RESUMO
Genomic instability (GI) predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells through the inhibition of RB1 and stimulator-of-interferon-genes (STING) to propagate cells with a high degree of GI. MiR-181a targeting of RB1 leads to profound nuclear defects and GI generating aberrant cytoplasmic DNA, however simultaneous miR-181a mediated inhibition of STING allows cells to bypass interferon mediated cell death. We also found that high miR-181a is associated with decreased IFNγ response and lymphocyte infiltration in patient tumors. DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation, thus, our findings are the first to identify a miRNA that can downregulate STING expression to suppress activation of intrinsic interferon signaling. This study introduces miR-181a as a putative biomarker and identifies the miR-181a-STING axis as a promising target for therapeutic exploitation.
Assuntos
Carcinogênese/genética , Transformação Celular Neoplásica/genética , Imunidade Inata/genética , MicroRNAs/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Núcleo Celular/patologia , Transformação Celular Neoplásica/patologia , Citocinese , Dano ao DNA , Células Epiteliais/patologia , Tubas Uterinas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Instabilidade Genômica , Células HEK293 , Humanos , Interferons/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , MicroRNAs/genética , Mitose , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismoRESUMO
miRNAs are important regulators of diverse cellular processes including proliferation, apoptosis, and differentiation. In the context of bone marrow derived stromal cell and adipose derived stromal cell differentiation, miRNAs are established regulators of both differentiation or stemness depending on their target. Furthermore, miRNA dysregulation can play a key role in various disease states. Here we show that miR-181a is regulated in a circadian manner and is induced during both immortalized bone marrow derived stromal cell (iBMSC) as well as primary patient adipose derived stromal cell (PASC) adipogenesis. Enhanced expression of miR-181a in iBMSCs and PASCs produced a robust increase in adipogenesis through the direct targeting of the circadian factor period circadian regulator 3 (PER3). Furthermore, we show that knocking down endogenous miR-181a expression in iBMSC has a profound inhibitory effect on iBMSC adipogenesis through its regulation of PER3. Additionally, we found that miR-181a regulates the circadian dependency of the adipogenesis master regulator PPARγ. Taken together, our data identify a previously unknown functional link between miR-181a and the circadian machinery in immortalized bone marrow stromal cells and adipose derived stromal cells highlighting its importance in iBMSC and ASC adipogenesis and circadian biology.
