Medical Research Center for Gene Regulation and Center for Creative Biomedical Scientists; Departments of.
Pathology and.
Clin Cancer Res. 2014 Aug 1;20(15):4115-28. doi: 10.1158/1078-0432.CCR-13-2863. Epub 2014 Jun 3.
EGF-stimulated signaling via EGF receptor (EGFR) is important in colorectal tumorigenesis and drug targeting. However, anti-EGFR therapy is not effective in a subset of patients with colorectal cancer, suggesting that unidentified EGF-stimulated pathways might play roles in colorectal cancer. Previously, we identified KAI1 C-terminal interacting tetraspanin (KITENIN) as a metastasis-enhancing gene and found it to be highly expressed in sporadic colorectal cancer tissues. We recently found that EGF further increases KITENIN-induced elevated AP-1 activity. Here we attempted to clarify this novel EGF-stimulated molecular pathway and its roles in colorectal cancer.
We analyzed how EGF modulates the downstream signaling pathway of oncogenic KITENIN in colorectal cancer cells. Biological alterations following EGF treatment were identified in KITENIN-overexpressed colorectal cancer cells with or without alteration of EGFR activity.
We identified the KITENIN/ErbB4-Dvl2-c-Jun axis as a novel downstream signal of EGF that is switched on under elevated KITENIN conditions in an EGFR-independent manner. This unconventional EGF signal upregulates c-Jun and enhances invasion and anchorage-independent growth of colorectal cancer cells. In addition, tumor tissues from metastatic patients with colorectal cancer who showed initial poor responses to cetuximab/chemotherapy expressed higher levels of KITENIN than did responders to therapy.
Our results highlight the role of an EGFR-independent EGF signal in mediating the invasiveness and tumorigenesis of colorectal cancer cells. This unconventional pathway might be related to the limited clinical efficacy of anti-EGFR agents in a subset of patients with colorectal cancer.
表皮生长因子受体（EGFR）刺激的信号转导在结直肠肿瘤发生和药物靶向中非常重要。然而，抗 EGFR 治疗在一部分结直肠癌患者中并不有效，这表明未被识别的表皮生长因子刺激途径可能在结直肠癌中发挥作用。先前，我们鉴定了 KAI1 端相互作用的四跨膜蛋白（KITENIN）作为一个促进转移的基因，并发现其在散发性结直肠癌组织中高度表达。我们最近发现，表皮生长因子进一步增加了 KITENIN 诱导的 AP-1 活性升高。在这里，我们试图阐明这种新的表皮生长因子刺激的分子途径及其在结直肠癌中的作用。
我们分析了表皮生长因子如何调节结直肠癌细胞中致癌 KITENIN 的下游信号通路。在 KITENIN 过表达的结直肠癌细胞中，我们在改变 EGFR 活性或不改变 EGFR 活性的情况下，分析了表皮生长因子处理后的生物学变化。
我们鉴定了 KITENIN/ErbB4-Dvl2-c-Jun 轴作为一种新的下游信号，在 KITENIN 水平升高的情况下，它以 EGFR 非依赖性的方式被激活。这种非传统的表皮生长因子信号上调了 c-Jun，增强了结直肠癌细胞的侵袭和无锚定生长。此外，来自转移性结直肠癌患者的肿瘤组织，这些患者在初始时对西妥昔单抗/化疗反应不佳，其 KITENIN 表达水平高于对治疗有反应的患者。
我们的研究结果强调了 EGFR 非依赖性表皮生长因子信号在介导结直肠癌细胞侵袭和肿瘤发生中的作用。这种非传统途径可能与抗 EGFR 药物在一部分结直肠癌患者中的临床疗效有限有关。
