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<p>Metastasis to distant organs represents the most fatal prognostic factor for colorectal cancer (CRC). The distant metastasis of tumor cells results from the collaborative effort of multiple subcellular structures, with dynamic cytoskeletal remodeling underlying this entire process. Here, we found that knockdown of KRT81 expression (shKRT81) inhibited the proliferation, invasion, and migration, while ectopic overexpression of KRT81 enhanced the CRC cells migration. Furthermore, we identified a potential downstream effector of KRT81, ezrin, a member of the ezrin/radixin/moesin (ERM) protein family that regulates cell morphology and motility. Phenotypically, the shKRT81 attenuated ezrin protein expression and reduced the number and length of filopodia in CRC cells, which were restored when KRT81 was re-overexpressed. Mechanistically, KRT81 formed a complex with ezrin, and recruitment of ezrin to the membrane and phosphorylation at the Thr567 residue were significantly abolished in shKRT81 cells. Interestingly, we found that Myosin 1B (MYO1B) might provide the driving force for the recruitment of ezrin. Notably, combinatorial inhibition (shKRT81 + ezrin-specific inhibitor) exerted significantly greater suppression of CRC cell migration and invasion than either intervention alone. Consistently, KRT81 expression was increased in CRC, and relatively high expression of KRT81 was associated with a poor prognosis. In summary, we identified a novel regulatory axis that involves KRT81, MYO1B, and ezrin, which regulates filopodia formation and migration behavior in CRC. Therefore, KRT81 may serve as a therapeutic target for CRC.</p><p></p>

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KRT81 promotes metastasis of colorectal cancer by acting as a protein scaffold for ezrin

  • 期刊论文

  • 发表日期：

    2025年12月17日

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  • Minghan Huang,
  • Wenqing Xie,
  • Meihua Wu,
  • Zhimei Ou,
  • Caibin Li,
  • Shuhui Ji,
  • Wanjun Liu,
  • Min Zhi,
  • Daici Chen

摘要

Metastasis to distant organs represents the most fatal prognostic factor for colorectal cancer (CRC). The distant metastasis of tumor cells results from the collaborative effort of multiple subcellular structures, with dynamic cytoskeletal remodeling underlying this entire process. Here, we found that knockdown of KRT81 expression (shKRT81) inhibited the proliferation, invasion, and migration, while ectopic overexpression of KRT81 enhanced the CRC cells migration. Furthermore, we identified a potential downstream effector of KRT81, ezrin, a member of the ezrin/radixin/moesin (ERM) protein family that regulates cell morphology and motility. Phenotypically, the shKRT81 attenuated ezrin protein expression and reduced the number and length of filopodia in CRC cells, which were restored when KRT81 was re-overexpressed. Mechanistically, KRT81 formed a complex with ezrin, and recruitment of ezrin to the membrane and phosphorylation at the Thr567 residue were significantly abolished in shKRT81 cells. Interestingly, we found that Myosin 1B (MYO1B) might provide the driving force for the recruitment of ezrin. Notably, combinatorial inhibition (shKRT81 + ezrin-specific inhibitor) exerted significantly greater suppression of CRC cell migration and invasion than either intervention alone. Consistently, KRT81 expression was increased in CRC, and relatively high expression of KRT81 was associated with a poor prognosis. In summary, we identified a novel regulatory axis that involves KRT81, MYO1B, and ezrin, which regulates filopodia formation and migration behavior in CRC. Therefore, KRT81 may serve as a therapeutic target for CRC.