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TNFα-mediated loss of β-catenin/E-cadherin association and subsequent increase in cell migration is partially restored by NKX3.1 expression in prostate cells.

Debelec-Butuner B, Alapinar C, Ertunc N, Gonen-Korkmaz C, Yörükoğlu K, Korkmaz KS - PLoS ONE (2014)

Bottom Line: Nevertheless, ectopic expression of NKX3.1, which is degraded upon proinflammatory cytokine exposure in inflammation, was found to induce the degradation of β-catenin by inhibiting Akt(S473) phosphorylation, therefore, partially rescued the disrupted β-catenin-E-cadherin interaction as well as the cell migration in LNCaP cells upon cytokine exposure.As, the disrupted localization of β-catenin at the cell membrane as well as increased Akt(S308) priming phosphorylation was observed in human prostate tissues with prostatic inflammatory atrophy (PIA), high-grade prostatic intraepithelial neoplasia (H-PIN) and carcinoma lesions correlated with loss of NKX3.1 expression.Thus, the data indicate that the β-catenin signaling; consequently sub-cellular localization is deregulated in inflammation, associates with prostatic atrophy and PIN pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, Cancer Biology Laboratory, Faculty of Engineering, Ege University, Bornova, Izmir, Turkey; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey.

ABSTRACT
Inflammation-induced carcinogenesis is associated with increased proliferation and migration/invasion of various types of tumor cells. In this study, altered β-catenin signaling upon TNFα exposure, and relation to loss of function of the tumor suppressor NKX3.1 was examined in prostate cancer cells. We used an in vitro prostate inflammation model to demonstrate altered sub-cellular localization of β-catenin following increased phosphorylation of Akt(S473) and GSK3β(S9). Consistently, we observed that subsequent increase in β-catenin transactivation enhanced c-myc, cyclin D1 and MMP2 expressions. Consequently, it was also observed that the β-catenin-E-cadherin association at the plasma membrane was disrupted during acute cytokine exposure. Additionally, it was demonstrated that disrupting cell-cell interactions led to increased migration of LNCaP cells in real-time migration assay. Nevertheless, ectopic expression of NKX3.1, which is degraded upon proinflammatory cytokine exposure in inflammation, was found to induce the degradation of β-catenin by inhibiting Akt(S473) phosphorylation, therefore, partially rescued the disrupted β-catenin-E-cadherin interaction as well as the cell migration in LNCaP cells upon cytokine exposure. As, the disrupted localization of β-catenin at the cell membrane as well as increased Akt(S308) priming phosphorylation was observed in human prostate tissues with prostatic inflammatory atrophy (PIA), high-grade prostatic intraepithelial neoplasia (H-PIN) and carcinoma lesions correlated with loss of NKX3.1 expression. Thus, the data indicate that the β-catenin signaling; consequently sub-cellular localization is deregulated in inflammation, associates with prostatic atrophy and PIN pathology.

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NKX3.1 and β-catenin expression variations might be related to macrophage infiltration in tissues consequent to inflammation.Tissues adjacent to the sections were used for β-catenin IHCs, and also used for NKX3.1 particularly in PIA and PIN regions. A. The sections were stained with hematoxylin-eosin dye and an NKX3.1 antibody. While these samples display stromal macrophage infiltration in most of the tissues adjacent to the normal and PIA regions, and not significant in PIN, broadly distributed NKX3.1 expression can be seen in PIN regions. High but not solely nuclear NKX3.1 expression was also shown in PIA and PIN in comparison to normal regions. B. Block arrows indicate the PIA gland and the small arrows show the cells with loss of NKX3.1 expression. The images were taken using 20× objective and also digitally magnified (smaller panels with blue rectangles). Negative (no Ab) staining controls were also provided.
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pone-0109868-g006: NKX3.1 and β-catenin expression variations might be related to macrophage infiltration in tissues consequent to inflammation.Tissues adjacent to the sections were used for β-catenin IHCs, and also used for NKX3.1 particularly in PIA and PIN regions. A. The sections were stained with hematoxylin-eosin dye and an NKX3.1 antibody. While these samples display stromal macrophage infiltration in most of the tissues adjacent to the normal and PIA regions, and not significant in PIN, broadly distributed NKX3.1 expression can be seen in PIN regions. High but not solely nuclear NKX3.1 expression was also shown in PIA and PIN in comparison to normal regions. B. Block arrows indicate the PIA gland and the small arrows show the cells with loss of NKX3.1 expression. The images were taken using 20× objective and also digitally magnified (smaller panels with blue rectangles). Negative (no Ab) staining controls were also provided.

