Therapeutic potential of ADAM17 modulation in gastric cancer through regulation of the EGFR and TNF-α signalling pathways.

A disintegrin and metalloproteinase 17 (ADAM17) is highly expressed in various tumours and affects tumour progression. In this study, ADAM17 expression in 60 gastric cancer and 20 normal gastric mucosal tissues was assessed using immunohistochemistry. ADAM17 expression was higher in gastric cancer tissues than in normal gastric mucosal tissues (P < 0.0005). A significant relationship was identified between ADAM17 expression and the depth of tumour invasion, metastasis, and carcinoma stage. Furthermore, the effects of ADAM17 knockdown on the proliferation, cell invasion, and apoptosis of human gastric carcinoma cells (SGC-7901) were determined. SGC-7901 cells were transfected with ADAM17-shRNA, and cell proliferation and migration were assessed using CCK-8 and transwell assays, respectively, to evaluate the role of ADAM17 in tumour proliferation and invasion. Furthermore, the EGFR signalling pathway, the cell membrane receptor-bound TNF-α level, and apoptosis were evaluated by western blotting and flow cytometry. The inhibition of cell proliferation and invasion was observed in the ADAM17 knockdown cells, which was associated with modulation of the EGFR signalling pathway. Apoptosis was increased, and TNF-α signalling was attenuated in the ADAM17 knockdown cells. Our study demonstrated that ADAM17 over-expression in gastric cancer tissues was closely associated with tumour proliferation, invasion, and apoptosis.

Global estimates of ambient NO2 concentrations and long-term health effects during 2000-2019.

High concentrations of ambient NO2 causes serious air pollution and could also pose great threats to human health. However, the long-term trends (20-year) and potential health effects of ambient NO2 exposure globally still shows high uncertainties. In this work, the field measurements, satellite dataset, GEOS-Chem output, and multiple geographical covariates were incorporated into the multi-stage model to investigate the global evolutions of ambient NO2 during 2000-2019. The results indicated that the cross-validation (CV) R2 values of ambient NO2 based on multi-stage model displayed satisfied performance (R2 = 0.78), which was superior to the individual model. Besides, the out-of-bag R2 was 0.75, which suggested the multi-stage model showed the better transferability. At the spatial scale, the NO2 concentrations followed the order of China (16.9 ± 9.0 µg/m3) > India (15.5 ± 5.6 µg/m3) > United States (10.7 ± 5.6 µg/m3) > Europe (7.7 ± 4.5 µg/m3), which was in consistent with the anthropogenic NOx emission. At the temporal scale, the ambient NO2 levels in China experienced persistent increases (0.29 µg/m3/year) during 2000-2013, whereas they showed slight decreases (-0.23 µg/m3/year) during 2013-2019. The ambient NO2 levels in the United States experienced continuous decreases during 2000-2019 (-0.20 µg/m3/year), while both of India and Europe remained relatively stable. Long-term NO2 exposure inevitably increased premature mortalities. The global premature all-cause mortalities associated with the excessive NO2 exposure increased from 288,169 (95% CI: 43,650, 527,971) to 461,301 (95% CI: 69,973, 843,996) in the past 20 years. This study would provide sufficient policy support for future ambient NO2 mitigation.

Tumor-derived exosomal ADAM17 promotes pre-metastatic niche formation by enhancing vascular permeability in colorectal cancer.

BACKGROUND: Hematological metastasis has been recognized as a crucial factor contributing to the high rates of metastasis and mortality observed in colorectal cancer (CRC). Notably, exosomes derived from cancer cells participate in the formation of CRC pre-metastatic niches; however, the mechanisms underlying their effects are largely unknown. While our preliminary research revealed the role of exosome-derived disintegrin and metalloproteinase 17 (ADAM17) in the early stages of CRC metastasis, the role of exosomal ADAM17 in CRC hematogenous metastasis remains unclear. METHODS: In the present study, we isolated and purified exosomes using ultracentrifugation and identified exosomal proteins through quantitative mass spectrometry. In vitro, co-culture assays were conducted to evaluate the impact of exosomal ADAM17 on the permeability of the blood vessel endothelium. Vascular endothelial cell resistance, the cell index, membrane protein separation, flow cytometry, and immunofluorescence were employed to investigate the mechanisms underlying exosomal ADAM17-induced vascular permeability. Additionally, a mouse model was established to elucidate the role of exosomal ADAM17 in the modulation of blood vessel permeability and pre-metastatic niche formation in vivo. RESULTS: Our clinical data indicated that ADAM17 derived from the circulating exosomes of patients with CRC could serve as a blood-based biomarker for predicting metastasis. The CRC-derived exosomal ADAM17 targeted vascular endothelial cells, thus enhancing vascular permeability by influencing vascular endothelial cadherin cell membrane localization. Moreover, exosomal ADAM17 mediated the formation of a pre-metastatic niche in nude mice by inducing vascular leakage, thereby promoting CRC metastasis. Nonetheless, ADAM17 selective inhibitors effectively reduced CRC metastasis in vivo. CONCLUSIONS: Our results suggest that exosomal ADAM17 plays a pivotal role in the hematogenous metastasis of CRC. Thus, this protein may serve as a valuable blood-based biomarker and potential drug target for CRC metastasis intervention.

Exosome-Derived ADAM17 Promotes Liver Metastasis in Colorectal Cancer.

Exosomes derived from cancer cells are deemed important drivers of pre-metastatic niche formation at distant organs, but the underlying mechanisms of their effects remain largely unknow. Although the role of ADAM17 in cancer cells has been well studied, the secreted ADAM17 effects transported via exosomes are less understood. Herein, we show that the level of exosome-derived ADAM17 is elevated in the serum of patients with metastatic colorectal cancer as well as in metastatic colorectal cancer cells. Furthermore, exosomal ADAM17 was shown to promote the migratory ability of colorectal cancer cells by cleaving the E-cadherin junction. Moreover, exosomal ADAM17 overexpression as well as RNA interference results highlighted its function as a tumor metastasis-promoting factor in colorectal cancer in vitro and in vivo. Taken together, our current work suggests that exosomal ADAM17 is involved in pre-metastatic niche formation and may be utilized as a blood-based biomarker of colorectal cancer metastasis.