Bae Jeong A, Kho Dhong Hyo, Sun Eun Gene, Ko Yoo-Seung, Yoon Somy, Lee Kyung Hwa, Ahn Kyu Youn, Lee Jae Hyuk, Joo Young Eun, Chung Ik Joo, Lee Sug Hyung, Kim Hangun, Kim Kyung Keun
Medical Research Center for Gene Regulation, Chonnam National University Medical School, Kwangju, Korea.
Department of Pathology, Chonnam National University Medical School, Kwangju, Korea.
Clin Cancer Res. 2016 Mar 1;22(5):1284-94. doi: 10.1158/1078-0432.CCR-15-0306. Epub 2015 Nov 2.
The molecular events in the malignant progression of colon adenoma after loss of adenomatous polyposis coli (APC) are not fully understood. KITENIN (KAI1 C-terminal interacting tetraspanin) increases the invasiveness of colorectal cancer cells, and we identified a novel EGFR-independent oncogenic signal of EGF that works under coexpressed KITENIN and ErbB4. Here we tested whether elevated KITENIN and ErbB4 contribute to further progression of intestinal adenoma following APC loss.
The intestinal tissues of villin-KITENIN transgenic mice in which villin-driven KITENIN expression induces increased c-Jun expression exhibit mild epithelial cell proliferation but no epithelial lineage changes compared with those of nontransgenic mice. Among the four ErbB4 isoforms, JM-a/CYT-2 and JM-b/CYT-2 exhibited the highest AP-1 activity when cells coexpressing KITENIN and each isoform were stimulated by EGF. Interestingly, predominant overexpression of the ErB4-CYT-2 mRNA as well as increased EGFR expression were observed in intestinal adenoma of APC(min/+) mice, which makes the microenvironment of activated EGF signaling. When we crossed villin-KITENIN mice with APC(min/+) mice, intestinal tumor tissues in the crossed mice showed the characteristics of early-stage invading adenocarcinoma. In patients with colorectal cancer, ErbB4-CYT-2 mRNA expression was significantly greater in tumor tissues than in normal adjacent tissues, but no significant differences in tumor tissue expression were found between different colorectal cancer stages. Furthermore, the mRNA expression of KITENIN and that of ErbB4-CYT-2 were positively correlated in human colorectal cancer tissue.
Elevated coexpression of KITENIN and ErbB4-CYT-2 promotes the transition of colon adenoma to adenocarcinoma within an APC loss-associated tumor microenvironment.
腺瘤性息肉病大肠杆菌（APC）缺失后结肠腺瘤恶性进展中的分子事件尚未完全明确。KITENIN（KAI1 C末端相互作用四跨膜蛋白）可增加结肠直肠癌细胞的侵袭性，并且我们鉴定出一种在共表达的KITENIN和ErbB4作用下发挥作用的新型不依赖表皮生长因子受体（EGFR）的表皮生长因子（EGF）致癌信号。在此，我们测试了KITENIN和ErbB4水平升高是否会导致APC缺失后肠道腺瘤的进一步进展。
与非转基因小鼠相比，在由绒毛蛋白驱动KITENIN表达诱导c-Jun表达增加的绒毛蛋白-KITENIN转基因小鼠的肠道组织中，观察到轻度上皮细胞增殖，但无上皮谱系变化。在四种ErbB4亚型中，当共表达KITENIN和各亚型的细胞受到EGF刺激时，JM-a/CYT-2和JM-b/CYT-2表现出最高的活化蛋白-1（AP-1）活性。有趣的是，在APC（min/+）小鼠的肠道腺瘤中观察到ErB4-CYT-2 mRNA的主要过表达以及EGFR表达增加，这构成了活化的EGF信号微环境。当我们将绒毛蛋白-KITENIN小鼠与APC（min/+）小鼠杂交时，杂交小鼠的肠道肿瘤组织表现出早期侵袭性腺癌的特征。在结直肠癌患者中，肿瘤组织中ErbB4-CYT-2 mRNA表达明显高于相邻正常组织，但不同结直肠癌阶段的肿瘤组织表达无显著差异。此外，在人结直肠癌组织中，KITENIN的mRNA表达与ErbB4-CYT-2的mRNA表达呈正相关。
KITENIN和ErbB4-CYT-2的共表达升高促进了APC缺失相关肿瘤微环境中结肠腺瘤向腺癌的转变。
