Department of Internal Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
Carcinogenesis. 2013 Sep;34(9):2109-18. doi: 10.1093/carcin/bgt142. Epub 2013 May 2.
Caveolin-1 (Cav1), a scaffold protein of membrane caveolae and coactivator of peroxisome proliferator-activated receptor gamma (PPARg), inhibits oncogenic signaling through Ras and wingless. However, the in vivo role of Cav1 in colorectal cancer (CRC) remained unknown. To test whether loss of Cav1 accelerates tumorigenesis, we generated a novel mouse model of CRC by crossing C57BL/6 Apc(min/+) with B6129 Cav1 knockout (Cav1-/-) mice. Apc(min/+) Cav1-/- mice developed large, microinvasive and vascularized intraepithelial adenocarcinomas in the distal colon and rectum with higher incidence than Apc(min/+) Cav1+/- and Apc(min/+) Cav1+/+ littermates. Intratumoral gene signatures related to Ras and wingless signaling were elevated, nuclear localization of PPARg protein and expression of PPARg-target genes were reduced independently of Cav1. The PPARg-agonist rosiglitazone prevented tumor formation in mice irrespectively of the Cav1 status and upregulated expression of the Ras-inhibitory protein docking protein-1. Thus, codeficiency of Cav1 and adenomatous polyposis coli facilitated formation of CRC, and activation of PPARg may offer novel strategies for treatment of CRC.
窖蛋白-1（Cav1）是质膜窖小窝的支架蛋白，也是过氧化物酶体增殖物激活受体γ（PPARg）的共激活因子，通过 Ras 和 Wnt 抑制致癌信号。然而，Cav1 在结直肠癌（CRC）中的体内作用尚不清楚。为了测试 Cav1 的缺失是否会加速肿瘤发生，我们通过将 C57BL/6 Apc(min/+)与 B6129 Cav1 敲除（Cav1-/-）小鼠杂交，生成了一种新型 CRC 小鼠模型。Apc(min/+) Cav1-/- 小鼠在远端结肠和直肠中形成了大的、微侵袭性和血管化的上皮内腺癌，其发生率高于 Apc(min/+) Cav1+/-和 Apc(min/+) Cav1+/+同窝仔鼠。与 Ras 和 Wnt 信号相关的肿瘤内基因特征升高，PPARg 蛋白的核定位和 PPARg 靶基因的表达独立于 Cav1 减少。PPARg 激动剂罗格列酮无论 Cav1 状态如何均可预防小鼠肿瘤形成，并上调 Ras 抑制蛋白对接蛋白-1 的表达。因此，Cav1 和腺瘤性结肠息肉病的共缺失促进了 CRC 的形成，而激活 PPARg 可能为 CRC 的治疗提供新策略。
