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Identification of the Genes Associated With the Invasion Process and Prognosis for Pancreatic Ductal Adenocarcinoma: Coexpression of Muc16 and Mesothelin
Seiko Hirono*, Masaji Tani, Manabu Kawai, Ken-Ichi Okada, Motoki Miyazawa, Atsushi Shimizu, Yuji Kitahata, Masaki Ueno, Shinya Hayami, Yoshinobu Shigekawa, Hiroki Yamaue
Second of Surgery, Wakayama Medical University, Wakayama, Japan
Objective; Pancreatic ductal adenocarcinoma (PDAC) appears to arise from pancreatic intraepithelial neoplasms (PanINs). Cancerous cells break through the basement membrane from PanIN-3, they evolve into infiltrating adenocarcinoma. The invasion process is the crucial step in PDAC, because cancer cells that invade the vasculature, or lymphatic or neural vessels, can progress further to metastasis only after obtaining infiltrating status, however, the genes related to invasion remain unclear. In this study, we identified specific molecular markers, MUC16 and mesothelin, that were associated with invasion in PDAC by gene expression profiling.
Methods; The microarray data of the infiltrating cancer and PanIN-3, which were harvested from an individual PDAC patient by laser microdissection, were compared to identify the specific genes for invasion process in PDAC. To investigate the effect of MUC16 and mesothelin expression on invasion and migration of pancreatic cancer cells, in vitro invasion and migration assays were performed in the membrane culture system. We analyzed the relationship between MUC16/mesothelin expression and PDAC clinicopathological factors by immunohistochemistry in 106 patients with PDAC.
Results; We focused on MUC16 and mesothelin among 87 genes that were significant up-regulated in infiltrating components compared to PanIN-3 in all PDAC patients by gene expression profiling, because MUC16 was the most differently expressed between two regions, and mesothelin was reported as MUC16 ligand in ovarian cancer. Immunohistochemical analysis revealed that MUC16 and mesothelin were expressed simultaneously only in infiltrating components and not expressed in both all PanIN lesions and normal pancreatic tissues, furthermore, the expression of these genes increased at the invasion front in PDAC. The immunoprecipitation assay showed binding of MUC16 and mesothelin in both cell liens and surgical tissues of PDAC. The down-regulation of MUC16 by shRNA and the blockage of MUC16 binding to mesothelin by antibody inhibited both invasion and migration of pancreatic cancer cell line. Immunohistochemical analysis for 106 PDAC patients showed that a tumor size >4.0 cm, serosal invasion, invasion of other organs, and lymphatic permeation occurred significantly more often in the MUC16 high/mesothelin high expression group than in the other groups, and MUC16 high/ mesothelin high expression was an independent prognostic factor for poor survival in PDAC patients (P=0.01, HR, 1.99, 95%CI, 1.15-3.41).
Conclusion; MUC16 and mesothelin are involved in invasion and migration of PDAC, and they clinically represent new prognostic biomarkers and might be new therapeutic targets for patients with PDAC.
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