Bladder cancer is the seventh most common malignant neoplasm and the eighth leading cause of cancer death worldwide, with an estimated 68,810 new cases and 14,100 deaths in the USA in 2008 alone 1 2 . This malignancy affects the lining of the urinary bladder with a complicated, multifactorial etiology, involving both genetic and environmental factors. There are two principal forms of bladder cancers: low-grade superficial tumors and high-grade invasive cancer. The former are often papillary and multifocal, occasionally progress to invasive disease, and have a good prognosis, while the latter are usually nodular, metastasize during the early phase, and have a poor prognosis 3 4 . Approximately 70% of the patients who are diagnosed initially with superficial bladder cancer do not face a life-threatening situation; however, up to 70% of these patients developing at least one recurrence within 5 years 5 . Thus, the clinical outcome of bladder cancer patients is still poor in spite of the considerable progress made in the treatment of this disease. The challenges for controlling bladder cancer are the prevention of the recurrent disease and the inhibition of the disease progression during the treatment course. Clinicopathological parameters such as tumor grade and stage have been used clinically to evaluate pathologic events of bladder cancer; however, their sensitivity is relatively low 6 . Accumulating studies have found different marker expression in this cancer. For example, Bahadir et al. 7 indicated that CD10 expression may be strongly correlated with high tumor grade and stage in urothelial carcinoma of the bladder, and that CD10 may be associated with tumor progression in bladder cancer pathogenesis; Yildiz et al. 8 found that dual staining by p53 + CK20 cocktail may allow for histologic correlation and diminish the risk of losing the area of interest in limited biopsy specimens. Therefore, identification of novel effective molecular markers is of great significance for the improvement of diagnostic and prognostic techniques, and for the development of more efficient therapeutic strategies for patients with bladder cancer.

MicroRNAs (miRNAs), small non-coding, single strand RNA molecules that negatively regulate gene expression at the post-transcriptional level 9 . MiRNAs can downregulate gene expression by inducing the degradation or impairing the translation of target mRNAs 10 . A single miRNA may regulate hundreds of target mRNAs that are frequently grouped in a specific biological pathway. In the current estimate, about 900 unique miRNAs are encoded in the human genome, in part controlling the expression of more than a third of human genes 11 . Accumulating studies have demonstrated that miRNAs play important roles in angiogenic signaling, cell proliferation, apoptosis avoidance, and tumor invasion pathways 12 . In this context, miRNAs have been identified as promising alternative biomarkers for detecting cancer, informing prognosis, and monitoring treatment response. Recent studies have found that more than 40 miRNAs are involved in the tumorigenesis and tumor progression of urological cancers 13 . Many researchers have studied miRNA expression in bladder cancer by using various gene expression profiling approaches. Song et al. 14 in 2010 performed the miRNA microarray analysis with 25 cases of bladder cancers and adjacent normal bladder tissues. They identified a panel of 51 differentially expressed miRNAs with at least 2-fold differences in expression compared with the normal controls, including 20 up-regulated and 31 down-regulated miRNAs. In particular, miR-100 was found to be downregulated in bladder cancer. In another report of Oliveira et al. 15 in 2011, enforced expression of miR-100 may inhibit cell growth and colony formation of human bladder cancer 5637 cells in vitro. However, the clinical significance of miR-100 in human bladder cancer has not yet been elucidated. Thus, the aim of this study was to investigate the diagnostic and prognostic values of miR-100 in this disease.

In our retrospective exploratory study, there are four main findings as following: first, the expression levels of miR-100 in bladder cancer tissues were significantly lower than those in adjacent normal tissues; next, low miR-100 expression was associated with advanced tumor progression in bladder cancer; then, low miR-100 expression was associated with shorter PFS and OS in bladder cancer; and finally, miR-100 was identified as an independent prognostic marker for bladder cancer. To our best of knowledge, this is the first study on the clinical significance of miR-100 expression using a large number of bladder cancer cases.

MiR-100, together with miR-99a and miR-99b, belongs to the miR-100 family. It is the oldest known animal miRNA and is extensively expressed in vertebrates 16 . Recent studies have demonstrated that the aberrant expression of miR-100 is associated with tumorigenesis and tumor progression. Notably, the roles of miR-100 in different cancers are quite contradictory as it can behave either as an oncogene or a tumor suppressor gene, depending on the tumor type examined. MiR-100 is downregulated in nasopharyngeal cancer, oral squamous cell carcinoma, ovarian cancer, hepatocellular carcinoma, hepatoblastoma and bladder cancer, whereas its upregulation has been described in acute myeloid leukemia, medulloblastomas, gastric cancer, pancreatic cancer and prostate cancer 17 18 19 20 21 22 23 24 25 26 27 . Especially in bladder cancer, both the previous studies of Oliveira et al. 15 and Song et al. 14 found the decreased expression of miR-100 in bladder cancer cells. In line with these findings, our data also validated the downregulation of miR-100 in a large number of clinical bladder cancer cases. Functionally, the aberrant expression of miR-100 in acute myeloid leukemia cells can promote cell proliferation and block granulocyte/monocyte differentiation 22 . Oral squamous cell carcinoma cells transfected with miR-100 may modify the expression of a number of oncogenes including ID1, EGR2, MMP13, and FGFR3 18 . Henson et al. 28 also demonstrated that miR-100 could be used therapeutically to increase the sensitivity of oral squamous cell carcinoma cells to ionizing radiation by decreasing the expression of the genes that confer radioresistance. These findings raise the possibility that miR-100 might have an important role in the development or pathogenesis of various cancers. Similarly, our data in the present study showed that the downregulation of miR-100 may more frequently occur in bladder cancer tissues with aggressive clinicopathological features and poor prognosis.

In conclusion, our data offer the convincing evidence that miR-100 may play an important role in the progression of bladder cancer and that the reduced expression of this miRNA may be independently associated with shorter PFS and OS of patients, suggesting that miR-100 might be a potential marker for further risk stratification in the treatment of this cancer. However, the mechanism by which miR-100 was downregulated in bladder cancer is still unclear. This study is hypothesis generating, and that further prospective analysis should be worth doing.

The authors’ declare that they have no competing interests.

SW and QL: wrote the manuscript, carried out study design and experiments; SX, YD, JY, ZC, and XF: collected the samples; WZ: carried out part of experiments; WW: wrote the manuscript and designed the study. All authors read and approved the final manuscript.