エストロゲン応答遺伝子COX7RP（cytochrome c oxidase subunit 7a related polypeptide) の子宮内膜癌における発現とその調節

摘要

Endometrial cancer is one of the most common gynecologic malignancies. Recent epidemiological studies show that the incidence rate of endometrial cancer is increasing in Japan. Although the exact cause of endometrial cancer is still obscured, estrogen appears to play an important role in endometrial cancer because prolonged exposure to unopposed estrogen has been reported as a risk factor for it. Indeed, Ishikawa cells derived from human endometrial cancer that express estrogen receptor α and β(ERα and ERβ) show estrogen dependent proliferation. ERs are ligand dependent transcription factors that regulate target gene transcription. Therefore, estrogen actions such as cell growth in endometrial cancer are exhibited by estrogen-responsive genes. However, it has not been fully elucidated how the estrogen-responsive genes mediate the progression of endometrial cancer. 　COX7RP has been isolated as an estrogen responsive-gene with an ER-binding human genomic fragment, EB1, obtained by the genomic-binding site cloning. COX7RP gene contains a perfect palindromic estrogen-responsive element (ERE) in the first intron. The expression of COX7RP mRNA is up-regulated by estrogen in human breast cancer MCF7 cells. Based on the homology of the amino acids, COX7RP is considered as a member of COX7a family which is a nuclear encoded subunit of cytochrome c oxidase (COX).　The present study aims to determine whether COX7RP as a novel estrogen-responsive gene associates with endometrial cancer. The expression of COX7RP mRNA is demonstrated to respond to estrogen and repressed by ICI 182, 780, a pure antagonist for ER in human endometrial cancer Ishikawa cells. The ERE-containing EB1 fragment activates transcription in response to estrogen. In addition, the correlations between COX7RP and ER mRNA expression levels are found in clinical samples of endometiral cancer. Western blot analysis detected COX7RP protein in a mitochondrial fraction of cell extracts by a rabbit polyclonal antibody raised against a C-terminal polypeptide of human COX7RP. Moreover, immunohistochemistry with this anti-COX7RP polyclonal antibody and a ERαantibody reveals that the COX7RP protein is localized in cytoplasm of endometrial cancer cells. In most of COX7RP positive cells, we also observed nuclear staining of ERα. 　Taken together, these results suggest that COX7RP is involved in the estrogen actions in endometrial cancer as a primary estrogen-responsive gene.