MUC1 Research Articles

MUC1, a therapeutic target in oncology

MUC1 is a large, highly glycosylated protein expressed on the apical membrane of many epithelial cells. With other members of the mucin family it contributes to the protection and function of mucosal cells. The intracellular part of the protein may also participate in signal transduction pathway, through multiple interactions with intracellular proteins. Overexpression of MUC1 is frequently observed in the majority of epithelial cancers and even in some haematological malignancies. In tumor cells, MUC1 loses apical distribution and is hypoglycosylated. These cancer-associated changes render it antigenic and make it an attractive target for a specific cancer immunotherapy. Several MUC1-based therapeutic cancer vaccines are currently under clinical investigation.

Clinicopathologic analysis of 92 cases of pancreatic cystic neoplasm

To study the clinicopathologic and immunohistochemical features of cystic neoplasms of the pancreas. Ninety-two cases of cystic neoplasm of pancreas were retrieved from the Department archival file during the period from 1999 to 2005. Histologic features were studied and the tumors were typed according to WHO classification. Immunohistochemistry was also carried out using paraffin-embedded tissues. The age of patients ranged from 16 to 80 years. The patients included 33 males and 59 females. The tumors varied from 2 cm to 21 cm in diameter. They consisted of intraductal papillary mucinous neoplasm (36/92), serous cystic neoplasm (18/92), solid pseudopapillary tumor (18/92), mucinous cystic neoplasm (14/92), cystic pancreatic ductal adenocarcinoma (4/92) and cystic pancreatic endocrine neoplasm (2/92). Immunohistochemical study revealed variable staining patterns, with frequent overlaps between different tumor types. In general, serous cystic neoplasm expressed MUC1, while mucinous cystic neoplasm was positive for MUC-5AC, intraductal papillary mucinous neoplasm for MUC-2 and cystic pancreatic ductal adenocarcinoma for MUC-1. On the other hand, solid pseudopapillary tumor expressed alpha-antitrypsin, alpha-antichymotrypsin, vimentin and progesterone receptor. Accurate diagnosis of pancreatic cystic neoplasms requires correlation of clinical findings, radiologic examination, histologic features and immunostaining results. Pathologic distinction is important because of different prognostic significance. Two-thirds of pancreatic cystic neoplasms are premalignant or malignant and warrant surgical resection, whereas the remaining one-third (including pseudocyst and serous cystadenoma) are benign and can be treated conservatively.

Diagnosis and differential diagnosis of intraductal papillary mucinous neoplasm of pancreas

To study the clinicopathologic features of intraductal papillary mucinous neoplasm (IPMN) and its distinction from mucinous cystic neoplasm of pancreas. The clinical, radiologic and histologic features of 17 cases of IPMN and 13 cases of mucinous cystic neoplasm (MCN) were reviewed. Mucin profiles (MUC1, MUC2 and MUC5AC) were studied by histology (HE) and immunohistochemistry (EnVision). 10 of the 17 cases of IPMN were males. 13 cases of the IPMN were located in head of pancreas. Communication with the main pancreatic duct was demonstrated in 15 cases. Histologically, there were mild to severe papillary ingrowths of dysplastic epithelial cells, associated with intervening normal or atrophic pancreatic parenchyma. Ovarian-like stroma was not seen. Ancillary investigations showed that MUC2 and MUC5AC were detected in tumor cells of 9 and 4 cases respectively. The 4 cases with invasive component showed MUC1 positivity. On the other hand, 11 of the 13 cases of MCN occurred in middle-aged to elderly females and were located in the body and tail of pancreas. Ovarian-like stroma was commonly seen and there was no connection with the main pancreatic duct. All non-invasive MCN, regardless of the degree of cytologic atypia, were positive for MUC5AC (but not MUC2). In the 2 cases with invasive component, MUC1 expression was observed, as in IPMN. The age and sex of patients, tumor location, absence of ovarian-like stroma, communication with main pancreatic duct and characteristic mucin profiles represent useful parameters in distinguishing IPMN from MCN of pancreas. The tumor cells of IPMN express mainly MUC2, while those of MCN express MUC5AC. MUC1 may also be a useful marker in demonstration of stromal invasion in these tumors.

