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Reciprocal activation between IL-6/STAT3 and NOX4/Akt signalings promotes proliferation and survival of non-small cell lung cancer cells.

Li J, Lan T, Zhang C, Zeng C, Hou J, Yang Z, Zhang M, Liu J, Liu B - Oncotarget (2015)

Bottom Line: Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer.Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC).The in vivo results were similar to those obtained in vitro.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacy Department, Guangdong Pharmaceutical University, Guangzhou 510006, China.

ABSTRACT
Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer. Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC). In our recent study, we confirmed that NADPH oxidase 4 (NOX4), an important source of reactive oxygen species (ROS) production in NSCLC cells, promotes malignant progression of NSCLC. However, whether the crosstalk of NOX4 and IL-6 signalings exists in NSCLC remains undentified. In this study, we show that NOX4 expression is positively correlated with IL-6 expression in NSCLC tissues. Exogenous IL-6 treatment significantly enhances NOX4/ROS/Akt signaling in NSCLC cells. NOX4 also enhances IL-6 production and activates IL-6/STAT3 signaling in NSCLC cells. Specifically, NOX4 is confirmed to functionally interplay with IL-6 to promote NSCLC cell proliferation and survival. The in vivo results were similar to those obtained in vitro. These data indicate a novel NOX4-dependent link among IL-6 in the NSCLC microenvironment, oxidative stress in NSCLC cells and autocrined IL-6 in NSCLC cells. NOX4/Akt and IL-6/STAT3 signalings can reciprocally and positively regulate each other, leading to enhanced NSCLC cell proliferation and survival. Therefore, NOX4 may serve as a promising target against NSCLC alone with IL-6 signaling.

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Related in: MedlinePlus

NOX4 is positively correlated with IL-6 levels of NSCLC(A) IHC staining indicating that IL-6 expression is upregulated in human NSCLC compared with adjacent normal lung tissues. (B) Western blotting analysis of NOX4 expression in 6 paired primary NSCLC tissues (T) and matched adjacent nontumor tissues (A). GAPDH was used as a loading control. (C) NOX4 expression associated with IL-6 expression in 152 primary human NSCLC specimens. Representative specimens with low and high levels of NOX4 are shown.
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Figure 1: NOX4 is positively correlated with IL-6 levels of NSCLC(A) IHC staining indicating that IL-6 expression is upregulated in human NSCLC compared with adjacent normal lung tissues. (B) Western blotting analysis of NOX4 expression in 6 paired primary NSCLC tissues (T) and matched adjacent nontumor tissues (A). GAPDH was used as a loading control. (C) NOX4 expression associated with IL-6 expression in 152 primary human NSCLC specimens. Representative specimens with low and high levels of NOX4 are shown.

Mentions: We first performed immunohistochemistry assay to determine the expression of IL-6 in NSCLC specimens. Immunohistochemical analysis showed that IL-6 was highly expressed in about 61% of NSCLC samples (93 of 152), whereas the adjacent normal tissues of NSCLC had much lower levels of IL-6 expression (Fig. 1A). The results of the IHC analysis are summarized in Table 1. We also collected 6 paired primary NSCLC tissues and matched adjacent nontumor tissues from the same patient and performed Western blotting in parallel to determine NOX4 expression. The results showed that NOX4 was elevated in all human NSCLC samples compared with the matched adjacent nontumor tissues (Fig. 1B). As a previous study indicates that NOX4 mediates hypoxia-induced IL-6 production in renal cell carcinoma cells [18], we next sought to the possible correlation of NOX4 and IL-6 expression levels in NSCLC. We found that IL-6 was also elevated in these NSCLC samples compared with the matched adjacent nontumor samples. In addition, statistical analysis showed a Spearman correlation coefficient of 0.93 (p = 0.017) and a Pearson correlation coefficient of 0.84 (p = 0.038) when the relative level of NOX4 expression was plotted against the relative level of IL-6 expression in these samples, suggesting a significant positive correlation between NOX4 and IL-6 expression in these samples (revised Fig. 1B). As shown in Fig. 1C, the clinical correlation studies in 152 specimens also showed that NOX4 levels were positively correlated with the expression of IL-6. The results of the IHC analysis are summarized in Table 2.


