Transcription factor POU6F1 is important for proliferation of clear cell adenocarcinoma of the ovary and is a potential new molecular target.
OBJECTIVE
Clear cell adenocarcinoma of the ovary often shows resistance to anticancer agents. It accounts for 20% of epithelial ovarian cancer in Japan versus around 5% in other countries. We investigated new molecules to use when developing molecular-targeting therapy for clear cell adenocarcinoma.


METHODS
Reverse transcriptase polymerase chain reaction and Western blot analysis were performed to confirm the expression of POU6F1 in several kinds of cell lines derived from epithelial ovarian carcinoma. Microarray analyses were performed using 2 ovarian cancer microarray data sets available on the Internet. Immunohistochemical staining was also done to confirm both the expression and the localization of POU6F1 using human ovarian epithelial ovarian carcinoma tissue specimens. In addition, the gene cluster located downstream of transcription factor POU6F1 was investigated to analyze its role in the proliferation of clear cell adenocarcinoma of the ovary via the lysophosphatidic acid receptor, a G protein-coupled receptor. Furthermore, RNA interference studies with small interfering RNA (siRNA) were performed to assess the effect of POU6F1 on proliferation of xenograft tumors after injection of clear cell adenocarcinoma cells into nude mice.


RESULTS
Expression of POU6F1 at messenger RNA and protein was confirmed in cell lines derived from epithelial ovarian carcinoma. The microarray analyses performed using the 2 ovarian cancer microarray data sets available on the Internet indicated that POU6F1 expression was significantly greater in clear cell adenocarcinoma. Immunostaining confirmed the nuclear localization of POU6F1 in clear cell adenocarcinoma (100%). Exposure to the siRNA for POU6F1 reduced the expression of lysophosphatidic acid receptors, which are G protein-coupled receptors involved in tumor cell proliferation. POU6F1 siRNA dose-dependently suppressed the proliferation of clear cell adenocarcinoma cell lines, and a similar effect was confirmed for tumors transplanted into nude mice.


CONCLUSIONS
Clear cell adenocarcinoma shows little response to standard therapy. The results of this study suggested that the transcription factor POU6F1 could be a new molecular target for treatment of this cancer.
Suzuki
Nao
N
Department of Obstetrics and Gynecology, St Marianna University School of Medicine, Kanagawa, Japan. nao@marianna-u.ac.jp
Yoshioka
Norihito
N
Uekawa
Atsushi
A
Matsumura
Noriomi
N
Tozawa
Akiko
A
Koike
Jyunki
J
Konishi
Ikuo
I
Kiguchi
Kazushige
K
Ishizuka
Bunpei
B
D018262:Adenocarcinoma, Clear Cell / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009097:Multienzyme Complexes / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000378:metabolism*; D050809:POU Domain Factors / Q000378:metabolism*; D043264:Phosphodiesterase I / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000378:metabolism; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D000099189:Lysophospholipase D
D009097:Multienzyme Complexes; D050809:POU Domain Factors; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C082703:POU6F1 protein, human