The ZEB2-dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer

被引：32

作者：

Sreekumar, Rahul ^{[1
]}

Al-Saihati, Hajir ^{[1
,2
]}

Emaduddin, Muhammad ^{[1
]}

Moutasim, Karwan ^{[1
]}

Mellone, Massimiliano ^{[1
]}

Patel, Ashish ^{[1
]}

Kilic, Seval ^{[1
]}

Cetin, Metin ^{[3
]}

Erdemir, Sule ^{[3
]}

Navio, Marta Salgado ^{[1
]}

Lopez, Maria Antonette ^{[1
]}

Curtis, Nathan ^{[4
]}

Yagci, Tamer ^{[3
]}

Primrose, John N. ^{[1
,4
]}

Price, Brendan D. ^{[5
]}

Berx, Geert ^{[6
,7
]}

Thomas, Gareth J. ^{[1
]}

Tulchinsky, Eugene ^{[8
]}

Mirnezami, Alex ^{[1
,2
]}

Sayan, A. Emre ^{[1
]}

机构：

[1] Univ Southampton, Canc Sci Div, Tremona Rd,Somers Bldg, Southampton SO16 6YD, Hants, England

[2] Univ Hafr Al Batin, Coll Appl Med Sci, Hafar Al Batin, Saudi Arabia

[3] Gebze Tech Univ, Dept Mol Biol & Genet, Gebze, Turkey

[4] Southampton Univ Hosp NHS Trust, Dept Surg, Southampton, Hants, England

[5] Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA

[6] Univ Ghent, Dept Biomed Mol Biol, Mol Cellular Oncol Lab, Ghent, Belgium

[7] Canc Res Inst Ghent CRIG, Ghent, Belgium

[8] Nazarbayev Univ, Dept Biomed Sci, Sch Med, Astana, Kazakhstan

来源：

MOLECULAR ONCOLOGY | 2021年 / 15卷 / 08期

基金：

英国医学研究理事会;

关键词：

DNA repair; EMT; ERCC1; oxaliplatin; ZEB2; TO-MESENCHYMAL TRANSITION; DNA-REPAIR; MOLECULAR-MECHANISMS; EXPRESSION; CELLS; ZEB1; CHEMOTHERAPY; PROTEINS; BLADDER; CHEMORESISTANCE;

D O I：

10.1002/1878-0261.12965

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：2065 / 2083

页数：19

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