Abstract
Our recent studies revealed that dual strands of certain pre-microRNAs, e.g., pre-miR-144, pre-miR-145, and pre-miR-150, act as antitumor microRNAs (miRNAs) in several cancers. The involvement of passenger strands of miRNAs in cancer pathogenesis is a novel concept in miRNA research. The analysis of a miRNA expression signature in clear cell renal cell carcinoma (ccRCC) has revealed that the guide strand of pre-miR-149 is significantly downregulated in cancer tissues. The aims of this study were to investigate the functional significance of miR-149’s guide strand (miR-149-5p) and passenger strand (miR-149-3p), and to identify the oncogenic genes regulated by these miRNAs in ccRCC cells. The ectopic expression of these miRNAs significantly inhibited cancer cell migration and invasion in ccRCC cells. Forkhead box protein M1 (FOXM1) was directly regulated by miR-149-5p and miR-149-3p in ccRCC cells. Knockdown studies using si-FOXM1 showed that the expression of FOXM1 enhanced RCC cell aggressiveness. Interestingly, the analysis of a large number of patients in the The Cancer Genome Atlas (TCGA) database (n = 260) demonstrated that patients with high FOXM1 expression had significantly shorter survival than did those with low FOXM1 expression (p = 1.5 × 10−6). Taken together, dual strands of pre-miR-149 (miR-149-5p and miR-149-3p) acted as antitumor miRNAs through the targeting of FOXM1 in ccRCC cells.
Highlights
Renal cell carcinoma (RCC) is the most common neoplasm of the kidney, and approximately 70–80% of RCCs are classified as clear cell-type [1]
The expression levels of miR-149-5p were significantly lower in cancerous tissues than in normal tissues, but there were no significant differences in the expression levels of miR-149-3p between cancerous tissues and non-cancerous tissues
Comparing the expression levels of two miRNAs, miR-149-5p and miR-149-3p in RCC cells, our data showed that the expression level of the miR-149-5p strand is more abundant than that of the miR-149-3p strand in RCC cells (Figure 1A,B)
Summary
Renal cell carcinoma (RCC) is the most common neoplasm of the kidney, and approximately 70–80% of RCCs are classified as clear cell-type (ccRCC) [1]. More than 270,000 patients are diagnosed with RCC every year, which is estimated to constitute approximately 3% of adult malignancies. Surgical resection remains the only known curative treatment for localized RCC, a significant percentage of these patients develop relapses or metastatic disease, which are associated with a poor prognosis [3]. Developed targeted molecular therapies and immunomodulatory agents are currently being widely used for patients with metastatic or recurrent RCC [4]. Those curative approaches are restricted to RCC patients in advanced stages of disease and the 5-year survival rate of the patients is only 5–10% [5]. To improve outcomes in patients with RCC, it is necessary to fully elucidate the molecular mechanisms of metastatic RCC based on new genomic approaches
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