MUC4 Mucin Potentiates Pancreatic Tumor Cell Proliferation, Survival, and Invasive Properties and Interferes with Its Interaction to Extracellular Matrix Proteins

Abstract

MUC4, a transmembrane mucin, is aberrantly expressed in pancreatic adenocarcinomas while remaining undetectable in the normal pancreas. Recent studies have shown that the expression of MUC4 is associated with the progression of pancreatic cancer and is inversely correlated with the prognosis of pancreatic cancer patients. In the present study, we have examined the phenotypic and molecular consequences of MUC4 silencing with an aim of establishing the mechanistic basis for its observed role in the pathogenesis of pancreatic cancer. The silencing of MUC4 expression was achieved by stable expression of a MUC4-specific short hairpin RNA in CD18/HPAF, a highly metastatic pancreatic adenocarcinoma cell line. A significant decrease in MUC4 expression was detected in MUC4-knockdown (CD18/HPAF-siMUC4) cells compared with the parental and scrambled short interfering RNA -transfected (CD18/HPAF-Scr) control cells by immunoblot analysis and immunofluorescence confocal microscopy. Consistent with our previous observation, inhibition of MUC4 expression restrained the pancreatic tumor cell growth and metastasis as shown in an orthotopic mouse model. Our in vitro studies revealed that MUC4-associated increase in tumor cell growth resulted from both the enhanced proliferation and reduced cell death. Furthermore, MUC4 expression was also associated with significantly increased invasiveness (P V 0.05) and changes in actin organization. The presence of MUC4 on the cell surface was shown to interfere with the tumor cell-extracellular matrix interactions, in part, by inhibiting the integrin-mediated cell adhesion. An altered expression of growth-and metastasis-associated genes (LI-cadherin, CEACAM6, RAC1, AnnexinA1, thrombomodulin, epiregulin, S100A4, TP53, TP53BP, caspase-2, caspase-3, caspase-7, plakoglobin, and neuregulin-2) was also observed as a consequence of the silencing of MUC4. In conclusion, our study provides experimental evidence that supports the functional significance of MUC4 in pancreatic cancer progression and indicates a novel role for MUC4 in cancer cell signaling. (Mol Cancer Res 2007;5(4):309 -20)

Role of microRNA-150 in solid tumors

“…1). This supports the aforementioned observations and indicates the important role of the MUC4 in pancreatic adenocarcinoma development and progression (21,23,24). A recent study has demonstrated the presence of a highly conserved miR-150 binding site at the 3'-UTR of MUC4 and that its direct interaction with miR-150 downregulated the endogenous MUC4 protein expression levels, as shown in Table I (25).…”

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

“…In this paper, we showed that MUC4 induces an increase in mitochondrial mass without changing the apoptotic index. However, in our MUC4 knockdown cell line model, we showed that endogenous overexpression of MUC4 is preventing apoptosis of the CD18/HPAF pancreatic cancer cells after 48 -72 h serum starvation (Chaturvedi et al, 2007). The lack of detection of any significant change in apoptosis and PARP activity in mini-MUC4-transfected cells might be due to the fact that apoptosis was induced by serum starving the cells for less than 24 h. The shorter duration of serum starvation was applied owing to the reason that Panc1 cells and their derivatives cannot survive for more than 24 h in serum-free media.…”

Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin

“…Using MUC4-knockdown and overexpression pancreatic cancer cell models, we have shown that MUC4 potentiates pancreatic tumour cell growth and metastasis by altering the behavioural properties of the tumour cells (Singh et al, 2004;Chaturvedi et al, 2007;Moniaux et al, 2007). Recently, the anti-apoptotic function of MUC4 in pancreatic cancer cells has been observed in our laboratory .…”

“…Recently, we have shown that the overexpression of MUC4 in mouse embryonic fibroblast cells confers oncogenic transformation . In addition, studies by overexpression and down-regulation of MUC4 in various pancreatic cancer cells showed its involvement in the development and progression of pancreatic cancer (Singh et al, 2004;Chaturvedi et al, 2007;Moniaux et al, 2007). Importantly, our recent studies have revealed that MUC4 interacts with HER2, a member of epidermal growth factor (EGF) receptor family and regulates its expression by post-translational mechanisms (Chaturvedi et al, 2008).…”