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Induction of protective and therapeutic anti-pancreatic cancer immunity using a reconstructed MUC1 DNA vaccine
Yefei Rong, Dayong Jin, Wenchuan Wu, Wenhui Lou, Danshong Wang, Tiantao Kuang, Xiaoling Ni, Xinyu Qin
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-191
Abstract: MUC1-various tandem repeat units(VNTR) DNA vaccine was produced by cloning one repeat of VNTR and inserting the cloned gene into the pcDNA3.1. In the preventive group, female C57BL/6 mice were immunized with the vaccine, pcDNA3.1 or PBS; and challenged with panc02-MUC1 or panc02 cell. In the therapeutic group the mice were challenged with panc02-MUC1 or panc02 cell, and then immunized with the vaccine, pcDNA3.1 or PBS. The tumor size and the survival time of the animals were compared between these groups.The DNA vaccine pcDNA3.1-VNTR could raise cytotoxic T lymphocyte (CTL) activity specific for MUC1. In the preventive experiment, the mice survival time was significantly longer in the vaccine group than in the control groups (P < 0.05). In the therapeutic experiment, the DNA vaccine prolonged the survival time of the panc02-MUC1-bearing mice (P < 0.05). In both the preventive and therapeutic experiments, the tumor size was significantly less in the vaccine group than in the control groups (P < 0.05). This pcDNA3.1-VNTR vaccine, however, could not prevent the mice attacked by panc02 cells and had no therapeutic effect on the mice attacked by panc02 cells.The MUC1 DNA vaccine pcDNA3.1-VNTR could induce a significant MUC1-specific CTL response; and had both prophylactic and therapeutic effect on panc02-MUC1 tumors. This vaccine might be used as a new adjuvant strategy against pancreatic cancer.Pancreatic adenocarcinoma is the fourth leading cause of cancer death in the world. However recent advances in diagnostics, staging, and therapy in pancreatic adenocarcinoma have not resulted in significant improvements in the long-term survival [1]. Median survival for all patients does not exceed 2 years with a 5-year survival rate less than 20% [2]. Therefore new approaches are necessary to improve the outcome of patients suffering from pancreatic cancer.Immunotherapy has recently become a feasible tumor specific therapy. MUC1 is a tumor-associated antigen that is over-express
MUC1 and colorectal cancer pathophysiology considerations  [cached]
Yaron Niv
World Journal of Gastroenterology , 2008,
Abstract: Several lines of evidence point towards a biological role of mucin and particularly MUC1 in colorectal cancer. A positive correlation was described between mucin secretion, proliferation, invasiveness, metastasis and bad prognosis. But, the role of MUC1 in cancer progression is still controversial and somewhat confusing. While Mukherjee and colleagues developed MUC1-specific immune therapy in a CRC model, Lillehoj and co-investigators showed recently that MUC1 inhibits cell proliferation by a β-catenin-dependent mechanism. In carcinoma cells the polarization of MUC1 is lost and the protein is over expressed at high levels over the entire cell surface. A competitive interaction between MUC1 and E-cadherin, through β-catenin binding, disrupts E-cadherin-mediated cell-cell interactions at sites of MUC1 expression. In addition, the complex of MUC1-β-catenin enters the nucleus and activates T-cell factor/leukocyte enhancing factor 1 transcription factors and activates gene expression. This mechanism may be similar to that just described for DCC and UNC5H, which induced apoptosis when not engaged with their ligand netrin, but mediate signals for proliferation, differentiation or migration when ligand bound.
A Minimal Fragment of MUC1 Mediates Growth of Cancer Cells  [PDF]
Sanjeev Mahanta, Shawn P. Fessler, Jaehong Park, Cynthia Bamdad
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002054
Abstract: The MUC1 protein is aberrantly expressed on many solid tumor cancers. In contrast to its apical clustering on healthy epithelial cells, it is uniformly distributed over cancer cells. However, a mechanistic link between aberrant expression and cancer has remained elusive. Herein, we report that a membrane-bound MUC1 cleavage product, that we call MUC1*, is the predominant form of the protein on cultured cancer cells and on cancerous tissues. Further, we demonstrate that transfection of a minimal fragment of MUC1, MUC1*1110, containing a mere forty-five (45) amino acids of the extracellular domain, is sufficient to confer the oncogenic activities that were previously attributed to the full-length protein. By comparison of molecular weight and function, it appears that MUC1* and MUC1*1110 are approximately equivalent. Evidence is presented that strongly supports a mechanism whereby dimerization of the extracellular domain of MUC1* activates the MAP kinase signaling cascade and stimulates cell growth. These findings suggest methods to manipulate this growth mechanism for therapeutic interventions in cancer treatments.
