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  • MicroRNA miRNA is a class of highly


    MicroRNA (miRNA) is a class of highly conserved, non-coding small molecules containing 19–25 nucleotides. miRNAs are involved in the regulation of genes associated with cancer development and progression and therefore can act as oncogenes, by contributing to tumor formation,17, 18 or as tumor suppressors, by inhibiting the expression of oncogenes in different types of cancer.19, 20 Many studies have shown that dysregulation of miRNAs plays a vital role in multiple biological processes associated with Biotin-16-dCTP sale cancer (BC), including differentiation, proliferation, cell cycle arrest, apoptosis, and metastasis.21, 22, 23 For example, our group has identified dysregulated miRNAs (e.g., miR-411) that are involved in BC cell function. Thus, the identification of an unknown dysregulated miRNA in human BC may provide valuable information for defining new biomarkers for BC prognosis and/or new targets for therapeutic paradigms. The current study found that miR-3687 expression was altered in human BC tissues and cell lines. We further explored the potential biological role and mechanisms underlying the miR-3687 regulation of human bladder tumorigenicity.
    Discussion BC is the 9th most common cancer in the world and the 14th leading cause of death. It is a serious international public health problem. According to the American Cancer Society, 79,030 new BC cases were diagnosed in the United States in 2017, with 16,870 deaths. In China, the age-standardized BC incidence rate is 7.68/100,000, and the standardized mortality rate is 3.03/100,000.31, 32, 33 At present, the main treatment strategy for early BC is surgery, followed by chemotherapy, radiotherapy, and biological treatment. Advanced BC is a prevalent life-threatening malignancy. Therefore, there is an urgent need to develop new diagnostic and therapeutic Biotin-16-dCTP sale targets so that BC can be caught earlier. Since tumor development in BC involves genetic alterations, epigenetic changes, and environmental factors, it is also critical to clarify the molecular mechanisms underlying its development and progression so as to improve diagnostic accuracy and clinical treatment. Previous reports have shown that the expression of miR-3687 is elevated in cancer, including renal cell carcinoma (RCC) and upper urinary tract urothelial carcinoma (UT-UC). Our study suggests that dysregulation of miR-3687 may be a common manifestation of renal cancer development and progression. miR-3687 is also elevated in other types of cancers. For example, miR-3687 is elevated in conjunctival melanoma and is associated with a higher risk of local recurrence of conjunctival melanoma. Compared with control cells, miR-3687 is upregulated in Het-1A immortalized, non-tumorigenic, esophageal epithelial cells treated with 20% cigarette smoke. On the other hand, miR-3687 is downregulated in breast cancer and colon cancer cell lines. Therefore, the role directly attributed to miR-3687 in enhancing cancer risk (in specific organ systems) remains controversial. However, in the current study, the TCGA database and fresh clinical paired human BC tissues collected from this study were used to assess miR-3687 expression in BC. miR-3687 levels were elevated in BC and promoted BC cell growth both in vitro and in vivo by upregulating cyclin E2 expression. Cyclin E2 is upregulated in many tumor types and appears to induce G0/G1 cell cycle arrest in human BC cells. Cyclin E2 is regulated by a variety of mechanisms at the transcriptional or post-transcriptional levels. Our data indicate that inhibition of miR-3687 expression results in downregulation of cyclin E2 mRNA levels and cyclin E2 promoter activity, indicating that cyclin E2 is regulated at the transcriptional level. TRANSFAC (Transcription Factor) binding site software showed that the cyclin E2 promoter region contains putative DNA binding sites for OCT2, CDX2, and FOXP1. Our data indicate that expression of FOXP1 was upregulated in UMUC3(miR-3687i) and T24(miR-3687i) compared to the scrambled nonsense vector control cells, whereas there was no significant change in OCT2 or CDX2. Further, knockdown of FOXP1 markedly increased cyclin E2 expression and BC cell growth and promoted the G0/G1 cell cycle transition in miR-3687-inhibited BC cells. Therefore, we draw the conclusion that FOXP1 is a downstream transcriptional regulator of miR-3687 that negatively regulates cyclin E2, which in turn binds the cyclin E2 promoter and inhibits cyclin E2 transcription, resulting in inhibition of the G0/G1 cell cycle transition and reduction in BC cell proliferation and tumor growth.