Molecular pathway of pancreatic cancer-associated neuropathic pain.

The pancreas is a heterocrine gland that has both exocrine and endocrine parts. Most pancreatic cancer begins in the cells that line the ducts of the pancreas and is called pancreatic ductal adenocarcinoma (PDAC). PDAC is the most encountered pancreatic cancer type. One of the most important characteristic features of PDAC is neuropathy which is primarily due to perineural invasion (PNI). PNI develops tumor microenvironment which includes overexpression of fibroblasts cells, macrophages, as well as angiogenesis which can be responsible for neuropathy pain. In tumor microenvironment inactive fibroblasts are converted into an active form that is cancer-associated fibroblasts (CAFs). Neurotrophins they also increase the level of Substance P, calcitonin gene-related peptide which is also involved in pain. Matrix metalloproteases are the zinc-associated proteases enzymes which activates proinflammatory interleukin-1ß into its activated form and are responsible for release and activation of Substance P which is responsible for neuropathic pain by transmitting pain signal via dorsal root ganglion. All the molecules and their role in being responsible for neuropathic pain are described below.

Use of S2.2/DOX Magnetic Nanoliposomes in MR Molecule Imaging and Targeted Thermochemotherapy for Breast Cancer In Vitro.

OBJECTIVE: To prepare S2.2/DOX magnetic nanoliposomes by combining the potential benefits of MNPs in MRI and the targeted performance of nano-drugs as an innovative method for integrated diagnosis and treatment of breast cancer (BC). METHODS: We created a S2.2-PEG-MZF/DOX molecular probe by using a lipid material to encapsulate PEG-MZF-NPs and doxorubicin (DOX), and a S2.2 aptamer to target MUC1 to conjugate with PEG-MZF/DOX nanoliposomes. The potential of probe for cell-specific targeting and magnetic resonance (MR) molecular imaging was evaluated by MR scanner and Prussian blue staining. Additionally, we explored the feasibility by using nanoliposome magnetic induction heating to interfere with MCF-7 (MUC1+) BC cells under the influence of an alternating magnetic field (AMF). RESULTS: PEG-MZF-NPs were biologically safe. The T2 relaxation rate of PEG-MZF-NPs was found to inhibit T2 signal in a concentration-dependent manner, and the T2 signal of the S2.2-PEG-MZF molecular probe in MCF-7 cells was significantly lower than that in PEG-MZF-NPs group. Moreover, the T2 signal reduction was more pronounced in MCF-7 cells than in the hepatoma cell line HepG2 (MUC1-), suggesting a strong MRI potential of the S2.2-PEG-MZF molecular probe. The S2.2-PEG-MZF/DOX nanoliposome was able to achieve the desired temperature range for tumor hyperthermia (42-44 °C) in vitro. The S2.2-PEG-MZF/DOX nanoliposome accompanied by magnetic fluid hyperthermia (MFH) could inhibit proliferation and invasion and induce apoptosis of MCF-7 cells. The effects of this approach were significantly higher than those observed in the other groups. CONCLUSION: We successfully developed a novel technique for BC diagnosis and treatment using thermochemotherapy under the guidance of MR molecular imaging. This approach holds great potential for improving the management of this devastating disease in the future.

Exploring dynamic change and influencing factors of TGF-ß1 and MUC1 in human breast milk, and their association with infantile diseases.

Background: Human breast milk, which comprises numerous bioactive compositions, has been well-demonstrated to be benefit to the infants in both short-term and long-term outcomes. We aim to determine the concentration of transforming growth factor beta 1 (TGF-ß1) and mucin 1 (MUC1) in human breast milk, identify their influencing factors, and explore their association with infantile diseases. Methods: Ninety paired mother-infants were enrolled in this study, and their demographic and clinical information was collected and analyzed. Paired colostrum and mature milk samples were collected from the healthy mothers within 5 days and at about 42 days after delivery, respectively. The concentrations of TGF-ß1 and MUC1 were determined by enzyme-linked immunosorbent assay. Results: The results showed that the concentrations of TGF-ß1 and MUC1 in human breast milk dynamically changed during lactation, and their concentrations were significantly higher in colostrum than in mature milk. