Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
Cancer Sci. 2012 Apr;103(4):739-46. doi: 10.1111/j.1349-7006.2012.02214.x. Epub 2012 Feb 23.
The invasion process is a crucial step for pancreatic ductal adenocarcinoma (PDAC); however, the genes related to invasion remain unclear. To identify specific genes for the invasion process, we compared microarray data for infiltrating cancer and PanIN-3, which were harvested from an individual PDAC patient by microdissection. Furthermore, immunohistochemical, coimmunoprecipitation and invasion analyses were performed to confirm the biologic significance of molecules identified by expression profile. In the present study, we focused on MUC16 and mesothelin among 87 genes that were significantly upregulated in infiltrating components compared to PanIN-3 in all PDAC patients, because MUC16 was the most differently expressed between two regions, and mesothelin was reported as the receptor for MUC16. Immunohistochemical analysis revealed that MUC16 and mesothelin were expressed simultaneously only in infiltrating components and increased at the invasion front, and binding of MUC16 and mesothelin was found in PDAC by immunoprecipitation assay. The downregulation of MUC16 by shRNA and the blockage of MUC16 binding to mesothelin by antibody inhibited both invasion and migration of pancreatic cancer cell line. MUC16 high/mesothelin high expression was an independent prognostic factor for poor survival in PDAC patients. In conclusion, we identified two specific genes, MUC16 and mesothelin, associated with the invasion process in patients with PDAC.
浸润过程是胰腺导管腺癌（PDAC）的关键步骤；然而，与浸润相关的基因仍不清楚。为了鉴定侵袭过程的特定基因，我们比较了通过显微解剖从个体 PDAC 患者中采集的浸润性癌症和 PanIN-3 的微阵列数据。此外，进行了免疫组织化学、共免疫沉淀和侵袭分析，以确认通过表达谱鉴定的分子的生物学意义。在本研究中，我们专注于在所有 PDAC 患者中与 PanIN-3 相比，在浸润性成分中显著上调的 87 个基因中的 MUC16 和间皮素，因为 MUC16 在两个区域之间的表达差异最大，并且间皮素被报道为 MUC16 的受体。免疫组织化学分析显示，MUC16 和间皮素仅在浸润性成分中同时表达，并在前侵袭部位增加，并且通过免疫沉淀测定在 PDAC 中发现了 MUC16 和间皮素的结合。通过 shRNA 下调 MUC16 表达和抗体阻断 MUC16 与间皮素的结合抑制了胰腺癌细胞系的侵袭和迁移。MUC16 高/间皮素高表达是 PDAC 患者预后不良的独立预后因素。总之，我们鉴定了与 PDAC 患者浸润过程相关的两个特定基因，MUC16 和间皮素。
