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

Mijung Kwon, Jae-Hoon Kim, Yevangelina Rybak, Alex Luna, Chel Hun Choi, Joon Yong Chung, Stephen M. Hewitt, Asha Adem, Elizabeth Tubridy, Juan Lin, Steven K. Libutti

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Filamin A interacting protein 1-like (FILIP1L) is an inhibitor of the canonical WNT pathway. WNT/β-catenin signaling and its downstream pathway, epithelialto- 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.

Original languageEnglish
Pages (from-to)77052-77070
Number of pages19
JournalOncotarget
Volume7
Issue number47
DOIs
Publication statusPublished - 2016 Jan 1

Fingerprint

Filamins
Ovarian Neoplasms
Catenins
Survival
Proteins
Neoplasm Metastasis
Centrosome

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Kwon, Mijung ; Kim, Jae-Hoon ; Rybak, Yevangelina ; Luna, Alex ; Choi, Chel Hun ; Chung, Joon Yong ; Hewitt, Stephen M. ; Adem, Asha ; Tubridy, Elizabeth ; Lin, Juan ; Libutti, Steven K. / Reduced expression of FILIP1L, a novel WNT pathway inhibitor, is associated with poor survival, progression and chemoresistance in ovarian cancer. In: Oncotarget. 2016 ; Vol. 7, No. 47. pp. 77052-77070.
@article{b60d663ff8ac4634a3d0ec446177d694,
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, epithelialto- 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.",
author = "Mijung Kwon and Jae-Hoon Kim and Yevangelina Rybak and Alex Luna and Choi, {Chel Hun} and Chung, {Joon Yong} and Hewitt, {Stephen M.} and Asha Adem and Elizabeth Tubridy and Juan Lin and Libutti, {Steven K.}",
year = "2016",
month = "1",
day = "1",
doi = "10.18632/oncotarget.12784",
language = "English",
volume = "7",
pages = "77052--77070",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "47",

}

Kwon, M, Kim, J-H, Rybak, Y, Luna, A, Choi, CH, Chung, JY, Hewitt, SM, Adem, A, Tubridy, E, Lin, J & Libutti, SK 2016, 'Reduced expression of FILIP1L, a novel WNT pathway inhibitor, is associated with poor survival, progression and chemoresistance in ovarian cancer', Oncotarget, vol. 7, no. 47, pp. 77052-77070. https://doi.org/10.18632/oncotarget.12784

Reduced expression of FILIP1L, a novel WNT pathway inhibitor, is associated with poor survival, progression and chemoresistance in ovarian cancer. / Kwon, Mijung; Kim, Jae-Hoon; Rybak, Yevangelina; Luna, Alex; Choi, Chel Hun; Chung, Joon Yong; Hewitt, Stephen M.; Adem, Asha; Tubridy, Elizabeth; Lin, Juan; Libutti, Steven K.

In: Oncotarget, Vol. 7, No. 47, 01.01.2016, p. 77052-77070.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reduced expression of FILIP1L, a novel WNT pathway inhibitor, is associated with poor survival, progression and chemoresistance in ovarian cancer

AU - Kwon, Mijung

AU - Kim, Jae-Hoon

AU - Rybak, Yevangelina

AU - Luna, Alex

AU - Choi, Chel Hun

AU - Chung, Joon Yong

AU - Hewitt, Stephen M.

AU - Adem, Asha

AU - Tubridy, Elizabeth

AU - Lin, Juan

AU - Libutti, Steven K.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Filamin A interacting protein 1-like (FILIP1L) is an inhibitor of the canonical WNT pathway. WNT/β-catenin signaling and its downstream pathway, epithelialto- 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.

AB - Filamin A interacting protein 1-like (FILIP1L) is an inhibitor of the canonical WNT pathway. WNT/β-catenin signaling and its downstream pathway, epithelialto- 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.

UR - http://www.scopus.com/inward/record.url?scp=84998816146&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84998816146&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.12784

DO - 10.18632/oncotarget.12784

M3 - Article

C2 - 27776341

AN - SCOPUS:84998816146

VL - 7

SP - 77052

EP - 77070

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 47

ER -