Variable number of tandem repeats polymorphism of MUC20 is associated with the progression of IgA nephropathy

The MUC20 gene is a novel up-regulated gene that was identified in renal tissues of patients with IgA nephropathy (IgAN) by restriction endonucleolytic analysis of differentially expressed sequences. The variable number of tandem repeats (VNTR) polymorphism of MUC20 was detected in different cell lines. In this study we determined the distribution of MUC20 VNTR polymorphism in the healthy population, and the association between the MUC20 VNTR polymorphism and the pathogenesis or progression of IgAN. 282 healthy and 503 proved IgAN patients by biopsy were involved in this investigation. 113 patients had been followed-up for 3.5 +/- 1.5 years. Genomic DNAs were extracted from peripheral blood leucocytes. MUC20 VNTR polymorphism was detected by PCR amplification and several representational PCR products were confirmed by sequencing. The MUC20 genes were divided into small alleles (repeat times <or= 3) and large alleles (repeat times > 3) according to the repeat times of MUC20 VNTR. These patients were classified into group SS, SL and LL. MUC20 allele frequencies and genotypes of IgAN patients were analyzed and compared with healthy population. In addition, the associations of MUC20 polymorphism with the clinical and pathological parameters at the time of renal biopsy were analyzed. The data followed up in different groups were compared. There was MUC20 VNTR polymorphism in healthy population with 2 - 6 repeats. The repeat fragment was 57bp. The most frequent alleles included 3(R(3)) and 4(R(4)) repeats; otherwise the least ones included 6(R(6)) repeats. The most frequent genotype was R(3)R(4), then R(3)R(3) and R(4)R(4); the least ones were R(2)R(2), R(3)R(6) and R(5)R(5). The frequencies of MUC20 alleles and genotypes in the IgAN patients were similar to healthy population. Initial ages, blood pressure, proteinuria, and renal function did not differ significantly among the three groups. There was no difference of the urinary osmotic pressure, urinary NAG (N-acetyl-B-D-glucosaminidase) and alpha1 microglobulin (alpha1-MG), and the semiquantitative scores of renal interstitial fibrosis and tubular atrophy in the three groups. IgAN patients with SL/LL genotype had higher odds ratio for progression of renal function (OR = 7.29, 95% CI: 1.68 - 31.60, P = 0.008) than the SS genotype. There were MUC20 VNTR polymorphisms in the healthy population. The polymorphism did not associate with the pathogenesis and the clinico-pathological parameters at the time of renal biopsy. The SL/LL genotype was likely to be a risk factor for rapid progression of renal function in the patients with IgAN.

Sialylated core 1 based O-linked glycans enhance the growth rate of mammary carcinoma cells in MUC1 transgenic mice.

The MUC1 mucin, found on the luminal surface of simple epithelial cells is upregulated and aberrantly glycosylated in many carcinomas particularly breast and ovarian. MUC1 expressed by normal mammary epithelial cells, carries core 2 glycans but in breast carcinomas the simple core 1 based glycans are added. The binding of the monoclonal antibody SM3 to its peptide epitope in the tandem repeat of MUC1 is blocked by the branched core 2 glycans found on MUC1 expressed by normal cells. Thus SM3 does not bind to MUC1 expressed by normal mammary epithelial cells but reacts with more than 90% of breast carcinomas, suggesting that the loss of at least some core 2 glycans is a very common event in breast carcinogenesis. To determine if the change in glycosylation observed in breast carcinomas confers an advantage to cancer cells, murine mammary carcinoma cell lines were developed that express MUC1 carrying core 2 or core 1 linked glycans. The in vivo growth rate in wild-type and nude mice were identical regardless of the O-glycosylation patterns. However, the tumors that grew out of wild-type mice lost most of their MUC1 expression. In contrast, in MUC1 transgenic mice, where expression of MUC1 was retained by the tumor, a striking difference in growth rate was observed. In these mice, cells expressing core 1 glycans grew significantly faster than cells expressing core 2 glycans. These data suggest that MUC1 transgenic mice are more tolerant to core 1 expressing tumors than to tumors expressing core 2.