MUC1 gene overexpressed in breast cancer: structure and transcriptional activity of the MUC1 promoter and role of estrogen receptor alpha (ERα) in regulation of the MUC1 gene expression
Joseph Z Zaretsky, Itay Barnea, Yael Aylon, Marat Gorivodsky, Daniel H Wreschner, Iafa Keydar
Molecular Cancer , 2006, DOI: 10.1186/1476-4598-5-57
Abstract: Using TRANSFAC and TSSG soft-ware programs the transcription factor binding sites of the MUC1 promoter were analyzed and a map of transcription cis-elements was constructed. The effect of different MUC1 promoter regions on MUC1 gene expression was monitored. Different regions of the MUC1 promoter were analyzed for their ability to control expression of specific MUC1 isoforms. Differences in the expression of human MUC1 gene transfected into mouse cells (heterologous artificial system) compared to human cells (homologous natural system) were observed. The role of estrogen on MUC1 isoform expression in human breast cancer cells, MCF-7 and T47D, was also analyzed. It was shown for the first time that synthesis of MUC1/SEC is dependent on estrogen whereas expression of MUC1/TM did not demonstrate such dependence. Moreover, the estrogen receptor alpha, ERα, could bind in vitro estrogen responsive cis-elements, EREs, that are present in the MUC1 promoter. The potential roles of different regions of the MUC1 promoter and ER in regulation of MUC1 gene expression are discussed.Analysis of the structure and transcriptional activity of the MUC1 promoter performed in this study helps to better understand the mechanisms controlling transcription of the MUC1 gene. The role of different regions of the MUC1 promoter in expression of the MUC1 isoforms and possible function of ERα in this process has been established. The data obtained in this study may help in development of molecular modalities for controlled regulation of the MUC1 gene thus contributing to progress in breast cancer gene therapy.The MUC1 gene belongs to a family of genes encoding mucin glycoproteins [1]. MUC1 is normally expressed on the apical surface of mammary epithelial cells. However, in breast adenocarcinoma and a number of epithelial tumors, MUC1 is upregulated with aberrant expression over the entire cell surface [1-4]. This characteristic makes the MUC1 protein valuable as a marker in breast cancer diagnos
Rela??o entre a express?o da MUC1 e os estadiamentos TNM e Astler-Coller no cancer colorretal
Morais, Paula Gabriela Melo;Lins Neto, Manoel álvaro de Freitas;Leal, Antenor Texeira;Miranda, Cláudio Torres de;Albuquerque, Mateus de Paula;
Revista Brasileira de Coloproctologia , 2008, DOI: 10.1590/S0101-98802008000200005
Abstract: the expression of tumor markers that correlates with the aggressiveness of cancers has been strongly investigated. having colorectal cancer a significant incidence, biomarkers that can evaluate it concerning this aspect are not an exception in this inquiry. aim: to establish a relation between aggressiveness of colorectal cancer according to tnm and astler-coller staging systems and the expression of mucin1 (muc1) in a determined sample of tumors. methods: 36 colorectal cancers resected by proctologists of the university hospital of ufal were examined regarding the presence of positive immunohistochemical reaction for muc1 in cytoplasmic patterns. after that, the positive cases and its stages were correlated. results: immunoexpression of muc1 occurred in 50% of the cases. among these, 61% were between stages t3 and t4; 39% between n1 and n2; all cases of the study were m0; and 40% were classified between c1 and c3 in astler-coller system. when evaluated muc1 positivity in each stage separately, a proportional increase of both was perceived, mainly in stages "n" and astler-coller. conclusion: the absence of imunohistochemical reactivity to muc1 did not exclude the possibility of evolution for an advanced staged tumor. however, its presence denotes evolution of colorectal cancer for more aggressive stages.
