Role of NRF-2, MDR-1, and TET-2 in Inflammatory Bowel Disease and Colorectal Carcinoma

Study purpose: Inflammatory Bowel Disease (IBD) is partly attributed to cytokine storm and infiltrating immune cells. As part of the cell defensive mechanisms, a transcription factor called nuclear factor erythroid 2-related factor 2 (NRF-2) activates genes encoding antioxidant enzymes. Additionally, NRF-2 has recently emerged as an important contributor to chemo-resistance in colon neoplasms, by upregulating multi-drug resistant protein 1 (MDR-1). In addition, epigenetic factors have been shown to influence the onset of IBD and of colorectal cancer. One of these epigenetic factors is the interplay between DNA methylation status. A DNA demethylating enzyme, coded by the ten-to-eleven translocation 2 [tet2], yields the methylcytosine dioxygenase TET-2. Recent studies have demonstrated a potential association between TET-2 and NRF-2 in IBD-associated colon cancer. This study aims to understand the alteration in the expression and activity of these markers under inflammatory conditions. Experimental procedures: NRF-2, MDR-1, and TET-2 expression level was evaluated in parental HT-29 cells and in HT-29 cells downregulated for TET-2 (HT-29shTET-2) and exposed to an inflammatory milieu; at the transcriptional level by quantitative real-time polymerase chain reaction (qPCR). Markers of the epithelial-to-mesenchymal transition (EMT, E-cadherin and N-cadherin) were also evaluated by qPCR and Western blotting. Summary of results: Under inflammatory conditions, NRF-2, MDR-1, and TET-2 expression levels increased. However, NRF-2 and MDR-1 expression levels were downregulated in HT-29shTET-2 cells. Interestingly, N-cadherin levels were higher in HT-29shTET-2 exposed to inflammatory media compared to parental HT-29. Conclusions: NRF-2 and MDR-1 expression levels increase upon exposure of HT-29 cells to inflammation. On the other hand, their expression is downregulated when TET-2 is downregulated, suggesting a potential demethylating role of TET-2 in activating NRF-2 and MDR-1 gene expression. Citation Format: Jessica Saliba, Ali Amhaz, Batoul Moussa, Souraya Ismail, Abdullah Shaito, Marwan El-Sabban. A potential role of NRF-2, MDR-1, and TET-2 in inflammatory bowel disease and colorectal carcinoma: An in vitro study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6577.