MAb RR-B7 against MUC1

MAb RR-B7 against MUC1

MAb RR-D40 against MUC1

MAb RR-D40 against MUC1

A study of correlation between early postoperative relapse with lymph node micrometastasis in patients with N0 esophageal cancer

To explore the correlation between early postoperative tumor relapse with lymph node micrometastasis in the patients with pN(0) esophageal cancer. Using reverse transcriptase-polymerase chain reaction (RT-PCR), one hundred and sixty-six regional lymph nodes obtained from forty-three patients with esophagus cancer without invasion of the tumor confirmed by histopathologic analysis (pN(0)) were studied for further detecting mRNA of Mucin1 (MUC1) gene and determining nodal micrometastasis. All the patients underwent radical resection and regional lymph node dissection. Patients were followed up for one year to detect early tumor relapse. Difference in relapse was compared by chi(2) test. MUC1 mRNA expression was identified for twenty-six lymph nodes (15.7%), in eighteen patients (42%) who were diagnosed as having nodal micrometastasis. TNM staging for these patients was up-regulated from stages I-II(A) to stages II(B)-III. Relapse disease was found in nine patients with lymph nodes micrometastasis and three patients without nodal micrometastasis (P < 0.05). Early tumor relapse after radical surgery in the patients with pN(0) esophageal cancer might be correlated with nodal micrometastasis.

EU-MUC7a against MUC7

EU-MUC7a against MUC7

Analysis of MUC1 gene in goat

MUC1 is a mucin-type glycoprotein; unlike secreted mucins it is a membrane component. During lactation it is present on the apical surface of the mammary cells as well as on the milk fat globule membrane (MFGM). In man and cattle extracellular domain shows a twenty-amino acid repeat rich in sites for O-glycosylation (serines and threonines). The motif is tandemly repeated a variable number of times in individual molecules giving rise to a VNTR polymorphism. The MUC1 structure and location suggest that associations between the molecular mass of variants and lactation traits as well as health traits may exist (Patton et al., 1995; Pallesen et al., 2001; Rasero et al., 2002).....

Detect ion of MUC1 and GST-P Gene by means of RT-PCR in Axillary Lymph Nodes Taken from Breast Cancer Patients

Detect ion of MUC1 and GST-P Gene by means of RT-PCR in Axillary Lymph Nodes Taken from Breast Cancer Patients

Evaluation of serum CA27.29, CA15-3 and CEA in patients with breast cancer.

The Truquant BR radioimmunoassay (RIA) using monoclonal antibody BR 27.29 to recognize a peptide sequence on the MUC-1 gene product for quantification of the CA 27.29 antigen in serum was used in this report to evaluate in 145 patients with breast cancer and compared the other conventional serum markers such as CA15-3 and CEA. The upper limit of normal (25 u/ml) was determined from CA27.29 values 12.4 +/- 4.1 u/ml (mean +/- 3 S.D.) for 112 female subjects apparently free of disease. The CA15-3 levels above 25 u/ml and CEA levels above 5 ng/ml were considered positive values. Thirty-seven cases of 145 patients studied had elevated CA 27.29 levels (sensitivity: 25.5%), 35 of 145 had positive CA15-3 levels (sensitivity 24.1%) and 27 of 145 patients had positive CEA levels (sensitivity: 18.6%) (p < 0.05). One hundred and ten cases of the breast cancer patients (75.8%) did not have metastatic disease. In this group CA 27.29 sensitivity was 6.4%, while CA15-3 sensitivity was 5.5% and CEA sensitivity was 4.5% (p > 0.05). Mean values were 10.2 +/- 9.2 u/ml for CA 27.29, 14.1 +/- 5.6 u/ml for CA 15-3 and 1.7 +/- 1.5 ng/ml for CEA. Thirty-five patients (24.2%) had metastatic disease. In this group CA 27.29 sensitivity was 85.7%, CA15-3 sensitivity was 82.8% and CEA sensitivity was 62.8% (p < 0.05). Mean values for CA27.29 was 152.6 +/- 131.6 u/ml, CA15-3 was 123.1 +/- 107.6 u/ml and 21.8 +/- 36.9 ng/ml of CEA. With regard to the correlation of three tumor markers with clinical stages, patients had significantly higher levels of CA27.29 than CEA, but they were similar to CA 15-3 in metastatic breast cancer. These results suggest CA27.29 to be more sensitive and specific than CEA, but that it is similar to CA15-3 for metastatic breast cancer detection and monitoring.