Novel MUC1 Aptamer Selectively Delivers Cytotoxic Agent to Cancer Cells In Vitro  [PDF]
Yan Hu, Jinhong Duan, Qimin Zhan, Fengdan Wang, Xin Lu, Xian-Da Yang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031970
Abstract: Chemotherapy is a primary treatment for cancer, but its efficacy is often limited by the adverse effects of cytotoxic agents. Targeted drug delivery may reduce the non-specific toxicity of chemotherapy by selectively directing anticancer drugs to tumor cells. MUC1 protein is an attractive target for tumor-specific drug delivery owning to its overexpression in most adenocarcinomas. In this study, a novel MUC1 aptamer is exploited as the targeting ligand for carrying doxorubicin (Dox) to cancer cells. We developed an 86-base DNA aptamer (MA3) that bound to a peptide epitope of MUC1 with a Kd of 38.3 nM and minimal cross reactivity to albumin. Using A549 lung cancer and MCF-7 breast cancer cells as MUC1-expressing models, MA3 was found to preferentially bind to MUC1-positive but not MUC1-negative cells. An aptamer-doxorubicin complex (Apt-Dox) was formulated by intercalating doxorubicin into the DNA structure of MA3. Apt-Dox was found capable of carrying doxorubicin into MUC1-positive tumor cells, while significantly reducing the drug intake by MUC1-negative cells. Moreover, Apt-Dox retained the efficacy of doxorubicin against MUC1-positive tumor cells, but lowered the toxicity to MUC1-negative cells (P<0.01). The results suggest that the MUC1 aptamer may have potential utility as a targeting ligand for selective delivery of cytotoxic agent to MUC1-expressing tumors.
MUC1-C Oncoprotein Regulates Glycolysis and Pyruvate Kinase m2 Activity in Cancer Cells  [PDF]
Michio Kosugi, Rehan Ahmad, Maroof Alam, Yasumitsu Uchida, Donald Kufe
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028234
Abstract: Aerobic glycolysis in cancer cells is regulated by multiple effectors that include Akt and pyruvate kinase M2 (PKM2). Mucin 1 (MUC1) is a heterodimeric glycoprotein that is aberrantly overexpressed by human breast and other carcinomas. Here we show that transformation of rat fibroblasts by the oncogenic MUC1-C subunit is associated with Akt-mediated increases in glucose uptake and lactate production, consistent with the stimulation of glycolysis. The results also demonstrate that the MUC1-C cytoplasmic domain binds directly to PKM2 at the B- and C-domains. Interaction between the MUC1-C cytoplasmic domain Cys-3 and the PKM2 C-domain Cys-474 was found to stimulate PKM2 activity. Conversely, epidermal growth factor receptor (EGFR)-mediated phosphorylation of the MUC1-C cytoplasmic domain on Tyr-46 conferred binding to PKM2 Lys-433 and inhibited PKM2 activity. In human breast cancer cells, silencing MUC1-C was associated with decreases in glucose uptake and lactate production, confirming involvement of MUC1-C in the regulation of glycolysis. In addition, EGFR-mediated phosphorylation of MUC1-C in breast cancer cells was associated with decreases in PKM2 activity. These findings indicate that the MUC1-C subunit regulates glycolysis and that this response is conferred in part by PKM2. Thus, the overexpression of MUC1-C oncoprotein in diverse human carcinomas could be of importance to the Warburg effect of aerobic glycolysis.
