ZEB1/miR-200c/AGR2: A New Regulatory Loop Modulating the Epithelial-Mesenchymal Transition in Lung Adenocarcinomas
Epithelial-mesenchymal transition (EMT) is a process involved not only in morphogenesis and embryonic development, but also in cancer progression, whereby tumor cells obtain a more aggressive metastatic phenotype. Anterior gradient protein 2 (AGR2) maintains the epithelial phenotype and blocks the i...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-06-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/6/1614 |
| _version_ | 1797564839105658880 |
|---|---|
| author | Lucia Sommerova Eva Ondrouskova Andrea Martisova Vassilis Zoumpourlis Sotirios Galtsidis Roman Hrstka |
| author_facet | Lucia Sommerova Eva Ondrouskova Andrea Martisova Vassilis Zoumpourlis Sotirios Galtsidis Roman Hrstka |
| author_sort | Lucia Sommerova |
| collection | DOAJ |
| description | Epithelial-mesenchymal transition (EMT) is a process involved not only in morphogenesis and embryonic development, but also in cancer progression, whereby tumor cells obtain a more aggressive metastatic phenotype. Anterior gradient protein 2 (AGR2) maintains the epithelial phenotype and blocks the induction of EMT, thus playing an undeniable role in tumor progression. However, the mechanism through which AGR2 expression is regulated, not only during EMT, but also in the early stages of cancer development, remains to be elucidated. In the present study, we show an inverse correlation of AGR2 with ZEB1 (zinc finger enhancer binding protein, δEF1) that was verified by analysis of several independent clinical data sets of lung adenocarcinomas. We also identified the ZEB1 binding site within the <i>AGR2</i> promoter region and confirmed <i>AGR2</i> as a novel molecular target of ZEB1. The overexpression of ZEB1 decreased the promoter activity of the <i>AGR2</i> gene, which resulted in reduced AGR2 protein level and the acquisition of a more invasive phenotype of these lung cancer cells. Conversely, silencing of <i>ZEB1</i> led not only to increased levels of AGR2 protein, but also attenuated the invasiveness of tumor cells. The <i>AGR2</i> knockout, vice versa, increased ZEB1 expression, indicating that the ZEB1/AGR2 regulatory axis may function in a double negative feedback loop. In conclusion, we revealed for the first time that ZEB1 regulates <i>AGR2</i> at the transcriptional level, while AGR2 presence contributes to <i>ZEB1</i> mRNA degradation. Thus, our data identify a new regulatory mechanism between AGR2 and ZEB1, two rivals in the EMT process, tightly associated with the development of metastasis. |
| first_indexed | 2024-03-10T19:03:37Z |
| format | Article |
| id | doaj.art-d07ed9245ce64a0a9b7f1f7dc003b456 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T19:03:37Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d07ed9245ce64a0a9b7f1f7dc003b4562023-11-20T04:16:49ZengMDPI AGCancers2072-66942020-06-01126161410.3390/cancers12061614ZEB1/miR-200c/AGR2: A New Regulatory Loop Modulating the Epithelial-Mesenchymal Transition in Lung AdenocarcinomasLucia Sommerova0Eva Ondrouskova1Andrea Martisova2Vassilis Zoumpourlis3Sotirios Galtsidis4Roman Hrstka5Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech RepublicResearch Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech RepublicResearch Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech RepublicBiomedical Applications Unit, Institute of Biology, Medicinal Chemistry & Biotechnology, NHRF 48 Vassileos Constantinou Ave., 11635 Athens, GreeceLife Sciences Research Unit, University of Luxembourg, Campus Belval, Biotech 1, Avenue des Hauts Fourneaux, L-4362 Esch-sur-Alzette, LuxembourgResearch Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech