Division of Disease Model Innovation, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Avian Zoonosis Research Center, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan.
Division of Disease Model Innovation, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
Biochem Biophys Res Commun. 2014 Jul 18;450(1):532-7. doi: 10.1016/j.bbrc.2014.06.009. Epub 2014 Jun 9.
Tumor-associated MUC1 binds to Siglec-9, which is expected to mediate tumor cell growth and negative immunomodulation. We hypothesized that a soluble form of Siglec-9 (sSiglec-9) competitively inhibits a binding of MUC1 to its receptor molecules like human Siglec-9, leading to provide antitumor benefit against MUC1-expressing tumor, and generated transgenic mouse lines expressing sSiglec-9 (sSiglec-9 Tg). When mammary tumor cells expressing MUC1 were intraperitoneally transplanted into sSiglec-9 Tg, tumor proliferation was slower with the lower histological malignancy as compared with non-transgenic mice. The sSiglec-9 was detected in the ascites caused by the tumor in the sSiglec-9 Tg, and sSiglec-9 and MUC1 were often colocalized on surfaces of the tumor cells. PCNA immunohistochemistry also revealed the reduced proliferation of the tumor cells in sSiglec-9 Tg. In sSiglec-9 Tg with remarkable suppression of tumor proliferation, MUC1 expressions were tend to be reduced. In the ascites of sSiglec-9 Tg bearing the tumor, T cells were uniformly infiltrated, whereas aggregations of degenerative T cells were often observed in the non-transgenic mice. These results suggest that sSiglec-9 has an antitumor benefit against MUC1-expressing tumor in the transgenic mice, which may avoid the negative immunomodulation and/or suppress tumor-associated MUC1 downstream signal transduction, and subsequent tumor proliferation.
肿瘤相关 MUC1 与 Siglec-9 结合，预计介导肿瘤细胞生长和负性免疫调节。我们假设可溶性 Siglec-9（sSiglec-9）可竞争性抑制 MUC1 与其受体分子（如人 Siglec-9）的结合，从而对表达 MUC1 的肿瘤提供抗肿瘤益处，并生成表达 sSiglec-9 的转基因小鼠系（sSiglec-9 Tg）。当表达 MUC1 的乳腺肿瘤细胞被腹膜内移植到 sSiglec-9 Tg 中时，与非转基因小鼠相比，肿瘤增殖较慢，组织学恶性程度较低。在 sSiglec-9 Tg 的腹水肿瘤中检测到 sSiglec-9，并且 sSiglec-9 和 MUC1 经常在肿瘤细胞表面共定位。PCNA 免疫组化也显示 sSiglec-9 Tg 中的肿瘤细胞增殖减少。在 sSiglec-9 Tg 中，肿瘤增殖受到显著抑制，MUC1 的表达也趋于减少。在携带肿瘤的 sSiglec-9 Tg 的腹水中，T 细胞均匀浸润，而非转基因小鼠中经常观察到退化 T 细胞的聚集。这些结果表明，sSiglec-9 对转基因小鼠中表达 MUC1 的肿瘤具有抗肿瘤益处，这可能避免了负性免疫调节和/或抑制肿瘤相关 MUC1 的下游信号转导，以及随后的肿瘤增殖。
