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MicroRNAs (miRNAs) are small non-coding RNAs that play a wide variety of critical roles in different biological processes by post-transcriptionally regulating gene expression. They access diverse regulatory pathways during various stages of cellular differentiation, growth, and apoptosis, and can contribute to both normal and diseased functions. One important family of miRNAs involved in these functions is the miR-125 family (miR-125a and miR-125b). Investigations have been made to increasingly uncover the mechanisms by which the miR-125 family regulates normal homeostasis and growth in a variety of cell types including immune cells, and how dysregulation of miR-125a and miR-125b can lead to disease pathogenesis and tumorigenesis. In this review, we summarize what is currently known about miR-125a and miR-125b, mainly focusing on their roles in immune cell development and function as well as tumor suppression and promotion. [ABSTRACT FROM AUTHOR]

Deregulation of several microRNAs (miRs) can influence critical developmental checkpoints during hematopoiesis as well as cell functions, eventually leading to the development of autoimmune disease or cancer. We found that miR-125b is expressed in bone marrow multipotent progenitors and myeloid cells but shut down in the B-cell lineage, and the gene encoding miR-125b lacked transcriptional activation markers in B cells. To understand the biological importance of the physiological silencing of miR-125b expression in B cells, we drove its expression in the B-cell lineage and found that dysregulated miR-125b expression impaired egress of immature B cells from the bone marrow to peripheral blood. Such impairment appeared to be mediated primarily by inhibited expression of the sphingosine-1- phosphate receptor 1 (S1PR1). Enforced expression of S1PR1 or clustered regularly interspaced short palindromic repeats/Cas9-mediated genome editing of the miR-125b targeting site in the S1PR1 39 untranslated region rescued the miR-125b-mediated defect in B-cell egress. In addition to impaired B-cell egress, miR-125b dysregulation initially reduced pre-B-cell output but later induced pre-B-cell lymphoma/leukemia in mice. Genetic deletion of IRF4 was found in miR-125b-induced B-cell cancer, but its role in oncogenic miR-125b-induced B-cell transformation is still unknown. Here, we further demonstrated an interaction of the effects of miR-125b and IRF4 in cancer induction by showing that miR125b-induced B-cell leukemia was greatly accelerated in IRF4 homozygous mutant mice. Thus, we conclude that physiological silencing of miR-125b is required for normal B-cell development and also acts as a mechanism of cancer suppression. [ABSTRACT FROM AUTHOR]