Aberrant Expression of MUC3 and MUC4 Membrane-Associated Mucins and Sialyl Lex Antigen in Pancreatic Intraepithelial Neoplasia

Park, Hee Ug; Kim, Jong Woo; Kim, Grace; Bae, Han Ik; Crawley, Suzanne C.; Yang, Stacey C.; Gum, James R.; Batra, Surinder K.; Rousseau, Karine; Swallow, Dallas M.; Sleisenger, Marvin H.; Kim, Young S.

doi:10.1097/00006676-200304000-00022

Cited by 94 publications

(95 citation statements)

References 35 publications

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“…It is not expressed in the normal adult pancreas (Buisine et al, 2000;Andrianifahanana et al, 2001). In pancreatic cancer and PanIN leisons, an aberrant expression of MUC4 has been observed (Swartz et al, 2002;Park et al, 2003), suggesting that molecular changes (genetic or epigenetic) implicated in the tumour progression may be linked to the MUC4 dysregulation. In the present study, we investigated the role of the CFTR in MUC4 regulation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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MUC4 mucin is a high molecular weight transmembrane glycoprotein that plays important roles in tumour biology. It is aberrantly expressed in pancreatic adenocarcinoma, while not being detectable in the normal pancreas. Previous studies have demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is defective in CF, is implicated in multiple cellular functions, including gene regulation. In the present study, using a CFTR-defective pancreatic cancer cell line and its derived subline expressing functional CFTR, we report that MUC4 expression is negatively regulated by CFTR. Short-interfering RNA (siRNA)-mediated silencing of CFTR also leads to an increased expression of MUC4. Additionally, our results suggest that CFTR-mediated regulation of MUC4 is cell densitydependent and is achieved by transcriptional and posttranslational mechanisms. Moreover, in a panel of pancreatic cancer cell lines and normal pancreas, we observed that CFTR was downregulated in pancreatic cancer cells and negatively correlated with MUC4 in most cases. An aberrant expression of MUC4 was also detected in the CF pancreas. Downregulation of CFTR in pancreatic adenocarcinoma and its inverse association with the tumour-linked mucin, MUC4, indicate novel function(s) of CFTR in pancreatic tumour biology and suggest the implication of new signalling pathway(s) in MUC4 regulation.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…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.…”

Section: Abnormal Expression Of Mucin Genes In Pcmentioning

confidence: 95%

“…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).…”

Section: Abnormal Expression Of Mucin Genes In Pcmentioning

confidence: 98%

“…The expression of mucin-associated carbohydrate antigens, sLe x and sTn, is associated with higher-grade PanIN lesions (Park et al, 2003) and is thought to result from a shift in the expression of glycosyltransferases. These mucin-associated antigens are known to bind endothelial cells through the P-and E-selectins, and the cell-adhesion molecule, ICAM-1 (Regimbald et al, 1996).…”

Section: Implication Of Mucins In the Pathogenesis Of Pcmentioning

confidence: 99%

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

et al. 2004

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Mucins are members of an expanding family of large multifunctional glycoproteins. Pancreatic mucins have important biological functions, including the protection, lubrication, and moisturisation of the surfaces of epithelial tissues lining ductal structures within the pancreas. Several lines of evidence support the notion that deregulated mucin production is a hallmark of inflammatory and neoplastic disorders of the pancreas. Herein, we discuss the factors that contribute to the lethality of pancreatic cancer as well as the key role played by mucins, particularly MUC1 and MUC4, in the development and progression of the disease. Aspects pertaining to the aberrant expression and glycosylation of mucins are discussed, with special emphasis on their potential impact on the design and implementation of adequate diagnostic and therapeutic strategies for combating this lethal malignancy.

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“…MUC4 is expressed by metaplastic ducts and its expression increases with increasing grade in pancreatic intraepithelial neoplasias (Swart et al, 2002;Park et al, 2003). A recent study has shown that MUC4 is a good candidate marker for early diagnosis of pancreatic cancer in fineneedle aspirates, exhibiting a 91% sensitivity and 100% specificity (Jhala et al, 2006).…”

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confidence: 99%

Human MUC4 mucin induces ultra-structural changes and tumorigenicity in pancreatic cancer cells

et al. 2007

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MUC4 is a type-1 transmembrane glycoprotein and is overexpressed in many carcinomas. It is a heterodimeric protein of 930 kDa, composed of a mucin-type subunit, MUC4a, and a membrane-bound growth factor-like subunit, MUC4b. MUC4 mRNA contains unique 5 0 and 3 0 coding sequences along with a large variable number of tandem repeat (VNTR) domain of 7 -19 kb. A direct association of MUC4 overexpression has been established with the degree of invasiveness and poor prognosis of pancreatic cancer.To understand the precise role of MUC4 in pancreatic cancer, we engineered a MUC4 complementary DNA construct, mini-MUC4, whose deduced protein (320 kDa) is comparable with that of wild-type MUC4 (930 kDa) but represents only 10% of VNTR. Stable ectopic expression of mini-MUC4 in two human pancreatic cancer cell lines, Panc1 and MiaPaCa, showed that MUC4 minigene expression follows a biosynthesis and localisation pattern similar to the wild-type MUC4. Expression of MUC4 resulted in increased growth, motility, and invasiveness of the pancreatic cancer cells in vitro. Ultra-structural examination of MUC4-transfected cells showed the presence of increased number and size of mitochondria. The MUC4-expressing cells also demonstrated an enhanced tumorigenicity in an orthotopic xenograft nude mice model, further supporting a direct role of MUC4 in inducing the cancer properties. In conclusion, our results suggest that MUC4 promotes tumorigenicity and is directly involved in growth and survival of the cancer cells.

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Aberrant Expression of MUC3 and MUC4 Membrane-Associated Mucins and Sialyl Lex Antigen in Pancreatic Intraepithelial Neoplasia

Cited by 94 publications

References 35 publications

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

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

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

Human MUC4 mucin induces ultra-structural changes and tumorigenicity in pancreatic cancer cells

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