The cox pathway in colorectal cancer (la vía de cox en el cáncer colorectal)

Resumen

The COX pathway is known to be altered in colorectal cancer (CRC) at different levels. However, the mechanisms underlying these alterations are in some cases not well characterized. In previous studies, we established that prostacyclin synthase (PTGIS) is hypermethylated and transcriptionally silenced in most CRC tumors, in comparison with paired normal mucosa (Frigola et al, 2005). This time, our group aimed to characterize the overall methylation status of the promoter regions of most of the genes implicated in this pathway in a panel of 35 CRC cases and 6 CRC cell lines. Noteworthy, we found 3 other genes recurrently hypermethylated in tumor samples, as well as fully methylated in all studied cell lines: PTGFR, PTGDR and PTGER3. On the other hand, we have not found any differences in the genes involved in the production and proliferative signaling of PGE2 (prostaglandin E2) and TBXA (thromboxane), being totally unmethylated in normal, tumor and cell line samples. Furthermore, we studied the functional implications of PTGIS silencing through transient transfections of full PTGIS cDNA into HCT116, a CRC cell line, and treatments of the same cell line with a prostacyclin analog, Iloprost. Both methods resulted in a cytostatic response, which points out a putative role of PTGIS silencing in tumoral maintenance and/or progression. Remarkably, in the Iloprost treatments, we found the best results at short times after exposure and at doses as low as 1nM, which might reflect the biological nature of prostacyclin receptor as a G-coupled-protein-receptor (GPCR). Further studies must be done to better understand the functional implications of the silencing of these genes in CRC and how we can use this knowledge to improve the current therapeutic strategies.