Fibrillin-1, induced by Aurora-A but inhibited by BRCA2, promotes ovarian cancer metastasis.
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.
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Ziliang
Z
Wang
Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Yang
Y
Liu
Department of Biology, Life and Environment Science College, Shanghai Normal University, Shanghai 200023, China.
Lili
L
Lu
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Lina
L
Yang
Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Sheng
S
Yin
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Yan
Y
Wang
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Zihao
Z
Qi
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Jiao
J
Meng
Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Rongyu
R
Zang
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Central Laboratory, the Fifth People's Hospital of Shanghai Fudan University, Shanghai 200240, China.
Gong
G
Yang
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002465:Cell Movement; D018572:Disease-Free Survival; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000556:secondary / Q000628:therapy; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D034622:RNA Interference; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D054392:Adipokines
D064096:Aurora Kinase A; D024682:BRCA2 Protein; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C551750:BRCA2 protein, human; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; C495901:TP53 protein, human; C576917:AURKA protein, human
Aurora-A; BRCA2; FBN1; SLUG; metastasis