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Background <p>Serum trefoil factor 3 (TFF3) has emerged as a promising biomarker for gastric cancer; however, its biological origin remains unclear.</p> Methods <p>Gastric cancer was induced by <i>Helicobacter pylori</i> infection combined with N-methyl-N-nitrosourea (MNU), whereas a rat model was established using N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) alone. Serum TFF levels were measured by ELISA. Organ-specific TFF3 expression, cytokine profiles, STAT3 activation, and epigenetic regulation were analyzed using RT-PCR, immunohistochemistry, multiplex assays, Western blotting, and ChIP–qPCR.</p> Results <p>Serum TFF1–3 levels were significantly elevated in gastric cancer–bearing mice, with TFF3 showing robust diagnostic performance. In rats, serum TFF3 levels remained unchanged after total gastrectomy. TFF3 expression was selectively upregulated in the liver, accompanied by STAT3 activation. Gastric IL-6 expression was increased, suggesting portal-mediated signaling to the liver. ChIP–qPCR demonstrated sustained enrichment of H3K27ac at the TFF3 locus following IL-6 stimulation.</p> Conclusions <p>Increased serum TFF3 in gastric cancer originates from the liver and is associated with IL-6–STAT3 signaling. Persistent elevation after gastrectomy may be explained by epigenetic activation, supporting the biological basis of TFF3 as a surrogate marker.</p>

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Hepatic origin of increased serum TFF3 in gastric cancer bearing subjects

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • Komei Kuge,
  • Junko Mukoyama,
  • Yoshimi Yasukawa,
  • Yuko Ishibashi,
  • Hiroki Masuda,
  • Tomohiko Yasuda,
  • Yasukazu Ohmoto,
  • Hideyuki Takeshima,
  • Akihisa Matsuda,
  • Hiroshi Yoshida,
  • Yasuyuki Seto,
  • James R. Goldenring,
  • Toshikazu Ushijima,
  • Sachiyo Nomura

摘要

Background

Serum trefoil factor 3 (TFF3) has emerged as a promising biomarker for gastric cancer; however, its biological origin remains unclear.

Methods

Gastric cancer was induced by Helicobacter pylori infection combined with N-methyl-N-nitrosourea (MNU), whereas a rat model was established using N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) alone. Serum TFF levels were measured by ELISA. Organ-specific TFF3 expression, cytokine profiles, STAT3 activation, and epigenetic regulation were analyzed using RT-PCR, immunohistochemistry, multiplex assays, Western blotting, and ChIP–qPCR.

Results

Serum TFF1–3 levels were significantly elevated in gastric cancer–bearing mice, with TFF3 showing robust diagnostic performance. In rats, serum TFF3 levels remained unchanged after total gastrectomy. TFF3 expression was selectively upregulated in the liver, accompanied by STAT3 activation. Gastric IL-6 expression was increased, suggesting portal-mediated signaling to the liver. ChIP–qPCR demonstrated sustained enrichment of H3K27ac at the TFF3 locus following IL-6 stimulation.

Conclusions

Increased serum TFF3 in gastric cancer originates from the liver and is associated with IL-6–STAT3 signaling. Persistent elevation after gastrectomy may be explained by epigenetic activation, supporting the biological basis of TFF3 as a surrogate marker.