Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium
Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium
复制标题
DOI：
10.1172/jci36435
复制
发表时间：
2009-09-01
影响因子：
15.9
通讯作者：
Threadgill, David W.
中科院分区：
文献类型：
--
作者：
Lee, Daekee;Yu, Ming;Threadgill, David W.
EGFR或密切相关的受体ERBB 2的药理学阻断在临床上对结直肠癌具有适度的疗效。尽管已知EGFR/ERBB家族的假激酶成员ERBB 3的上调有助于其他癌症中的EGFR抑制剂抗性，但其在正常和恶性肠上皮中的功能尚未确定。我们在这里已经表明，小鼠的肠上皮细胞与Erbb 3的精氨酸特异性基因消融表现出没有细胞学异常，但表现出ERBB 4的表达和敏感性肠损伤的损失。相比之下，在结肠癌的Apc（Min）小鼠模型中，精氨酸特异性Erbb 3消融导致几乎完全不存在肠肿瘤。与缺乏ERBB 3的非转化上皮不同，缺乏ERBB 3的肠肿瘤具有减少的PI 3 K/AKT信号传导，这通过肿瘤特异性增加半胱天冬酶-3介导的凋亡导致肿瘤发生的减弱。与表明ERBB 3-ERBB 4异二聚体有助于结肠癌存活的小鼠数据一致，在KRAS突变体人结肠癌细胞系中实验诱导的ERBB 3损失与ERBB 4表达损失相关，并且ERBB 3或ERBB 4的siRNA敲低导致细胞凋亡水平升高。这些结果表明，ERBB 3假激酶在支持肠道肿瘤发生中具有重要作用，并表明ERBB 3可能是治疗结直肠癌的有希望的靶点。
Pharmacologic blockade of EGFR or the closely related receptor ERBB2 has modest efficacy against colorectal cancers in the clinic. Although the upregulation of ERBB3, a pseudo-kinase member of the EGFR/ERBB family, is known to contribute to EGFR inhibitor resistance in other cancers, its functions in normal and malignant intestinal epithelium have not been defined. We have shown here that the intestinal epithelium of mice with intestine-specific genetic ablation of Erbb3 exhibits no cytological abnormalities but does exhibit loss of expression of ERBB4 and sensitivity to intestinal damage. By contrast, intestine-specific Erbb3 ablation resulted in almost complete absence of intestinal tumors in the Apc(Min) mouse model of colon cancer. Unlike nontransformed epithelium lacking ERBB3, intestinal tumors lacking ERBB3 had reduced PI3K/AKT signaling, which led to attenuation of tumorigenesis via a tumor-specific increase in caspase-3-mediated apoptosis. Consistent with the mouse data, which suggest that ERBB3-ERBB4 heterodimers contribute to colon cancer survival, experimentally induced loss of ERBB3 in a KRAS mutant human colon cancer cell line was associated with loss of ERBB4 expression, and siRNA knockdown of either ERBB3 or ERBB4 resulted in elevated levels of apoptosis. These results indicate that the ERBB3 pseudo-kinase has essential roles in supporting intestinal tumorigenesis and suggest that ERBB3 may be a promising target for the treatment of colorectal cancers.