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Background <p>Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis, which is often driven by chromosomal amplifications at 1q. Vacuolar sorting protein 45&#xa0;(VPS45), a gene located on chromosome 1q, is involved in the endocytic recycling pathway; however, its role in HCC remains unclear. In this study, we aimed to investigate the functional significance of VPS45 in the progression of HCC.</p> Methods <p>VPS45 expression was analyzed using public databases, clinical HCC samples, and cell lines. Functional assays, including VPS45 knockout and rescue experiments, were conducted to assess the effect on tumor progression in vitro and in vivo. The molecular mechanisms underlying VPS45 function, particularly its role in β1 integrin recycling and FAK-AKT signaling activation, were also explored.</p> Results <p>VPS45 expression was significantly elevated in HCC owing to DNA copy number amplification and correlated with poor prognosis. Moreover, VPS45 knockout suppressed cell proliferation, migration, and invasion, while promoting apoptosis. VPS45 interacted with syntaxin16 and rabenosyn-5 to facilitate the recycling of β1 integrin to the cell membrane, thereby activating FAK-AKT signaling, which promotes oncogenic phenotypes. In xenograft models, VPS45 knockout significantly suppressed tumor growth, further supporting its role in HCC progression.</p> Conclusions <p>VPS45 is a key oncogene in HCC that promotes tumor progression by enhancing β1 integrin recycling and activating FAK-AKT signaling. Given its strong association with poor prognosis and tumor malignancy, VPS45 may serve as a promising prognostic biomarker and a potential therapeutic target for HCC.</p>

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VPS45 promotes the progression of hepatocellular carcinoma by recycling β1 integrin to the cell membrane via the endocytic pathway

  • 期刊论文

  • 发表日期：

    2025年6月20日

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  • Takashi Ofuchi,
  • Hajime Otsu,
  • Kiyotaka Hosoda,
  • Tomohiko Ikehara,
  • Akinori Tsujimoto,
  • Satoshi Higuchi,
  • Shohei Shibuta,
  • Yuya Ono,
  • Kosuke Hirose,
  • Yasuo Tsuda,
  • Yusuke Yonemura,
  • Takaaki Masuda,
  • Hiromitsu Hayashi,
  • Masaaki Iwatsuki,
  • Koshi Mimori

摘要

Background

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis, which is often driven by chromosomal amplifications at 1q. Vacuolar sorting protein 45 (VPS45), a gene located on chromosome 1q, is involved in the endocytic recycling pathway; however, its role in HCC remains unclear. In this study, we aimed to investigate the functional significance of VPS45 in the progression of HCC.

Methods

VPS45 expression was analyzed using public databases, clinical HCC samples, and cell lines. Functional assays, including VPS45 knockout and rescue experiments, were conducted to assess the effect on tumor progression in vitro and in vivo. The molecular mechanisms underlying VPS45 function, particularly its role in β1 integrin recycling and FAK-AKT signaling activation, were also explored.

Results

VPS45 expression was significantly elevated in HCC owing to DNA copy number amplification and correlated with poor prognosis. Moreover, VPS45 knockout suppressed cell proliferation, migration, and invasion, while promoting apoptosis. VPS45 interacted with syntaxin16 and rabenosyn-5 to facilitate the recycling of β1 integrin to the cell membrane, thereby activating FAK-AKT signaling, which promotes oncogenic phenotypes. In xenograft models, VPS45 knockout significantly suppressed tumor growth, further supporting its role in HCC progression.

Conclusions

VPS45 is a key oncogene in HCC that promotes tumor progression by enhancing β1 integrin recycling and activating FAK-AKT signaling. Given its strong association with poor prognosis and tumor malignancy, VPS45 may serve as a promising prognostic biomarker and a potential therapeutic target for HCC.