Molecular mechanisms of stem cell disorders - Micrornas and epigenetics

Stem cells are characterized by their ability to self-renew and differentiate into cells in the tissues, and have an important role in the maintenance of tissues and/or organs. Even in cancers in which accumulated gene mutations drive the abnormalities in cell proliferation and differentiation, the presence of stem cells, called cancer stem cells, has been proposed. Current observations suggest that cancer stem cells have properties reminiscent of normal stem cells and have pivotal roles in tumor development, recurrence, and metastasis. Because cells in a multicellular organism contain basically the same genetic information, the mechanisms that regulate gene expression, such as microRNAs and epigenetics, are critical for the proper differentiation of stem cells. Indeed, studies have shown that cooperative interactions between microRNAs and epigenetics regulate stem cell properties. We have previously reported that the microRNAs in the miR-200 clusters are coordinately downregulated in human breast cancer stem cells and normal breast stem cells. Among them, miR-200c targets the Polycomb group protein BMI1, a critical regulator of stem cell functions. The expression of the miR-200 precursor is regulated by histone modifications and Polycomb group proteins. Moreover, miR-22 targets a DNA demethylase and suppresses the expression of the miR-200 precursor, thereby enhances the expression of BMI1. Considering the recent development of therapies that target cancer stem cells and/or epigenetics, understanding the molecular mechanisms for stem cell regulation is becoming increasingly important.