Abstract
Introduction
Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder characterized by the dysfunction of the dystrophin protein, resulting in atrophy of skeletal muscles, paralysis, cardiopulmonary complications, and premature death. Current literature emphasizes skeletal and cardiac muscle pathology in DMD, while the role of dystrophin dysfunction in smooth muscle biology remains poorly understood. Moreover, the potential link between DMD-associated genomic instability and susceptibility to cellular transformation, or gastrointestinal cancers, has not been systematically explored. This study pinpoints novel relationships between DMD and gastrointestinal (GI) and gastroesophageal (GE) cancers. We hypothesize that the deletion or mutation of the DMD gene results in compensatory activation of oncogenic pathways (e.g., MYC) in skeletal muscle and GI or GE tissues.
Methods
A bioinformatics model for DMD was developed by integrating multi-omics and functional meta-analyses derived from trusted databases (Human Protein Atlas and cBioPortal for Cancer Genomics). This model revealed that men with gastric cancers frequently exhibit deletions in the DMD gene locus. Key genes on the X-chromosome were selected to incorporate into a genetic panel that features a ‘deleted hotspot’ region along with compensatory gene loci located on chromosomes 3, 8, and 17. This panel captures pathogenic DMD deletions and compensatory oncogenic mechanisms indicating the novel characterization of a genetic connection between DMD and GI or GE cancers. We profiled seven genes of interest (MECOM, MUC20, MYC, DMD, FOXO4, AGO2, and KDM6A) and determined that they were differentially expressed between a DMD control cell line, human foreskin fibroblasts (HFFs), and gastric cancer cell lines (SNU-1, SNU-16, SNU-407, SNU-C4, GP2d) using PCR, Southern blotting, Western blotting, and immunohistochemical (IHC) staining.
Results
PCR analysis demonstrated upregulation of AGO2 and KDM6A and downregulation of AR in SNU-1, SNU-16, SNU-407, SNU-C4, and GP2d cell lines compared to HFF. MECOM, MUC20, and MYC were upregulated in SNU-16, SNU-407, SNU-C4, and GP2d, but downregulated in SNU-1. DMD was downregulated in SNU-1, while FOXO4 was downregulated in SNU-1 and SNU-16. Southern blot and Western blot analyses demonstrated increased MYC, MUC20, and MECOM expression and decreased DMD and FOXO4 expression in SNU-16 compared to HFF. IHC staining further demonstrated increased MYC expression and decreased DMD expression in cancerous tissue compared to non-cancerous tissue.
Conclusion
By identifying shared genomic features between DMD, GI, and GE cancers, this work reveals a novel connection between dystrophin loss and amplification-driven oncogenic pathways, highlighting opportunities for biomarker discovery and targeted therapeutic strategies involving oncogene amplification and tumor suppressor gene downregulation. These findings suggest that DMD mutations may serve as a biomarker for gastric cancer risk and warrant further investigation as potential targets for cancer risk assessment and therapeutic development.