Coexpression of MUC16 and mesothelin is related to the invasion process in pancreatic ductal adenocarcinoma

Abstract

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. (Cancer Sci 2012; 103: 739-746) F or most patients with pancreatic ductal adenocarcinoma (PDAC), the diagnosis is made at an advanced stage;(1) the survival rate for these patients is dismal because PDAC has a propensity for early local invasion and vascular dissemination.(2) The genetic and biochemical determinants of the process of invasion and metastasis in PDAC are still largely unknown.Pancreatic ductal adenocarcinoma appears to arise from histologically well-defined precursor lesions in the ducts of the pancreas, called pancreatic intraepithelial neoplasms (PanIN). (3,4) PanIN are graded based on their degree of architectural and nuclear atypia and are categorized into a four-tier classification, including PanIN-1A, 1B, 2 and 3.(5) PanIN-3 lesions demonstrate widespread loss of nuclear polarity, nuclear atypia and frequent mitoses, and whereas cancerous cells break through the basement membrane, 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. In the present study, we identified specific molecular markers associated with invasion in PDAC, which might be useful not only as early diagnostic markers but also as new therapeutic targets for patients with PDAC.

Intracellular localization of mesothelin predicts patient prognosis of extrahepatic bile duct cancer

“…In this study, we confirmed that mesothelin expression is a prominent prognostic factor for EHBDCA patients as well as for other tumors such as pancreatic cancer and ovarian carcinoma described previously (12,15,23). Furthermore, we revealed that the expression pattern of mesothelin, in luminal membrane or cytoplasm, could be a more evident prediction factor for these patients.…”

Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis

“…MSLN is expressed in several human malignancies, including mesotheliomas and ovarian cancer. Studies of patients with ovarian cancer have identified the cancer antigen CA125 as an MSLN ligand (20)(21)(22)(23), which is widely used as a diagnostic marker (with the exception of pregnancy and liver cirrhosis, which are considered false-positives) (24). Since high expression of MSLN is linked to increased tumor proliferation and invasion, MSLN is a novel Cholestatic liver fibrosis is caused by obstruction of the biliary tract and is associated with early activation of portal fibroblasts (PFs) that express Thy-1, fibulin 2, and the recently identified marker mesothelin (MSLN).…”

C-ERC/mesothelin provokes lymphatic invasion of colorectal adenocarcinoma

“…As summarized in Table 3, "high-level expression" was detected in 45 cases (49.5 %), whereas "low-level expression" was detected in 46 cases (50.5 %), although "high-level expression" of mesothelin was not correlated with clinicopathological parameters such as histological grade, T-factor and metastasis. Recent studies reported that higher mesothelin expression was found to be associated with shorter patients' survival in ovarian and pancreatic cancer [31][32][33]; therefore, we also examined the correlation of mesothelin overexpression with overall survival (OS) in the CRC patients. Contrary to our expectation, the group of "high-level expression" of mesothelin was not correlated with OS compared to the group of "low-level expression" of mesothelin (P = 0.26, Supplemental Fig.…”