MUC4 Expression Increases Progressively in Pancreatic Intraepithelial Neoplasia

Abstract

Pancreatic adenocarcinoma is believed to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs) that undergo a series of architectural, cytologic, and genetic changes, a progression model similar to the adenoma-carcinoma sequence in the colon. The apomucin MUC4 has been implicated in invasive pancreatic adenocarcinoma. MUC4 expression is not detectable at the RNA level in normal pancreas but is detectable at high levels in invasive pancreatic adenocarcinoma. We documented the pattern of expression of MUC4 in PanINs by studying a series of 71 PanIN lesions immunohistochemically using a new monoclonal antibody to MUC4. Five (17%) of 30 PanIN-1 lesions, 10 (36%) of 28 PanIN-2 lesions, 11 (85%) of 13 PanIN-3 lesions, and 25 (89%) of 28 invasive adenocarcinomas labeled with the MUC4 antibody used in the study. In addition, afew nonneoplastic lesions labeled with the MUC4 antibody, including reactive ducts in chronic pancreatitis, atrophic ducts filled with inspissated secretions, and ducts showing squamous metaplasia. Our data help establish the patterns of MUC4 expression in neoplastic precursors in the pancreas and add further support to the progression model for pancreatic adenocarcinoma.

Multiple roles of mucins in pancreatic cancer, a lethal and challenging malignancy

“…MUC5B is moderately expressed, while MUC1 and MUC5AC are weakly detected in the adult pancreas (Yonezawa et al, 1997;Yonezawa et al, 1999;Andrianifahanana et al, 2001;Terris et al, 2002). We have previously reported that the overexpression of the MUC1 gene as well as the aberrant expression of MUC4 were associated with the development and progression of PC (Swartz et al, 2002;Park et al, 2003). In the normal pancreas, the expression of MUC1 is confined to the apical membrane of the intralobular ductules.…”

“…Atypical intraductal lesions can progress to invasive adenocarcinoma (Brat et al, 1998). MUC4 is expressed by metasplastic ducts and its expression increases with a higher grade of PanINs (Swartz et al, 2002;Park et al, 2003). Similarly, MUC1 expression also increases with the progression of PanIN lesions ( Figure 1B), whereas MUC2 expression remains unchanged (Adsay et al, 2002).…”

DNA copy number gains in head and neck squamous cell carcinoma

“…gains on 3q29, we evaluated gene expression data in HNSCC published by Ginos et al (2004) for genes on 3q29 and found frequent overexpression of several genes, including mucin 4 (MUC4), a gene found to be amplified overexpressed in pancreatic cancers (Swartz et al, 2002) with oncogenic abilities (Singh et al, 2004). MUC4 mRNA levels were upregulated in at least 35% HNSCC cases.…”

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms

“…Recent studies have provided compelling evidence implicating the MUC4 mucin in the pathogenesis of pancreatic cancer (Komatsu et al, 2000;Swartz et al, 2002;Singh et al, 2004). Expression analysis of MUC4 in increasing grade pancreatic intraepithelial neoplastic lesions (PanINs) and pancreatic adenocarcinoma demonstrated a positive correlation of MUC4 with the disease progression (Swartz et al, 2002). Moreover, silencing of MUC4 expression in pancreatic cancer cells led to reduced tumor growth and metastasis, suggesting an important role of MUC4 in pancreatic tumour development (Singh et al, 2004).…”