MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1-regulated pathways in mice. Blood
ABSTRACT MicroRNAs (miRNAs) are pivotal for regulation of hematopoiesis but their critical targets remain largely unknown. Here, we show that ectopic expression of miR-17, -20,-93 and -106, all AAAGUGC seed-containing miRNAs, increases proliferation, colony outgrowth and replating capacity of myeloid progenitors and results in enhanced P-ERK levels. We found that these miRNAs are endogenously and abundantly expressed in myeloid progenitors and down-regulated in mature neutrophils. Quantitative proteomics identified sequestosome 1 (SQSTM1), an ubiquitin-binding protein and regulator of autophagy-mediated protein degradation, as a major target for these miRNAs in myeloid progenitors. In addition, we found increased expression of Sqstm1 transcripts during CSF3-induced neutrophil differentiation of 32D-CSF3R cells and an inverse correlation of SQSTM1 protein levels and miR-106 expression in AML samples. ShRNA-mediated silencing of Sqstm1 phenocopied the effects of ectopic miR-17/20/93/106 expression in hematopoietic progenitors in vitro and in mice. Further, SQSTM1 binds to the ligand-activated colony-stimulating factor 3 receptor (CSF3R) mainly in the late endosomal compartment, but not in LC3 positive autophagosomes. SQSTM1 regulates CSF3R stability and ligand-induced mitogen-activated protein kinase signaling. We demonstrate that AAAGUGC seed-containing miRNAs promote cell expansion, replating capacity and signaling in hematopoietic cells by interference with SQSTM1-regulated pathways.
Full-textDOI: · Available from: Jeroen A A Demmers, Aug 31, 2015
- SourceAvailable from: Ramesh C Nayak
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- "All together, these data indicate that the effect of p62 deficiency on HP egress is non-cell-autonomous. It has been reported that overexpression of AAAGUGC seedcontaining microRNA promotes cell expansion, replating capacity , and signaling in hematopoietic cells by interfering with p62- regulated pathways in myeloid cell lines and that these changes may reflect the effect of p62 deficiency on HSC and myeloid progenitor mobilization (Meenhuis et al., 2011). To identify whether p62 regulates in vivo hematopoietic cell proliferation, we analyzed the cell cycle status of primary WT and p62-deficient as well as WT hematopoietic cells engrafted in full chimeric WT HM and p62 À/À HM mice. "
ABSTRACT: In the bone marrow (BM), hematopoietic progenitors (HPs) reside in specific anatomical niches near osteoblasts (Obs), macrophages (MΦs), and other cells forming the BM microenvironment. A connection between immunosurveillance and traffic of HP has been demonstrated, but the regulatory signals that instruct the immune regulation of HP circulation are unknown. We discovered that the BM microenvironment deficiency of p62, an autophagy regulator and signal organizer, results in loss of autophagic repression of macrophage contact-dependent activation of Ob NF-κB signaling. Consequently, Ob p62-deficient mice lose bone, Ob Ccl4 expression, and HP chemotaxis toward Cxcl12, resulting in egress of short-term hematopoietic stem cells and myeloid progenitors. Finally, Ccl4 expression and myeloid progenitor egress are reversed by deficiency of the p62 PB1-binding partner Nbr1. A functional "MΦ-Ob niche" is required for myeloid progenitor/short-term stem cell retention, in which Ob p62 is required to maintain NF-κB signaling repression, osteogenesis, and BM progenitor retention.Cell Reports 12/2014; 9(6):2084-97. DOI:10.1016/j.celrep.2014.11.031 · 8.36 Impact Factor
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- "Recent studies identified a number of miRNAs as a novel player in tightly controlling autophagy and maintaining cell viability as well as intracellular homeostasis [86, 87]. The polycistron miR-17~92 and its paralog miR-106b-25, two miRNA clusters frequently highly expressed in HCC [88, 89], were identified as regulators of autophagy by targeting p62, a multifunctional signal transducer modulating transportation of polyubiquitinated proteins for proteasome degradation . Ectopic expression of these two clusters significantly promotes cell proliferation and differentiation capacity of myeloid progenitors. "
ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and ranks third in the leading causes of cancer patient's death. Cancer stem cells (HSCs), also known as tumor-initiating cells, have been reported in multiple subtypes of HCC and are considered as the master regulators of HCC initiation, chemotherapy drug resistance, tumor metastasis, and progression. In spite of their clinical importance, the detailed mechanism about how HSCs are intricately regulated in the molecular level remains elusive. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, has been demonstrated to serve as a vital player in modulating a number of biological activities ranging from embryogenesis to programmed cell death as well as the maintenance of HSCs. In this review, we synthesize these latest findings of miRNA regulation of HSCs and try to elucidate their mechanistic roles in orchestrating cellular equilibrium. This recent progress underlies the functional role of miRNA in cellular transformation of liver cancer, which has largely extended our knowledge how HSCs are controlled by miRNA network, and in the development of novel miRNA-based anticancer therapies specifically targeting HSCs in the coming future.12/2013; 2013(21):358902. DOI:10.1155/2013/358902
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- "The mRNA of several autophagy-related genes contains, in fact, the target sequence for miRNAs belonging to different families, with either oncosuppressive or oncogenic activities. For instance, Beclin-1 mRNA can be targeted by oncosuppressive members of the miR30 family  and by oncogenic miR-376b ; the mRNA of ATG4C is down-regulated by oncogenic miR-376b  and that of ATG4D by oncosuppressive miR-101 ; the mRNA of p62/SQSTM is targeted by MiR-17/20/93 and 106 , while the expression of MAP-LC3 can be affected by miR196 , and the translation of ATG7 mRNA is suppressed by miR375 . "
ABSTRACT: Autophagy is a lysosomal-driven catabolic process that contributes to preserve cell and tissue homeostases through the regular elimination of damaged, aged and redundant self-constituents. In normal cells, autophagy protects from DNA mutation and carcinogenesis by preventive elimination of pro-oxidative mitochondria and protein aggregates. Mutations in oncogenes and oncosuppressor genes dysregulate autophagy. Up-regulated autophagy may confer chemo- and radio-resistance to cancer cells, and also a pro-survival advantage in cancer cells experiencing oxygen and nutrient shortage. This fact is the rationale for using autophagy inhibitors along with anti-neoplastic therapies. Yet, aberrant hyper-induction of autophagy can lead to cell death, and this phenomenon could also be exploited for cancer therapy. The actual level of autophagy in the cancer cell is greatly affected by vascularization, inflammation, and stromal cell infiltration. In addition, small non-coding microRNAs have recently emerged as important epigenetic modulators of autophagy. The present review focuses on the potential involvement of macroautophagy, and on its genetic and epigenetic regulation, in ovarian cancer pathogenesis and progression.Journal of Ovarian Research 09/2012; 5(1):22. DOI:10.1186/1757-2215-5-22 · 2.43 Impact Factor