Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas
Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas
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DOI：
10.1172/jci40728
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发表时间：
2010-03-01
影响因子：
15.9
通讯作者：
Goldenring, James R.
中科院分区：
文献类型：
--
作者：
Nam, Ki Taek;Lee, Hyuk-Joon;Goldenring, James R.
上皮细胞的转化与细胞极性的丧失有关，这包括细胞形态的改变以及质膜蛋白补体的变化。Rab蛋白调节向细胞膜的极化运输，因此代表这种肿瘤转变的潜在调节剂。在这里，我们已经证明了Rab 25在小鼠和人类肠道肿瘤中的肿瘤抑制功能。人结直肠腺癌表现出Rab 25表达的降低，与分期无关，Rab 25表达水平降低与患者生存期显著缩短相关。在野生型小鼠中，Rab 25在肠隐窝增殖细胞的腔细胞中强烈表达。虽然Rab 25缺陷型小鼠没有表现出大体病理学，但与亲本Apc（Min/+）小鼠相比，与Rab 25缺陷型背景杂交的Apc（Min/+）小鼠显示肠息肉增加4倍，结肠肿瘤增加2倍。Rab 25缺陷小鼠绒毛细胞侧膜中的β 1整合素染色减少，并且这种模式在与Apc（Min/+）背景杂交的Rab 25缺陷小鼠中加重。此外，Smad 3（+/-）小鼠杂交到Rab 25缺陷的背景下，结肠肿瘤形成显着增加。综上所述，这些结果表明Rab 25可能通过调节蛋白质运输到细胞表面而在肠上皮细胞中起肿瘤抑制剂的作用。
Transformation of epithelial cells is associated with loss of cell polarity, which includes alterations in cell morphology as well as changes in the complement of plasma membrane proteins. Rab proteins regulate polarized trafficking to the cell membrane and therefore represent potential regulators of this neoplastic transition. Here we have demonstrated a tumor suppressor function for Rab25 in intestinal neoplasia in both mice and humans. Human colorectal adenocarcinomas exhibited reductions in Rab25 expression independent of stage, with lower Rab25 expression levels correlating with substantially shorter patient survival. In wild-type mice, Rab25 was strongly expressed in cells luminal to the proliferating cells of intestinal crypts. While Rab25-deficient mice did not exhibit gross pathology, Apc(Min/+) mice crossed onto a Rab25-deficient background showed a 4-fold increase in intestinal polyps and a 2-fold increase in colonic tumors compared with parental Apc(Min/+) mice. Rab25-deficient mice had decreased beta(1) integrin staining in the lateral membranes of villus cells, and this pattern was accentuated in Rab25-deficient mice crossed onto the Apc(Min/+) background. Additionally, Smad3(+/-)mice crossed onto a Rab25-deficient background demonstrated a marked increase in colonic tumor formation. Taken together, these results suggest that Rab25 may function as a tumor suppressor in intestinal epithelial cells through regulation of protein trafficking to the cell surface.