Over expression of hypoxia-inducible factor-1alpha in renal and bladder cancer cells increases tumorigenic potency.
OBJECTIVE
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcriptional factor that regulates genes involved in the response to hypoxia. We evaluated the effects of HIF-1alpha over expression on the tumorigenic potency of renal cell carcinoma VMRC cells and bladder cancer EJ cells in vitro and in vivo.


METHODS
We introduced HIF-1alpha expression vectors into VMRC and EJ cells, and generated the HIF-1alpha over expressing cell lines VMRC-HIF1alpha and EJ-HIF1alpha, and the vector only transfected cell lines VMRC-neo and EJ-neo. We then evaluated in vitro cell proliferation and in vivo tumor growth of these cell lines after subcutaneous injection into athymic nude mice.


RESULTS
In vitro studies showed that HIF-1alpha over expression in VMRC and EJ cells accelerated cell proliferation during the confluent growth phase and rendered these cells resistant to hypoxic stress. Furthermore, in vivo studies revealed that all 4 types of cancer cells (VMRC-neo, VMRC-HIF1alpha, EJ-neo and EJ-HIF1alpha) formed tumors in nude mice and the size of VMRC-HIF1alpha cell derived xenografts was much larger than that of VMRC-neo cell derived xenografts. Although HIF-1alpha over expression did not affect the size of EJ cell derived xenografts, histological examination showed that there was only a small area of necrosis in EJ-HIF1alpha cell derived xenografts, whereas a large area of central necrosis was observed in EJ-neo cell derived xenografts. It was also found that HIF-1alpha over expression increased intratumor microvessel density in the xenografts.


CONCLUSIONS
These results suggest that HIF-1alpha may have important roles in bladder and renal cancer angiogenesis and proliferation.
Kondo
Yukihiro
Y
Department of Urology, Nippon Medical School, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Hamada
Junko
J
Kobayashi
Chie
C
Nakamura
Ryosuke
R
Suzuki
Yasutomo
Y
Kimata
Ryoji
R
Nishimura
Taiji
T
Kitagawa
Takayuki
T
Kunimoto
Manabu
M
Imura
Nobumasa
N
Hara
Shuntaro
S
D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors