The ZEB2-dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer.
The ZEB2-dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer.
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DOI：
10.1002/1878-0261.12965
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发表时间：
2021-08
影响因子：
6.6
通讯作者：
Sayan AE
中科院分区：
文献类型：
--
作者：
Sreekumar R;Al-Saihati H;Emaduddin M;Moutasim K;Mellone M;Patel A;Kilic S;Cetin M;Erdemir S;Navio MS;Lopez MA;Curtis N;Yagci T;Primrose JN;Price BD;Berx G;Thomas GJ;Tulchinsky E;Mirnezami A;Sayan AE
对辅助化疗的抵抗是结直肠癌（CRC）治疗中的主要临床问题。本研究的目的是阐明上皮间质转化（EMT）诱导蛋白ZEB2在CRC化疗耐药性中的作用，并揭示其潜在机制。我们按照观察性生物标志物研究指南对原发性CRC和匹配的CRC肝转移瘤进行了ZEB2的IHC和临床结局的相关性分析。原发性肿瘤中的ZEB 2表达是接受辅助FOLFOX化疗患者总生存期和无病生存期降低的独立预后标志物。在96%的肝转移瘤中，ZEB 2表达得以保留。ZEB 2依赖性EMT转录程序主要通过上调ERCC1基因和NER途径中的其他组分激活核苷酸切除修复（NER）途径，导致奥沙利铂治疗后CRC细胞活力增强。在一项随机和设盲临床前研究中，使用小鼠原位模型评估，ERCC1过表达CRC细胞在体内对奥沙利铂无应答。我们的研究结果表明，ZEB2是肿瘤对化疗的反应和CRC患者复发风险的生物标志物。我们认为ZEB2‐ERCC1轴是CRC化疗耐药的关键决定因素。在这里，我们发现ZEB2标记的表达降低了原发性和继发性结直肠癌（CRC）的总体和无病生存期。ZEB 2过表达通过转录激活核苷酸切除修复基因ERCC 1和ERCC 4促进体外和体内奥沙利铂耐药性。总的来说，ZEB 2是一种有前途的生物标志物，可预测CRC的治疗反应和转移能力。
Resistance to adjuvant chemotherapy is a major clinical problem in the treatment of colorectal cancer (CRC). The aim of this study was to elucidate the role of an epithelial to mesenchymal transition (EMT)‐inducing protein, ZEB2, in chemoresistance of CRC, and to uncover the underlying mechanism. We performed IHC for ZEB2 and association analyses with clinical outcomes on primary CRC and matched CRC liver metastases in compliance with observational biomarker study guidelines. ZEB2 expression in primary tumours was an independent prognostic marker of reduced overall survival and disease‐free survival in patients who received adjuvant FOLFOX chemotherapy. ZEB2 expression was retained in 96% of liver metastases. The ZEB2‐dependent EMT transcriptional programme activated nucleotide excision repair (NER) pathway largely via upregulation of the ERCC1 gene and other components in NER pathway, leading to enhanced viability of CRC cells upon oxaliplatin treatment. ERCC1‐overexpressing CRC cells did not respond to oxaliplatin in vivo, as assessed using a murine orthotopic model in a randomised and blinded preclinical study. Our findings show that ZEB2 is a biomarker of tumour response to chemotherapy and risk of recurrence in CRC patients. We propose that the ZEB2‐ERCC1 axis is a key determinant of chemoresistance in CRC. Here, we show that the expression of ZEB2 marks reduced overall and disease‐free survival in primary and secondary colorectal cancers (CRCs). ZEB2 overexpression promoted chemoresistance to oxaliplatin in vitro and in vivo by transcriptionally activating nucleotide excision repair genes ERCC1 and ERCC4. Overall ZEB2 is a promising biomarker predicting both therapy response and metastatic ability of CRCs.
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影响因子：
--
作者：
Ahn JY;Lee JS;Min HY;Lee HY
通讯作者：
Lee HY
miR-224表达在结直肠癌转移中的临床和生物学意义。
影响因子：
24.5
作者：
Ling H;Pickard K;Ivan C;Isella C;Ikuo M;Mitter R;Spizzo R;Bullock M;Braicu C;Pileczki V;Vincent K;Pichler M;Stiegelbauer V;Hoefler G;Almeida MI;Hsiao A;Zhang X;Primrose J;Packham G;Liu K;Bojja K;Gafà R;Xiao L;Rossi S;Song JH;Vannini I;Fanini F;Kopetz S;Zweidler-McKay P;Wang X;Ionescu C;Irimie A;Fabbri M;Lanza G;Hamilton SR;Berindan-Neagoe I;Medico E;Mirnezami A;Calin GA;Nicoloso MS
通讯作者：
Nicoloso MS
影响因子：
24.5
作者：
Hur K;Toiyama Y;Takahashi M;Balaguer F;Nagasaka T;Koike J;Hemmi H;Koi M;Boland CR;Goel A
通讯作者：
Goel A
DOI：
10.1056/nejmoa1214271
发表时间：
2013-03-21
期刊：
The New England journal of medicine
影响因子：
--
作者：
Friboulet L;Olaussen KA;Pignon JP;Shepherd FA;Tsao MS;Graziano S;Kratzke R;Douillard JY;Seymour L;Pirker R;Filipits M;André F;Solary E;Ponsonnailles F;Robin A;Stoclin A;Dorvault N;Commo F;Adam J;Vanhecke E;Saulnier P;Thomale J;Le Chevalier T;Dunant A;Rousseau V;Le Teuff G;Brambilla E;Soria JC
通讯作者：
Soria JC
影响因子：
5.7
作者：
Azuma, Koichi;Komohara, Yoshihiro;Aizawa, Hisamichi
通讯作者：
Aizawa, Hisamichi