Abstract
BackgroundTwist2 has been shown to promote human tumor invasion as in breast cancer and cervical cancer. However, whether Twist2 promotes human ovarian cancer progression remains to be elucidated. Here, we investigate the role of Twist2 in ovarian cancer invasion and metastasis as well as the underlying molecular mechanisms.MethodsTwist2 expression was detected by Immunohistochemistry (IHC) on tissue microarray of human ovarian cancers with scoring procedure according to the staining intensity and pattern. Twist2 gene was stably introduced into SKOV-3 ovarian cancer cells to examine the changes of cellular morphology, motility, invasiveness, and EMT molecular markers.ResultsTwist2 expression is significantly increased in ovarian cancers along with the FIGO disease stage, indicating that Twist2 may be associated with ovarian cancer metastasis. Overexpression of Twist2 induced the EMT phenotype including downregulation of E-cadherin, and upregulation of N-cadherin and β-catenin in human ovarian cancer cells, suggesting that Twist2 might promote β-catenin release from the E-cadherin/β-catenin complex through inhibition of E-cadherin. Thus, β-catenin degradation was inhibited due to inhibition of APC, and the Wnt/β-catenin pathway was then activated by nuclear β-catenin accumulation, which may activate transcription of downstream target genes to promote tumor invasion and metastasis. Collectively, these data indicated that β-catenin is involved in Twist2-induced EMT in ovarian cancer.ConclusionOur data indicates that upregulation of Twist2 is correlated with the FIGO stage in human ovarian cancers. In this report, we demonstrated that nuclear β-catenin is accumulated in Twist2-induced EMT cells to facilitates ovarian cancer invasion and metastasis.
Highlights
Despite recent advance in the understanding of ovarian cancer development and progression, ovarian cancer remains has the highest associated mortality rate of gynecologic malignancy in mostly western countries due to the advanced stage of disease at diagnosis
Increased Twist2 expression was correlated with FIGO stage in primary ovarian cancer
IHC analyses indicated the presence of high levels of Twist2 in cancer cells of primary ovarian tumors on tissue array (Figure 1)
Summary
Despite recent advance in the understanding of ovarian cancer development and progression, ovarian cancer remains has the highest associated mortality rate of gynecologic malignancy in mostly western countries due to the advanced stage of disease at diagnosis (stages III–IV). Recent literature suggests that the epithelial to mesenchymal transition (EMT) plays a critical role in the progression of ovarian carcinomas [3,4]. EMT is defined by a complex molecular and cellular program by which epithelial cells lose their differentiated characteristics such as cell-cell adhesion, apical-basal polarity, lack of cell motility and gain of mesenchymal features including motility, invasiveness and increased resistance to apoptosis [5]. It has been suggested that primary EOC may undergo an EMT process during local invasion in the peritoneum and retain mesenchymal features in advanced tumors. Twist has been shown to promote human tumor invasion as in breast cancer and cervical cancer. Whether Twist promotes human ovarian cancer progression remains to be elucidated. We investigate the role of Twist in ovarian cancer invasion and metastasis as well as the underlying molecular mechanisms
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