Reduced expression of FILIP1L, a novel WNT pathway inhibitor, is associated with poor survival, progression and chemoresistance in ovarian cancer

// Mijung Kwon 1, * , Jae-Hoon Kim 3, 4, * , Yevangelina Rybak 1 , Alex Luna 1 , Chel Hun Choi 5, 6 , Joon-Yong Chung 6 , Stephen M. Hewitt 6 , Asha Adem 1 , Elizabeth Tubridy 1 , Juan Lin 2 , Steven K. Libutti 1 1 Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA 2 Division of Biostatistics, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA 3 Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 135-720, Korea 4 Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul 135-720, Korea 5 Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea 6 Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA * These authors contributed equally to this work Correspondence to: Steven K. Libutti, email: slibutti@montefiore.org Mijung Kwon, email: mijung.kwon@einstein.yu.edu Keywords: ovarian cancer, prognosis, metastasis, chemoresistance, WNT Received: July 20, 2016      Accepted: October 17, 2016      Published: October 20, 2016 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.