宮 﨑純

Secreted by the placental trophoblast, human chorionic gonadotropin (hCG) is an important hormone during pregnancy and is required for the maintenance of pregnancy. Previous studies have shown that dys-regulation of hCG expression is associated with preeclampsia. However, the exact relationship between altered hCG levels and development of preeclampsia is unknown. Metastasis associated protein 3 (MTA3), a chromatin remodeling protein, is abundantly expressed in the placental trophoblasts, but its function is unknown. In breast cancer, MTA3 has been shown to repress the expression of Snail and cell migration. However, whether MTA3 acts similarly in the trophoblast has not been investigated. In the present study, we examined the role of MTA3 in regulating the hCG beta-subunit gene (gene name: CGB5) and Snail expression in the trophoblast cell line, BeWo, as well as its relevance to the high hCG expression levels seen in preeclampsia. First, we investigated MTA3 expression in preeclamptic placenta as compared to normal control placenta via gene expression microarray and qRT-PCR and found that MTA3 was significantly down-regulated, whereas both CGB5 and Snail were up-regulated in preeclamptic placenta. Secondly, we knocked down MTA3 gene in trophoblast cell line BeWo and found Snail and hCG were both up-regulated, suggesting that MTA3 represses Snail and hCG gene expression in trophoblasts. Next, we cloned the CGB5 and Snail promoters into the pGL3-basic vector individually and found that silencing of MTA3 by siRNA resulted in an increase of both CGB5 and Snail promoter activities. To confirm that this MTA3 inhibition is a direct effect, we performed a chromatin immune-precipitation (ChIP) assay and found that MTA3 occupied the proximal promoter regions of both Snail and hCG within BeWo cells. Furthermore, we examined MTA3 expression in placental trophoblast by immunohistochemistry and found that MTA3 expression was higher in villous cytotrophoblasts versus syncytiotrophoblasts, which supports an inverse association of MTA3 with hCG expression. Lastly, using the well-characterized trophoblast fusion model, we examined MTA3 and hCG levels in forskolin-treated BeWo cells and found that MTA3 down-regulation was accompanied by an up-regulation of hCG. These data further suggest that MTA3 is repressing placental hCG expression. In summary, MTA3 plays a critical role in repressing hCG and Snail in placenta trophoblast and its deregulation is associated with preeclampsia. (C) 2013 Elsevier Inc. All rights reserved.

【目的】39歳以下の若年子宮頸癌の臨床的特徴を再検討した。【方法】1999〜2011年に当院で治療したIB期以上の275例を対象とし、39歳以下(A群)と40歳以上(B群)における以下の臨床病理学的所見を比較した。(1)頻度、(2)組織型(扁平上皮癌;以下SCC、腺癌;以下AD、腺扁平上皮癌;以下AS、その他)、(3)ステージ、(4)I+II期で手術施行例の臨床病理学的因子と予後、(5)III、IV期癌の予後。【結果】(1)A群:69例(25.1%)、B群:206例(74.9%)で、A群の頻度は2005年以前と以降で差はなかった。(2)組織型はA群:SCC45例(65.2%)、AD+AS20例(29.0%)、その他4例(5.8%)、B群:SCC152例(73.8%)、AD+AS50例(24.3%)、その他4例(1.9%)で差はなかった。(3)ステージはA群:I期50例、II期12例、III期3例、IV期4例、B群:I期77例、II期69例、III期35例、IV期25例で、A群で有意にI+II期が多く認められた(p=0.001)。(4)I+II期で手術を施行したA群59例とB群116例の比較では、組織型、筋層浸潤の程度、脈管侵襲の有無、リンパ節転移頻度、リンパ節転移個数、術後補助療法に差はなく、A群vsB群の無増悪生存(progression-free survival;以下PFS)、全生存(overall survival;以下OS)はそれぞれ78.8%vs74.1%、85.4%vs79.5%と同等であった。(5)III+IV期の予後は両群同等であったが、IIIB期に関してはA群vsB群のPFS、OSはそれぞれ0%vs34.9%(p=0.142)、0%vs59.5%(p=0.028)と症例数は少ないものの、A群の全生存は有意に予後不良であった。【結論】若年子宮頸癌はI、II期癌が有意に多く、その予後は40歳以上の症例と同等、むしろ良好であるが、その一方で進行癌の予後は不良である可能性が示唆された。(著者抄録)