RESUMEN
Idiopathic pulmonary fibrosis (IPF) has been linked to chronic lung inflammation. Drosha ribonuclease III (DROSHA), a class 2 ribonuclease III enzyme, plays a key role in microRNA (miRNA) biogenesis. However, the mechanisms by which DROSHA affects the lung inflammation during idiopathic pulmonary fibrosis (IPF) remain unclear. Here, we demonstrate that DROSHA regulates the absent in melanoma 2 (AIM2) inflammasome activation during idiopathic pulmonary fibrosis (IPF). Both DROSHA and AIM2 protein expression were elevated in alveolar macrophages of patients with IPF. We also found that DROSHA and AIM2 protein expression were increased in alveolar macrophages of lung tissues in a mouse model of bleomycin-induced pulmonary fibrosis. DROSHA deficiency suppressed AIM2 inflammasome-dependent caspase-1 activation and interleukin (IL)-1ß and IL-18 secretion in primary mouse alveolar macrophages and bone marrow-derived macrophages (BMDMs). Transduction of microRNA (miRNA) increased the formation of the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks, which is required for AIM2 inflammasome activation in BMDMs. Our results suggest that DROSHA promotes AIM2 inflammasome activation-dependent lung inflammation during IPF.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Fibrosis Pulmonar Idiopática/patología , Inflamasomas/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos/metabolismo , Neumonía , Ribonucleasa III/fisiología , Adulto , Anciano , Animales , Células Cultivadas , Enfermedad Crónica , Femenino , Humanos , Macrófagos/patología , Macrófagos Alveolares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neumonía/metabolismo , Neumonía/patologíaRESUMEN
PURPOSE: In the metastatic process, interactions between circulating tumor cells (CTCs) and the extracellular matrix or surrounding cells are required. ß1-Integrin may mediate these interactions. The aim of this study was to investigate whether ß1-integrin is associated with the detection of CTCs in colorectal cancer. METHODS: We enrolled 30 patients with colorectal cancer (experimental group) and 30 patients with benign diseases (control group). Blood samples were obtained from each group, carcinoembryonic antigen (CEA) mRNA for CTCs marker and ß1-integrin mRNA levels were estimated by using reverse transcription-polymerase chain reaction, and the results were compared between the two groups. In the experimental group, preoperative results were compared with postoperative results for each marker. In addition, we analyzed the correlation between the expressions of ß1-integrin and CEA. RESULTS: CEA mRNA was detected more frequently in colorectal cancer patients than in control patients (P = 0.008). CEA mRNA was significantly reduced after surgery in the colorectal cancer patients (P = 0.032). ß1-Integrin mRNA was detected more in colorectal cancer patients than in the patients with benign diseases (P < 0.001). In colorectal cancer patients, expression of ß1-integrin mRNA was detected more for advanced-stage cancer than for early-stage cancer (P = 0.033) and was significantly decreased after surgery (P < 0.001). In addition, expression of ß1-integrin mRNA was significantly associated with that of CEA mRNA in colorectal cancer patients (P = 0.001). CONCLUSION: In conclusion, ß1-integrin is a potential factor for forming a prognosis following surgical resection in colorectal cancer patients. ß1-Integrin may be a candidate for use as a marker for early detection of micrometastatic tumor cells and for monitoring the therapeutic response in colorectal cancer patients.