MUC1 alters oncogenic events and transcription in human breast cancer cells
Christine L Hattrup, Sandra J Gendler
Breast Cancer Research , 2006, DOI: 10.1186/bcr1515
Abstract: To clarify the role of MUC1 in cancer, we transfected two breast cancer cell lines (MDA-MB-468 and BT-20) with small interfering (si)RNA directed against MUC1 and analyzed transcriptional responses and oncogenic events (proliferation, apoptosis and invasion).Transcription of several genes was altered after transfection of MUC1 siRNA, including decreased MAP2K1 (MEK1), JUN, PDGFA, CDC25A, VEGF and ITGAV (integrin αv), and increased TNF, RAF1, and MMP2. Additional changes were seen at the protein level, such as increased expression of c-Myc, heightened phosphorylation of AKT, and decreased activation of MEK1/2 and ERK1/2. These were correlated with cellular events, as MUC1 siRNA in the MDA-MB-468 line decreased proliferation and invasion, and increased stress-induced apoptosis. Intriguingly, BT-20 cells displayed similar levels of apoptosis regardless of siRNA, and actually increased proliferation after MUC1 siRNA.These results further the growing knowledge of the role of MUC1 in transcription, and suggest that the regulation of MUC1 in breast cancer may be more complex than previously appreciated. The differences between these two cell lines emphasize the importance of understanding the context of cell-specific signaling events when analyzing the oncogenic functions of MUC1, and caution against generalizing the results of individual cell lines without adequate confirmation in intact biological systems.MUC1 is the founding member of the mucin family: proteins characterized by heavy O-glycosylation centering around a variable number of tandem repeats that are rich in serine and threonine residues [1,2]. MUC1 is a transmembrane heterodimer with one subunit solely extracellular (MUC1-EX), and the other subunit composed of a short extracellular stem, a single transmembrane domain, and the cytoplasmic tail (together called the MUC1-CT). MUC1 possesses both pro- and anti-adhesive capacities, as the MUC1-EX provides binding sites for a variety of adhesion proteins, while its
Novel Aptamer-Nanoparticle Bioconjugates Enhances Delivery of Anticancer Drug to MUC1-Positive Cancer Cells In Vitro  [PDF]
Chenchen Yu, Yan Hu, Jinhong Duan, Wei Yuan, Chen Wang, Haiyan Xu, Xian-Da Yang
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024077
Abstract: MUC1 protein is an attractive target for anticancer drug delivery owing to its overexpression in most adenocarcinomas. In this study, a reported MUC1 protein aptamer is exploited as the targeting agent of a nanoparticle-based drug delivery system. Paclitaxel (PTX) loaded poly (lactic-co-glycolic-acid) (PLGA) nanoparticles were formulated by an emulsion/evaporation method, and MUC1 aptamers (Apt) were conjugated to the particle surface through a DNA spacer. The aptamer conjugated nanoparticles (Apt-NPs) are about 225.3 nm in size with a stable in vitro drug release profile. Using MCF-7 breast cancer cell as a MUC1-overexpressing model, the MUC1 aptamer increased the uptake of nanoparticles into the target cells as measured by flow cytometry. Moreover, the PTX loaded Apt-NPs enhanced in vitro drug delivery and cytotoxicity to MUC1+ cancer cells, as compared with non-targeted nanoparticles that lack the MUC1 aptamer (P<0.01). The behavior of this novel aptamer-nanoparticle bioconjugates suggests that MUC1 aptamers may have application potential in targeted drug delivery towards MUC1-overexpressing tumors.
The role of MUC1 and MUC3 in the biology and prognosis of colorectal cancer
Timothy J Duncan, Nicholas FS Watson, Ahmad H Al-Attar, John H Scholefield, Lindy G Durrant
World Journal of Surgical Oncology , 2007, DOI: 10.1186/1477-7819-5-31
Abstract: A tissue micro-array was prepared from tumour samples of 462 consecutive patients undergoing resection of a primary colorectal cancer. A comprehensive prospectively recorded data base with mean follow up of 75 months was collected and included common clinicopathological variables and disease specific survival. Immunohistochemical analysis of MUC1 and MUC3 expression was performed using antibodies NCL-MUC1 and 1143/B7 respectively, results were correlated with the variables within the database.Positive expression of MUC1 and MUC3 was seen in 32% and 74% of tumours respectively. On univariate analysis no correlation was seen with either MUC1 or MUC3 and any of the clinicopathological variables including tumour grade and stage, vascular invasion and tumour type. Kaplan-Meier analysis demonstrated a significant reduction in disease specific survival with MUC1 positive tumours (p = 0.038), this was not seen with MUC3 (p = 0.552). On multivariate analysis, using Cox proportional hazards model, MUC1 expression was shown to be an independent marker of prognosis (HR 1.339, 95%CI 1.002–1.790, p = 0.048).MUC1 expression in colorectal cancer is an independent marker of poor prognosis, even when vascular invasion is included in the analysis. These results support previous studies suggesting a role for MUC1 in colorectal cancer development possibly through its effects on cell adhesion.Colorectal cancer is the second most common cause of cancer related death in the developed world [1], in consequence advances in our understanding and treatment of colorectal cancers can potentially have a huge impact on cancer morbidity and mortality. Currently much of our understanding of cancer behaviour, including the prediction of likely patient outcomes, is based on histopathological parameters, and from this treatment is tailored to individual patients. At present TNM stage, tumour type and resection margin status are the most widely used parameters in planning adjuvant treatment. Tumour grad
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