Search

Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer (1-3). MicroRNAs play important roles in physiology and disease (4,5), and present tremendous therapeutic potential (6). Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-β-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers., We examined the levels of several cancer-related microRNAs (miRNAs) during a time course of bone marrow osteoclastogenesis assay (Fig. 1a). While the expression of an osteoclast marker tartrate-resistant acid phosphatase [...]

miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, [...]

We here present and demonstrate a novel technique based on isotachophoresis (ITP) for the quantification of global microRNA (miRNA) abundance in total RNA. We leverage the selectivity of ITP to concentrate miRNA and exclude longer RNA molecules from the focused zone. We designed a novel ITP strategy where we initially establish three contiguous zones of sieving polymer, electrolyte, and denaturant concentrations. This allows for successive preconcentration, selection, and detection of miRNA. We optimized chemistry in each zone for high sensitivity and exquisite selectivity for miRNA. This technique allows for the measurement of the total miRNA content in a sample and its comparison between different cell types and tissues. We demonstrated and validated the efficacy of this technique by comparing global miRNA abundance in subconfluent and confluent cell cultures. 10.1021/ac102496m

Altered glucose metabolism in cancer cells is termed the Warburg effect, which describes the propensity of most cancer cells to take up glucose avidly and convert it primarily to lactate, despite available oxygen (1,2). Notwithstanding the renewed interest in the Warburg effect, cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate (3). Glutamine, which is highly transported into proliferating cells (4,5), is a major source of energy and nitrogen for biosynthesis, and a carbon substrate for anabolic processes in cancer cells, but the regulation of glutamine metabolism is not well understood (1,6). Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs, (7,8) and stimulate cell proliferation (9), transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells. This leads to upregulation of glutamine catabolism (10). Glutaminase converts glutamine to glutamate, which is further catabolized through the tricarboxylic acid cycle for the production of ATP or serves as substrate for glutathione synthesis (11). The unique means by which Myc regulates glutaminase uncovers a previously unsuspected link between Myc regulation of miRNAs, glutamine metabolism, and energy and reactive oxygen species homeostasis., Oncogenes and tumour suppressors have been linked to the regulation of glucose metabolism, thereby connecting genetic alterations in cancers to their glucose metabolic phenotype (1,2). In particular, the MYC oncogene [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tibs.2008.06.008 Byline: Raghu R. Chivukula (1)(2), Joshua T. Mendell (1)(3)(4) Abstract: MicroRNAs (miRNAs) have attracted considerable attention because of their important roles in development, normal physiology, and disease states including cancer. Recent studies have identified specific miRNAs that regulate the cell cycle and have documented that the loss or gain of miRNA-mediated cell-cycle control contributes to malignancy. miRNAs regulate classic cell-cycle control pathways by directly targeting proteins such as E2F transcription factors, cyclin-dependent kinases (Cdks), cyclins and Cdk inhibitors. Moreover, from recent findings, it has been suggested that miRNAs themselves might be subject to cell-cycle dependent regulation. Together, these observations indicate that the reciprocal control of RNA silencing and the metazoan cell cycle impacts cellular behavior and disease. Author Affiliation: (1) McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA (2) Program in Human Genetics and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA (3) Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA (4) Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA