ABSTRACT
BACKGROUND: Tumorigenic phenotype of M2 tumor-associated macrophages promote tumor progression in response to exosomes cues imposed by tumor cells. However, the effect and underlying mechanisms of clear cell renal cell carcinoma (ccRCC)-derived exosomes (ccRCC-exo) on instructing macrophages phenotype remains unclear. METHODS: Macrophages were cocultured with ccRCC-exo and then evaluate the polarization of macrophages and migration of ccRCC cells. The effect and mechanism of lncRNA AP000439.2 overexpressed or deleted exosomes on macrophages M2 polarization were examined. Xenograft tumor mice model was used for in vivo validation. RESULTS: The ccRCC-exo significantly activated macrophages to M2 phenotype presented by increased expression of transforming growth factor-beta (TGF-ß) and interleukin 10 (IL-10) at mRNA and protein levels, and these M2 macrophages in turn facilitating the migration of ccRCC cells. LncRNA AP000439.2 was highly enriched in the ccRCC-exo. Overexpression of exosomal AP000439.2 promoted M2 macrophage polarization whereas AP000439.2-deficient exosome had the opposite effects. Nuclear-localized AP000439.2 directly interacted with signal transducer and activator of transcription 3 (STAT3) proteins and phosphorylated STAT3 in macrophages. RNA-Seq results showed overexpression of AP000439.2 activated NF-κB signaling pathway. Silencing of STAT3 suppressed overexpression of AP000439.2-induced up-regulation of TGF-ß and IL-10 expression, and p65 phosphorylation. AP000439.2-deleted exosome inhibited tumor growth in vivo. CONCLUSION: Exosomes from ccRCC deliver AP000439.2 to promote M2 macrophage polarization via STAT3, thus enhancing ccRCC progression, indicating exosomal AP000439.2 might be a novel therapeutic target in ccRCC. Video Abstract.
Subject(s)
Carcinoma, Renal Cell , Exosomes , Kidney Neoplasms , MicroRNAs , RNA, Long Noncoding , Animals , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Exosomes/metabolism , Humans , Interleukin-10/metabolism , Kidney Neoplasms/metabolism , Macrophage Activation/genetics , Macrophages/metabolism , Mice , MicroRNAs/genetics , NF-kappa B/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , RNA, Messenger/metabolism , STAT3 Transcription Factor/metabolism , Transforming Growth Factor beta/metabolism , Transforming Growth Factors/metabolismABSTRACT
BACKGROUND: Postoperative delirium is described as one of the most common complications for elderly patients with unknown pathophysiological pathways. In this present study, we analyzed the clinical and biochemical parameters in elderly patients with or without a delirium after open abdominal surgery to investigate the possible predicative factors for a delirium. MATERIALS AND METHODS: Patients aged ≥60 years scheduled to undergo elective gastrointestinal tumor resection via laparotomy from July 2012 to June 2015 were enrolled in this study. Demographic and clinical data, characteristics of the surgical and anesthetic procedure, biochemical parameters were compared between patients with or without a delirium. Multivariate logistic regression testing was used for the evaluation of independent risk factors for postoperative delirium. RESULTS: Overall, 112 participants were enrolled in this study, 49 of which were diagnosed with postoperative delirium. Patients with a delirium had an older age (P = 0.013) and a lower Mini-Mental State Examination (MMSE) score (P < 0.01) compared with those patients who had no delirium. The duration of surgery and anesthesia, the levels of neopterin, C-reactive protein, interleukin-6, insulin-like growth factor-1 in patients with a delirium were significantly higher than those without a delirium (P < 0.05). Independent risk factors in the logistic regression for postoperative delirium were the levels of neopterin and MMSE scores. CONCLUSIONS: Our present study suggested the potential roles of neopterin and MMSE scores in the pathophysiology and prediction of delirium in elderly patients after open abdominal surgery.
