Over-expression of hypoxia-inducible factor 1 alpha in ovarian clear cell carcinoma.
OBJECTIVE
Unlike other histological types of epithelial ovarian carcinoma, ovarian clear cell carcinoma is known to have very poor response to therapy even when discovered in its early stages. Since tumor hypoxia has been shown to be strongly associated with poor prognosis, deregulation of the representative factor of tissue hypoxia; hypoxia-inducible factor 1 alpha (HIF-1alpha) and related protein; Von Hippel-Lindau (VHL) may be associated with poor prognosis of ovarian clear cell carcinoma.


METHODS
Immunolocalization of both HIF-1alpha and VHL was performed on 56 cases of paraffin-embedded tissue sections of four different histological types of epithelial ovarian carcinoma and 5 cases of benign ovarian tumors as a control. Quantitative RT-PCR analysis of both HIF1A and VHL was performed on RNA isolated from 61 microdissected frozen tissues of four different histological types of epithelial ovarian carcinoma and 6 cases of normal ovarian epithelial cells. Expression levels of HIF-1alpha and VHL in different histological types and correlation between HIF-1alpha and VHL were determined by nonparametric analysis by Kruskal-Wallis and Spearman's test.


RESULTS
HIF-1alpha expression levels were significantly higher in ovarian clear cell carcinoma than in other histological types (P=0.001). We found no correlation between mRNA and protein expression level in any type of carcinoma specimens. Among endometrioid, serous, and mucinous carcinoma, there were no differences in HIF-1alpha expression (P=0.643). There was a negative correlation between HIF-1alpha and VHL in serous (r=-0.661, P=0.027) and in endometrioid carcinoma (r=-0.657 P=0.039), but no correlation was found between HIF-1alpha and VHL expression levels in ovarian clear cell carcinoma (P=0.60).


CONCLUSIONS
The results suggest that the role of hypoxia may change according to the histological type of ovarian carcinoma. High expression of HIF-1alpha and its independence from VHL in ovarian clear cell carcinoma may confer chemoresistance in this histological type.
Lee
Sunyoung
S
Department of Obstetrics, Gynecology and Reproductive Biology, Division of Gynecologic Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Garner
Elizabeth I O
EI
Welch
William R
WR
Berkowitz
Ross S
RS
Mok
Samuel C
SC
D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D007150:Immunohistochemistry; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000096:biosynthesis / Q000235:genetics
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human