Background Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. Methods Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages. Results In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells. Conclusions These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.
Vegetation phenology is a key biological indicator for monitoring terrestrial ecosystems and global change, and regions with the most obvious phenological changes in vegetation are primarily located at high latitudes and altitudes. Over the past three decades, investigations of obvious phenological changes in vegetation at middle and high latitudes in the Northern Hemisphere have provided significant contributions to understanding global climate change. In this study, phenological parameters were extracted from the Global Inventory Modeling and Mapping Studies (GIMMS) Normalized Difference Vegetation Index (NDVI3g) to analyze the spatial and temporal characteristics of vegetation phenological changes above 40°N in the Northern Hemisphere from 1982-2013. The results showed that the start of season (SOS) was significantly advanced (−2.2 ± 0.6 days· decade −1 , p < 0.05) and that the end of season (EOS) was slightly delayed (0.78 ± 0.6 days· decade −1 , p = 0.21) over the entire study area in the initial 21 years . When the time scale was extended to 2013, the change rate of the SOS and EOS was significantly reduced; in addition, the SOS was delayed (3.2 ± 1.7 days· decade −1 , p < 0.05), and the EOS was advanced (4.5 ± 0.9 days· decade −1 , p < 0.05) over the entire study area in the last 11 years (2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013). The trends of advanced SOS and delayed EOS over the past three decades OPEN ACCESSRemote Sens. 2015, 7 10974 were slower than those over the initial two decades on a hemispheric scale. The change trends showed obvious variability with different vegetation types and were greater for woody plants than for herbaceous plants. For broad-leaved forest, the SOS was significantly advanced (2 ± 0.5 days· decade −1 , p < 0.05) and the EOS was significantly delayed (2.7 ± 0.6 days· decade −1 , p < 0.05) from 1982-2013. The trend of delayed EOS was greater than that of advanced SOS for different vegetation types. With respect to the spatial distribution of phenological trends in the Northern Hemisphere, the trends of advanced SOS and delayed EOS were strongest in Europe followed by North America, and the trends were least significant in Asia. Coniferous forest, shrub forest, grassland, and the entire study area have the same change trends for the two time periods (1982-2002 and 2003-2013), and the increased rate of the phenology parameters has decelerated over the most recent decade. The length of season (LOS) of broad-leaved forest and mixed forest over the past 32 years shows a strong increased trend, and simultaneously, the SOS and EOS show an advanced trend and a delayed trend, respectively.
Tumor repopulation during therapy is an important cause of treatment failure. Strategies to overcome repopulation are arising in parallel with advances in the comprehension of underlying biological mechanisms. Here, we reveal a new mechanism by which high mobility group box 1 (HMGB1) released by dying cells during radiotherapy or chemotherapy could stimulate living tumor cell proliferationInhibition or genetic ablation of HMGB1 suppressed tumor cell proliferation. This effect was due to binding of HMGB1with the member receptor for advanced glycation end-products (RAGE), which activated downstream ERK and p38 signaling pathway and promoted cell proliferation. Furthermore, higher HMGB1 expression in tumor tissue correlated with poor overall survival and higher HMGB1 concentration was detected in serum of patients who accepted radiotherapy. Collectively, the results from this study suggested that interaction between dead cells and surviving cells might influence the fate of tumor. HMGB1 could be a novel tumor promoter with therapeutic and prognostic relevance in cancers.
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