Abstract
miRNAs are involved in cancer development and progression, acting as tumor suppressors or oncogenes. In this study, miRNA profiling was conducted on 10 paired bladder cancer tissues using 20 GeneChip miRNA Array, and 10 differentially expressed miRNAs were identified in bladder cancer and adjacent noncancerous tissues of any disease stage/grade. After being validated on expanded cohort of 67 paired bladder cancer tissues and 10 human bladder cancer cell lines by quantitative real-time PCR (qRT-PCR), it was found that miR-100 was downregulated most significantly in cancer tissues. Ectopic restoration of miR-100 expression in bladder cancer cells suppressed cell proliferation and motility, induced cell-cycle arrest in vitro, and inhibited tumorigenesis in vivo both in subcutaneous and in intravesical passage. Bioinformatic analysis showed that the mTOR gene was a direct target of miR-100. siRNA-mediated mTOR knockdown phenocopied the effect of miR-100 in bladder cancer cell lines. In addition, the cancerous metastatic nude mouse model established on the basis of primary bladder cancer cell lines suggested that miR-100/mTOR regulated cell motility and was associated with tumor metastasis. Both mTOR and p70S6K (downstream messenger) presented higher expression levels in distant metastatic foci such as in liver and kidney metastases than in primary tumor. Taken together, miR-100 may act as a tumor suppressor in bladder cancer, and reintroduction of this mature miRNA into tumor tissue may prove to be a therapeutic strategy by reducing the expression of target genes.
Highlights
It is estimated that bladder cancer accounts for 69,250 new cases of cancer and 14,990 cancer-related deaths in the United States in 2011 [1]
We focused on miR-100, as our previous miRNA array analysis on 10 pairs of human bladder cancer and adjacent noncancerous tissues showed that miR-100 was stably downregulated and presented highly fold-changed expression both in non–muscle-invasive bladder cancer (NMIBC) and in muscle-invasive bladder cancer (MIBC)
Results miR-100 expression is decreased in human bladder cancer tissues
Summary
It is estimated that bladder cancer accounts for 69,250 new cases of cancer and 14,990 cancer-related deaths in the United States in 2011 [1]. It is the fourth most common cancer in men and the eighth leading cause of death from cancer. The disease presents in 2 different forms: non–muscle-invasive bladder cancer (NMIBC; stage Ta and T1) and muscle-invasive bladder cancer (MIBC; stage T2–4). NMIBC represents a heterogeneous group of tumors, from completely benign noninvasive papillary tumors that rarely progress to invasive papillary lamina propria high-grade tumors that progress to MIBC in about 60% cases as shown by long-term followups [2].
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