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Background <p>Lung adenocarcinoma (LUAD) is a prevalent and deadly form of lung cancer. Exercise has been shown to inhibit LUAD progression, yet the underlying molecular mechanisms remain unclear. The transcription factor POU2F2 has been implicated in LUAD tumorigenesis, but its precise role and regulatory targets have not been fully elucidated.</p> Methods <p>POU2F2 expression in LUAD cell lines (HCC4006, Calu-3, NCI-H2009) and normal lung epithelial cells (BEAS-2B) was assessed by qRT-PCR and Western blot. Functional assays (CCK-8, EdU, flow cytometry, TUNEL) were performed following shRNA-mediated knockdown of POU2F2 or SPOCD1 and upregulation of POU2F2. Mechanistic studies included bioinformatics, dual-luciferase assay, ChIP, DNA pull-down, and Western blot. In vivo tumor growth was evaluated via xenograft models with Ki67 IHC.</p> Results <p>Exercise suppressed POU2F2 expression, which was otherwise elevated in LUAD cells. Knockdown of POU2F2 or its downstream target SPOCD1 reduced proliferation and increased apoptosis. Mechanistically, POU2F2 directly bound to and activated the SPOCD1 promoter, thereby enhancing PI3K/AKT pathway signaling. Rescue experiments confirmed that SPOCD1 mediates POU2F2’s oncogenic effects. In vivo, POU2F2 knockdown inhibited tumor growth and Ki67 expression.</p> Conclusions <p>Exercise suppresses LUAD progression by downregulating POU2F2, thereby disrupting the POU2F2–SPOCD1–PI3K/AKT axis. This pathway plays a critical role in LUAD cell survival and may serve as a promising therapeutic target.</p> Key points <p>Exercise inhibits LUAD progression by downregulating the oncogenic transcription factor POU2F2. The POU2F2-SPOCD1 axis exerts its oncogenic function by activating the PI3K/AKT pathway. The POU2F2-SPOCD1 axis may represent a promising therapeutic target for LUAD.</p> Graphical abstract

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Exercise inhibits proliferation and induces apoptosis of lung adenocarcinoma cells via the POU2F2-SPOCD1-PI3K/AKT signaling axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月8日

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  • Shujing Shi,
  • Yumu Leng,
  • Linfei Yang,
  • Buyi Zhu,
  • Haixin Tan,
  • Fengming Wang,
  • Jiaqi Pan,
  • Zhenhua Yang,
  • Wei Gu,
  • Weiwei He

摘要

Background

Lung adenocarcinoma (LUAD) is a prevalent and deadly form of lung cancer. Exercise has been shown to inhibit LUAD progression, yet the underlying molecular mechanisms remain unclear. The transcription factor POU2F2 has been implicated in LUAD tumorigenesis, but its precise role and regulatory targets have not been fully elucidated.

Methods

POU2F2 expression in LUAD cell lines (HCC4006, Calu-3, NCI-H2009) and normal lung epithelial cells (BEAS-2B) was assessed by qRT-PCR and Western blot. Functional assays (CCK-8, EdU, flow cytometry, TUNEL) were performed following shRNA-mediated knockdown of POU2F2 or SPOCD1 and upregulation of POU2F2. Mechanistic studies included bioinformatics, dual-luciferase assay, ChIP, DNA pull-down, and Western blot. In vivo tumor growth was evaluated via xenograft models with Ki67 IHC.

Results

Exercise suppressed POU2F2 expression, which was otherwise elevated in LUAD cells. Knockdown of POU2F2 or its downstream target SPOCD1 reduced proliferation and increased apoptosis. Mechanistically, POU2F2 directly bound to and activated the SPOCD1 promoter, thereby enhancing PI3K/AKT pathway signaling. Rescue experiments confirmed that SPOCD1 mediates POU2F2’s oncogenic effects. In vivo, POU2F2 knockdown inhibited tumor growth and Ki67 expression.

Conclusions

Exercise suppresses LUAD progression by downregulating POU2F2, thereby disrupting the POU2F2–SPOCD1–PI3K/AKT axis. This pathway plays a critical role in LUAD cell survival and may serve as a promising therapeutic target.

Key points

Exercise inhibits LUAD progression by downregulating the oncogenic transcription factor POU2F2. The POU2F2-SPOCD1 axis exerts its oncogenic function by activating the PI3K/AKT pathway. The POU2F2-SPOCD1 axis may represent a promising therapeutic target for LUAD.

Graphical abstract