Abstract 5701: MUC13 expression renders radio-resistance in human colorectal cancer cells through NRF2 signaling pathway

Abstract Background: Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer worldwide and poses a significant public health challenge due to its high incidence and mortality rates. A critical challenge in the management of CRC is the development of radio resistance, which compromises the efficacy of radiotherapy. Identifying novel molecular mechanisms that contribute to radio-resistance in CRC are imperative. Recently, we and others have reported that MUC13 as a pivotal factor in CRC progression and metastasis; however, its role in chemoresistance has not yet thoroughly elucidated. In this study, we have investigated the influence of MUC13 expression on radio-resistance in CRC cells. Methodology: To evaluate the influence of MUC13 on the radio-resistance of CRC cells, we generated genetically modified cell lines exhibiting either MUC13 overexpression (MUC13-OE) or knockdown (MUC13-KO). These cell lines were subjected to X-ray irradiation (0-6 Gray) to assess the effects of MUC13 modulation on critical cellular functions and tumorigenic features (proliferation, migration, and invasion). Furthermore, we quantified the expression levels of NRF2 and its nuclear localization post-irradiation to delineate the interplay between MUC13 and NRF2 signaling pathways. IHC analysis of patient-derived tissue samples was conducted to ascertain the expression profiles of MUC13 and NRF2 proteins, complemented by bioinformatics analysis utilizing various public databases to investigate the correlation between these two molecules. Results: Our findings reveal that the ectopic expression of MUC13 (MUC13-OE) in CRC cells caused a higher level resistance to radiotherapy (X-ray)-induced apoptosis as compared to MUC13 knockdown (MUC13-KO) cells. Additionally, MUC13-OE cells exhibited significantly enhanced migratory and invasive capabilities as compared to MUC13 KO cells after radiation treatments. This effect was correlated with the upregulation of NRF2 expression and its enhanced nuclear localization. Interestingly, a robust correlation between the expression levels of MUC13 and NRF2 was observed in human CRC tumors. This observation was supported by bioinformatics analyses. Moreover, we noted modulation of additional oxidative stress regulators, including HO-1, Keap1, and NQO1, which are critical mediators of cellular responses to oxidative stress. Collectively, these results implicate MUC13 as an important modulator of NRF2 signaling pathway. Conclusion: In this study, we for the first time delineate the influence of MUC13 on CRC radio-resistance. We have also established a relationship between MUC13 and NRF2 expression/subcellular localization, that might contribute to MUC13 mediated radio-resistance in CRC patients. Thus, strategic repression of MUC13 by small molecule inhibitors/siRNAs might improve the therapeutic outcome of radiotherapy in CRC patients. Citation Format: Shabnam Malik, Mohammed Sikander, Daniel Zubieta, Kyle Doxtater, Manish K. Tripathi, Sheema Khan, Murali M. Yallapu, Everardo Cobos, Subhash Chauhan. MUC13 expression renders radio-resistance in human colorectal cancer cells through NRF2 signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5701.