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Macrophages promote benzopyrene-induced tumor transformation of human bronchial epithelial cells by activation of NF-κB and STAT3 signaling in a bionic airway chip culture and in animal models.

Li E, Xu Z, Zhao H, Sun Z, Wang L, Guo Z, Zhao Y, Gao Z, Wang Q - Oncotarget (2015)

Bottom Line: Blockage of interleukin (IL)-6 or tumor necrosis factor (TNF)-α signaling or inhibition of NF-κB, STAT3, or cyclinD1 expression abrogated the effect of macrophages on malignant transformation in the bionic airway chip culture.Similarly, blockage of NF-κB, STAT3, or cyclinD1 using siRNA transfection decreased the carcinogen-induced tumorigenesis in rats.We demonstrated that macrophages are critical in promoting lung tumorigenesis and that the macrophage-initiated TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways are primarily responsible for promoting lung tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.

ABSTRACT
We investigated the role of macrophages in promoting benzopyrene (BaP)-induced malignant transformation of human bronchial epithelial cells using a BaP-induced tumor transformation model with a bionic airway chip in vitro and in animal models. The bionic airway chip culture data showed that macrophages promoted BaP-induced malignant transformation of human bronchial epithelial cells, which was mediated by nuclear factor (NF)-κB and STAT3 pathways to induce cell proliferation, colony formation in chip culture, and tumorigenicity in nude mice. Blockage of interleukin (IL)-6 or tumor necrosis factor (TNF)-α signaling or inhibition of NF-κB, STAT3, or cyclinD1 expression abrogated the effect of macrophages on malignant transformation in the bionic airway chip culture. In vivo, macrophages promoted lung tumorigenesis in a carcinogen-induced animal model. Similarly, blockage of NF-κB, STAT3, or cyclinD1 using siRNA transfection decreased the carcinogen-induced tumorigenesis in rats. We demonstrated that macrophages are critical in promoting lung tumorigenesis and that the macrophage-initiated TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways are primarily responsible for promoting lung tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

Activation of the NF-κB and STAT3 signaling pathways in lung cancerA, Western blot. Expression levels of TNF-α, IL-6, NF-κB, STAT3, and cyclinD1 proteins in lung cancer tissues. B, Immunofluorescence assay. Proteins of the NF-κB and STAT3 signaling pathways were detected during the malignant transformation of 16HBE cells by an immunofluorescence assay. Scale bar, 10 μm. C, Western blot. Proteins of the NF-κB and STAT3 signaling pathways were assayed during the malignant transformation of 16HBE cells by western blot.
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Figure 6: Activation of the NF-κB and STAT3 signaling pathways in lung cancerA, Western blot. Expression levels of TNF-α, IL-6, NF-κB, STAT3, and cyclinD1 proteins in lung cancer tissues. B, Immunofluorescence assay. Proteins of the NF-κB and STAT3 signaling pathways were detected during the malignant transformation of 16HBE cells by an immunofluorescence assay. Scale bar, 10 μm. C, Western blot. Proteins of the NF-κB and STAT3 signaling pathways were assayed during the malignant transformation of 16HBE cells by western blot.

Mentions: To demonstrate the critical role of the TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways in the malignant transformation of 16HBE cells, we first detected the expression levels of TNF-α, IL-6, NF-κB, STAT3, and cyclinD1 in lung cancer tissues. As shown in Fig. 6A, NF-κB, STAT3, and cyclinD1 were expressed in almost all of the cancerous and adjacent lung tissues. However, the expression of NF-κB, STAT3, and cyclinD1 in the lung cancer tissues was significantly higher than that in the adjacent tissues. Furthermore, we dynamically detected the protein levels of the above signaling molecules in cells cultured in the bionic airway chip. NF-κB, STAT3, and cyclinD1 proteins were activated in the bronchial epithelial cells from higher passages after exposure to BaP. Furthermore, macrophages were able to activate NF-κB, STAT3, and cyclinD1 proteins (Fig. 6B). In addition, the expression of NF-κB, STAT3, and cyclinD1 proteins was induced in different passages of cells after exposure to BaP (Fig. 6C).


