Does Retinol Prevent Colorectal Cancer Metastasis?

远处结直肠癌转移患者的5年生存率为10%。维甲酸已经 显示出减少癌细胞生长，但它们在转移中的作用很少受到关注。我们的长期 目的是了解膳食维生素A（视黄醇）如何抑制结直肠癌进展。我们有 显示视黄醇降低了抗视黄酸的结肠癌细胞的侵袭，和Akt磷酸化， β-连环蛋白和基质金属蛋白酶7（MMP 7）水平。我们的目标是（1）确定维生素 A抑制体内转移和（2）阐明视黄醇用于抑制侵袭的信号通路。要求1 将使用脾内注射人结肠癌细胞的裸鼠来诱导肝转移。二十 小鼠将消耗维生素A充足的对照饮食。额外的小鼠将消耗含有以下成分的饮食： 将维生素A的量增加至200，000 ILJ/kg饮食。肝转移的数量和大小将 测定我们希望补充维生素A能减少转移灶的数量和大小。目标2将 确定视黄醇减少侵袭的信号通路。视黄醇降低Akt磷酸化 而组成型活性Akt阻断了视黄醇对侵袭的作用。Akt磷酸化减少导致 GSKSbeta活性增加。GSKSbeta靶向β-连环蛋白进行蛋白体降解。多余核 β-连环蛋白增加有利于转移的基因（例如MMP 7）的表达。活性成分， Akt的显性负性形式，以及过表达或siRNA技术来改变GSKS β和β- 连环蛋白水平将决定每种蛋白质对细胞侵袭、生长和MMP 7 mRNA水平的影响。到 连接目标1和2将在从目标1中使用的小鼠切除的肿瘤中测量每种蛋白质。我们预计 视黄醇将降低Akt和GSKS β磷酸化以及β-连环蛋白和MMP 7水平， 体外和体内。本申请的目标与NCI和PA# 04-108的目标一致。 具体来说，我们将研究营养素维生素A预防结肠癌转移的能力， 确定视黄醇用于减少转移的信号通路。 结肠癌转移的存活率非常低。维生素A降低结肠癌的能力 在实验室实验中，细胞移动并侵入组织。这个应用程序将确定维生素A是否可以 减少小鼠的转移和受维生素A影响的调节转移的蛋白质。

The five-year survival rate for patients with distant colorectal cancer metastasis is 10%. Retinoids have been shown to decrease cancer cell growth, but their role in metastasis has received little attention. Our long-term objective is to understand how dietary vitamin A (retinol) inhibits colorectal cancer progression. We have shown that retinol decreases retinoic acid-resistant colon cancer cell invasion, and Akt phosphorylation, beta-catenin, and matrixmetalloproteinase 7 (MMP7) levels in vitro. Our aims are (1) to determine if vitamin A inhibits metastasis in vivo and (2) to elucidate the signaling pathway retinol uses to inhibit invasion. Aim 1 will use nude mice injected intrasplenically with human colon cancer cells to induce liver metastases. Twenty mice will consume a vitamin A sufficient control diet. Additional mice will consume a diets containing increasing amounts of vitamin A up to 200,000 ILJ/kg diet. Hepatic metastases number and size will be determined. We expect vitamin A supplementation to decrease metastases number and size. Aim 2 will determine the signaling pathway by which retinol decreases invasion. Retinol decreases Akt phosphorylation and constitutively active Akt blocks the effect of retinol on invasion. Decreased Akt phosphorylation results in increased GSKSbeta activity. GSKSbeta targets beta-catenin for proteosomal degradation. Excess nuclear beta-catenin increases the expression of genes favoring metastasis (e.g.MMP7). Constitutively active and dominant negative forms of Akt, and overexpression or siRNA technology to alter GSKSbeta and beta- catenin levels will determine the effect of each protein on cell invasion, growth, and MMP7 mRNA levels. To link Aim 1 and 2 each protein will be measured in tumors excised from the mice used in Aim 1. We expect that retinol will decrease Akt and GSKSbeta phosphorylation as well as beta-catenin, and MMP7 levels in vitro and in vivo. The goals of this application are consistent with those of the NCI and PA# 04-108. Specifically, we will examine the ability of a nutrient, vitamin A, to prevent colon cancer metastasis and determine the signaling pathway retinol uses to decrease metastasis. The survival rate from colon cancer metastasis is very low. Vitamin A decreases the ability of colon cancer cells to move and invade tissues in laboratory experiments. This application will determine if vitamin A can decrease metastasis in mice and the proteins affected by vitamin A that regulate metastasis.