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<p>Amphiregulin (AREG) functions as an epidermal growth factor receptor (EGFR) ligand that modulates signaling and supports nuclear processes involved in DNA replication and repair in colorectal cancer (CRC). Immunohistochemistry and western blot revealed high expression of AREG in CRC tumors compared to other CRCs. Our findings indicate that AREG translocates into the nucleus, a process potentially facilitated by the inhibition of endocytosis. Transcriptomic analyses suggest an association between AREG expression and genes regulating EGFR signaling, replication fork dynamics, and homologous recombination. Depletion of AREG via siRNA or CRISPR-Cas9 led to S/G₂ arrest, replication tract shortening, and increased RAD51, RPA, and γH2AX foci, resulting in a 40–60% reduction in proliferation effects that were not fully recapitulated by small-molecule EGFR inhibitors. In xenograft models, AREG knockout reduced tumor growth and suppressed the phosphorylation of EGFR, ERK, STAT3, and BRAF. Furthermore, combining AREG loss with EGFR inhibition appeared to enhance antitumor effects. These findings suggest that AREG may function as a mediator of EGFR signaling and genome maintenance in CRC.</p>

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Amphiregulin drives EGFR-dependent genome stability in colorectal cancer and represents a targetable vulnerability

  • 期刊论文

  • 发表日期：

    2026年6月15日

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  • Sun-Ji Park,
  • Sung-Woo Lee,
  • Heegyum Moon,
  • Su-Min Jung,
  • Jin-Man Kim,
  • Dong-Seok Lee,
  • Eui-Hwan Choi

摘要

Amphiregulin (AREG) functions as an epidermal growth factor receptor (EGFR) ligand that modulates signaling and supports nuclear processes involved in DNA replication and repair in colorectal cancer (CRC). Immunohistochemistry and western blot revealed high expression of AREG in CRC tumors compared to other CRCs. Our findings indicate that AREG translocates into the nucleus, a process potentially facilitated by the inhibition of endocytosis. Transcriptomic analyses suggest an association between AREG expression and genes regulating EGFR signaling, replication fork dynamics, and homologous recombination. Depletion of AREG via siRNA or CRISPR-Cas9 led to S/G₂ arrest, replication tract shortening, and increased RAD51, RPA, and γH2AX foci, resulting in a 40–60% reduction in proliferation effects that were not fully recapitulated by small-molecule EGFR inhibitors. In xenograft models, AREG knockout reduced tumor growth and suppressed the phosphorylation of EGFR, ERK, STAT3, and BRAF. Furthermore, combining AREG loss with EGFR inhibition appeared to enhance antitumor effects. These findings suggest that AREG may function as a mediator of EGFR signaling and genome maintenance in CRC.