Abstract
The mRNA-destabilizing protein ZFP36 has been previously described as a tumor suppressor whose expression is lost during colorectal cancer development. In order to evaluate its role in this disease, we restored ZFP36 expression in different cell contexts, showing that the presence of this protein impairs the epithelial-to-mesenchymal transition (EMT) and induces a higher susceptibility to anoikis. Consistently, we found that ZFP36 inhibits the expression of three key transcription factors involved in EMT: ZEB1, MACC1 and SOX9. Finally, we observed for the first time that its expression negatively correlates with the activity of Wnt/β-catenin pathway, which is constitutively activated in colorectal cancer. This evidence provides a clue on the mechanism leading to the loss of ZFP36 in CRC.
Highlights
Colorectal cancer (CRC) is a neoplasia affecting mucosa of large intestine and that develops through a multistage process resulting from the accumulation of multiple genetic mutations [1]
It does not result significantly differentially expressed in Mts vs CRC comparison, even though the tendency toward decrease is constant when considering the progression represented by normal colon mucosa (Normal), CRC and Mts samples
Today several publications show that its expression is commonly deficient in a large number of cancer cell types when compared to normal cells [21]
Summary
Colorectal cancer (CRC) is a neoplasia affecting mucosa of large intestine and that develops through a multistage process resulting from the accumulation of multiple genetic mutations [1]. A reorganization of the cytoskeleton takes place, followed by changes in cell shape, acquisition of motility and, in many cases, the ability to degrade extracellular matrix [4] All these events are supported by a down-regulation of epithelial-related genes’ expression in favour of an increased expression of mesenchymal specific genes. TWIST proteins are basic helix-loop-helix (bHLH) transcription factors and, to SNAIL, they downregulate epithelial genes and activate mesenchymal genes’ expression. Other genes, such as Sex-determining Region Y box 9 (SOX9) and Metastasis-associated in colon cancer-1 (MACC1) are dysregulated in colon carcinoma and play a fundamental role at the onset of EMT [8, 9]
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