miRNA let-7c promotes granulocytic differentiation in acute myeloid leukemia

Pelosi, Andrea; Careccia, Silvia; Lulli, Valentina; Romania, Paolo; Marziali, Giovanna; Testa, Ugo; Lavorgna, Serena; Lo‐Coco, Francesco; Petti, Maria Concetta; Calabretta, Bruno; Levrero, Massimo; Piaggio, Giulia; Rizzo, Maria Giulia

doi:10.1038/onc.2012.398

Cited by 63 publications

(45 citation statements)

References 35 publications

(62 reference statements)

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“…For example, Lin28 levels decrease rapidly during ARTICLE all-trans retinoic acid (ATRA)-induced differentiation of mouse embryonic carcinoma cells 28 , and during ATRA-induced differentiation of human promyelocytic leukemia NB4 cells, let-7 miRNA levels increase 29 . As predicted, NB4 differentiation led to a dramatic decrease in Lin28B levels and a sharp decline in SUMO1 and SUMO2/3 conjugates ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Şahin¹,

Ferhi²,

Carnec³

et al. 2014

Nat Commun

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Small ubiquitin-related modifier (SUMO) protein conjugation onto target proteins regulates multiple cellular functions, including defence against pathogens, stemness and senescence. SUMO1 peptides are limiting in quantity and are thus mainly conjugated to high-affinity targets. Conjugation of SUMO2/3 paralogues is primarily stress inducible and may initiate target degradation. Here we demonstrate that the expression of SUMO1/2/3 is dramatically enhanced by interferons through an miRNA-based mechanism involving the Lin28/let-7 axis, a master regulator of stemness. Normal haematopoietic progenitors indeed display much higher SUMO contents than their differentiated progeny. Critically, SUMOs contribute to the antiviral effects of interferons against HSV1 or HIV. Promyelocytic leukemia (PML) nuclear bodies are interferon-induced domains, which facilitate sumoylation of a subset of targets. Our findings thus identify an integrated interferon-responsive PML/SUMO pathway that impedes viral replication by enhancing SUMO conjugation and possibly also modifying the repertoire of targets. Interferon-enhanced post-translational modifications may be essential for senescence or stem cell self-renewal, and initiate SUMO-dependent proteolysis.

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Section: Resultsmentioning

confidence: 99%

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Şahin¹,

Ferhi²,

Carnec³

et al. 2014

Nat Commun

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“…While let-7c was shown to stimulate granulocytic differentiation in AML cell lines and primary blasts, miR-100 inhibited it (Zheng et al 2012;Pelosi et al 2013). Also, in other cellular contexts, let-7 acts as a tumor suppressor, negatively regulating oncogenes such as MYC, RAS, and HMGA2 (Johnson et al 2005;Lee and Dutta 2007).…”

mentioning

confidence: 99%

miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

et al. 2014

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Although regulation of stem cell homeostasis by microRNAs (miRNAs) is well studied, it is unclear how individual miRNAs genomically encoded within an organized polycistron can interact to induce an integrated phenotype. miR-99a/100, let-7, and miR-125b paralogs are encoded in two tricistrons on human chromosomes 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Here, we show that miR-99a/100~125b tricistrons are transcribed as a polycistronic message transactivated by the homeobox transcription factor HOXA10. Integrative analysis of global gene expression profiling, miRNA target prediction, and pathway architecture revealed that miR-99a/100, let-7, and miR-125b functionally converge at the combinatorial block of the transforming growth factor b (TGFb) pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, down-regulation of tumor suppressor genes adenomatous polyposis coli (APC)/APC2 stabilizes active b-catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFb signaling, the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo while favoring megakaryocytic differentiation. Hence, our study explains the high phylogenetic conservation of the miR-99a/100~125b tricistrons controlling stem cell homeostasis, the deregulation of which contributes to the development of AMKL.

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“…For example, the ectopic expression of let-7c promoted the granulocytic differentiation of AML cell lines and primary blasts by targeting PBX2. Restoration of let-7c also inhibited cell proliferation, clonogenicity and the anchorage-independent growth of PCa cells in vitro and led to decreased metastasis in colorectal cancer by targeting MMP11 and PBX3 (Han et al, 2012;Nadiminty et al, 2012;Pelosi et al, 2012). In lung cancer, let-7c inhibited growth and cell cycle progression in vitro (Johnson et al, 2007;Esquela-Kerscher et al, 2008).…”

Section: Let-7c Inhibits Nsclc Cell Proliferation By Targeting Hoxa1mentioning

confidence: 97%

Let-7c Inhibits NSCLC Cell Proliferation by Targeting HOXA1

Zhan

Qu²,

Guo³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Objective: The aim of the present study was to explore mechanisms by which let-7c suppresses NSCLC cell proliferation. Methods: The expression level of let-7c was quantified by qRT-PCR. A549 and H1299 cells were transfected with let-7c mimics to restore the expression of let-7c. The effects of let-7c were then assessed by cell proliferation, colony formation and cell cycle assay. Mouse experiments were used to confirm the effect of let-7c on tumorigenicity in vivo. Luciferase reporter assays and Western blotting were performed to identify target genes for let-7c. Results: HOXA1 was identified as a novel target of let-7c. MTS, colony formation and flow cytometry assays demonstrated that forced expression of let-7c inhibited NSCLC cell proliferation by inducing G1 arrest in vitro, consistent with inhibitory effects induced by knockdown of HOXA1. Mouse experiments demonstrated that let-7c expression suppressed tumorigenesis. Furthermore, we found that let-7c could regulate the expression of HOXA1 downstream effectors CCND1, CDC25A and CDK2. Conclusions: Collectively, these results demonstrate let-7c inhibits NSCLC cell proliferation and tumorigenesis by partial direct targeting of the HOXA1 pathway, which suggests that restoration of let-7c expression may thus offer a potential therapeutic intervention strategy for NSCLC.

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miRNA let-7c promotes granulocytic differentiation in acute myeloid leukemia

Cited by 63 publications

References 35 publications

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

Let-7c Inhibits NSCLC Cell Proliferation by Targeting HOXA1

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