DLX2 Promotes Gastric Cancer Epithelial‒Mesenchymal Transition and Malignant Progression through the PI3K/AKT Signaling Pathway

Wenjing Chen^1,2*Xietao Chen^1,2Xuanfu Chi^1,3Wenpiao Yu^1,2Jinji Jin^1,2Jun Cheng^2,4*

• ¹Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
• ²Wenzhou Medical University, Wenzhou, China
• ³Alberta Institute, Wenzhou Medical University, Wenzhou, China
• ⁴The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

Gastric cancer (GC) remains a significant global health challenge, ranking fifth in incidence and fourth in mortality worldwide. Despite advancements in treatment, the prognosis for GC patients remains poor, largely due to late diagnosis and aggressive tumor behavior. This study investigated the role of distal-less homeobox 2 (DLX2) in GC progression, focusing on its potential to activate the PI3K/AKT signaling pathway and induce epithelial‒mesenchymal transition (EMT), thereby promoting tumor proliferation, invasion, and metastasis. We hypothesize that DLX2 serves as an independent prognostic marker and modulates the tumor immune microenvironment. Using bioinformatics analysis of GC RNA sequencing data from The Cancer Genome Atlas (TCGA), we identified DLX2 as a significant prognostic factor, with high expression correlating with reduced survival rates. In vitro experiments involving cell transfection and Western blotting confirmed that DLX2 overexpression enhances EMT marker expression and PI3K/AKT pathway activation. Functional assays, including cell proliferation, wound healing, and Transwell assays, demonstrated increased tumor cell migration and invasion upon DLX2 overexpression. In vivo xenograft models further validated these findings, showing accelerated tumor growth in DLX2-overexpressing cells. Additionally, immune scoring analysis revealed a significant association between DLX2 expression and immune/stromal scores, suggesting its role in the tumor immune microenvironment. Our results establish DLX2 as a critical regulator of GC malignancy, highlighting its potential as a therapeutic target. Future research should explore DLX2-targeted therapies to improve GC patient outcomes, offering a promising avenue for precision oncology.