TGF-beta downregulates CAIII expression via MAPK and PI3K signaling pathways in colon carcinoma and osteosarcoma cells

Identification of cancer-associated genes is critical for developing effective treatments of colorectal cancer (CRC). A limited number of studies have examined the mechanisms and genes underlying CRC. Abnormal transforming growth factor beta (TGF-beta) expression was observed at different stages of carcinoma. We examined the effect of cancer-related cytokine TGF-beta on carbonic anhydrase (CA) III gene expression in colon cancer HT-29 cells. TGF-beta (500 U/mL) downregulated CAIII gene expression at both the mRNA and protein levels. Transient transfection experiments indicated that different CAIII promoter constructs were active in HT-29 cells. TGF-beta reduced transcriptional activity of all promoter constructs, indicating that the potential response element for TGF-beta-directed transcription lies within the -108/+86 region of the CAIII promoter. According to the non-Smad pathway inhibitory assay, TGF-beta downregulated the CAIII gene through mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphoinositide-3-kinase (PI3K) pathways. The same decreasing effect was determined in the Saos-2, osteosarcoma cell line, indicating that the effect of TGF-beta on CAIII was not tissue-specific. However, examination of PI3K and MAPK/ERK signaling pathways with suitable inhibitors revealed that the PI3K but not the MAPK/ERK pathway was responsible for TGF-beta downregulation.