Abstract
Aim:Colorectal cancer (CRC) is the third leading cancer-related cause of death due to its propensity to metastasize. Epithelial-mesenchymal transition (EMT) is a multistep process important for invasion and metastasis of CRC. Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor highly expressed in differentiated cells of the intestinal epithelium. KLF4 has been shown to play a tumor suppressor role during CRC tumorigenesis - its loss accelerates development and progression of cancer. The present study examined the relationship between KLF4 and markers of EMT in CRC.Methods:Immunofluorescence staining for KLF4 and EMT markers was performed on archived patient samples after colorectal cancer resection and on colonic tissues of mice with colitis-associated cancer.Results:We found that KLF4 expression is lost in tumor sections obtained from CRC patients and in those of mouse colon following azoxymethane and dextran sodium sulfate (AOM/DSS) treatment when compared to their respective normal appearing mucosa. Importantly, in CRC patient tumor sections, we observed a negative correlation between KLF4 levels and mesenchymal markers including TWIST, β-catenin, claudin-1, N-cadherin, and vimentin. Similarly, in tumor tissues from AOM/DSS-treated mice, KLF4 levels were negatively correlated with mesenchymal markers including SNAI2, β-catenin, and vimentin and positively correlated with the epithelial marker E-cadherin.Conclusion:These findings suggest that the loss of KLF4 expression is a potentially significant indicator of EMT in CRC.
Highlights
Colorectal cancer (CRC) is the third leading cause of the cancer-related deaths often with metastasis to the liver, lung, and bone[1,2]
We found that Krüppel-like factor 4 (KLF4) expression is lost in tumor sections obtained from CRC patients and in those of mouse colon following azoxymethane and dextran sodium sulfate (AOM/DSS) treatment when compared to their respective normal appearing mucosa
In CRC patient tumor sections, we observed a negative correlation between KLF4 levels and mesenchymal markers including TWIST, β-catenin, claudin-1, N-cadherin, and www.jcmtjournal.com
Summary
Colorectal cancer (CRC) is the third leading cause of the cancer-related deaths often with metastasis to the liver, lung, and bone[1,2]. During the EMT process, epithelial cells lose apical-basal polarity that is accompanied by reorganization of cytoskeleton and reprogramming of the signaling pathways that allow for an increase in motility and the development of an invasive phenotype. This multistep complex process is characterized by modifications in the expression of a host of transcription factors and specific cell-surface proteins, as well as reorganization and expression of cytoskeletal proteins, and production of enzymes that degrade the ECM[3]. The activation of the EMT program has been suggested to be the critical mechanism for the acquisition of malignant phenotypes by epithelial cancer cells[3]
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