title: Reduced expression of FILIP1L, a novel WNT pathway inhibitor, is associated with poor survival, progression and chemoresistance in ovarian cancer.
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.
authors: Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Mijung
authors: M
authors: Kwon
authors: Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 135-720, Korea.|Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul 135-720, Korea.
authors: Jae-Hoon
authors: JH
authors: Kim
authors: Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Yevangelina
authors: Y
authors: Rybak
authors: Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Alex
authors: A
authors: Luna
authors: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.|Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Chel Hun
authors: CH
authors: Choi
authors: Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Joon-Yong
authors: JY
authors: Chung
authors: Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Stephen M
authors: SM
authors: Hewitt
authors: Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Asha
authors: A
authors: Adem
authors: Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Elizabeth
authors: E
authors: Tubridy
authors: Division of Biostatistics, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Juan
authors: J
authors: Lin
authors: Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Steven K
authors: SK
authors: Libutti
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011379:Prognosis; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C504459:FILIP1L protein, human; D047908:Intracellular Signaling Peptides and Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D051176:beta Catenin
keywords: WNT; chemoresistance; metastasis; ovarian cancer; prognosis