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<p>Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare and aggressive liver cancer for which effective targeted therapies have not been established. We analyzed claudin expression in cHCC-CCA cell lines (KMCH-1 and KMCH-2) and found that claudin-2 was markedly overexpressed relative to hepatocellular carcinoma and cholangiocarcinoma cell lines, as well as primary hepatocytes. This upregulation was associated with the Wnt/β-catenin signaling pathway, a major regulator of cell proliferation. Claudin-2 knockdown reduced cell viability in both cHCC-CCA cell lines examined, suggesting that claudin-2 supports viability in these cell line models. To test whether claudin-2 function can be modulated extracellularly, we synthesized peptides mimicking the first extracellular loop (ECL1) of claudin-2. Among them, the C-terminal peptide Ex1C selectively reduced the viability of cHCC-CCA cell lines examined, but not that of other cells lacking claudin-2 overexpression. Ex1C suppressed proliferation without inducing cell death and significantly inhibited adhesion of KMCH-2 and KMCH-1 cells to primary hepatocytes. As Ex1C exhibited homotypic self-association, these effects are consistent with interference with ECL1-dependent claudin-2 interactions. Collectively, our findings identify claudin-2 as a characteristic molecular feature of the examined cHCC-CCA cell lines and support the utility of extracellular loop-mimetic peptides as probes to dissect claudin-dependent regulation of proliferation and cell adhesion.</p>

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Claudin-2 extracellular loop 1-mimetic peptides functionally inhibit combined hepatocellular-cholangiocarcinoma cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • Takeshi Honda,
  • Yuka Kondo,
  • Tatsuya Sakaguchi,
  • Yuichiro Higashimoto,
  • Hirohisa Yano,
  • Hironori Koga

摘要

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare and aggressive liver cancer for which effective targeted therapies have not been established. We analyzed claudin expression in cHCC-CCA cell lines (KMCH-1 and KMCH-2) and found that claudin-2 was markedly overexpressed relative to hepatocellular carcinoma and cholangiocarcinoma cell lines, as well as primary hepatocytes. This upregulation was associated with the Wnt/β-catenin signaling pathway, a major regulator of cell proliferation. Claudin-2 knockdown reduced cell viability in both cHCC-CCA cell lines examined, suggesting that claudin-2 supports viability in these cell line models. To test whether claudin-2 function can be modulated extracellularly, we synthesized peptides mimicking the first extracellular loop (ECL1) of claudin-2. Among them, the C-terminal peptide Ex1C selectively reduced the viability of cHCC-CCA cell lines examined, but not that of other cells lacking claudin-2 overexpression. Ex1C suppressed proliferation without inducing cell death and significantly inhibited adhesion of KMCH-2 and KMCH-1 cells to primary hepatocytes. As Ex1C exhibited homotypic self-association, these effects are consistent with interference with ECL1-dependent claudin-2 interactions. Collectively, our findings identify claudin-2 as a characteristic molecular feature of the examined cHCC-CCA cell lines and support the utility of extracellular loop-mimetic peptides as probes to dissect claudin-dependent regulation of proliferation and cell adhesion.