Mentions: Human radical prostatectomy specimens from 14 patients with prostatic inflammatory disease and prostate cancer were examined. The sample sizes were (42, 38, 24 and 24) for normal, proliferative inflammatory atrophy (PIA), H-PIN and cancer samples respectively. We examined these tissue sections for β-catenin and NKX3.1 expression using immunohistochemistry (IHC) staining. β-catenin was found uniformly expressed in the normal prostate epithelium with a remarkably low cytoplasmic expression with apparent membrane localization in the histological sections. However, the sections from different stages of prostate pathology exhibited a substantial increase (average expression values for normal: 46, PIA: 68, PIN: 72 and cancer: 63) in cytoplasmic β-catenin level when compared to normal epithelium (Figure 5). As, these significant increases (t-test values are given in Figure 5M) in β-catenin expression strongly associate with PIA, H-PIN and adenocarcinomas, cytoplasmic β-catenin levels are found remarkably high in atrophic glands (Figure 5N). Furthermore, the luminal cells in normal glands exhibited highly nuclear localization of NKX3.1, which was altered to cytoplasmic accumulation in cells from regions exhibiting PIA, PIN and PCa morphology. Also, partial or complete loss of NKX3.1 expression was demonstrated in some of the PIA regions in comparison to normal prostate epithelium (Figure 6) as it was previously reported [24]. Therefore, we suggest that cytoplasmic β-catenin accumulation subsequent to loss of functional NKX3.1 (Figure 6A) correlates with prostatic inflammatory atrophy, most likely facilitates the tumor heterogeneity (Figure 6B) and initiation that can be suppressed by androgen regulated NKX3.1 expression in prostate.


TNFα-mediated loss of β-catenin/E-cadherin association and subsequent increase in cell migration is partially restored by NKX3.1 expression in prostate cells.

Debelec-Butuner B, Alapinar C, Ertunc N, Gonen-Korkmaz C, Yörükoğlu K, Korkmaz KS - PLoS ONE (2014)

NKX3.1 and β-catenin expression variations might be related to macrophage infiltration in tissues consequent to inflammation.Tissues adjacent to the sections were used for β-catenin IHCs, and also used for NKX3.1 particularly in PIA and PIN regions. A. The sections were stained with hematoxylin-eosin dye and an NKX3.1 antibody. While these samples display stromal macrophage infiltration in most of the tissues adjacent to the normal and PIA regions, and not significant in PIN, broadly distributed NKX3.1 expression can be seen in PIN regions. High but not solely nuclear NKX3.1 expression was also shown in PIA and PIN in comparison to normal regions. B. Block arrows indicate the PIA gland and the small arrows show the cells with loss of NKX3.1 expression. The images were taken using 20× objective and also digitally magnified (smaller panels with blue rectangles). Negative (no Ab) staining controls were also provided.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4215977&req=5

