Abstract
Filamin A interacting protein 1-like (FILIP1L) is an inhibitor of the canonical WNT pathway. WNT/β-catenin signaling and its downstream pathway, epithelial-to-mesenchymal transition (EMT), play a key role in ovarian cancer metastasis and chemoresistance. To study the clinical implications of FILIP1L in regulating the WNT/β-catenin pathway, the expression of FILIP1L, β-catenin, SNAIL and SLUG was analyzed by immunohistochemistry on tissue microarrays of 369 ovarian samples ranging from normal to metastatic. In addition, the results were validated in mouse model and in vitro cell culture. In the present study, we demonstrated that FILIP1L expression was inversely correlated with poor prognosis, stage and chemoresistance in ovarian cancer. Notably, low FILIP1L expression was independent negative prognostic factor with respect to overall and disease-free survival. FILIP1L inhibited peritoneal metastases in orthotopic mouse model. FILIP1L knockdown induced chemoresistance in ovarian cancer cells and this phenotype was rescued by simultaneous knockdown of FILIP1L and SLUG, an EMT activator. We also demonstrated that FILIP1L regulates β-catenin degradation. FILIP1L co-localizes with phospho-β-catenin and increases phospho-β-catenin at the centrosomes, destined for proteosomal degradation. Finally, we showed that FILIP1L regulates EMT. Overall, these findings suggest that FILIP1L promotes β-catenin degradation and suppresses EMT, thereby inhibiting metastases and chemoresistance. Our study provides the first clinical relevance of FILIP1L in human cancer, and suggests that FILIP1L may be a novel prognostic marker for chemotherapy in ovarian cancer patients. Further, the modulation of FILIP1L expression may have the potential to be a target for cancer therapy.
Highlights
Ovarian cancer is the most general cause of death from gynecological cancers and the fifth leading cause of death from all cancers in women [1]
We show that Filamin A interacting protein 1-like (FILIP1L) is a marker of prognosis, stage and chemosensitivity in ovarian cancer
We showed that loss of FILIP1L expression increases with tumor progression, resulting in a significant difference between primary and metastatic ovarian cancer samples, whereas the levels of β-catenin and SLUG increase with tumor progression (Figure 1A, 1B and Supplementary Figure S1A)
Summary
Ovarian cancer is the most general cause of death from gynecological cancers and the fifth leading cause of death from all cancers in women [1]. Most patients are diagnosed with advanced stage metastatic disease [1]. The standard cytotoxic systemic regimens consist of platinum and a taxane, and most patients attain initial complete clinical remission [2]. The overall survival rate, while improved by recent advances in targeted therapy, remains poor, with the five-year survival rate below 25% for stage III-IV disease [1, 4]. A better understanding of the pathways involved in metastasis and chemoresistance is crucial for the development of more effective therapies in ovarian cancer
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