Abstract
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 AGR2 promoter region and confirmed AGR2 as a novel molecular target of ZEB1. The overexpression of ZEB1 decreased the promoter activity of the AGR2 gene, which resulted in reduced AGR2 protein level and the acquisition of a more invasive phenotype of these lung cancer cells. Conversely, silencing of ZEB1 led not only to increased levels of AGR2 protein, but also attenuated the invasiveness of tumor cells. The AGR2 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 AGR2 at the transcriptional level, while AGR2 presence contributes to ZEB1 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.
Highlights
The development of metastasis represents the most crucial challenge in the treatment of cancer and remains the major cause of cancer related death
Our study emerged from three pieces of currently available knowledge about Anterior gradient protein 2 (AGR2) and ZEB1: a) AGR2, to all epithelial proteins, is downregulated during the Epithelial-mesenchymal transition (EMT) process [24]; b) upregulation of the EMT-associated transcription factor (EMT-transcription factors (TFs)) ZEB1 represses the expression of epithelial proteins, among which E-cadherin serves as a prominent example of ZEB1 targets [5]; and c)
We used the CBioPortal database [26,27] to analyze the mutual relation linking AGR2 and E-cadherin (CDH1) (Figure 1A) in cancer cell lines listed in the Cancer Cell Line Encyclopedia [28]
Summary
The development of metastasis represents the most crucial challenge in the treatment of cancer and remains the major cause of cancer related death. Metastatic spread of cancer represents a complex program, during which cancer cells must undergo many changes associated with increased motility, invasiveness, and loss of cell-cell junctions. This conversion is an adaptation of the normal developmental process called epithelial-mesenchymal transition (EMT). The intermediate or hybrid epithelial/mesenchymal phenotypes are characterized by the co-existence of both epithelial and mesenchymal traits and differ in combined expression of epithelial and mesenchymal markers reflecting the ability of the cells to acquire an EMT-associated phenotype manifested by stemness, tumorigenicity, metastatic ability, and resistance to therapy [1,2,3]. The switch in gene expression and associated phenotypic conversion is achieved by the orchestrated and coordinated action of transcription factors (TFs), which bind to their corresponding sequences, leading to the repression of epithelial markers (such as E-cadherin) and to the activation of genes associated with the mesenchymal phenotype [4,5]
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