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hsa-let-7b-5p-associated BUB1/TMPO-AS1 ceRNA axis identified as a potential biomarker in lung adenocarcinoma
Bhavika Baweja1, Prerna Vats1, Chainsee Saini1
1Department of Biosciences, Manipal University Jaipur, Dehmi Kalan, Jaipur-Ajmer Expressway, Jaipur, Rajasthan, 303007, India.
Objective:
BUB1, a key mitotic checkpoint kinase, is often dysregulated in cancer, yet its regulatory mechanism remains unclear. This study investigates the BUB1-centered miRNA-lncRNA-mRNA (ceRNA) network, its role in cell cycle regulation and immune modulation.
Methods:
Prognostic significance and expression profiles were assessed using TCGA-based databases such as KM Plotter, UALCAN, OncoDB, ENCORI, GEPIA2, Lung Cancer Explorer, and TCGAnalyzeR. Transcription factors were identified via Enrichr, and a ceRNA network was constructed using miRNet. Binding affinity and folding energy between BUB1, miRNA, and lncRNA were predicted using miRWalk and RNA22v2. Molecular docking evaluated interactions with natural compounds, chemotherapeutics, and inhibitor. Immune subpopulations were visualized using the SPRING viewer and correlation analysis with the immune cells was conducted using the GSCA and TIMER2.0 databases.
Results:
BUB1 overexpression correlated with poor LUAD prognosis, especially in smokers (HR = 1.76), with transcriptomic analysis showing a 2.46 log2-fold increase in BUB1 transcript levels in tumor. TF-E2F1 and lncRNA-TMPO-AS1 were positively correlated with BUB1 (R = 0.664 and R = 0.632, respectively), while miRNA hsa-let-7b-5p showed a negative correlation (R = - 0.366). TMPO-AS1 exhibited an inverse association with hsa-let-7b-5p, suggesting a molecular sponge formation, repressing its tumor-suppressive activity. Docking revealed strong binding affinity of hesperidin (- 9.4 kcal/mol) with BUB1. Additionally, BUB1 expression negatively correlated with CD4⁺ T cells, suggesting an immunosuppressive role.
Conclusion:
This study identifies the BUB1/E2F1/TMPO-AS1/hsa-let-7b-5p axis as a potential prognostic biomarker and therapeutic target in LUAD. Targeting hsa-let-7b-5p may modulate this network, offering opportunities for both diagnostic and prognostic interventions.
Insights
The BUB1 mitotic kinase, often dysregulated in lung cancer, is linked to poor prognosis. A ceRNA network involving BUB1, E2F1, TMPO-AS1, and hsa-let-7b-5p presents a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- BUB1 (Budding uninhibited by benzimidazoles 1) is a critical mitotic checkpoint kinase frequently dysregulated in various cancers.
- The precise regulatory mechanisms governing BUB1 function, particularly its role in cancer progression and immune evasion, remain incompletely understood.
Purpose of the Study:
- To elucidate the BUB1-centered competing endogenous RNA (ceRNA) network in lung adenocarcinoma (LUAD).
- To investigate the network's involvement in cell cycle regulation and immune modulation.
- To identify potential prognostic biomarkers and therapeutic targets within this network.
Main Methods:
- Utilized TCGA-based databases (KM Plotter, UALCAN, etc.) for prognostic and expression analyses.
- Identified transcription factors and constructed the ceRNA network using Enrichr and miRNet.
- Predicted binding affinities using miRWalk and RNA22v2; performed molecular docking.
- Analyzed immune cell correlations using GSCA and TIMER2.0.
Main Results:
- BUB1 overexpression correlates with poor LUAD prognosis, particularly in smokers, with significantly increased transcript levels in tumors.
- Positive correlations were observed between BUB1, TF-E2F1, and lncRNA-TMPO-AS1; a negative correlation was found with miRNA hsa-let-7b-5p.
- TMPO-AS1 acts as a molecular sponge for hsa-let-7b-5p, diminishing its tumor-suppressive activity. Hesperidin showed strong binding affinity with BUB1.
- BUB1 expression negatively correlated with CD4+ T cells, indicating an immunosuppressive role.
Conclusions:
- The BUB1/E2F1/TMPO-AS1/hsa-let-7b-5p axis is identified as a potential prognostic biomarker and therapeutic target in LUAD.
- Modulating this network, potentially by targeting hsa-let-7b-5p, offers avenues for diagnostic and prognostic interventions in LUAD.
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