Article

Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism.

Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.
Carcinogenesis (Impact Factor: 5.27). 09/2008; 29(12):2243-51. DOI: 10.1093/carcin/bgn199
Source: PubMed

ABSTRACT Epithelial-mesenchymal transition (EMT) is a normal physiological process that regulates tissue development, remodeling and repair; however, aberrant EMT also elicits disease development in humans, including lung fibrosis, rheumatoid arthritis and cancer cell metastasis. Transforming growth factor-beta (TGF-beta) is a master regulator of EMT in normal mammary epithelial cells (MECs), wherein this pleiotropic cytokine also functions as a potent suppressor of mammary tumorigenesis. In contrast, malignant MECs typically evolve resistance to TGF-beta-mediated cytostasis and develop the ability to proliferate, invade and metastasize when stimulated by TGF-beta. It therefore stands to reason that establishing how TGF-beta promotes EMT may offer new insights into targeting the oncogenic activities of TGF-beta in human breast cancers. By monitoring alterations in the actin cytoskeleton and various markers of EMT, we show here that the TGF-beta gene target, fibulin-5 (FBLN5), initiates EMT and enhances that induced by TGF-beta. Whereas normal MECs contain few FBLN5 transcripts, those induced to undergo EMT by TGF-beta show significant upregulation of FBLN5 messenger RNA, suggesting that EMT and the dedifferentiation of MECs override the repression of FBLN5 expression in polarized MECs. We also show that FBLN5 stimulated matrix metalloproteinase expression and activity, leading to MEC invasion and EMT, to elevated Twist expression and to reduced E-cadherin expression. Finally, FBLN5 promoted anchorage-independent growth in normal and malignant MECs, as well as enhanced the growth of 4T1 tumors in mice. Taken together, these findings identify a novel EMT and tumor-promoting function for FBLN5 in developing and progressing breast cancers.

0 Followers
 · 
113 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dysregulation of BCL6 plays critical oncogenic roles and facilitates tumorigenesis in various malignancies. However, whether the aberrant expression of BCL6 in ovarian carcinoma is associated with malignancy, metastasis or prognosis remains unknown. Our study aimed to investigate the expression of BCL6 in ovarian carcinoma and its possible correlation with clinicopathological features as well as patient survival to reveal its biological effects in ovarian tumor progression. Immunochemistry analysis was performed in 105 cases of ovarian carcinoma covering the histological types of serous, endometrioid and clear cell. Spearman analysis was used to calculate the correlation between pathological parameters and the expression of BCL6. Kaplan-Meier method and Cox proportional hazards analysis were used to analyze the disease-specific survival (DSS) and disease-free survival (DFS). We also assessed whether overexpression and knockdown of BCL6 influence in vitro cell proliferation, cell cycle progression, as well as tumor cell invasion and migration. The expression of BCL6 was higher in all three major kinds of ovarian cancer in comparison with paratumorous epithelium. BCL6 expression was tightly correlated with FIGO staging, lymph node metastasis and recurrence. Higher expression of BCL6 led to a significantly poorer DSS and DFS and multivariate analysis revealed that BCL6 was an independent risk factor of DSS and DFS. Enforced overexpression of BCL6 in ovarian tumor cells stimulated proliferation by inducing G1-S transition, and promoted tumor cell invasion and migration. Conversely, RNA interference-mediated silencing BCL6 expression inhibited proliferation by altered cell cycle progression and reduced the ability of the cells to migrate, and invade the extracellular matrix in culture. Our study suggests that the inappropriate activation of BCL6 predicts poor prognosis and promotes tumor progression in ovarian carcinoma. Targeting BCL6 could be a novel therapeutic choice for treating ovarian carcinoma patients.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Fibulin-5 has been considered as a tumor suppressor through inhibiting tumor growth and invasion. Reduced expression of Fibulin-5 is frequently observed in various human cancers. In this study, we investigate the clinical significance of Fibulin-5 and its role in hepatocellular carcinoma (HCC) cell migration and invasion. The expression of Fibulin-5 was evaluated by qRT-PCR and immunoblotting in HCC and matched noncancerous tissues. Fibulin-5 was over-expressed or knocked down by a retrovirus-mediated expression plasmid or a specific siRNA in HCC cells. Boyden chamber and Transwell assays were used to test HCC cell migration and invasion. Immunostaining was performed to determine matrix metalloproteinase-7 (MMP-7) expression in HCC specimens. MMP-7 retroviruses and siRNA were used to alter MMP-7 expression in HCC cells. In our study, the expression levels of Fibulin-5 protein and mRNA were down-regulated in HCC tissues as compared with those in matched noncancerous tissues. Reduced expression of Fibulin-5 was observed in all HCC cell lines (HepG2, SMMC-7721, MHCC97L, Hep3B, MHCC97H and HCC-LM3) as compare with that in a non-transformed hepatic cell line (LO2). Low expression of Fibulin-5 was significantly correlated with poor prognostic features including multiple tumor nodes, venous infiltration, high Edmondson-Steiner grading and advanced tumor-node-metastasis (TNM) tumor stage. Furthermore, we demonstrated that Fibulin-5 was a novel independent prognostic marker for predicting 5-year survival of HCC patients. Our in vitro studies showed that Fibulin-5 overexpression inhibited HCC cell migration and invasion. While Fibulin-5 knockdown increased the number of migrated and invaded HCC cells. Fibulin-5 negatively regulated MMP-7 abundance in HCC cells. Moreover, the inverse correlation between Fibulin-5 and MMP-7 expressions was observed in HCC tissues. Mechanistically, we disclosed that MMP-7 knockdown reduced the number of migrated and invaded HCC cells. Restoring MMP-7 expression abrogated the suppressive effect of Fibulin-5 on HCC cell migration and invasion in vitro, suggesting that Fibulin-5 exerted its anti-metastatic function, at least in part, by down-regulating the expression of MMP-7 in HCC cells. These results indicate that Fibulin-5 may serve as a prognostic biomarker and inhibits HCC invasion and metastasis by suppressing MMP-7 expression.
    BMC Cancer 12/2014; 14(1):938. DOI:10.1186/1471-2407-14-938 · 3.32 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To explore the effect of Fibulin-5 expression on cell proliferation and invasion in human gastric cancer patients.
    Asian Pacific Journal of Tropical Medicine 10/2014; 7(10):787-791. DOI:10.1016/S1995-7645(14)60137-1 · 0.93 Impact Factor

Full-text (2 Sources)

Download
104 Downloads
Available from
May 21, 2014