Cell Motility and Spreading Are Suppressed by HOXA4 in Ovarian Cancer Cells: Possible Involvement of β1 Integrin
Cell Motility and Spreading Are Suppressed by HOXA4 in Ovarian Cancer Cells: Possible Involvement of β1 Integrin
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DOI：
10.1158/1541-7786.mcr-08-0466
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发表时间：
2009-09-01
影响因子：
5.2
通讯作者：
Auersperg, Nelly
中科院分区：
文献类型：
--
作者：
Klausen, Christian;Leung, Peter C. K.;Auersperg, Nelly
HOX 基因是控制形态发生、器官发生和分化的转录因子。越来越多的证据表明 HOX 基因在卵巢癌进展中发挥作用；然而，很少有研究明确定义其功能作用和作用机制。我们之前表明，与非侵袭性上皮性卵巢肿瘤相比，HOXA4 表达在侵袭性上皮性卵巢肿瘤中增加。然而，HOXA4 抑制细胞迁移，表明侵袭性肿瘤中 HOXA4 表达升高构成了稳态反应。在本研究中，我们使用 siRNA 和在多个细胞系中强制表达来确定 HOXA4 在调节 Transwell 迁移/侵袭和细胞/集落形态中的作用。内源性 HOXA4 的敲低会增加 OVCAR-8 和 OVCAR-3 细胞的迁移，但不会增加基质胶的侵袭。 HOXA4 敲低还增加了细胞在塑料或纤连蛋白上的铺展，减少了细胞间粘附，并增加了二维和三维培养物中的丝状伪足。这些变化与αV或β3整合素以及E-或N-钙粘蛋白的显着变化无关。然而，HOXA4 的下调显着降低了细胞集落和细胞聚集体中的 β1 整合素蛋白水平，但不降低单个非贴壁细胞的水平。它对 β1 整合素、α5 整合素或纤连蛋白 mRNA 水平没有影响。相反，CaOV-3 细胞中 HOXA4 的过表达抑制了跨孔迁移并增加了 β1 整合素蛋白水平。我们的结果证实 HOXA4 抑制细胞运动，显示它抑制细胞扩散和丝状伪足形成，同时增强细胞间粘附，并表明 β1 整合素在介导这些变化中的作用。这些观察结果支持这样的假设：侵袭性卵巢肿瘤中 HOXA4 的过度表达是一种稳态、侵袭抑制反应。 (摩尔癌症研究 2009;7(9):1425-37)
HOX genes are transcription factors that control morphogenesis, organogenesis and differentiation. Increasing evidence suggests that HOX genes play a role in ovarian cancer progression; however few studies have defined functional roles and mechanisms of action. We showed previously that HOXA4 expression is increased in invasive, compared to noninvasive, epithelial ovarian tumors. However, HOXA4 suppressed cell migration suggesting that elevated HOXA4 expression in invasive tumors constitutes a homeostatic response. In the present study, we used siRNA and forced-expression in multiple cell lines to define the role of HOXA4 in the regulation of transwell migration/invasion and cellular/colony morphology. Knockdown of endogenous HOXA4 increased migration, but not Matrigel invasion, of OVCAR-8 and OVCAR-3 cells. HOXA4 knockdown also increased cell spreading on plastic or fibronectin, reduced cell-cell adhesion, and increased filopodia in two- and three-dimensional cultures. These changes were not associated with significant changes in alpha V or beta 3 integrin and E- or N-cadherin. However, down-regulation of HOXA4 significantly reduced beta 1 integrin protein levels within cell colonies and cell aggregates, but not of single, nonadherent cells. It had no effect on beta 1 integrin, alpha 5 integrin, or fibronectin mRNA levels. Conversely, overexpression of HOXA4 in CaOV-3 cells suppressed transwell migration and increased beta 1 integrin protein levels. Our results confirm that HOXA4 inhibits cell motility, show that it suppresses cell spreading and filopodia formation while enhancing cell-cell adhesion, and suggest a role for beta 1 integrin in mediating these changes. These observations support the hypothesis that overexpression of HOXA4 in invasive ovarian tumors is a homeostatic, invasion-suppressive response. (Mol Cancer Res 2009;7(9):1425-37)