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As an independent unfavorable prognostic factor, IL-8 promotes metastasis of nasopharyngeal carcinoma through induction of epithelial-mesenchymal transition and activation of AKT signaling.

Li XJ, Peng LX, Shao JY, Lu WH, Zhang JX, Chen S, Chen ZY, Xiang YQ, Bao YN, Zheng FJ, Zeng MS, Kang TB, Zeng YX, Teh BT, Qian CN - Carcinogenesis (2012)

Bottom Line: Suppression of IL-8 by short-hairpin RNA reduced the expression of IL-8 in S18 cells and subsequently inhibited migration, invasion, and hepatic metastasis of the cells without influencing cellular growth.Further, IL-8-promoted migration and invasion could be abolished by either the application of the phosphoinositide-3-kinase inhibitor LY294002 or the knock down of AKT expression by using small-interfering RNA.In summary, IL-8 serves as an independent prognostic indicator of overall survival, disease-free survival, and metastasis-free survival for patients with NPC.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong 510060, P R China.

ABSTRACT
Nasopharyngeal carcinoma (NPC) has the highest metastatic potential among head and neck cancers. Distant metastasis is the major cause of treatment failure. The role of interleukin-8 (IL-8) in NPC progression remains unknown. Our multivariate survival analyses of 255 patients with NPC revealed that higher IL-8 expression in primary NPC tissue was an independent prognostic factor for overall survival, disease-free survival, and distant metastasis-free survival of the patients. In vitro study revealed that IL-8 was highly expressed in the established high-metastasis NPC clone S18 relative to the low-metastasis cells. Suppression of IL-8 by short-hairpin RNA reduced the expression of IL-8 in S18 cells and subsequently inhibited migration, invasion, and hepatic metastasis of the cells without influencing cellular growth. Overexpression of IL-8 in S26 cells resulted in increased migration, invasion, and metastasis capabilities of the cells without affecting cellular growth. Exogenous IL-8 enhanced the migration and invasion of low-metastasis CNE-2 cells in a dose-dependent manner. An epithelial-mesenchymal transition (EMT) could be induced by IL-8 in various NPC cell lines. The high level of phosphorylated AKT in S18 cells could be suppressed by knocking down IL-8 expression. Further, IL-8-promoted migration and invasion could be abolished by either the application of the phosphoinositide-3-kinase inhibitor LY294002 or the knock down of AKT expression by using small-interfering RNA. In summary, IL-8 serves as an independent prognostic indicator of overall survival, disease-free survival, and metastasis-free survival for patients with NPC. IL-8 promotes NPC metastasis via autocrine and paracrine means, involving activation of AKT signaling and inducing EMT in NPC cells.

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IL-8 promotes NPC cell migration and invasion through AKT activation. (A) Immunoblots of whole-cell lysates using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (B) Immunoblots of whole-cell lysates from S26 cells expressing IL-8 or the empty vector after pretreatment with 20 μM LY294002 for 30min, using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (C) Migratory and invasive abilities of S26 cells expressing IL-8 or the empty vector evaluated by Transwell assay after pretreatment with LY294002. (D) Immunoblots of whole-cell lysates from S26 cells expressing IL-8 or the empty vector 36h after transfection with AKT siRNA or a scrambled siRNA, using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (E) Migratory and invasive abilities of S26 cells expressing IL-8 or the empty vector as evaluated by Transwell assay after transfection with AKT siRNA or the scrambled siRNA. Photomicrographs are at 100×. Bars correspond to mean ± SD of three independent experiments. β-actin served as the loading control.
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Figure 4: IL-8 promotes NPC cell migration and invasion through AKT activation. (A) Immunoblots of whole-cell lysates using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (B) Immunoblots of whole-cell lysates from S26 cells expressing IL-8 or the empty vector after pretreatment with 20 μM LY294002 for 30min, using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (C) Migratory and invasive abilities of S26 cells expressing IL-8 or the empty vector evaluated by Transwell assay after pretreatment with LY294002. (D) Immunoblots of whole-cell lysates from S26 cells expressing IL-8 or the empty vector 36h after transfection with AKT siRNA or a scrambled siRNA, using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (E) Migratory and invasive abilities of S26 cells expressing IL-8 or the empty vector as evaluated by Transwell assay after transfection with AKT siRNA or the scrambled siRNA. Photomicrographs are at 100×. Bars correspond to mean ± SD of three independent experiments. β-actin served as the loading control.

Mentions: High levels of total AKT and phosphorylated AKT were found in S18 cells. Knocking down IL-8 in S18 cells could dramatically reduce phospho-AKT level and also slightly affect total AKT level (Figure 4A). Overexpression of IL-8 in S26 and HONE-1 cells upregulated phospho-AKT (Figure 4A); this effect could be abolished by the phosphoinositide-3-kinase inhibitor LY294002 (Figure 4B). The total AKT levels were also slightly increased by IL-8 overexpression in the low-metastasis S26 and HONE-1 cells (Figure 4A). The enhanced migration and invasion in S26 cells caused by overexpressing IL-8 was suppressed by LY294002 (Figure 4C), but it could also be abolished by knocking down AKT using siRNA (Figure 4D,4E). All of these findings confirmed that the IL-8 promotion of cellular motility in NPC cells depends on AKT signaling.


