MicroRNA-1280 Inhibits Invasion and Metastasis by Targeting ROCK1 in Bladder Cancer

Department of Urology, VA Medical Center and UCSF, San Francisco, California, United States of America.
PLoS ONE (Impact Factor: 3.23). 10/2012; 7(10):e46743. DOI: 10.1371/journal.pone.0046743
Source: PubMed


MicroRNAs (miRNAs) are non-protein-coding sequences that can function as oncogenes or tumor suppressor genes. This study documents the tumor suppressor role of miR-1280 in bladder cancer. Quantitative real-time PCR and in situ hybridization analyses showed that miR-1280 is significantly down-regulated in bladder cancer cell lines and tumors compared to a non-malignant cell line or normal tissue samples. To decipher the functional significance of miR-1280 in bladder cancer, we ectopically over-expressed miR-1280 in bladder cancer cell lines. Over-expression of miR-1280 had antiproliferative effects and impaired colony formation of bladder cancer cell lines. FACS (fluorescence activated cell sorting) analysis revealed that re-expression of miR-1280 in bladder cancer cells induced G2-M cell cycle arrest and apoptosis. Our results demonstrate that miR-1280 inhibited migration and invasion of bladder cancer cell lines. miR-1280 also attenuated ROCK1 and RhoC protein expression. Luciferase reporter assays demonstrated that oncogene ROCK1 is a direct target of miR-1280 in bladder cancer. This study also indicates that miR-1280 may be of diagnostic and prognostic importance in bladder cancer. For instance, ROC analysis showed that miR-1280 expression can distinguish between malignant and normal bladder cancer cases and Kaplan-Meier analysis revealed that patients with miR-1280 high expression had higher overall survival compared to those with low miR-1280 expression. In conclusion, this is the first study to document that miR-1280 functions as a tumor suppressor by targeting oncogene ROCK1 to invasion/migration and metastasis. Various compounds are currently being used as ROCK1 inhibitors; therefore restoration of tumor suppressor miR-1280 might be therapeutically useful either alone or in combination with these compounds in the treatment of bladder cancer.

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Available from: Shinichiro Fukuhara
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    • "In addition, we identified 5 miRNAs: miR-130a, miR-1280, miR-590-5p, miR-1308, miR-17*, which to the best of our knowledge, have not previously been implicated in breast cancer (Table 2). Of note, miR-130a has been shown to be associated with chemotherapy response in ovarian cancer and lung cancer cell lines, while miR-1280 has recently been demonstrated to inhibit invasion and metastasis by targeting ROCK1 when over-expressed in bladder cancer [22-24]. miR-590-5p has been reported to enhance (via the tumour suppressor PBRM1) or inhibit (via S100A10) cell growth and invasion depending on the cellular context, however, the function of miR-1308 and miR-17* has not been extensively studied [25,26]. "
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    • "Recently, miRNAs were identified to have significant roles in tumorigenesis (15). Previous studies have demonstrated that certain miRNAs are significantly deregulated in bladder cancer and may function as tumor suppressors (17,18). However, the role of miRNA-159-3p in the development of bladder cancer remains unknown. "
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    • "Thus, miRNAs are being assessed as potential biomarkers to aid in the diagnosis and prognosis of different types of cancers [7], [8]. Several human miRNAs have been shown to be dysregulated in bladder cancer, including miR-1280, miR-203, miR-125b and miR-133a [9], [10], [11], [12] and contribute to the development and progression of the disease. Here we report that miR-23b is significantly down-regulated in bladder cancer tissues and cell lines and that high expression level of miR-23b positively correlate with higher overall survival of patients after surgery. "
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