Abstract
BIRC5 encodes the protein survivin, a member of the inhibitor of apoptosis family. Survivin is highly expressed in a variety of cancers but has very low expression in the corresponding normal tissues, and its expression is often associated with tumor metastasis and chemoresistance. We report that survivin was highly expressed in ovarian cancer and strongly correlated with patient overall poor survival. For the first time, we provide experimental evidence that survivin is involved in epithelial to mesenchymal transition (EMT) in ovarian cancer cells. Lentiviral CRISPR/Cas9 nickase vector mediated BIRC5 gene editing led to the inhibition of EMT by upregulating epithelial cell marker, cytokeratin 7 and downregulating mesenchymal markers: snail2, β-catenin, and vimentin in both ovarian cancer SKOV3 and OVCAR3 cells. Consistent with this molecular approach, pharmacological treatment of ovarian cancer cells using a small molecule survivin inhibitor, YM155 also inhibited EMT in these ovarian cancer cell lines. Overexpression of BIRC5 promoted EMT in SKOV3 cells. Using molecular or pharmacological approaches, we found that cell proliferation, migration, and invasion were significantly inhibited following BIRC5 disruption in both cell lines. Inhibition of BIRC5 expression also sensitized cell responses to paclitaxel treatment. Moreover, loss of BIRC5 expression attenuated TGFβ signaling in both SKOV3 and OVCAR3 cells. Collectively, our studies demonstrated that disruption of BIRC5 expression inhibited EMT by attenuating the TGFβ pathway in ovarian cancer cells.
Highlights
Ovarian cancer is therapeutically challenging and has the highest mortality rate among gynecological malignancies
All these data suggest that BIRC5 is highly expressed in high grade serous ovarian cancer and the level of survivin overexpression is associated with poor prognosis
BIRC5 was highly expressed in high grade serous ovarian carcinoma compared with ovarian, fallopian tube epithelia, and peritoneal fluid based on a large number of cancer patients from three different databases and current study
Summary
Ovarian cancer is therapeutically challenging and has the highest mortality rate among gynecological malignancies. Ovarian cancer is rarely detected early, and the majority of patients are already at advanced stages at the time of diagnosis. Ovarian cancers primarily metastasize through peritoneal dissemination from the primary tumor site to other distant organs including the omentum, colon, and liver. This metastatic process is often accompanied by ascitic fluid accumulation, which is associated with tumor metastasis and chemoresistance, further contributing to a poor survival rate in patients [2, 3]. The current therapeutic approaches are limited due to a lack of understanding the molecular mechanisms underlying tumor metastasis and chemoresistance
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