Macrophages promote benzopyrene-induced tumor transformation of human bronchial epithelial cells by activation of NF-κB and STAT3 signaling in a bionic airway chip culture and in animal models.

Li E, Xu Z, Zhao H, Sun Z, Wang L, Guo Z, Zhao Y, Gao Z, Wang Q - Oncotarget (2015)

Activation of the NF-κB and STAT3 signaling pathways in lung cancerA, Western blot. Expression levels of TNF-α, IL-6, NF-κB, STAT3, and cyclinD1 proteins in lung cancer tissues. B, Immunofluorescence assay. Proteins of the NF-κB and STAT3 signaling pathways were detected during the malignant transformation of 16HBE cells by an immunofluorescence assay. Scale bar, 10 μm. C, Western blot. Proteins of the NF-κB and STAT3 signaling pathways were assayed during the malignant transformation of 16HBE cells by western blot.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496191&req=5

Figure 6: Activation of the NF-κB and STAT3 signaling pathways in lung cancerA, Western blot. Expression levels of TNF-α, IL-6, NF-κB, STAT3, and cyclinD1 proteins in lung cancer tissues. B, Immunofluorescence assay. Proteins of the NF-κB and STAT3 signaling pathways were detected during the malignant transformation of 16HBE cells by an immunofluorescence assay. Scale bar, 10 μm. C, Western blot. Proteins of the NF-κB and STAT3 signaling pathways were assayed during the malignant transformation of 16HBE cells by western blot.
Mentions: To demonstrate the critical role of the TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways in the malignant transformation of 16HBE cells, we first detected the expression levels of TNF-α, IL-6, NF-κB, STAT3, and cyclinD1 in lung cancer tissues. As shown in Fig. 6A, NF-κB, STAT3, and cyclinD1 were expressed in almost all of the cancerous and adjacent lung tissues. However, the expression of NF-κB, STAT3, and cyclinD1 in the lung cancer tissues was significantly higher than that in the adjacent tissues. Furthermore, we dynamically detected the protein levels of the above signaling molecules in cells cultured in the bionic airway chip. NF-κB, STAT3, and cyclinD1 proteins were activated in the bronchial epithelial cells from higher passages after exposure to BaP. Furthermore, macrophages were able to activate NF-κB, STAT3, and cyclinD1 proteins (Fig. 6B). In addition, the expression of NF-κB, STAT3, and cyclinD1 proteins was induced in different passages of cells after exposure to BaP (Fig. 6C).

Bottom Line: Blockage of interleukin (IL)-6 or tumor necrosis factor (TNF)-α signaling or inhibition of NF-κB, STAT3, or cyclinD1 expression abrogated the effect of macrophages on malignant transformation in the bionic airway chip culture.Similarly, blockage of NF-κB, STAT3, or cyclinD1 using siRNA transfection decreased the carcinogen-induced tumorigenesis in rats.We demonstrated that macrophages are critical in promoting lung tumorigenesis and that the macrophage-initiated TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways are primarily responsible for promoting lung tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.

ABSTRACT
We investigated the role of macrophages in promoting benzopyrene (BaP)-induced malignant transformation of human bronchial epithelial cells using a BaP-induced tumor transformation model with a bionic airway chip in vitro and in animal models. The bionic airway chip culture data showed that macrophages promoted BaP-induced malignant transformation of human bronchial epithelial cells, which was mediated by nuclear factor (NF)-κB and STAT3 pathways to induce cell proliferation, colony formation in chip culture, and tumorigenicity in nude mice. Blockage of interleukin (IL)-6 or tumor necrosis factor (TNF)-α signaling or inhibition of NF-κB, STAT3, or cyclinD1 expression abrogated the effect of macrophages on malignant transformation in the bionic airway chip culture. In vivo, macrophages promoted lung tumorigenesis in a carcinogen-induced animal model. Similarly, blockage of NF-κB, STAT3, or cyclinD1 using siRNA transfection decreased the carcinogen-induced tumorigenesis in rats. We demonstrated that macrophages are critical in promoting lung tumorigenesis and that the macrophage-initiated TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways are primarily responsible for promoting lung tumorigenesis.

No MeSH data available.


Related in: MedlinePlus