@Article{or.2025.071739,
AUTHOR = {Shulong Zhang, Yijun Zhao, Li Geng, Feihong Song, Li Feng, Jun Jiang, Qianqian Cai, Fei Fan},
TITLE = {<i>DNASE1L3</i> Mediates Hepatocellular Carcinoma Tumor Growth and Organoid Models via the Wnt/<b>β</b>-Catenin Signaling Pathway},
JOURNAL = {Oncology Research},
VOLUME = {34},
YEAR = {2026},
NUMBER = {3},
PAGES = {--},
URL = {http://www.techscience.com/or/v34n3/66266},
ISSN = {1555-3906},
ABSTRACT = { <b>Background:</b> Hepatocellular carcinoma (HCC) is a highly lethal malignancy driven by both intrinsic oncogenic pathways and immune microenvironmental regulation. Emerging evidence suggests that <i>DNASE1L3</i> may influence tumor biology and immune responses; however, its specific roles in HCC progression and macrophage-mediated regulation remain unclear. This study aimed to elucidate the biological functions of <i>DNASE1L3</i> in HCC and to determine how it modulates tumor behavior and immune interactions. <b>Methods:</b> Bioinformatics analyses of the GSE41804 and Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) datasets were used to identify hub genes. Functional assays assessed the impact of <i>DNASE1L3</i> on HCC cell proliferation, migration, invasion, and cell cycle progression. The effects of <i>DNASE1L3</i> on macrophage polarization and the Wnt/β-catenin signaling pathway were examined using a co-culture system. An HCC organoid model was established to further validate its regulatory function. <b>Results:</b> Eight prognostic signature genes were identified, with <i>deoxyribonuclease I-like 3 (DNase I-like 3)</i> selected as the hub gene. <i>DNASE1L3</i> overexpression suppressed HCC cell growth, inhibited migration and invasion, induced G1 arrest, and modulated epithelial-mesenchymal transition (EMT) markers. <i>DNASE1L3</i> knockdown promoted M2-like macrophage polarization. Mechanistically, <i>DNASE1L3</i> interacted with β-catenin to enhance its ubiquitination and degradation, thereby inhibiting Wnt/β-catenin signaling and reducing PD-L1 expression. <i>DNASE1L3</i> overexpression similarly restricted organoid growth and suppressed pathway activity. <b>Conclusion:</b> <i>DNASE1L3</i> acts as a negative regulator of HCC progression by targeting the Wnt/β-catenin pathway and reducing PD-L1 expression, thereby influencing both tumor cell behavior and macrophage-mediated immune responses.},
DOI = {10.32604/or.2025.071739}
}