The Role of HOXC6 in the Tumorigenesis and Progression of Right Sided Colon Cancer
Introduction. Colon cancer is the fourth most common cancer in the United States, and it is the second deadliest form of cancer1. There are differences in the way cancer presents in the colon depending on whether it is in the proximal, or right colon, and distal, or left colon. This is likely due to their embryological differences, with the right colon arising from the midgut, and the left colon arising from the hindgut2,3. Right sided colon cancer (RCC) is typically more common in females, is diagnosed at an older age, and has a worse prognosis than left sided colon cancers4–6. Studies have found that the HOXC6 gene is uniquely overexpressed in RCC. This upregulation has an impact on a variety of genes and pathways that contribute to the progression of cancer, such as the MLH1 gene, epithelial-mesenchymal transition (EMT), and the Wnt/beta-catenin pathway. Other studies have shown that silencing the HOXC6 gene could be a potential target in treating RCC7,8. Methods. The Cancer Genome Atlas was used to obtain data on the upregulation of the HOXC6 gene in right versus left sided colon cancers, and the data was processed using BioConductor. A tissue microarray containing 110 RCC samples was used for immunohistochemistry staining to evaluate HOXC6 expression. Overexpression plasmids were transfected into cells to induce HOXC6 overexpression, and siRNA was used to silence its expression. Cell invasion and migration was studied by Transwell assays with or without Matrigel, and the cells were stained with crystal violet before being counted using light microscopy. Detection of secreted DKK1 was performed using DKK1-specific ELISA kits. Mice were injected with tumor cells and were divided into three groups: control, HOXC6-OE, and HOXC6-KD. Results. Overexpression of HOXC6 promoted metastasis and invasion of RCC. A negative correlation was found between the expression of HOXC6 and MLH1. HOXC6 overexpression contributed to the activation of the Wnt pathway and EMT. DKK1, a Wnt inhibitor, was upregulated 13.8 fold in HOXC6-OE cells, but was found to not be secreted from the cell. Silencing of HOXC6 was found to make tumor cells more sensitive to 5-FU and Irinotecan, two common chemotherapy drugs7,8. Conclusions. Studies have found that the overexpression of HOXC6 contributes to the metastasis of RCC by silencing MLH1, activating EMT, and preventing the negative regulation of the Wnt pathway by preventing the secretion of DKK1. Silencing of HOXC6 enhances the effects of 5-FU and irinotecan, and thus serves as a potential target in the treatment of RCC.
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