P38 regulates the Wnt inhibitor Dickkopf-1 in breast cancer.
P38 regulates the Wnt inhibitor Dickkopf-1 in breast cancer.
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DOI：
10.1016/j.bbrc.2015.09.101
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发表时间：
2015-10
影响因子：
3.1
通讯作者：
T. Rachner;A. Göbel;A. Browne;J. Hötzel;M. Rauner;L. Hofbauer
中科院分区：
文献类型：
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作者：
T. Rachner;A. Göbel;A. Browne;J. Hötzel;M. Rauner;L. Hofbauer
Dickkopf-1(DKK-1)是典型的Wnt信号的抑制因子，通过损害成骨细胞的活性与溶骨性骨转移的进展有关。此外，越来越多的证据支持DKK-1的直接抗肿瘤作用。P38丝裂原活化蛋白激酶(MAPK)调节与细胞周期、细胞凋亡和肿瘤发生有关的细胞内反应。P38抑制剂目前正在接受治疗恶性肿瘤的临床评估。然而，p38在乳腺癌中对DKK-1的影响仍然难以捉摸。在这项工作中，我们发现使用SB202190或LY2228820抑制p38可以有效地抑制MDA-231和MCF-7乳腺癌细胞以及黑色素瘤来源的MDA-435细胞DKK-1的表达。反之亦然，茴香霉素激活p38信号诱导DKK-1表达。对97例乳腺癌组织中DKK-1表达的免疫组织化学分析显示，与p38低表达的肿瘤相比，p38高表达与DKK-1的高表达有关。综上所述，这些结果支持p38在溶骨性肿瘤中调节DKK-1的作用，并值得进一步研究p38抑制用于治疗恶性骨病的可能性。
Dickkopf-1 (DKK-1) is an inhibitor of canonical Wnt signalling and has been associated with the progression of osteolytic bone metastases by impairing osteoblast activity. In addition, there is growing evidence supporting a direct anti-tumour effect of DKK-1. The p38 mitogen-activated protein kinase (MAPK) regulates intracellular responses that have been linked to cell cycle, apoptosis and tumorigenesis. P38 inhibitors are currently under clinical evaluation for the treatment of malignancies. However, the influence of p38 on DKK-1 in breast cancer remains elusive. In this work, we show that p38 inhibition using SB202190 or LY2228820 potently suppressed DKK-1 expression by MDA-231 and MCF-7 breast cancer cell lines as well melanoma derived MDA-435 cells.Vice versa, activation of p38 signalling by anisomycin induced DKK-1 expression. Immunohistochemical analysis of DKK-1 expression in 97 breast cancer samples revealed that high expression of p38 was associated with a higher expression of DKK-1 compared to tumours with low p38 expression. In conclusion, these results support a role of p38 in the regulation of DKK-1 in osteolytic tumours and warrant further research on the potential of p38 inhibition for the treatment of malignant bone disease.