ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression.
ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression.
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DOI：
10.1158/0008-5472.can-11-1262
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发表时间：
2011-11-15
期刊：
影响因子：
11.2
通讯作者：
DuBois RN
中科院分区：
文献类型：
--
作者：
Kim SH;Park YY;Kim SW;Lee JS;Wang D;DuBois RN
前列腺素 E2 (PGE2) 是结直肠癌中发现的最丰富的 COX-2 衍生前列腺素，可通过多种信号通路促进肿瘤细胞增殖和存活。然而，PGE2 在肿瘤缺氧中的作用尚不清楚。在这里，我们展示了 PGE2 和缺氧对增强 ANGPTL4 表达的协同作用，并且 ANGPTL4 的升高促进结直肠癌的生长。在缺氧条件下，PGE2 在 mRNA 和蛋白质水平上诱导 ANGPTL4 表达。此外，缺氧会诱导一种 PGE2 受体，即 EP1。在缺氧条件下，EP1 的激活会增强 ANGPTL4 的表达，而其拮抗剂对 EP1 的阻断会抑制 PGE2 对 ANGPTL4 的诱导。重要的是，ANGPTL4 的过度表达可促进体外和体内的细胞增殖和肿瘤生长。此外，使用 ANGPTL4 重组蛋白治疗可通过影响 STAT1 信号传导来增加结直肠癌细胞增殖。 MAPK 和 Src 通路介导 ANGPTL4 诱导的 STAT1 表达和激活。这些结果与人类疾病相关，因为我们发现 ANGPTL4 和 STAT1 的表达在 50% 测试的人类结直肠癌中升高，并且结直肠癌中 COX-2 和 ANGPTL4 以及 STAT1 表达之间存在正相关。总的来说，这些发现表明 PGE2 在缺氧条件下通过 ANGPTL4 促进癌细胞增殖发挥重要作用。
Prostaglandin E2 (PGE2), the most abundant COX-2–derived prostaglandin found in colorectal cancer, promotes tumor cell proliferation and survival via multiple signaling pathways. However, the role of PGE2 in tumor hypoxia is not well understood. Here, we show a synergistic effect of PGE2 and hypoxia on enhancing ANGPTL4 expression and that elevation of ANGPTL4 promotes colorectal cancer growth. PGE2 induces ANGPTL4 expression at both the mRNA and protein levels under hypoxic conditions. Moreover, hypoxia induces one of the PGE2 receptors, namely EP1. Activation of EP1 enhances ANGPTL4 expression, whereas blockage of EP1 by its antagonist inhibits PGE2 induction of ANGPTL4 under hypoxic conditions. Importantly, over-expression of ANGPTL4 promotes cell proliferation and tumor growth in vitro and in vivo. In addition, treatment with ANGPTL4 recombinant protein increases colorectal carcinoma cell proliferation through effects on STAT1 signaling. The MAPK and Src pathways mediate ANGPTL4-induced STAT1 expression and activation. These results are relevant to human disease since we found that the expression of ANGPTL4 and STAT1 are elevated in 50% of human colorectal cancers tested and there is a positive correlation between COX-2 and ANGPTL4 as well STAT1 expression in colorectal carcinomas. Collectively, these findings suggest that PGE2 plays an important role in promoting cancer cell proliferation via ANGPTL4 under hypoxic conditions.