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Background <p>Esophageal Adenocarcinoma (EAC) is an aggressive malignancy with poor prognosis. The rising incidence of EAC in the past few decades underscores the need to better understand the molecular features of EAC. The role of the transcriptional co-factor Limb-Bud and Heart (LBH), implicated in embryonic development and Wnt signaling, remains unclearly characterized in gastrointestinal cancers. Given the importance of gastroesophageal reflux disease and acidic bile salts (ABS) exposure in EAC tumorigenesis and progression, we investigated the role of LBH in EAC carcinogenesis.</p> Hypothesis/objectives <p>We hypothesized that LBH promotes tumor progression in EAC by enhancing proliferation and survival, particularly under reflux-like conditions.</p> Methods <p>LBH expression levels were compared between normal and EACs using publicly available databases, patient samples, and cell lines. Functional roles were assessed using siRNA knockdown and overexpression models in EAC cell lines, followed by BrdU incorporation, colony formation, luciferase reporter assays, qRT-PCR, and western blot analysis of pathway markers.</p> Results <p>LBH expression was significantly elevated in EAC tissues and cell lines compared to non-neoplastic esophageal tissues. Knockdown of LBH reduced proliferation, viability, and colony formation, while overexpression had opposite effects. BrdU assays confirmed decreased proliferation with knockdown and increased proliferation with overexpression. Mechanistically, LBH upregulated the Wnt signaling pathway. LBH depletion suppressed β-catenin, cyclin D1, and Wnt transcriptional activity, while overexpression induced activation of these pathways. ABS treatment induced β-catenin and cyclin D1 expression and increased Wnt activity, and these effects were diminished with LBH knockdown. At the transcriptional level, LBH depletion decreased mRNA expression of proliferation-associated markers (PCNA, FOXM1, and CCND1), confirming its role in driving tumor growth. Importantly, LBH knockdown also induced apoptosis and suppressed cell survival signaling. Western blot analysis showed decreased BCL-xL and BCL2 levels with increased PARP cleavage. Similarly qRT-PCR showed reduced BCL2 and BCL-xL, and increased BIM, consistent with heightened apoptosis and reduced survival.</p> Conclusion <p>LBH plays an important role in activation of signaling pathways that promote cell proliferation and survival in EAC. These findings warrant further investigation for testing the therapeutic potential of targeting LBH in EAC.</p>

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Limb-bud and heart (LBH) promotes expansion and survival of esophageal adenocarcinoma cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Sydnee Fo,
  • Heng Lu,
  • Lei Chen,
  • Dunfa Peng,
  • Zheng Chen,
  • Wael El-Rifai,
  • Farah Ballout

摘要

Background

Esophageal Adenocarcinoma (EAC) is an aggressive malignancy with poor prognosis. The rising incidence of EAC in the past few decades underscores the need to better understand the molecular features of EAC. The role of the transcriptional co-factor Limb-Bud and Heart (LBH), implicated in embryonic development and Wnt signaling, remains unclearly characterized in gastrointestinal cancers. Given the importance of gastroesophageal reflux disease and acidic bile salts (ABS) exposure in EAC tumorigenesis and progression, we investigated the role of LBH in EAC carcinogenesis.

Hypothesis/objectives

We hypothesized that LBH promotes tumor progression in EAC by enhancing proliferation and survival, particularly under reflux-like conditions.

Methods

LBH expression levels were compared between normal and EACs using publicly available databases, patient samples, and cell lines. Functional roles were assessed using siRNA knockdown and overexpression models in EAC cell lines, followed by BrdU incorporation, colony formation, luciferase reporter assays, qRT-PCR, and western blot analysis of pathway markers.

Results

LBH expression was significantly elevated in EAC tissues and cell lines compared to non-neoplastic esophageal tissues. Knockdown of LBH reduced proliferation, viability, and colony formation, while overexpression had opposite effects. BrdU assays confirmed decreased proliferation with knockdown and increased proliferation with overexpression. Mechanistically, LBH upregulated the Wnt signaling pathway. LBH depletion suppressed β-catenin, cyclin D1, and Wnt transcriptional activity, while overexpression induced activation of these pathways. ABS treatment induced β-catenin and cyclin D1 expression and increased Wnt activity, and these effects were diminished with LBH knockdown. At the transcriptional level, LBH depletion decreased mRNA expression of proliferation-associated markers (PCNA, FOXM1, and CCND1), confirming its role in driving tumor growth. Importantly, LBH knockdown also induced apoptosis and suppressed cell survival signaling. Western blot analysis showed decreased BCL-xL and BCL2 levels with increased PARP cleavage. Similarly qRT-PCR showed reduced BCL2 and BCL-xL, and increased BIM, consistent with heightened apoptosis and reduced survival.

Conclusion

LBH plays an important role in activation of signaling pathways that promote cell proliferation and survival in EAC. These findings warrant further investigation for testing the therapeutic potential of targeting LBH in EAC.