An A13 repeat within the 3'-untranslated region of epidermal growth factor receptor (EGFR) is frequently mutated in microsatellite instability colon cancers and is associated with increased EGFR expression.
An A13 repeat within the 3'-untranslated region of epidermal growth factor receptor (EGFR) is frequently mutated in microsatellite instability colon cancers and is associated with increased EGFR expression.
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DOI：
10.1158/0008-5472.can-09-0986
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发表时间：
2009-10-01
期刊：
影响因子：
11.2
通讯作者：
Mariadason JM
中科院分区：
文献类型：
--
作者：
Yuan Z;Shin J;Wilson A;Goel S;Ling YH;Ahmed N;Dopeso H;Jhawer M;Nasser S;Montagna C;Fordyce K;Augenlicht LH;Aaltonen LA;Arango D;Weber TK;Mariadason JM
具有微卫星不稳定性（MSI）的结直肠癌具有与微卫星稳定性（MSS）CRC不同的临床、病理、遗传和表观遗传特征。对一组结肠癌细胞系中EGFR mRNA和蛋白质表达水平的检查发现，多个具有微卫星不稳定性的细胞系中EGFR表达强烈。虽然没有观察到EGFR过表达与内含子1中CA二核苷酸重复序列长度之间的关系，但在64%的MSI细胞系和69%的MSI结肠肿瘤中鉴定了EGFR基因3 '-UTR内的变体A13/A14重复序列，其通过单核苷酸或二核苷酸腺苷缺失而突变。利用Tet-Off系统，我们证明了这种突变增加了结肠癌细胞中EGFR mRNA的稳定性，为MSI结肠癌细胞系中EGFR过表达提供了机制基础。为了确定这种突变是MSI结肠癌中的驱动事件还是旁观事件，我们检查了EGFR 3 'UTR突变MSI细胞系中EGFR的药理学和分子抑制的作用。具有EGFR 3 'UTR突变并且对于Ras/BRAF和PIK 3CA/PTEN途径中的下游信号传导介质是野生型的细胞系对EGFR抑制敏感，而在这些信号传导介质中具有突变的那些细胞系则不敏感。此外，在下游信号传导介质的野生型细胞系中，具有EGFR 3 'UTR突变的那些细胞系比EGFR 3' UTR WT细胞对EGFR抑制更敏感，表明该突变为MSI结肠肿瘤的该子集提供了生长优势。
Colorectal cancers with microsatellite instability (MSI) have clinical, pathological, genetic, and epigenetic features distinct from microsatellite stable (MSS) CRC. Examination of EGFR mRNA and protein expression levels in a panel of colon cancer cell lines identified strong expression of EGFR in multiple cell lines with microsatellite instability. While no relationship between EGFR overexpression and the length of a CA dinucleotide repeat in intron 1 was observed, a variant A13/A14 repeat sequence within the 3’-UTR of the EGFR gene was identified which was mutated by either mono or dinucleotide adenosine deletions in 64% of MSI cell lines, and 69% of MSI colon tumors. Utilizing a Tet-Off system we demonstrate that this mutation increases EGFR mRNA stability in colon cancer cells, providing a mechanistic basis for EGFR over-expression in MSI colon cancer cell lines. To determine whether this mutation is a driver or a bystander event in MSI colon cancer, we examined the effect of pharmacological and molecular inhibition of EGFR in EGFR 3’UTR mutant MSI cell lines. Cell lines with an EGFR 3’UTR mutation and which were wild type for downstream signaling mediators in the Ras/BRAF and PIK3CA/PTEN pathways were sensitive to EGFR inhibition, while those harboring mutations in these signaling mediators were not. Furthermore, in cell lines wild type for downstream signaling mediators, those with EGFR 3’UTR mutations were more sensitive to EGFR inhibition than EGFR 3’UTR WT cells, suggesting this mutation provides a growth advantage to this subset of MSI colon tumors.