Secreted MUC1 mucins lacking their cytoplasmic part and carrying sialyl-Lewis a and x epitopes from a tumor cell line and sera of colon carcinoma patients can inhibit HL-60 leukocyte adhesion to E-selectin-expressing endothelial cells.

A secreted MUC1 mucin from the spent medium of the colon carcinoma cell line COLO 205 carrying sialyl-Lewis a and x epitopes (H-CanAg) was purified by trichloroacetic acid precipitation and Superose 6 gel filtration. The purified H-CanAg inhibited adhesion of the leukocyte cell line HL-60 to E-selectin transfected COS-1 cells or interleukin-1 beta (IL-1 beta)-activated human umbilical vein endothelial cells. Sera from two patients with advanced colon carcinoma containing high concentrations of sialyl-Lewis a and x activity inhibited HL-60 cell adhesion to E-selectin-expressing COS-1 cells and IL-1 beta-activated endothelial cells. After affinity column absorption of the sialyl-Lewis a activity, the sera also lost most of their sialyl-Lewis x activity and at the same time their adhesion inhibitory effect. A large part of the sialyl-Lewis a/x activity in the two patients was found in fractions containing mucins having a MUC1 apoprotein, as shown by its size, and reactivity with the two anti-MUC1 apoprotein monoclonal antibodies, Ma552 and HMFG-2. The cell-adhesion inhibitory effect of the purified sialyl-Lewis a-carrying MUC1 mucin fraction from the sera of the two patients was stronger than that of smaller sized sialyl-Lewis a-carrying mucin-type glycoproteins also found in the patient sera. The MUC1 mucin fraction secreted by the COLO 205 cells and from the two sera were all shown to lack their C-terminal portion, in contrast to the MUC1 mucin from cells. It is hypothesized that sialyl-Lewis a- and/or x-containing mucins, especially MUC1, secreted by tumors can interact with E-selectin on endothelial cells and thus inhibit leukocyte adhesion.

Quantitation of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in plasma and cerebrospinal fluid using solid-phase extraction and high-performance liquid chromatography with electrochemical detection.

An original, sensitive, and specific high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of morphine and its two major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), in human plasma and cerebrospinal fluid (CSF) and in rat plasma, using hydromorphone as the internal standard. Solid-phase extraction was used to separate morphine and its glucuronide metabolites from plasma constituents. Extraction efficiencies of morphine, M3G, and M6G from human plasma samples (0.5 ml) were 84, 87, and 88%, respectively. Extraction efficiencies of morphine, M3G, and M6G did not differ significantly (p > 0.05) between human plasma and CSF or rat plasma. Morphine, M3G, M6G, and hydromorphone were separated on a 10 mu C8 Resolve radially compressed cartridge using a mobile phase comprising methanol:acetonitrile:phosphate buffer, (0.0125M pH 7.5; 10:10:80), in which 11 mg/L of cetyltrimethylammonium bromide (cetrimide) was dissolved. Quantitation was achieved using a single electrochemical detector at ambient temperature (23 degrees C). Standard curves were linear over the ranges 0.020-2.190, 0.027-2.709, and 0.027-0.542 microM for morphine, M3G, and M6G, respectively. Lower limits of detection for morphine, M3G, and M6G in human plasma and CSF samples (0.5 ml) were 0.020, 0.027, and 0.027 microM, respectively. Corresponding lower limits of detection in rat plasma (0.1 ml) were 0.102, 0.135, and 0.135 microM, respectively. Intraassay precision for low and high concentrations of morphine, M3G, and M6G were < 23 and < 8% respectively. Similarly, interassay accuracy for low and medium concentrations of morphine, M3G, and M6G were < 17% and were < 9% for high concentrations.