Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumor Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong 264003, PR China.
Department of Pathology, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264099, PR China.
Neoplasia. 2024 Dec;58:101067. doi: 10.1016/j.neo.2024.101067. Epub 2024 Oct 8.
We previously reported that immunoglobulin superfamily member 9 (IGSF9) as a tumor specific immune checkpoint promoted the tumor immune escape, however, as an adhesion molecule, whether IGSF9 promotes tumor invasion and metastasis has not been reported. Here, the full length, the intracellular domain (ID) not extracellular domain (ECD) of IGSF9 could alter tumor cell morphology from a flat and polygonal shape to elongated strips, suggesting that IGSF9 signal pathway has the potential to mediate epithelial-to-mesenchymal transition (EMT). Real-time PCR and western blotting also showed that the mesenchymal markers were significantly up-regulated, and the epithelial markers were significantly down-regulated in IGSF9 and IGSF9-ID groups. Meanwhile, immunofluorescence showed that β-catenin was clearly translocated into the nucleus in IGSF9 and IGSF9-ID groups. The in vitro and in vivo data showed that IGSF9, IGSF9-ID and ECD could promote tumor invasion and metastasis. Mechanistically, IGSF9-ID could recruit GSK-3β to result in the accumulation and nuclear translocation of β-catenin to trigger EMT. Anti-IGSF9 could significantly inhibit the invasion and metastasis, and IGSF9 is an effective candidate for lung cancer therapy.
我们之前报道了免疫球蛋白超家族成员 9（IGSF9）作为一种肿瘤特异性免疫检查点，促进肿瘤免疫逃逸，然而，作为一种黏附分子，IGSF9 是否促进肿瘤侵袭和转移尚未报道。在这里，全长和细胞内结构域（ID）而非细胞外结构域（ECD）的 IGSF9 可使肿瘤细胞形态从扁平多角形变为细长带形，这表明 IGSF9 信号通路有可能介导上皮-间充质转化（EMT）。实时 PCR 和 Western blot 也显示，IGSF9 和 IGSF9-ID 组中的间充质标志物显著上调，上皮标志物显著下调。同时，免疫荧光显示 IGSF9 和 IGSF9-ID 组中β-catenin 明显转位到细胞核中。体外和体内数据表明，IGSF9、IGSF9-ID 和 ECD 均可促进肿瘤侵袭和转移。在机制上，IGSF9-ID 可募集 GSK-3β 导致β-catenin 的积累和核转位，从而引发 EMT。抗 IGSF9 可显著抑制侵袭和转移，IGSF9 是肺癌治疗的有效候选药物。