Reciprocal activation between IL-6/STAT3 and NOX4/Akt signalings promotes proliferation and survival of non-small cell lung cancer cells.

Li J, Lan T, Zhang C, Zeng C, Hou J, Yang Z, Zhang M, Liu J, Liu B - Oncotarget (2015)

NOX4 is positively correlated with IL-6 levels of NSCLC(A) IHC staining indicating that IL-6 expression is upregulated in human NSCLC compared with adjacent normal lung tissues. (B) Western blotting analysis of NOX4 expression in 6 paired primary NSCLC tissues (T) and matched adjacent nontumor tissues (A). GAPDH was used as a loading control. (C) NOX4 expression associated with IL-6 expression in 152 primary human NSCLC specimens. Representative specimens with low and high levels of NOX4 are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4359215&req=5

Figure 1: NOX4 is positively correlated with IL-6 levels of NSCLC(A) IHC staining indicating that IL-6 expression is upregulated in human NSCLC compared with adjacent normal lung tissues. (B) Western blotting analysis of NOX4 expression in 6 paired primary NSCLC tissues (T) and matched adjacent nontumor tissues (A). GAPDH was used as a loading control. (C) NOX4 expression associated with IL-6 expression in 152 primary human NSCLC specimens. Representative specimens with low and high levels of NOX4 are shown.
Mentions: We first performed immunohistochemistry assay to determine the expression of IL-6 in NSCLC specimens. Immunohistochemical analysis showed that IL-6 was highly expressed in about 61% of NSCLC samples (93 of 152), whereas the adjacent normal tissues of NSCLC had much lower levels of IL-6 expression (Fig. 1A). The results of the IHC analysis are summarized in Table 1. We also collected 6 paired primary NSCLC tissues and matched adjacent nontumor tissues from the same patient and performed Western blotting in parallel to determine NOX4 expression. The results showed that NOX4 was elevated in all human NSCLC samples compared with the matched adjacent nontumor tissues (Fig. 1B). As a previous study indicates that NOX4 mediates hypoxia-induced IL-6 production in renal cell carcinoma cells [18], we next sought to the possible correlation of NOX4 and IL-6 expression levels in NSCLC. We found that IL-6 was also elevated in these NSCLC samples compared with the matched adjacent nontumor samples. In addition, statistical analysis showed a Spearman correlation coefficient of 0.93 (p = 0.017) and a Pearson correlation coefficient of 0.84 (p = 0.038) when the relative level of NOX4 expression was plotted against the relative level of IL-6 expression in these samples, suggesting a significant positive correlation between NOX4 and IL-6 expression in these samples (revised Fig. 1B). As shown in Fig. 1C, the clinical correlation studies in 152 specimens also showed that NOX4 levels were positively correlated with the expression of IL-6. The results of the IHC analysis are summarized in Table 2.

Bottom Line: Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer.Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC).The in vivo results were similar to those obtained in vitro.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacy Department, Guangdong Pharmaceutical University, Guangzhou 510006, China.

ABSTRACT
Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer. Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC). In our recent study, we confirmed that NADPH oxidase 4 (NOX4), an important source of reactive oxygen species (ROS) production in NSCLC cells, promotes malignant progression of NSCLC. However, whether the crosstalk of NOX4 and IL-6 signalings exists in NSCLC remains undentified. In this study, we show that NOX4 expression is positively correlated with IL-6 expression in NSCLC tissues. Exogenous IL-6 treatment significantly enhances NOX4/ROS/Akt signaling in NSCLC cells. NOX4 also enhances IL-6 production and activates IL-6/STAT3 signaling in NSCLC cells. Specifically, NOX4 is confirmed to functionally interplay with IL-6 to promote NSCLC cell proliferation and survival. The in vivo results were similar to those obtained in vitro. These data indicate a novel NOX4-dependent link among IL-6 in the NSCLC microenvironment, oxidative stress in NSCLC cells and autocrined IL-6 in NSCLC cells. NOX4/Akt and IL-6/STAT3 signalings can reciprocally and positively regulate each other, leading to enhanced NSCLC cell proliferation and survival. Therefore, NOX4 may serve as a promising target against NSCLC alone with IL-6 signaling.

Show MeSH
Related in: MedlinePlus