Loss of Betaglycan Contributes to the Malignant Properties of Human Granulosa Tumor Cells
Loss of Betaglycan Contributes to the Malignant Properties of Human Granulosa Tumor Cells
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DOI：
10.1210/me.2008-0300
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发表时间：
2009-04-01
影响因子：
--
通讯作者：
Stenvers, Kaye L.
中科院分区：
文献类型：
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作者：
Bilandzic, Maree;Chu, Simon;Stenvers, Kaye L.
Betaglycan 是一种 III 型 TGFβ 受体，可调节细胞对抑制素和 TGFβ 的敏感性。先前的研究表明，β聚糖在某些人类上皮癌中充当肿瘤抑制剂。然而，β聚糖在卵巢颗粒细胞瘤（GCT）中的作用尚不清楚。本研究的目的是确定人类 GCT 是否表现出 β-聚糖表达，如果是，该受体对肿瘤生物学有何影响。使用实时 PCR 来量化人类 GCT（n = 17）和正常绝经前卵巢（n = 11）中的 β 聚糖转录本。该分析表明，与正常卵巢相比，GCT 的平均 β 聚糖 mRNA 水平显着降低 2 倍（P < 0.05）。同样，两种人 GCT 细胞系 KGN 和 COV434 在荧光素酶报告基因检测中表现出低 β 聚糖表达，并且对 TGF β 和抑制素 A 的反应性较差，但通过稳定转染野生型 β 聚糖可以恢复这种反应。 Betaglycan 显着增加 COV434 (P < 0.05) 和 KGN (P < 0.0001) 细胞的粘附，减少细胞通过 Matrigel 的侵袭，并抑制伤口愈合。每个 GCT 细胞系中 TGF β 和/或抑制素结合缺陷的突变形式的β聚糖的表达表明，β聚糖对伤口愈合的抑制作用与β聚糖的抑制素结合区域密切相关。此外，INHA mRNA表达的敲低消除了β聚糖介导的对伤口愈合和侵袭的抑制，而INHA沉默和TGFβ中和消除了β聚糖介导的对底物粘附的增加。这些数据表明，β 聚糖的丢失有助于 GCT 的发病机制。 (分子内分泌学 23: 539-548, 2009)
Betaglycan is a type III TGF beta receptor that modulates cellular sensitivity to inhibins and TGF beta. Previous studies have suggested that betaglycan acts as a tumor suppressor in certain human epithelial cancers. However, the roles of betaglycan in ovarian granulosa cell tumors (GCTs) are poorly understood. The objective of this study was to determine whether human GCTs exhibit betaglycan expression and, if so, what impact this receptor has on tumor biology. Real-time PCR was used to quantify betaglycan transcripts in human GCTs (n = 17) and normal premenopausal ovaries (n = 11). This analysis established that GCTs exhibited a significant 2-fold lower mean betaglycan mRNA level as compared with the normal ovary (P < 0.05). Similarly, two human GCT cell lines, KGN and COV434, exhibited low betaglycan expression and poor responsiveness to TGF beta and inhibin A in luciferase reporter assays, which was restored by stable transfection of wild-type betaglycan. Betaglycan significantly increased the adhesion of COV434 (P < 0.05) and KGN (P < 0.0001) cells, decreased cellular invasion through Matrigel, and inhibited wound healing. Expression of mutant forms of betaglycan that are defective in TGF beta and/or inhibin binding in each GCT cell line revealed that the inhibitory effects of betaglycan on wound healing were most strongly linked to the inhibin-binding region of betaglycan. Furthermore, knockdown of INHA mRNA expression abrogated the betaglycan-mediated inhibition of wound healing and invasion, whereas both INHA silencing and TGF beta neutralization abolished the betaglycan-mediated increase in adhesion to substrate. These data suggest that loss of betaglycan contributes to the pathogenesis of GCTs. (Molecular Endocrinology 23: 539-548, 2009)