As an independent unfavorable prognostic factor, IL-8 promotes metastasis of nasopharyngeal carcinoma through induction of epithelial-mesenchymal transition and activation of AKT signaling.

Li XJ, Peng LX, Shao JY, Lu WH, Zhang JX, Chen S, Chen ZY, Xiang YQ, Bao YN, Zheng FJ, Zeng MS, Kang TB, Zeng YX, Teh BT, Qian CN - Carcinogenesis (2012)

IL-8 promotes NPC cell migration and invasion through AKT activation. (A) Immunoblots of whole-cell lysates using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (B) Immunoblots of whole-cell lysates from S26 cells expressing IL-8 or the empty vector after pretreatment with 20 μM LY294002 for 30min, using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (C) Migratory and invasive abilities of S26 cells expressing IL-8 or the empty vector evaluated by Transwell assay after pretreatment with LY294002. (D) Immunoblots of whole-cell lysates from S26 cells expressing IL-8 or the empty vector 36h after transfection with AKT siRNA or a scrambled siRNA, using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (E) Migratory and invasive abilities of S26 cells expressing IL-8 or the empty vector as evaluated by Transwell assay after transfection with AKT siRNA or the scrambled siRNA. Photomicrographs are at 100×. Bars correspond to mean ± SD of three independent experiments. β-actin served as the loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3405654&req=5

Figure 4: IL-8 promotes NPC cell migration and invasion through AKT activation. (A) Immunoblots of whole-cell lysates using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (B) Immunoblots of whole-cell lysates from S26 cells expressing IL-8 or the empty vector after pretreatment with 20 μM LY294002 for 30min, using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (C) Migratory and invasive abilities of S26 cells expressing IL-8 or the empty vector evaluated by Transwell assay after pretreatment with LY294002. (D) Immunoblots of whole-cell lysates from S26 cells expressing IL-8 or the empty vector 36h after transfection with AKT siRNA or a scrambled siRNA, using anti-phospho-AKT (Ser473) or anti-AKT (pan) antibody. (E) Migratory and invasive abilities of S26 cells expressing IL-8 or the empty vector as evaluated by Transwell assay after transfection with AKT siRNA or the scrambled siRNA. Photomicrographs are at 100×. Bars correspond to mean ± SD of three independent experiments. β-actin served as the loading control.
Mentions: High levels of total AKT and phosphorylated AKT were found in S18 cells. Knocking down IL-8 in S18 cells could dramatically reduce phospho-AKT level and also slightly affect total AKT level (Figure 4A). Overexpression of IL-8 in S26 and HONE-1 cells upregulated phospho-AKT (Figure 4A); this effect could be abolished by the phosphoinositide-3-kinase inhibitor LY294002 (Figure 4B). The total AKT levels were also slightly increased by IL-8 overexpression in the low-metastasis S26 and HONE-1 cells (Figure 4A). The enhanced migration and invasion in S26 cells caused by overexpressing IL-8 was suppressed by LY294002 (Figure 4C), but it could also be abolished by knocking down AKT using siRNA (Figure 4D,4E). All of these findings confirmed that the IL-8 promotion of cellular motility in NPC cells depends on AKT signaling.

Bottom Line: Suppression of IL-8 by short-hairpin RNA reduced the expression of IL-8 in S18 cells and subsequently inhibited migration, invasion, and hepatic metastasis of the cells without influencing cellular growth.Further, IL-8-promoted migration and invasion could be abolished by either the application of the phosphoinositide-3-kinase inhibitor LY294002 or the knock down of AKT expression by using small-interfering RNA.In summary, IL-8 serves as an independent prognostic indicator of overall survival, disease-free survival, and metastasis-free survival for patients with NPC.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong 510060, P R China.

ABSTRACT
Nasopharyngeal carcinoma (NPC) has the highest metastatic potential among head and neck cancers. Distant metastasis is the major cause of treatment failure. The role of interleukin-8 (IL-8) in NPC progression remains unknown. Our multivariate survival analyses of 255 patients with NPC revealed that higher IL-8 expression in primary NPC tissue was an independent prognostic factor for overall survival, disease-free survival, and distant metastasis-free survival of the patients. In vitro study revealed that IL-8 was highly expressed in the established high-metastasis NPC clone S18 relative to the low-metastasis cells. Suppression of IL-8 by short-hairpin RNA reduced the expression of IL-8 in S18 cells and subsequently inhibited migration, invasion, and hepatic metastasis of the cells without influencing cellular growth. Overexpression of IL-8 in S26 cells resulted in increased migration, invasion, and metastasis capabilities of the cells without affecting cellular growth. Exogenous IL-8 enhanced the migration and invasion of low-metastasis CNE-2 cells in a dose-dependent manner. An epithelial-mesenchymal transition (EMT) could be induced by IL-8 in various NPC cell lines. The high level of phosphorylated AKT in S18 cells could be suppressed by knocking down IL-8 expression. Further, IL-8-promoted migration and invasion could be abolished by either the application of the phosphoinositide-3-kinase inhibitor LY294002 or the knock down of AKT expression by using small-interfering RNA. In summary, IL-8 serves as an independent prognostic indicator of overall survival, disease-free survival, and metastasis-free survival for patients with NPC. IL-8 promotes NPC metastasis via autocrine and paracrine means, involving activation of AKT signaling and inducing EMT in NPC cells.

Show MeSH
Related in: MedlinePlus