<br>FBXW7-ZEB2 轴连接 EMT 和肿瘤微环境，促进结直肠癌干细胞和化疗耐药。,Oncogenesis

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FBXW7-ZEB2 轴连接 EMT 和肿瘤微环境，促进结直肠癌干细胞和化疗耐药。
Oncogenesis ( IF 5.9 ) Pub Date : 2019-02-19 , DOI: 10.1038/s41389-019-0125-3
Ningning Li _{1,

2} , Roya Babaei-Jadidi ₁ , Federica Lorenzi _{1,

3} , Bradley Spencer-Dene ₄ , Philip Clarke ₅ , Enric Domingo ₆ , Eugene Tulchinsky _{7,

8} , Robert G J Vries ₉ , David Kerr ₁₀ , Yihang Pan ₂ , Yulong He ₂ , David O Bates ₅ , Ian Tomlinson ₆ , Hans Clevers ₉ , Abdolrahman S Nateri ₁

Affiliation

Cancer Genetics and Stem Cell Group, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK.
The Seventh Affiliated Hospital of Sun Yat-sen University, 518107, Shenzhen, China.
The Institute of Cancer Research, Surrey, SM2 5NG, UK.
Advanced Cell Diagnostics, Henry Wellcome Building of Genomic Medicine, Oxford, OX3 7BN, UK.
Cancer Biology Unit, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK.
Wellcome Trust Centre for Human Genetics, Henry Wellcome Building of Genomic Medicine, Oxford, OX3 7BN, UK.
Department of Cancer Studies, University of Leicester, Leicester, UK.
Moscow Institute of Physics and Technology, Dolgoprudny, Moscow region, Russia.
Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht and University Medical Centre Utrecht, Uppsalalaan 8, 3584CT, Utrecht, Netherlands.
John Radcliffe Hospital, Nuffield Division of Clinical Laboratory Sciences, Oxford, OX3 9DU, UK.

由于被称为癌症干细胞样细胞（CSC）的干细胞样细胞的存活，结直肠癌（CRC）患者在化疗后出现复发。 CSC 的起源与上皮间质转化 (EMT) 过程有关。目前，人们对 EMT 项目如何使肿瘤微环境中的 CSC 逃避化疗的影响仍知之甚少。这项研究确定了导致耐药 CSC 群体形成的关键分子途径。使用改良的酵母2杂交系统和基于2D凝胶的蛋白质组学方法，我们证明E3-泛素连接酶FBXW7以磷酸化依赖性方式直接结合并降解EMT诱导转录因子ZEB2。 FBXW7 的缺失会诱导 EMT，而这种 EMT 可以通过敲低 ZEB2 来有效逆转。 FBXW7-ZEB2 轴调节重要的癌细胞特征，例如干性/去分化、化疗耐药性以及体外、离体和动物转移模型中的细胞迁移。癌症组织中ZEB2的高表达定义了患者癌症相关基质和小鼠肠道类器官中ZEB2表达的减少，这表明肿瘤-基质串扰可以调节微环境和EMT激活。因此，我们的研究揭示了一种新的分子机制，通过该机制，CRC 细胞表现出对化疗的耐药性和转移潜力的差异。

"点击查看英文标题和摘要"

An FBXW7-ZEB2 axis links EMT and tumour microenvironment to promote colorectal cancer stem cells and chemoresistance.

Colorectal cancer (CRC) patients develop recurrence after chemotherapy owing to the survival of stem cell-like cells referred to as cancer stem-like cells (CSCs). The origin of CSCs is linked to the epithelial-mesenchymal transition (EMT) process. Currently, it remains poorly understood how EMT programmes enable CSCs residing in the tumour microenvironment to escape the effects of chemotherapy. This study identifies a key molecular pathway that is responsible for the formation of drug-resistant CSC populations. Using a modified yeast-2-hybrid system and 2D gel-based proteomics methods, we show that the E3-ubiquitin ligase FBXW7 directly binds and degrades the EMT-inducing transcription factor ZEB2 in a phosphorylation-dependent manner. Loss of FBXW7 induces an EMT that can be effectively reversed by knockdown of ZEB2. The FBXW7-ZEB2 axis regulates such important cancer cell features, as stemness/dedifferentiation, chemoresistance and cell migration in vitro, ex vivo and in animal models of metastasis. High expression of ZEB2 in cancer tissues defines the reduced ZEB2 expression in the cancer-associated stroma in patients and in murine intestinal organoids, demonstrating a tumour-stromal crosstalk that modulates a niche and EMT activation. Our study thus uncovers a new molecular mechanism, by which the CRC cells display differences in resistance to chemotherapy and metastatic potential.

更新日期：2019-07-05

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