What is the clinical evidence from this study?

Study design: Observational. Population: Bladder cancer (n=100). Intervention: LDB2 expression vs. Normal tissues / Low LDB2 expression. Primary outcome: Diagnostic performance (AUC) in distinguishing tumor from normal tissues (TCGA cohort) (AUC 0.91, 95% CI 0.86-0.96).

What does this research mean for the field?

LDB2 demonstrates strong diagnostic performance in distinguishing bladder cancer from normal tissues with an AUC of 0.91, and its expression correlates with favorable prognosis and reduced metastasis by activating the p38 MAPK/ERK1/2/JNK signaling pathway. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

November 18, 2025Open Access

LDB2 is a novel diagnostic and prognostic biomarker and inhibits bladder cancer metastasis by activating p38 MAPK/ERK1/2/JNK signaling pathway

YLYue LiHebei Medical University BZBin ZhaoMarine Biology Institute of Shandong Province WGWenzhi GaoPeking University

Key Result

LDB2 demonstrated strong diagnostic performance in distinguishing bladder cancer from normal tissues with an AUC of 0.91, and its expression correlated with favorable prognosis and reduced metastasis.

Study Design

Type

Observational (n=100)

Multicenter

Structured PICO

Does LDB2 expression correlate with prognosis and inhibit metastasis in bladder cancer?

Population

124 clinical samples of bladder cancer (8 paired BLCA and adjacent non-tumorous tissues, 16 additional BLCA-adjacent non-cancer tissue pairs, 100 FFPE BLCA blocks), TCGA-BLCA cohort (412 tumor, 19 normal), GEO datasets (GSE37815, GSE13507, GSE39281), and human bladder cancer cell lines (T24, 5637, EJ, RT112, J82).

Intervention

LDB2 knockdown via shRNA and LDB2 overexpression via lentiviral vectors in bladder cancer cell lines.

Comparator

Control vectors and normal bladder tissues/cells.

Outcome

LDB2 expression levels, diagnostic performance (AUC), prognostic significance (survival), cell proliferation, migration, invasion, and MAPK pathway phosphorylation.surrogate

LDB2 acts as a tumor suppressor in bladder cancer, inhibiting metastasis via the p38 MAPK/ERK1/2/JNK pathway, and serves as a potential diagnostic and prognostic biomarker.

Main Result

Effect estimate: AUC 0.91 (95% CI 0.86-0.96)

Limitations

Lack of in vivo validation of LDB2's tumor-suppressive function.
Only two bladder cancer cell lines (5637 and T24) were used for functional experiments, which may not fully capture molecular heterogeneity.
The precise molecular mechanisms underlying LDB2's regulation of the MAPK pathway remain unclear.
The clinical relevance of LDB2 as a diagnostic or prognostic biomarker requires validation in large, prospective patient cohorts.

Abstract

LIM domain binding protein 2 (LDB2), a transcriptional co-regulator of the LIM protein family, is reported to be downregulated in various tumors. However, its role in bladder cancer (BLCA) remains undefined. This study analyzed the molecular mechanism of LDB2 in inhibiting the metastasis of bladder cancer and its diagnostic and prognostic value in BLCA. We integrated The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets with enrichment analysis to evaluate the expression, diagnostic potential, and prognostic significance of LDB2 in BLCA. Immunohistochemistry (IHC) was performed to assess LDB2 expression in normal and metastatic tissues and its correlation with clinical stage and prognosis. Functional assays, including clonogenic and Transwell assays, were conducted in LDB2 knockdown and overexpression cell lines to examine its role in proliferation, migration, and invasion. Gene expression was assessed at both mRNA and protein levels using qPCR and Western blot. Additionally, CIBERSORT analysis was performed to explore the correlation between LDB2 expression and immune cell infiltration in BLCA. LDB2 expression was significantly lower in metastatic bladder cancer tissues compared with normal bladder tissues (all p < 0.001). Its expression was positively correlated with early clinical stage and favorable prognosis (all p < 0.05), Moreover, LDB2 showed strong diagnostic performance in distinguishing tumor from normal tissues, with AUC values of 0.91 (95% CI 0.86-0.96) in the TCGA cohort and 0.96 (95% CI 0.88-1.00) in the GSE37815 dataset. Furthermore, in vitro assays demonstrated that LDB2 knockdown significantly promoted invasion, metastasis, and colony formation in bladder cancer cells, whereas its overexpression suppressed these malignant behaviors. Mechanistic studies revealed that LDB2 knockdown markedly reduced the phosphorylation of key MAPK pathway components, including p38 MAPK, ERK1/2, and JNK, whereas LDB2 overexpression enhanced their phosphorylation. Immune infiltration analysis indicated that elevated LDB2 expression was associated with increased immune cell infiltration, particularly showing significant correlations with macrophages and mast cells. LDB2 may serve as a novel diagnostic biomarker and tumor suppressor by inhibiting proliferation, invasion, and metastasis via activation of the p38 MAPK/ERK1/2/JNK pathway and modulating the tumor immune microenvironment.

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