Translational cancer research · 2026
PTTG1-DLX2 axis drives malignant progression of lung adenocarcinoma by activating the WNT/β-catenin signaling pathway.
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Chen Huili, Zhang Xinyu, Lian Xiaofu, Wang Ziqiang, Zhang Feiyue, Zhang Jing, Min Shengping, Yang Shasha, Wang Xiaojing, Lian Chaoqun
Аннотация
BACKGROUND: Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality, and the molecular drivers that promote its malignant progression are not fully characterized. This study aimed to define the oncogenic function of pituitary tumor transforming gene 1 (PTTG1) in LUAD and to elucidate its mechanistic relationship with distal-less homeobox 2 (DLX2) and the WNT/β-catenin signaling pathway.
METHODS: PTTG1 expression, clinical relevance, and its association with tumor-infiltrating cells were analyzed using public datasets. Functional assays, including cell proliferation, migration, invasion, and cell-cycle analysis, were performed following PTTG1 overexpression or CRISPR/Cas9-mediated knockout (KO) in LUAD cell lines. Protein interaction between PTTG1 and DLX2 was examined using co-immunoprecipitation. β-catenin activation and downstream targets were assessed to evaluate WNT pathway involvement. Subcutaneous xenograft models and rescue experiments were applied to investigate the contribution of the PTTG1-DLX2 axis to LUAD tumor growth.
RESULTS: PTTG1 was markedly upregulated in LUAD and associated with poorer patient survival. Higher PTTG1 expression correlated with lower CD8+ T-cell infiltration. Functional studies demonstrated that PTTG1 enhanced LUAD cell proliferation, invasive capacity, and cycle progression, whereas CRISPR-mediated KO significantly impaired these malignant phenotypes. Co-immunoprecipitation confirmed a physical interaction between PTTG1 and DLX2, and PTTG1 modulation influenced β-catenin activity accompanied by increased expression of canonical downstream effectors. Restoration of DLX2 expression rescued the reduced tumorigenic activities observed in PTTG1-deficient cells. Xenograft experiments further confirmed that PTTG1 promotes LUAD tumor growth in vivo.
CONCLUSIONS: This study identifies a PTTG1-DLX2-β-catenin signaling axis that drives LUAD malignant progression. These findings highlight PTTG1 as an important molecular driver and a potential therapeutic target in LUAD.
METHODS: PTTG1 expression, clinical relevance, and its association with tumor-infiltrating cells were analyzed using public datasets. Functional assays, including cell proliferation, migration, invasion, and cell-cycle analysis, were performed following PTTG1 overexpression or CRISPR/Cas9-mediated knockout (KO) in LUAD cell lines. Protein interaction between PTTG1 and DLX2 was examined using co-immunoprecipitation. β-catenin activation and downstream targets were assessed to evaluate WNT pathway involvement. Subcutaneous xenograft models and rescue experiments were applied to investigate the contribution of the PTTG1-DLX2 axis to LUAD tumor growth.
RESULTS: PTTG1 was markedly upregulated in LUAD and associated with poorer patient survival. Higher PTTG1 expression correlated with lower CD8+ T-cell infiltration. Functional studies demonstrated that PTTG1 enhanced LUAD cell proliferation, invasive capacity, and cycle progression, whereas CRISPR-mediated KO significantly impaired these malignant phenotypes. Co-immunoprecipitation confirmed a physical interaction between PTTG1 and DLX2, and PTTG1 modulation influenced β-catenin activity accompanied by increased expression of canonical downstream effectors. Restoration of DLX2 expression rescued the reduced tumorigenic activities observed in PTTG1-deficient cells. Xenograft experiments further confirmed that PTTG1 promotes LUAD tumor growth in vivo.
CONCLUSIONS: This study identifies a PTTG1-DLX2-β-catenin signaling axis that drives LUAD malignant progression. These findings highlight PTTG1 as an important molecular driver and a potential therapeutic target in LUAD.