RESUMO
The microRNAs encoded by the miR-17â¼92 polycistron are commonly overexpressed in cancer and orchestrate a wide range of oncogenic functions. Here, we identify a mechanism for miR-17â¼92 oncogenic function through the disruption of endogenous microRNA (miRNA) processing. We show that, upon oncogenic overexpression of the miR-17â¼92 primary transcript (pri-miR-17â¼92), the microprocessor complex remains associated with partially processed intermediates that aberrantly accumulate. These intermediates reflect a series of hierarchical and conserved steps in the early processing of the pri-miR-17â¼92 transcript. Encumbrance of the microprocessor by miR-17â¼92 intermediates leads to the broad but selective downregulation of co-expressed polycistronic miRNAs, including miRNAs derived from tumor-suppressive miR-34b/c and from the Dlk1-Dio3 polycistrons. We propose that the identified steps of polycistronic miR-17â¼92 biogenesis contribute to the oncogenic re-wiring of gene regulation networks. Our results reveal previously unappreciated functional paradigms for polycistronic miRNAs in cancer.
Assuntos
Carcinogênese/genética , MicroRNAs/genética , Processamento Pós-Transcricional do RNA/genética , Proteínas de Ligação ao Cálcio/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Iodeto Peroxidase/genética , Proteínas de Membrana/genética , MicroRNAs/biossíntese , Conformação de Ácido NucleicoRESUMO
A 4-year-old recently castrated male alpaca was referred for preputial prolapse of 4 d duration. Clinical findings upon admission were a 5 cm edematous preputial prolapse with the exposed preputial epithelium ulcerated and slightly necrotic. Initial therapy included NSAIDs and local treatment. A severe local inflammatory reaction with a consequent paraphimosis occurred on the penis and prepuce presumptively secondary to the use of a common compound ointment (i.e., tetracycline, scarlet oil, and lanolin) 24 h after its application. Medical treatment and local debridement were unsuccessful in reducing the paraphimosis. The prolapse was successfully reduced by traction of the penis through a para-preputial incision under general anesthesia. The alpaca was discharged after 22 d in hospital. The alpaca is still in the herd 24 mo after discharge with no prolapse recurrence.
Traitement chirurgical d'un paraphimosis chez un alpaga castré secondaire à une avulsion p réputiale. Un alpaga mâle de 4 ans récemment castré a été référé pour un prolapsus préputial d'une durée de 4 jours. Les signes cliniques à l'admission étaient un prolapsus préputial oedémateux de 5 cm avec l'épithélium préputial exposé ulcéré et légèrement nécrotique. Le traitement initial comprenait des AINS et un traitement local. Une réaction inflammatoire locale sévère avec un paraphimosis conséquent s'est produite sur le pénis et le prépuce, vraisemblablement secondaire à l'utilisation d'une pommade composée conventionnelle (i.e. tétracycline, huile scarlet et lanoline) 24 heures après son application. Le traitement médical et le débridement local n'ont pas réussi à réduire le paraphimosis. Le prolapsus a été réduit avec succès par traction du pénis à travers une incision parapréputiale sous anesthésie générale. L'alpaga est sorti après 22 jours d'hospitalisation. L'alpaga est toujours dans le troupeau 24 mois après sa sortie sans récidive de prolapsus.(Traduit par Dr Serge Messier).
Assuntos
Camelídeos Americanos , Parafimose , Ferida Cirúrgica , Animais , Masculino , Parafimose/cirurgia , Parafimose/veterinária , Pênis/cirurgia , Ferida Cirúrgica/veterináriaRESUMO
Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated miR-17â¼92 expression in Myc+ lymphoma cells promotes increased apoptosis to biguanide treatment in vitro and in vivo. This effect is driven by the miR-17-dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in Myc+ lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17â¼92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17â¼92 expression as a potential biomarker for biguanide sensitivity in malignancies.