miRNA-130a Targets ATG2B and DICER1 to Inhibit Autophagy and Trigger Killing of Chronic Lymphocytic Leukemia Cells

Abstract

Toxicity and relapses from the immunochemotherapy used to treat chronic lymphocytic leukemia (CLL) prompt continued interest in gentle but effective targeted treatment options for the mainly elderly population suffering from this disease. Here, we report the definition of critical CLL cell survival pathways that can be targeted by ectopic reexpression of the miRNA genes miR-130a and miR-143 which are widely downregulated in CLL. Notably, miR-130a inhibited autophagy by reducing autophagosome formation, an effect mediated by downregulation of the genes ATG2B and DICER1, the latter of which is a major component of the miRNA silencing machinery. In support of the concept of a fundamental connection between miRNA disregulation and altered autophagic flux in this cancer, we showed that RNA interference-mediated knockdown of DICER1 expression was sufficient to reduce autophagy in primary or established cultures of CLL cells. Together, our findings show that miR-130a modulates cell survival programs by regulating autophagic flux, and they define roles for miR-130a and Dicer1 in a regulatory feedback loop that mediates CLL cell survival. Cancer Res; 72(7);

miRNA-130a regulates C/EBP-ε expression during granulopoiesis

“…Decreased expression of Dicer-1 by miR-130a causes downregulation of several miRNAs in the cell, which could explain the complexity of cell changes when manipulating internal levels of miR-130a in cells. 38 In summary, our study reveals miR-130a as an important regulator of C/EBP-e protein expression and thereby also as a regulator of normal granulopoiesis. …”

Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension

“…Of the 8 miR-130/301 family members listed in TargetScan, we chose 4 members to study (miR-130a/b and miR-301a/b), based on their conserved expression in rodent and human pulmonary vascular cell types. Members of this miRNA family have been studied to a modest degree, mainly as isolated factors in cancer progression (13,14) and non-PH-related diseases (15)(16)(17)(18). Notably, these miRNAs share the same seed sequence (nucleotides 2-8) and consequently putative targets ( Figure 1B), but they are encoded at separate chromosomal loci, indicating that distinct transcriptional events modulate their expression.…”

microRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells

“…To date, an increasing number of miRNAs are being discovered as key regulators of many different cellular processes, in particular those related to autophagy death in cells of different tumor, like melanoma, 37 hepatocellular carcinoma, 38 myelogenous leukemia, 39 colon, 40 cervical, 41 and breast cancer; 42 however, to date, only few reports identified miRNA sequences (i.e., miR-30a, miR-21, and miR10b) directly involved in the regulation of the autophagic process in glioma cells. [43][44][45] Among oncogenic miRNAs, one of the best-characterized is miR-17-92, a polycistronic miRNA cluster, designated as OncomiR-1.…”