Lee Daekee, Yu Ming, Lee Eunjung, Kim Hyunok, Yang Yanan, Kim Kyoungmi, Pannicia Christina, Kurie Jonathan M, Threadgill David W
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
J Clin Invest. 2009 Sep;119(9):2702-13. doi: 10.1172/JCI36435. Epub 2009 Aug 17.
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 ApcMin 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.
在临床上，对表皮生长因子受体（EGFR）或与之密切相关的受体ERBB2进行药物阻断，对结直肠癌的疗效有限。虽然已知EGFR/ERBB家族的假激酶成员ERBB3的上调会导致其他癌症对EGFR抑制剂产生耐药性，但其在正常和恶性肠上皮中的功能尚未明确。我们在此表明，肠道特异性基因敲除Erbb3的小鼠肠上皮没有细胞学异常，但确实表现出ERBB4表达缺失以及对肠道损伤敏感。相比之下，在结肠癌的ApcMin小鼠模型中，肠道特异性敲除Erbb3几乎完全没有肠道肿瘤。与缺乏ERBB3的未转化上皮不同，缺乏ERBB3的肠道肿瘤PI3K/AKT信号传导减少，这通过caspase-3介导的凋亡在肿瘤特异性增加而导致肿瘤发生减弱。与小鼠数据一致，表明ERBB3-ERBB4异二聚体有助于结肠癌存活，在KRAS突变的人结肠癌细胞系中实验性诱导的ERBB3缺失与ERBB4表达缺失相关，并且ERBB3或ERBB4的小干扰RNA敲低导致凋亡水平升高。这些结果表明，ERBB3假激酶在支持肠道肿瘤发生中起重要作用，并提示ERBB3可能是治疗结直肠癌的一个有前景的靶点。
