 3-methyladenine restored cell death in HIF-2alpha-knockdown clones comparable to wildtype cells. CONCLUSION: An HIF-1alpha-knockdown increases HIF-2alpha expression and shifts the balance of Bcl-2 family members toward survival. The knockdown of HIF-2alpha raises autophagic activity and attenuates apoptosis by enhancing HIF-1alpha expression. Our data indicate that enhanced expression of one HIF-isoform causes a survival advantage in hepatocellular carcinoma development.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1527-3350
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
51
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2183-92
pubmed:meshHeading
pubmed-meshheading:20513003-Apoptosis, pubmed-meshheading:20513003-Autophagy, pubmed-meshheading:20513003-Basic Helix-Loop-Helix Transcription Factors, pubmed-meshheading:20513003-Carcinoma, Hepatocellular, pubmed-meshheading:20513003-Caspase 3, pubmed-meshheading:20513003-Cell Enlargement, pubmed-meshheading:20513003-Cell Survival, pubmed-meshheading:20513003-Gene Knockdown Techniques, pubmed-meshheading:20513003-Hep G2 Cells, pubmed-meshheading:20513003-Humans, pubmed-meshheading:20513003-Hypoxia-Inducible Factor 1, alpha Subunit, pubmed-meshheading:20513003-Liver Neoplasms, pubmed-meshheading:20513003-Membrane Proteins, pubmed-meshheading:20513003-Proto-Oncogene Proteins, pubmed-meshheading:20513003-Spheroids, Cellular, pubmed-meshheading:20513003-Tumor Cells, Cultured, pubmed-meshheading:20513003-Up-Regulation, pubmed-meshheading:20513003-bcl-2-Associated X Protein, pubmed-meshheading:20513003-bcl-X Protein
pubmed:year
2010
pubmed:articleTitle
Roles of hypoxia-inducible factor-1alpha (HIF-1alpha) versus HIF-2alpha in the survival of hepatocellular tumor spheroids.
pubmed:affiliation
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't