RepublicEpithelial-mesenchymal transition (EMT) is a process involved not only in morphogenesis and embryonic development, but also in cancer progression, whereby tumor cells obtain a more aggressive metastatic phenotype. Anterior gradient protein 2 (AGR2) maintains the epithelial phenotype and blocks the induction of EMT, thus playing an undeniable role in tumor progression. However, the mechanism through which AGR2 expression is regulated, not only during EMT, but also in the early stages of cancer development, remains to be elucidated. In the present study, we show an inverse correlation of AGR2 with ZEB1 (zinc finger enhancer binding protein, δEF1) that was verified by analysis of several independent clinical data sets of lung adenocarcinomas. We also identified the ZEB1 binding site within the <i>AGR2</i> promoter region and confirmed <i>AGR2</i> as a novel molecular target of ZEB1. The overexpression of ZEB1 decreased the promoter activity of the <i>AGR2</i> gene, which resulted in reduced AGR2 protein level and the acquisition of a more invasive phenotype of these lung cancer cells. Conversely, silencing of <i>ZEB1</i> led not only to increased levels of AGR2 protein, but also attenuated the invasiveness of tumor cells. The <i>AGR2</i> knockout, vice versa, increased ZEB1 expression, indicating that the ZEB1/AGR2 regulatory axis may function in a double negative feedback loop. In conclusion, we revealed for the first time that ZEB1 regulates <i>AGR2</i> at the transcriptional level, while AGR2 presence contributes to <i>ZEB1</i> mRNA degradation. Thus, our data identify a new regulatory mechanism between AGR2 and ZEB1, two rivals in the EMT process, tightly associated with the development of metastasis.https://www.mdpi.com/2072-6694/12/6/1614AGR2EMTZEB1cancer |
| spellingShingle | Lucia Sommerova Eva Ondrouskova Andrea Martisova Vassilis Zoumpourlis Sotirios Galtsidis Roman Hrstka ZEB1/miR-200c/AGR2: A New Regulatory Loop Modulating the Epithelial-Mesenchymal Transition in Lung Adenocarcinomas Cancers AGR2 EMT ZEB1 cancer |
| title | ZEB1/miR-200c/AGR2: A New Regulatory Loop Modulating the Epithelial-Mesenchymal Transition in Lung Adenocarcinomas |
| title_full | ZEB1/miR-200c/AGR2: A New Regulatory Loop Modulating the Epithelial-Mesenchymal Transition in Lung Adenocarcinomas |
| title_fullStr | ZEB1/miR-200c/AGR2: A New Regulatory Loop Modulating the Epithelial-Mesenchymal Transition in Lung Adenocarcinomas |
| title_full_unstemmed | ZEB1/miR-200c/AGR2: A New Regulatory Loop Modulating the Epithelial-Mesenchymal Transition in Lung Adenocarcinomas |
| title_short | ZEB1/miR-200c/AGR2: A New Regulatory Loop Modulating the Epithelial-Mesenchymal Transition in Lung Adenocarcinomas |
| title_sort | zeb1 mir 200c agr2 a new regulatory loop modulating the epithelial mesenchymal transition in lung adenocarcinomas |
| topic | AGR2 EMT ZEB1 cancer |
| url | https://www.mdpi.com/2072-6694/12/6/1614 |
| work_keys_str_mv | AT luciasommerova zeb1mir200cagr2anewregulatoryloopmodulatingtheepithelialmesenchymaltransitioninlungadenocarcinomas AT evaondrouskova zeb1mir200cagr2anewregulatoryloopmodulatingtheepithelialmesenchymaltransitioninlungadenocarcinomas AT andreamartisova zeb1mir200cagr2anewregulatoryloopmodulatingtheepithelialmesenchymaltransitioninlungadenocarcinomas AT vassiliszoumpourlis zeb1mir200cagr2anewregulatoryloopmodulatingtheepithelialmesenchymaltransitioninlungadenocarcinomas AT sotiriosgaltsidis zeb1mir200cagr2anewregulatoryloopmodulatingtheepithelialmesenchymaltransitioninlungadenocarcinomas AT romanhrstka zeb1mir200cagr2anewregulatoryloopmodulatingtheepithelialmesenchymaltransitioninlungadenocarcinomas |