Fibrillin-1, induced by Aurora-A but inhibited by BRCA2, promotes ovarian cancer metastasis

// Ziliang Wang 1, 3, * , Yang Liu 2, 3, * , Lili Lu 4 , Lina Yang 1, 3 , Sheng Yin 2, 3 , Yan Wang 1, 3 , Zihao Qi 1, 3 , Jiao Meng 1, 3 , Rongyu Zang 2, 3 , Gong Yang 1, 3, 5 1 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China 2 Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China 3 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China 4 Department of Biology, Life and Environment Science College, Shanghai Normal University, Shanghai 200023, China 5 Central Laboratory, the Fifth People's Hospital of Shanghai Fudan University, Shanghai 200240, China * These authors have contributed equally to this work Correspondence to: Rongyu Zang, e-mail: ryzang@yahoo.com Gong Yang, e-mail: yanggong@fudan.edu.cn Keywords: Aurora-A, BRCA2, FBN1, SLUG, Metastasis Received: September 11, 2014 Accepted: January 08, 2015 Published: February 13, 2015 ABSTRACT While Aurora-A (Aur A) provokes, BRCA2 restrains primary tumorigenesis, the roles of Aur A and BRCA2 in cancer metastasis remains unclear. Here, we show that the metastatic promoting markers SLUG, FBN1, and MMP2, 9, 13 are either stimulated or suppressed by Aur A or BRCA2, but the metastatic suppressors E-cadherin, β-catenin, and p53 are either inhibited or promoted by Aur A or BRCA2, leading to enhanced or reduced cell migration and invasion. Further study suggests that FBN1 inhibits E-cadherin and β-catenin, but stimulates MMP2, 9, 13. Depletion of SLUG abrogates FBN1 and MMP9, but increases E-cadherin, while p53 decreases both SLUG and FBN1. Animal assays demonstrate that FBN1 promotes both ovarian tumorigenesis and metastasis. Clinically, overexpression of BRCA2 or Aur A in ovarian cancer tissues predicts good or poor overall and disease free survivals. High expression of SLUG or FBN1 indicates poor overall survivals, whereas high expression of FBN1 but not of SLUG predicts poor disease free survival. No significant associations between p53 expression and patient survivals were found. Overall, FBN1, acts at the downstream of Aur A and BRCA2, promotes ovarian cancer metastasis through the p53 and SLUG-associated signaling, which may be useful for ovarian cancer diagnosis and treatment.