image: (A) The expression status of the MEN1 gene in BLCA datasets based on the TCGA database. (B) The correlation between the MEN1 gene and tumor stages in BLCA tissues based on the TCGA database. (C) The survival analysis indicates that the MEN1 gene is a risk factor and is related to the survival and prognosis of BLCA tissues based on the GEO database (GSE31684 and GSE13507). (D) Representative immunohistochemistry staining images are presented for immunostaining of menin in different stages of BLCA tissues. Scale bar, 100 μm. (E) Enrichment analysis of the high expression of the MEN1 gene of BLCA patients based on GSEA 4.2.3 software (https://www.gsea-msigdb.org/gsea/index.jsp). (F) The correlation between the MEN1 gene and cell cycle checkpoint-related markers in BLCA based on the TCGA database. (G, H) The quantitative real-time PCR and western blotting assays analyzed the expression level of the MEN1 gene and menin protein in human immortalized uroepithelial cell line (SV-HUC-1) and BLCA cell lines (T24, 5637, and HT-1197), respectively. (I) Images of representative nude mouse xenograft model studies. T24 tumor xenografts excised from male BALB/c (nu/nu) nude mice after 28 days of treatments with the in vivo RNA interfering of MEN1 knockdown (MEN1-KD group) or control. (J) Days versus tumor volume curves for T24 tumor xenografts showed that MEN1-KD inhibited tumor growth compared with the control group. (K) Representative immunohistochemistry staining images of menin, Ki67, CDK2, and CDK4 were presented in MEN1-KD-treated or control-treated T24 xenograft nude mice tissues. Scale bar, 50 μm. ns, non-significant; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.001 versus control. MEN1, multiple endocrine neoplasia type 1; BLCA, bladder cancer; CDK2/4, cyclin-dependent kinase 2/4.
Credit: Qing Shi, Xiang Pan, Shiheng Zhang, Mengyuan Wu, Meiqi Xu, Yun-Qi Li, Li Zhong, Zi-Qi Wang, Wanhai Xu, Yakun Luo
Bladder cancer (BLCA) is one of the most prevalent malignancies of the urinary system, prone to recurrence, metastasis, and drug resistance. Its complex biological characteristics underscore the need to explore the molecular mechanisms underlying various aspects of BLCA tumorigenesis, while concurrently identifying novel therapeutic targets.
Menin, encoded by the MEN1 gene, has been implicated in the initiation and progression of various cancers, including leukemia, breast, prostate, and liver cancers; however, its role in the progression of BLCA remains elusive.
A recent study published in the Genes & Diseases journal, conducted by researchers from Harbin Medical University, Chongqing Three Gorges Medical College, Shanghai Jiaotong University School of Medicine, and Université Claude Bernard Lyon 1, investigated the role of menin and its associated mechanisms in the progression of bladder cancer.
Initial mRNA and protein expression analysis of human BCLA tissues revealed that higher MEN1 levels were associated with poor overall survival, correlated positively with patients' age, tumor stage & lymph node metastasis, and with high levels of cell-cycle-related proteins. At the same time, its knockdown decreased xenograft tumor size in a nude mouse model, which establishes its oncogenic role in BLCA.
MEN1 knockdown inhibited BLCA proliferation and induced G1/S phase cell cycle arrest, suggesting that menin promotes proliferation by enhancing cell cycle transition in these cells. Consequently, RNA sequencing and KEGG analysis revealed the enrichment of differentially expressed genes in pathways including the Wnt signaling, cell cycle, autophagy, TNF signaling, mitophagy, polycomb repressive complex, nucleotide excision repair, DNA replication, and apoptosis, among others. Additionally, MEN1-KD downregulates β-catenin at both the mRNA and protein levels. Mechanistically, menin regulates CTNNB1 transcription by binding to its proximal promoter, thus activating the Wnt/β-catenin signaling pathway in BLCA cells.
The authors further showed that menin upregulates TFAP2C expression by binding to its proximal promoter, mediated by the MLL complex, in BLCA cells, which suggests that TFAP2C is a new downstream target for menin in BLCA cells. Experiments involving TFAP2C and CTNNB1 knockdown unravelled that TFAP2C regulates CTNNB1 gene transcription by binding to its proximal promoter, and that TFAP2C is essential for menin-mediated CTNNB1 transcription in BLCA cells.
Furthermore, BAY-15522, a small molecule inhibitor of menin, was shown to suppress the proliferation and growth of BLCA tumors via inhibiting the menin/TFAP2C/β-catenin signaling axis, which further validates the tumorigenic role of menin in BLCA progression.
In conclusion, this study demonstrated that menin promotes BLCA malignancy by enhancing TFAP2C/β-catenin signaling, suggesting its potential as a therapeutic target and prognostic marker in BLCA.
Reference
Title of the original paper: Menin facilitates the cell proliferation of bladder cancer via modulating the TFAP2C/β-catenin axis
Journal: Genes & Diseases
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DOI: https://doi.org/10.1016/j.gendis.2025.101565
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