pone-0109868-g006: NKX3.1 and β-catenin expression variations might be related to macrophage infiltration in tissues consequent to inflammation.Tissues adjacent to the sections were used for β-catenin IHCs, and also used for NKX3.1 particularly in PIA and PIN regions. A. The sections were stained with hematoxylin-eosin dye and an NKX3.1 antibody. While these samples display stromal macrophage infiltration in most of the tissues adjacent to the normal and PIA regions, and not significant in PIN, broadly distributed NKX3.1 expression can be seen in PIN regions. High but not solely nuclear NKX3.1 expression was also shown in PIA and PIN in comparison to normal regions. B. Block arrows indicate the PIA gland and the small arrows show the cells with loss of NKX3.1 expression. The images were taken using 20× objective and also digitally magnified (smaller panels with blue rectangles). Negative (no Ab) staining controls were also provided.
Mentions: Human radical prostatectomy specimens from 14 patients with prostatic inflammatory disease and prostate cancer were examined. The sample sizes were (42, 38, 24 and 24) for normal, proliferative inflammatory atrophy (PIA), H-PIN and cancer samples respectively. We examined these tissue sections for β-catenin and NKX3.1 expression using immunohistochemistry (IHC) staining. β-catenin was found uniformly expressed in the normal prostate epithelium with a remarkably low cytoplasmic expression with apparent membrane localization in the histological sections. However, the sections from different stages of prostate pathology exhibited a substantial increase (average expression values for normal: 46, PIA: 68, PIN: 72 and cancer: 63) in cytoplasmic β-catenin level when compared to normal epithelium (Figure 5). As, these significant increases (t-test values are given in Figure 5M) in β-catenin expression strongly associate with PIA, H-PIN and adenocarcinomas, cytoplasmic β-catenin levels are found remarkably high in atrophic glands (Figure 5N). Furthermore, the luminal cells in normal glands exhibited highly nuclear localization of NKX3.1, which was altered to cytoplasmic accumulation in cells from regions exhibiting PIA, PIN and PCa morphology. Also, partial or complete loss of NKX3.1 expression was demonstrated in some of the PIA regions in comparison to normal prostate epithelium (Figure 6) as it was previously reported [24]. Therefore, we suggest that cytoplasmic β-catenin accumulation subsequent to loss of functional NKX3.1 (Figure 6A) correlates with prostatic inflammatory atrophy, most likely facilitates the tumor heterogeneity (Figure 6B) and initiation that can be suppressed by androgen regulated NKX3.1 expression in prostate.

Bottom Line: Nevertheless, ectopic expression of NKX3.1, which is degraded upon proinflammatory cytokine exposure in inflammation, was found to induce the degradation of β-catenin by inhibiting Akt(S473) phosphorylation, therefore, partially rescued the disrupted β-catenin-E-cadherin interaction as well as the cell migration in LNCaP cells upon cytokine exposure.As, the disrupted localization of β-catenin at the cell membrane as well as increased Akt(S308) priming phosphorylation was observed in human prostate tissues with prostatic inflammatory atrophy (PIA), high-grade prostatic intraepithelial neoplasia (H-PIN) and carcinoma lesions correlated with loss of NKX3.1 expression.Thus, the data indicate that the β-catenin signaling; consequently sub-cellular localization is deregulated in inflammation, associates with prostatic atrophy and PIN pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, Cancer Biology Laboratory, Faculty of Engineering, Ege University, Bornova, Izmir, Turkey; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey.

ABSTRACT
Inflammation-induced carcinogenesis is associated with increased proliferation and migration/invasion of various types of tumor cells. In this study, altered β-catenin signaling upon TNFα exposure, and relation to loss of function of the tumor suppressor NKX3.1 was examined in prostate cancer cells. We used an in vitro prostate inflammation model to demonstrate altered sub-cellular localization of β-catenin following increased phosphorylation of Akt(S473) and GSK3β(S9). Consistently, we observed that subsequent increase in β-catenin transactivation enhanced c-myc, cyclin D1 and MMP2 expressions. Consequently, it was also observed that the β-catenin-E-cadherin association at the plasma membrane was disrupted during acute cytokine exposure. Additionally, it was demonstrated that disrupting cell-cell interactions led to increased migration of LNCaP cells in real-time migration assay. Nevertheless, ectopic expression of NKX3.1, which is degraded upon proinflammatory cytokine exposure in inflammation, was found to induce the degradation of β-catenin by inhibiting Akt(S473) phosphorylation, therefore, partially rescued the disrupted β-catenin-E-cadherin interaction as well as the cell migration in LNCaP cells upon cytokine exposure. As, the disrupted localization of β-catenin at the cell membrane as well as increased Akt(S308) priming phosphorylation was observed in human prostate tissues with prostatic inflammatory atrophy (PIA), high-grade prostatic intraepithelial neoplasia (H-PIN) and carcinoma lesions correlated with loss of NKX3.1 expression. Thus, the data indicate that the β-catenin signaling; consequently sub-cellular localization is deregulated in inflammation, associates with prostatic atrophy and PIN pathology.

Show MeSH
Related in: MedlinePlus