Abstract
BackgroundBladder cancer is one of the most common cancers worldwide. Fibulin-1, a multi-functional extracellular matrix protein, has been demonstrated to be involved in many kinds of cancers, while its function in bladder cancer remains unclear. So here we investigated the expression and function of fibulin-1 in Bladder cancer.MethodsWe used real-time PCR, Western blot analysis and immunohistochemistry to determine the expression of fibulin-1 in Bladder cancer cells and patient tissues respectively. Methylation-specific PCR and quantitative sequencing were used to examine the methylation status of FBLN1 gene promoter. Eukaryotic expression plasmid and lentiviral vector were used to overexpress fibulin-1 in Bladder cancer cells 5637, HT-1376 to investigate its function in vitro and in vivo.ResultsWe identified that fibulin-1 was significantly down-regulated in bladder cancer, and its dysregulation was associated with non-muscle-invasive bladder cancer (NMIBC) grade and recurrence. The promoter region of FBLN1 was generally methylated in bladder cancer cell lines and tissues, further investigation in patient tissues showed that the methylation status was associated with the fibulin-1 expression. Overexpression of fibulin-1 significantly suppressed tumor growth, induced tumor cell apoptosis, decreased cell motility, and inhibited angiogenesis in cultured bladder cancer cells and xenograft tumor in nude mice.ConclusionsAltogether, our results indicated that fibulin-1 expression is associated with NMIBC grade and recurrence, it is epigenetically down-regulated and functions as a tumor suppressor gene and angiogenesis inhibitor in bladder cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-677) contains supplementary material, which is available to authorized users.
Highlights
Bladder cancer is one of the most common cancers worldwide
Using IHC analysis of 139 non-muscle invasive bladder cancer patient tissue samples, we found the expression of fibulin-1 in Non-muscle invasive BC (NMIBC) was associated with tumor grade, indicated that loss of fibulin-1 expression may contribute to bladder cancer progression, these results accord with our previously observations of fibulin-5 in bladder cancer tissues [30]
The expression of fibulin-1 in cancer cell lines was a little different with tissue samples. 5637 cells, which derived from a grade 2 bladder transitional cell carcinoma had the lower fibulin-1 expression than J82 or T24 cells which originated from high grade, invasive human bladder cancer
Summary
Bladder cancer is one of the most common cancers worldwide. Fibulin-1, a multi-functional extracellular matrix protein, has been demonstrated to be involved in many kinds of cancers, while its function in bladder cancer remains unclear. 75% of patients with BC present with a disease that is confined to the mucosa (stage Ta, CIS) or submucosa (stage T1). These categories are grouped as non-muscle-invasive bladder tumors. Genome-wide association studies of bladder cancer identified single-nucleotide polymorphisms (SNPs) on chromosome 8q24, upstream of the MYC oncogene, on chromosome 3q28 near the TP63 tumor suppressor gene [5], and in the PSCA gene to be associated with bladder cancer risk [6]. It is well established that aberrant hypermethylation of the promoter region of tumor suppressor genes is associated with transcriptional silencing, and that hypermethylation is an alternative mechanism of functional inactivation [9] promoter hypermethylation of tumor-related gene has been proposed as a novel biomarker for detecting cancer and predicting prognosis [10]
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