Pro-Oncogenic Role of Alternative p38 Mitogen-Activated Protein Kinases p38γ and p38δ, Linking Inflammation and Cancer in Colitis-Associated Colon Cancer
Pro-Oncogenic Role of Alternative p38 Mitogen-Activated Protein Kinases p38γ and p38δ, Linking Inflammation and Cancer in Colitis-Associated Colon Cancer
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DOI：
10.1158/0008-5472.can-14-0870
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发表时间：
2014-11-01
期刊：
影响因子：
11.2
通讯作者：
Cuenda, Ana
中科院分区：
文献类型：
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作者：
del Reino, Paloma;Alsina-Beauchamp, Dayanira;Cuenda, Ana
p38 MAPK信号转导涉及导致癌症发展和进展的过程的调节。慢性炎症是已知的肿瘤发生的危险因素，但这种关联的确切机制在很大程度上仍然未知。相关的p38 α MAPK（MAPK 14）蛋白p38 γ（MAPK 12）和p38 δ（MAPK 13）最近显示出调节免疫应答，尽管它们在肿瘤发生中的作用仍然存在争议，并且它们在炎症相关癌症中的功能尚未被研究。我们使用氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）结肠炎相关结肠癌模型，在野生型（WT）、p38 γ-、p38 δ-和p38 γ/δ-缺陷（p38 γ/δ（-/-））小鼠中分析了p38 γ和p38 δ在结肠炎相关结肠癌中的作用。我们发现，p38 γ/δ缺陷显着降低肿瘤形成，在平行的减少促炎细胞因子和趋化因子的生产。p38 γ/δ（-/-）小鼠结肠中白细胞群体的分析显示，与WT小鼠相比，巨噬细胞和中性粒细胞募集较少。此外，移植了p38 γ/δ（-/-）骨髓的WT嵌合小鼠比移植了WT骨髓的WT小鼠具有更少的肿瘤，而与移植了p38 γ/δ（-/-）骨髓的p38 γ/δ（-/-）小鼠相比，移植了WT骨髓的p38 γ/δ（-/-）嵌合小鼠中的肿瘤数量显著增加。总之，我们的研究结果表明，p38 γ和p38 δ是通过调节造血细胞对损伤的反应而形成结肠炎相关结肠癌的核心，并验证了p38 γ和p38 δ作为癌症治疗的潜在靶点。(C)2014年AACR。
p38 MAPK signaling has been implicated in the regulation of processes leading to cancer development and progression. Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association remains largely unknown. The related p38 alpha MAPK (MAPK14) proteins p38 gamma (MAPK12) and p38 delta (MAPK13) were recently shown to modulate the immune response, although their role in tumorigenesis remains controversial and their function in inflammation-associated cancer has not been studied. We analyzed the role of p38 gamma and p38 delta in colon cancer associated to colitis using the azoxymethane/dextran sodium sulphate (AOM/DSS) colitis-associated colon cancer model in wild-type (WT), p38 gamma-, p38 delta-, and p38 gamma/delta-deficient (p38 gamma/delta(-/-)) mice. We found that p38 gamma/delta deficiency significantly decreased tumor formation, in parallel with a decrease in proinflammatory cytokine and chemokine production. Analysis of leukocyte populations in p38 gamma/delta(-/-) mouse colon showed less macrophage and neutrophil recruitment than in WT mice. Furthermore, WT chimeric mice with transplanted p38 gamma/delta(-/-) bone marrow had less tumors than WT mice transplanted with WT bone marrow, whereas tumor number was significantly increased in p38 gamma/delta(-/-) chimeric mice with WT bone marrow compared with p38 gamma/delta(-/-) mice transplanted with p38 gamma/delta(-/-) bone marrow. Together, our results establish that p38 gamma and p38 delta are central to colitis-associated colon cancer formation through regulation of hematopoietic cell response to injury, and validate p38 gamma and p38 delta as potential targets for cancer therapy. (C) 2014 AACR.