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

Wang Z, Liu Y, Lu L, Yang L, Yin S, Wang Y, Qi Z, Meng J, Zang R, Yang G - Oncotarget (2015)

Bottom Line: Depletion of SLUG abrogates FBN1 and MMP9, but increases E-cadherin, while p53 decreases both SLUG and FBN1.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

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.

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Related in: MedlinePlus

The negative correlation between Aur A and BRCA2 regulates the expression levels of metastasis-related proteins(A) Detection of Aurora-A or BRCA2 by Western blotting in OVCA429, OVCA429/Aur A shRNA, OVCA429/BRCA2 cDNA, OVCA420, OVCA420/Aur A cDNA, and OVCA420/BRCA2 shRNA cells. (B) Immunoblotting analyses of p53, FBN1, and other metastasis-associated proteins. β-actin was used as a loading control.
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Figure 1: The negative correlation between Aur A and BRCA2 regulates the expression levels of metastasis-related proteins(A) Detection of Aurora-A or BRCA2 by Western blotting in OVCA429, OVCA429/Aur A shRNA, OVCA429/BRCA2 cDNA, OVCA420, OVCA420/Aur A cDNA, and OVCA420/BRCA2 shRNA cells. (B) Immunoblotting analyses of p53, FBN1, and other metastasis-associated proteins. β-actin was used as a loading control.

Mentions: To assess the effect of Aur A or BRCA2 on cell invasion and migration, we delivered Aur A shRNA or BRCA2 cDNA into OVCA429 cells, which generated OVCA429/Aur A shRNA cells and OVCA429/BRCA2 cDNA cells, and Aur A cDNA or BRCA2 shRNA into OVCA420 cells, which generated OVCA420/Aur A cDNA cells and OVCA420/BRCA2 shRNA cells. The immunoblotting analysis showed that the expression level of Aur A was decreased in OVCA429/Aur A shRNA and OVCA420/BRCA2 cDNA cells, but was increased in OVCA420/Aur A cDNA and OVCA420/BRCA2 shRNA cells (Figure 1A). At the same time, the expression level of BRCA2 was increased in OVCA429/Aur A shRNA and OVCA420/BRCA2 cDNA cells, but was decreased in OVCA420/Aur A cDNA and OVCA420/BRCA2 shRNA cells (Figure 1A). These results suggest a mutual suppression between Aur A and BRCR2.


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

Wang Z, Liu Y, Lu L, Yang L, Yin S, Wang Y, Qi Z, Meng J, Zang R, Yang G - Oncotarget (2015)

The negative correlation between Aur A and BRCA2 regulates the expression levels of metastasis-related proteins(A) Detection of Aurora-A or BRCA2 by Western blotting in OVCA429, OVCA429/Aur A shRNA, OVCA429/BRCA2 cDNA, OVCA420, OVCA420/Aur A cDNA, and OVCA420/BRCA2 shRNA cells. (B) Immunoblotting analyses of p53, FBN1, and other metastasis-associated proteins. β-actin was used as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466642&req=5

Figure 1: The negative correlation between Aur A and BRCA2 regulates the expression levels of metastasis-related proteins(A) Detection of Aurora-A or BRCA2 by Western blotting in OVCA429, OVCA429/Aur A shRNA, OVCA429/BRCA2 cDNA, OVCA420, OVCA420/Aur A cDNA, and OVCA420/BRCA2 shRNA cells. (B) Immunoblotting analyses of p53, FBN1, and other metastasis-associated proteins. β-actin was used as a loading control.
Mentions: To assess the effect of Aur A or BRCA2 on cell invasion and migration, we delivered Aur A shRNA or BRCA2 cDNA into OVCA429 cells, which generated OVCA429/Aur A shRNA cells and OVCA429/BRCA2 cDNA cells, and Aur A cDNA or BRCA2 shRNA into OVCA420 cells, which generated OVCA420/Aur A cDNA cells and OVCA420/BRCA2 shRNA cells. The immunoblotting analysis showed that the expression level of Aur A was decreased in OVCA429/Aur A shRNA and OVCA420/BRCA2 cDNA cells, but was increased in OVCA420/Aur A cDNA and OVCA420/BRCA2 shRNA cells (Figure 1A). At the same time, the expression level of BRCA2 was increased in OVCA429/Aur A shRNA and OVCA420/BRCA2 cDNA cells, but was decreased in OVCA420/Aur A cDNA and OVCA420/BRCA2 shRNA cells (Figure 1A). These results suggest a mutual suppression between Aur A and BRCR2.

Bottom Line: Depletion of SLUG abrogates FBN1 and MMP9, but increases E-cadherin, while p53 decreases both SLUG and FBN1.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

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.

Show MeSH
Related in: MedlinePlus