MACC1 Induces Tumor Progression in Transgenic Mice and Colorectal Cancer Patients via Increased Pluripotency Markers Nanog and Oct4
MACC1 Induces Tumor Progression in Transgenic Mice and Colorectal Cancer Patients via Increased Pluripotency Markers Nanog and Oct4
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DOI：
10.1158/1078-0432.ccr-15-1425
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发表时间：
2016-06-01
影响因子：
11.5
通讯作者：
Stein, Ulrike
中科院分区：
文献类型：
--
作者：
Lemos, Clara;Hardt, Markus S.;Stein, Ulrike
目的：我们先前已确定MACC1基因是结直肠癌转移和患者生存的一个强有力的预后生物标志物。在此，我们首次报道了MACC1转基因小鼠模型的建立。实验设计：我们建立了由绒毛蛋白启动子驱动的MACC1转基因过表达的小鼠，并将其与ApcMin小鼠(VILMACC1APC(Min))杂交。结果：VIL-MACC1Apc(Min)小鼠显著增加了肿瘤总数(P=0.0056)。这在较大的肿瘤中尤其明显(直径为3毫米；P=0.0024)。详细的组织病理学分析表明，VIL-MACC1/APC(Min)小鼠的肿瘤具有更高的侵袭性表型，因此其生存时间显著低于APC(Min)小鼠(P=0.03)。分子分析显示，在VIL-MACC1/APC(Min)小鼠的肿瘤中，Wnt和多能性信号增强。具体地说，我们观察到与APC(Min)对照组相比，这些肿瘤中多能标志物Oct4和Nanog的表达显著上调。最后，我们还可以在体外验证Oct4和Nanog在60例结直肠癌患者的队列中受MACc1调控，并与MACc1水平强烈相关(分别为r=0.7005和r=0.6808；P>；0.0001和P>；0.0002)。结论：我们提供了MACc1诱导结直肠癌肿瘤进展的原理证据，至少部分是通过新发现的MACc1/Nanog/Oct4轴起作用的。这些发现可能对设计新的治疗干预策略以限制肿瘤进展具有重要意义。(C)2016年AACR。
Purpose: We have previously identified the gene MACC1 as a strong prognostic biomarker for colorectal cancer metastasis and patient survival. Here, we report for the first time the generation of transgenic mouse models for MACC1.Experimental Design: We generated mice with transgenic overexpression of MACC1 in the intestine driven by the villin promoter (vil-MACC1) and crossed them with ApcMin mice (vilMACC1/Apc(Min)).Results: vil-MACC1/Apc(Min) mice significantly increased the total number of tumors (P = 0.0056). This was particularly apparent in large tumors (>= 3-mm diameter; P = 0.0024). A detailed histopathologic analysis of these lesions demonstrated that the tumors from the vil-MACC1/Apc(Min) mice had a more invasive phenotype and, consequently, showed a significantly reduced survival time than Apc(Min) mice (P = 0.03). Molecular analysis revealed an increased Wnt and pluripotency signaling in the tumors of vil-MACC1/Apc(Min) mice. Specifically, we observed a prominent upregulation of the pluripotency markers Oct4 and Nanog in these tumors compared with Apc(Min) controls. Finally, we could also validate that Oct4 and Nanog are regulated by MACC1 in vitro and strongly correlate with MACC1 levels in a cohort of 60 tumors of colorectal cancer patients (r = 0.7005 and r = 0.6808, respectively; P > 0.0001 and P > 0.0002, respectively).Conclusions: We provide proof of principle that MACC1-induced tumor progression in colorectal cancer acts, at least in part, via the newly discovered MACC1/Nanog/Oct4 axis. These findings might have important implications for the design of novel therapeutic intervention strategies to restrict tumor progression. (C) 2016 AACR.