MicroRNAs (miRNAs) comprise species of short noncoding RNA that regulate gene expression post‐transcriptionally. Recent studies have demonstrated that epigenetic mechanisms, including DNA methylation and histone modification, not only regulate the expression of protein‐encoding genes, but also miRNAs, such as let‐7a, miR‐9, miR‐34a, miR‐124, miR‐137, miR‐148 and miR‐203. Conversely, another subset of miRNAs controls the expression of important epigenetic regulators, including DNA methyltransferases, histone deacetylases and polycomb group genes. This complicated network of feedback between miRNAs and epigenetic pathways appears to form an epigenetics–miRNA regulatory circuit, and to organize the whole gene expression profile. When this regulatory circuit is disrupted, normal physiological functions are interfered with, contributing to various disease processes. The present minireview details recent discoveries involving the epigenetics–miRNA regulatory circuit, suggesting possible biological insights into gene‐regulatory mechanisms that may underlie a variety of diseases.

Negative feedback is a crucial physiological regulatory mechanism, but no such regulator of angiogenesis has been established. Here we report a novel angiogenesis inhibitor that is induced in endothelial cells (ECs) by angiogenic factors and inhibits angiogenesis in an autocrine manner. We have performed cDNA microarray analysis to survey VEGF-inducible genes in human ECs. We characterized one such gene, KIAA1036, whose function had been uncharacterized. The recombinant protein inhibited migration, proliferation, and network formation by ECs as well as angiogenesis in vivo. This inhibitory effect was selective to ECs, as the protein did not affect the migration of smooth muscle cells or fibroblasts. Specific elimination of the expression of KIAA1036 in ECs restored their responsiveness to a higher concentration of VEGF. The expression of KIAA1036 was selective to ECs, and hypoxia or TNF-alpha abrogated its inducible expression. As this molecule is preferentially expressed in ECs, we designated it "vasohibin." Transfection of Lewis lung carcinoma cells with the vasohibin gene did not affect the proliferation of cancer cells in vitro, but did inhibit tumor growth and tumor angiogenesis in vivo. We propose vasohibin to be an endothelium-derived negative feedback regulator of angiogenesis.

Negative feedback is a crucial physiological regulatory mechanism, but no such regulator of angiogenesis has been established. Here we report a novel angiogenesis inhibitor that is induced in endothelial cells (ECs) by angiogenic factors and inhibits angiogenesis in an autocrine manner. We have performed cDNA microarray analysis to survey VEGF-inducible genes in human ECs. We characterized one such gene, KIAA1036, whose function had been uncharacterized. The recombinant protein inhibited migration, proliferation, and network formation by ECs as well as angiogenesis in vivo. This inhibitory effect was selective to ECs, as the protein did not affect the migration of smooth muscle cells or fibroblasts. Specific elimination of the expression of KIAA1036 in ECs restored their responsiveness to a higher concentration of VEGF. The expression of KIAA1036 was selective to ECs, and hypoxia or TNF-α abrogated its inducible expression. As this molecule is preferentially expressed in ECs, we designated it "vasohibin." Transfection of Lewis lung carcinoma cells with the vasohibin gene did not affect the proliferation of cancer cells in vitro, but did inhibit tumor growth and tumor angiogenesis in vivo. We propose vasohibin to be an endothelium-derived negative feedback regulator of angiogenesis.

The importance of microRNAs (miRNAs) in human malignancies has been well recognized. Here, we report that the expression of microRNA-210 (miR-210) is down-regulated in human esophageal squamous cell carcinoma and derived cell lines. Marked decreases in the level of miR-210 were observed especially in poorly differentiated carcinomas. We found that miR-210 inhibits cancer cell survival and proliferation by inducing cell death and cell cycle arrest in G 1 /G 0 and G 2 /M. Finally, we identified fibroblast growth factor receptor-like 1 (FGFRL1) as a target of miR-210 in esophageal squamous cell carcinoma and demonstrated that FGFRL1 accelerates cancer cell proliferation by preventing cell cycle arrest in G 1 /G 0 . Taken together, our findings show an important role for miR-210 as a tumor-suppressive microRNA with effects on cancer cell proliferation. MicroRNAs (miRNAs)2 are evolutionarily conserved small noncoding RNAs (20 -23 nucleotides) that bind to complementary sequences in the 3Ј-untranslated region (UTR) of target messenger RNAs (mRNAs) and regulate gene expression by the cleavage of target mRNAs and/or translational inhibition (1). Currently, Ͼ800 human miRNAs have been identified and registered in the miRNA database, miRBase (2). miRNAs play important roles in the differentiation of various cell types and in the initiation and progression of cancer, and it has been shown that the expression of some miRNAs is altered during cell differentiation and in malignancies (1, 3, 4).In a recent study, we identified microRNA-210 (miR-210) as one of the miRNAs that is markedly differentially expressed during the process of epithelial differentiation (3). It has been reported that miR-210 expression is down-regulated during epithelial-mesenchymal transition, the aberrant activation of which triggers cancer pathology (5). Carcinomas are derived from epithelial cells, and poor prognosis in patients with carcinoma is associated with the disruption of characteristics of differentiated epithelial cells, such as cell junctions and polarity (6 -8). Hence, given that the expression of miR-210 appears to be correlated well with epithelial differentiation, miR-210 might play a suppressive role in carcinomas. In support of this idea, allelic deletions at the miR-210 locus have been observed in 64% of cases of ovarian cancer (9), and ectopic expression of miR-210 represses tumor growth when human cancer cell lines are implanted into immunodeficient mice (10). However, the clinical roles of miR-210 in carcinomas and the mechanisms by which it represses tumor growth remain unknown.In this study, we investigated the functional role of miR-210 in the growth of carcinomas and the mechanism by which it acts using clinical samples as well as cell lines of esophageal squamous cell carcinoma (ESCC). ESCC is a highly aggressive malignancy with a 5-year survival rate of 10% worldwide. It has been used as a model to study the mechanisms of dysregulated epithelial differentiation and epithelial-mesenchymal transition in carcinomas (11, 12). E...