Epithelial-Specific Deletion of 11β-HSD2 Hinders Apcmin/+ Mouse Tumorigenesis
Epithelial-Specific Deletion of 11β-HSD2 Hinders Apcmin/+ Mouse Tumorigenesis
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DOI：
10.1158/1541-7786.mcr-13-0084-t
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发表时间：
2013-09-01
影响因子：
5.2
通讯作者：
Zhang, Ming-Zhi
中科院分区：
文献类型：
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作者：
Jiang, Li;Yang, Shilin;Zhang, Ming-Zhi
环氧合酶-2（考克斯-2）衍生的前列腺素E2（PGE 2）促进结直肠肿瘤的发生。糖皮质激素是内源性和有效的考克斯-2抑制剂，其局部作用通过II型11 β-羟基类固醇脱氢酶（11 β-HSD 2）介导的代谢下调。以前，据报道，11 β-HSD 2在人结肠和Apc（min/+）小鼠肠腺瘤中增加，并且与增加的考克斯-2相关，并且11 β-HSD 2抑制抑制考克斯-2途径并减少肿瘤发生。因为11 β-HSD 2在Apc（min/+）小鼠肠腺瘤基质和上皮细胞中表达，所以在肠上皮细胞中选择性缺失11 β-HSD 2（Vil-Cre-HSD 2（-/-）Apc（min/+））产生Apc（min/+）小鼠。肠上皮细胞中11 β-HSD 2的缺失导致Apc（min/+）小鼠肠肿瘤发生的显著抑制。免疫染色显示腺瘤上皮中11 β-HSD 2和考克斯-2表达减少，而Vil-Cre-HSD 2（-/-）Apc（min/+）小鼠中基质考克斯-2表达完整。在Vil-Cre-HSD 2（-/-）Apc（min/+）小鼠肠腺瘤中，p53和p21 mRNA和蛋白均增加，同时pRb降低，表明糖皮质激素介导的G1期阻滞。进一步的研究表明，REDD 1（在发育和DNA损伤反应中受调节1），一种抑制mTOR信号传导的新型应激诱导基因，增加了，而mTOR信号传导途径受到抑制。因此，在Vil-Cre-HSD 2（-/-）Apc（min/+）小鼠中，上皮细胞11 β-HSD 2缺陷导致肿瘤细胞内活性糖皮质激素增加导致考克斯-2表达减弱、细胞周期停滞增加和mTOR信号传导抑制，从而抑制腺瘤的发生和生长。(C)2013年AACR。
Cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) promotes colorectal tumorigenesis. Glucocorticoids are endogenous and potent COX-2 inhibitors, and their local actions are downregulated by 11 beta-hydroxysteroid dehydrogenase type II (11 beta-HSD2)-mediated metabolism. Previously, it was reported that 11 beta-HSD2 is increased in human colonic and Apc(min/+) mouse intestinal adenomas and correlated with increased COX-2, and 11 beta-HSD2 inhibition suppressed the COX-2 pathway and decreased tumorigenesis. Because 11 beta-HSD2 is expressed in Apc(min/+) mouse intestinal adenoma stromal and epithelial cells, Apc(min/+) mice were generated with selective deletion of 11 beta-HSD2 in intestinal epithelial cells (Vil-Cre-HSD2(-/-) Apc(min/+)). Deletion of 11 beta-HSD2 in intestinal epithelia led to marked inhibition of Apc(min/+) mouse intestinal tumorigenesis. Immunostaining indicated decreased 11 beta-HSD2 and COX-2 expression in adenoma epithelia, whereas stromal COX-2 expression was intact in Vil-Cre-HSD2(-/-) Apc(min/+) mice. In Vil-Cre-HSD2(-/-) Apc(min/+) mouse intestinal adenomas, both p53 and p21 mRNA and protein were increased, with a concomitant decrease in pRb, indicating glucocorticoid-mediated G1-arrest. Further study revealed that REDD1 (regulated in development and DNA damage responses 1), a novel stress-induced gene that inhibits mTOR signaling, was increased, whereas the mTOR signaling pathway was inhibited. Therefore, in Vil-Cre-HSD2(-/-) Apc(min/+) mice, epithelial cell 11 beta-HSD2 deficiency leads to inhibition of adenoma initiation and growth by attenuation of COX-2 expression, increased cell-cycle arrest, and inhibition of mTOR signaling as a result of increased tumor intracellular active glucocorticoids. (C) 2013 AACR.