Abstract
Ovarian cancer is a highly invasive and metastatic disease with a poor prognosis if diagnosed at an advanced stage, which is often the case. Recent studies argue that ovarian cancer cells that have undergone epithelial-to-mesenchymal transition (EMT) acquire aggressive malignant properties, but the relevant molecular mechanisms in this setting are not well-understood. Here, we report findings from an siRNA screen that identified the homeobox transcription factor ALX1 as a novel regulator of EMT. RNA interference-mediated attenuation of ALX1 expression restored E-cadherin expression and cell-cell junction formation in ovarian cancer cells, suppressing cell invasion, anchorage-independent growth, and tumor formation. Conversely, enforced expression of ALX1 in ovarian cancer cells or nontumorigenic epithelial cells induced EMT. We found that ALX1 upregulated expression of the key EMT regulator Snail (SNAI1) and that it mediated EMT activation and cell invasion by ALX1. Our results define the ALX1/Snail axis as a novel EMT pathway that mediates cancer invasion.
Highlights
Ovarian cancer is a highly metastatic disease and the most lethal of the gynecologic malignancies
We show that Aristaless-like homeobox1 (ALX1) induces epithelial-to-mesenchymal transition (EMT) and cell invasion in ovarian cancer cells by promoting Snail expression
Depletion of ALX1 induces reversion of EMT To search for novel transcription factors associated with
Summary
Ovarian cancer is a highly metastatic disease and the most lethal of the gynecologic malignancies. Despite advances in cytotoxic therapies for numerous types of cancer, the current therapies available to patients with ovarian cancer in advanced stages have little effect, as evidenced by the poor 5year survival rate [1, 2]. To provide insight that will enable the development of new therapeutic strategies, it is crucial to elucidate the molecular mechanisms that promote the invasive and metastatic properties of ovarian cancer cells. Recent studies have shown that a morphologic conversion, known as epithelial-to-mesenchymal transition (EMT), is associated with the acquisition of malignant characteristics in ovarian cancer cells [3,4,5,6,7,8].
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