Mathematical modeling of HOX gene regulation in colorectal cancer
Date
2025
Authors
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Publisher
University of Delaware
Abstract
Human HOX genes are essential transcription factors that govern embryonic development and play critical roles in tumorigenesis. In colorectal cancer (CRC), their expression is tightly regulated by both the WNT and retinoic acid (RA) signaling pathways. While prior studies have explored these pathways individually, limited work has addressed their combined influence on CRC progression. This dissertation bridges that gap by introducing a novel mathematical model that captures the dynamic interactions among the HOX, WNT, and RA pathways. We develop a system of nonlinear ODEs to describe the reaction kinetics within a complex biochemical network involving these three pathways, which are fundamental to tissue homeostasis and cancer development. ☐
The model focuses on two key HOX genes, HOXA5 and HOXA13, which are differentially involved in CRC development and treatment response. By incorporating these genes within the RA and WNT regulatory networks, the model captures the antagonistic relationship between HOXA5 and WNT signaling, mediated in part through repression by the MYC:MIZ1 complex. This complex plays a crucial role in stemness regulation by inhibiting HOXA5 transcription. Simulation results support biological findings that highlight HOXA5 as a tumor suppressor and a potential biomarker in CRC, particularly through its inverse regulation of WNT activity. ☐ Moreover, the model integrates CYP26A1, an enzyme that metabolizes RA and mediates feedback between the WNT and RA pathways. This addition enables the simulation of all-trans retinoic acid (ATRA) treatment, revealing that CYP26A1 activity can counteract or override the therapeutic effects of ATRA. The findings suggest that under wild-type APC (wt-APC) conditions, simultaneous modulation of ATRA levels and CYP26A1 expression may enhance treatment efficacy, offering a new direction for targeted CRC therapy.
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Keywords
Colorectal cancer, HOX gene regulation, Mathematical modeling of cancer, Retinoid acid treatment, Stemness dynamics, Wnt signaling pathway