Conservation of epigenetic regulation by the MLL3/4 tumour suppressor in planarian pluripotent stem cells

Currently, little is known about the evolution of epigenetic regulation in animal stem cells. Here we demonstrate, using the planarian stem cell system to investigate the role of the COMPASS family of MLL3/4 histone methyltransferases that their function as tumor suppressors in mammalian stem cells is conserved over a long evolutionary distance. To investigate the potential conservation of a genome-wide epigenetic regulatory program in animal stem cells, we assess the effects of Mll3/4 loss of function by performing RNA-seq and ChIP-seq on the G2/M planarian stem cell population, part of which contributes to the formation of outgrowths. We find many oncogenes and tumor suppressors among the affected genes that are likely candidates for mediating MLL3/4 tumor suppression function. Our work demonstrates conservation of an important epigenetic regulatory program in animals and highlights the utility of the planarian model system for studying epigenetic regulation

Osteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo

Bone metabolism is regulated by the cooperative activity between bone-forming osteoblasts and bone-resorbing osteoclasts. However, the mechanisms mediating the switch between the osteoblastic and osteoclastic phases have not been fully elucidated. Here, we identify a specific subset of mature osteoblast-derived extracellular vesicles that inhibit bone formation and enhance osteoclastogenesis. Intravital imaging reveals that mature osteoblasts secrete and capture extracellular vesicles, referred to as small osteoblast vesicles (SOVs). Co-culture experiments demonstrate that SOVs suppress osteoblast differentiation and enhance the expression of receptor activator of NF-κB ligand, thereby inducing osteoclast differentiation. We also elucidate that the SOV-enriched microRNA miR-143 inhibits Runt-related transcription factor 2, a master regulator of osteoblastogenesis, by targeting the mRNA expression of its dimerization partner, core-binding factor β. In summary, we identify SOVs as a mode of cell-to-cell communication, controlling the dynamic transition from bone-forming to bone-resorbing phases in vivo.Uenaka M., Yamashita E., Kikuta J., et al. Osteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo. Nature Communications 13, 1066 (2022); https://doi.org/10.1038/s41467-022-28673-2

The Progression of Liver Fibrosis Is Related with Overexpression of the miR-199 and 200 Families

Chronic hepatitis C (CH) can develop into liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Liver fibrosis and HCC development are strongly correlated, but there is no effective treatment against fibrosis because the critical mechanism of progression of liver fibrosis is not fully understood. microRNAs (miRNAs) are now essential to the molecular mechanisms of several biological processes. In order to clarify how the aberrant expression of miRNAs participates in development of the liver fibrosis, we analyzed the liver fibrosis in mouse liver fibrosis model and human clinical samples

Cross-talk between cancer cells and their neighbors via miRNA in extracellular vesicles: an emerging player in cancer metastasis

Abstract Cancer metastasis is the major cause of mortality in cancer cases and is responsible for cancer deaths. It is known that cancer cells communicate with surrounding microenvironmental cells, such as fibroblast cells, immune cells, and endothelial cells, to create a cancer microenvironment for their progression. Extracellular vesicles (EVs) are small vesicles that can be secreted by most types of cells and play an important role in cell-to-cell communications via transferring bioactive cargos, including variable RNAs, such as microRNAs (miRNAs), to recipient cells. miRNAs are a class of small noncoding RNAs that posttranscriptionally regulate gene expression. The transfer of them to recipient cells influences the metastatic process of primary tumors. In this review, we summarize the function of miRNAs packaged in EVs in cancer metastasis and discuss the clinical utility of miRNAs in EVs

An Insight into the Roles of MicroRNAs and Exosomes in Sarcoma

Sarcomas are rare solid tumors, but at least one-third of patients with sarcoma die from tumor-related disease. MicroRNA (miRNA) is a noncoding RNA that regulates gene expression in all cells and plays a key role in the progression of cancers. Recently, it was identified that miRNAs are transferred between cells by enclosure in extracellular vesicles, especially exosomes. The exosome is a 100 nm-sized membraned vesicle that is secreted by many kinds of cells and contains miRNA, mRNA, DNA, and proteins. Cancer uses exosomes to influence not only the tumor microenvironment but also the distant organ to create a premetastatic niche. The progression of sarcoma is also regulated by miRNAs and exosomes. These miRNAs and exosomes can be targeted as biomarkers and treatments. In this review, we summarize the studies of miRNA and exosomes in sarcoma

A Challenge to Aging Society by microRNA in Extracellular Vesicles: microRNA in Extracellular Vesicles as Promising Biomarkers and Novel Therapeutic Targets in Multiple Myeloma

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells and is the second most common hematological cancer. MM frequently occurs in the elderly population with the median age as the middle sixties. Over the last 10 years, the prognosis of MM has been dramatically improved by new therapeutic drugs; however, MM is still incurable. The pathogenesis of MM is still unclear, thus greater understanding of the molecular mechanisms of MM malignancy is desirable. Recently, microRNAs (miRNAs) were shown to modulate the expression of genes critical for MM pathogenesis. In addition, miRNAs are secreted via extracellular vesicles (EVs), which are released from various cell types including MM cells, and these miRNAs are involved in multiple types of cell-cell interactions, which lead to the malignancy of MM. In this review, we summarize the current knowledge regarding the role of miRNA secretion via EVs and of EVs themselves in MM development. We also discuss the potential clinical applications of EVs as promising biomarkers and new therapeutic targets for improving the outcome of MM, resulting in a brighter future for aging societies