Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA.
Lab Invest. 2012 Aug;92(8):1203-12. doi: 10.1038/labinvest.2012.83. Epub 2012 May 28.
The transmembrane glycoprotein CD98 regulates integrin signaling that in turn controls cell proliferation and survival. CD98 expression is upregulated in various carcinomas, including colorectal cancer. Recently, by generating gain- and loss-of-function mouse models featuring genetic manipulation of CD98 expression specifically in intestinal epithelial cells (IECs), we have explored the crucial role of CD98 in the regulation of intestinal homeostasis and inflammation-associated tumorigenesis. In the present study, we investigated the contribution of CD98 to intestinal tumorigenesis in Apc(Min/+) mice and the underlying mechanism of action. Mice featuring IEC-specific CD98 overexpression (Tg animals) were crossed with Apc(Min/+) mice, and the characteristics of intestinal adenoma formation were assessed. Compared with Apc(Min/+) mice, Tg/Apc(Min/+) animals exhibited increases in both intestinal tumor incidence and tumor size; these parameters correlated with enhanced proliferation and decreased apoptosis of IECs. IEC-specific CD98 overexpression resulted in increased synthesis of the oncogenic proteins c-myc and cyclin-D1 in Apc(Min/+) mice, independently of the Wnt-APC-β-catenin pathway, suggesting the implication of CD98 overexpression-mediated Erk activation. IEC-specific CD98 overexpression enhanced the production of proinflammatory cytokines and chemokines that are crucial for tumorigenesis. We validated our results in mice exhibiting IEC-specific CD98 downregulation (CD98(flox/+)VillinCre animals). IEC-specific CD98 downregulation efficiently attenuated tumor incidence and growth in Apc(Min/+) mice. The reduction of intestinal tumorigenesis upon IEC-specific CD98 downregulation was caused by the attenuation of IEC proliferation and cytokine/chemokine production. In conclusion, we show that CD98 exerts an oncogenic activity in terms of intestinal tumorigenesis, via an ability to regulate tumor growth and survival.
跨膜糖蛋白 CD98 调节整合素信号转导，进而控制细胞增殖和存活。CD98 的表达在上皮细胞，包括结直肠癌在内的各种癌中上调。最近，通过生成特异性在肠上皮细胞（IEC）中进行 CD98 表达基因操作的增益和缺失功能的小鼠模型，我们探讨了 CD98 在调节肠道稳态和炎症相关肿瘤发生中的关键作用。在本研究中，我们研究了 CD98 对 Apc(Min/+) 小鼠肠道肿瘤发生的贡献及其作用机制。具有 IEC 特异性 CD98 过表达（Tg 动物）的小鼠与 Apc(Min/+) 小鼠杂交，评估肠道腺瘤形成的特征。与 Apc(Min/+) 小鼠相比，Tg/Apc(Min/+) 动物的肠道肿瘤发生率和肿瘤大小均增加；这些参数与 IEC 增殖增强和凋亡减少相关。IEC 特异性 CD98 过表达导致 Apc(Min/+) 小鼠中致癌蛋白 c-myc 和 cyclin-D1 的合成增加，这与 Wnt-APC-β-catenin 途径无关，提示 CD98 过表达介导的 Erk 激活的影响。IEC 特异性 CD98 过表达增强了促炎细胞因子和趋化因子的产生，这些细胞因子和趋化因子对于肿瘤发生至关重要。我们在具有 IEC 特异性 CD98 下调（CD98(flox/+)VillinCre 动物）的小鼠中验证了我们的结果。IEC 特异性 CD98 下调可有效降低 Apc(Min/+) 小鼠的肿瘤发生率和生长。IEC 特异性 CD98 下调降低肠道肿瘤发生是由于 IEC 增殖和细胞因子/趋化因子产生的减弱所致。总之，我们表明 CD98 通过调节肿瘤生长和存活来发挥其在肠道肿瘤发生中的致癌活性。
