Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
Single Cell Genomics, Human Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Pathol Res Pract. 2024 Oct;262:155562. doi: 10.1016/j.prp.2024.155562. Epub 2024 Aug 24.
Mesothelin (MSLN) is expressed in the mesothelium in normal tissues but is overexpressed in various malignant tumors. In this study, we searched for genes that were more frequently expressed in cases of endometrioid carcinoma (EC) with the MELF (microcystic, elongated, and fragmented) pattern using laser microdissection and RNA sequencing, and found that MSLN was predominantly expressed in cases with the MELF pattern. The role of MSLN in EC was analyzed by generating MSLN-knockout and -knockdown EC cell lines. MSLN promoted migration and epithelial-mesenchymal transition (EMT). Moreover, we found that cadherin-6 (CDH6) expression was regulated by MSLN. MSLN is known to bind to cancer antigen 125 (CA125), and we found that CA125 can regulate CDH6 expression via MSLN. Immunohistochemical investigations showed that MSLN, CA125, and CDH6 expression levels were considerably elevated in EC with the MELF pattern. The expression of CA125 was similar to that of MSLN not only in terms of immunohistochemical staining intensity but also the blood level of CA125. Our results showed that MSLN contributes to the migration and EMT of EC cells through upstream CA125 and downstream CDH6. Therefore, MSLN has potential as a therapeutic target for EC with the MELF pattern.
间皮素 (MSLN) 在正常组织的间皮中表达，但在各种恶性肿瘤中过度表达。在这项研究中，我们使用激光显微切割和 RNA 测序，搜索了在具有微囊状、拉长和碎片化 (MELF) 模式的子宫内膜样癌 (EC) 病例中更频繁表达的基因，发现 MSLN 在具有 MELF 模式的病例中表达更为显著。通过生成 MSLN 敲除和敲低 EC 细胞系，分析了 MSLN 在 EC 中的作用。MSLN 促进迁移和上皮间质转化 (EMT)。此外，我们发现钙粘蛋白-6 (CDH6) 的表达受 MSLN 调控。MSLN 已知与癌症抗原 125 (CA125) 结合，我们发现 CA125 可以通过 MSLN 调节 CDH6 的表达。免疫组织化学研究表明，具有 MELF 模式的 EC 中 MSLN、CA125 和 CDH6 的表达水平显著升高。CA125 的表达不仅在免疫组织化学染色强度方面，而且在 CA125 的血液水平方面与 MSLN 相似。我们的结果表明，MSLN 通过上游 CA125 和下游 CDH6 促进 EC 细胞的迁移和 EMT。因此，MSLN 有可能成为具有 MELF 模式的 EC 的治疗靶点。
