Transgenic Expression of Human Lysophosphatidic Acid Receptor LPA2 in Mouse Intestinal Epithelial Cells Induces Intestinal Dysplasia.
Transgenic Expression of Human Lysophosphatidic Acid Receptor LPA2 in Mouse Intestinal Epithelial Cells Induces Intestinal Dysplasia.
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DOI：
10.1371/journal.pone.0154527
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yun CC
中科院分区：
文献类型：
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作者：
Yoshida M;He P;Yun CC
溶血磷脂酸（LPA）作用于LPA2受体介导多种与肿瘤发生相关的病理作用。在结直肠癌啮齿动物模型中，缺乏LPA2可减缓肿瘤进展，但是否单独过表达LPA2可导致肠道恶性转化尚未研究。在这项研究中，我们在绒毛蛋白启动子的控制下，在肠上皮细胞（IECs）中表达了人LPA2。不到4%的f1代小鼠有转基因（TG）人LPA2的种系传播；因此，72个基因型中只有3只F1小鼠有TG表达。这些TG小鼠出现贫血和便血，并在出生后不久死亡。TG小鼠的体型比同年龄、同性别的野生型小鼠小。形态学分析显示TG - LPA2结肠IECs过度增殖，导致结肠隐窝深度增加。令人惊讶的是，TG小肠绒毛变钝，IEC增殖和不典型增生减少。在肠和结肠中，LPA2的TG表达损害了终末上皮的分化，与上皮发育不良一致。此外，我们发现在方正小鼠肠道中观察到上皮异常增生，LPA2过表达与上皮异常增生有关。目前的研究表明，仅LPA2过表达可导致肠道发育不良。
Lysophosphatidic acid (LPA) acts on LPA2 receptor to mediate multiple pathological effects that are associated with tumorigenesis. The absence of LPA2 attenuates tumor progression in rodent models of colorectal cancer, but whether overexpression of LPA2 alone can lead to malignant transformation in the intestinal tract has not been studied. In this study, we expressed human LPA2 in intestinal epithelial cells (IECs) under control of the villin promoter. Less than 4% of F1-generation mice had germline transmission of transgenic (TG) human LPA2; as such only 3 F1 mice out of 72 genotyped had TG expression. These TG mice appeared anemic with hematochezia and died shortly after birth. TG mice were smaller in size compared with the wild type mouse of the same age and sex. Morphological analysis showed that TG LPA2 colon had hyper-proliferation of IECs resulting in increased colonic crypt depth. Surprisingly, TG small intestine had villus blunting and decreased IEC proliferation and dysplasia. In both intestine and colon, TG expression of LPA2 compromised the terminal epithelial differentiation, consistent with epithelial dysplasia. Furthermore, we showed that epithelial dysplasia was observed in founder mouse intestine, correlating LPA2 overexpression with epithelial dysplasia. The current study demonstrates that overexpression of LPA2 alone can lead to intestinal dysplasia.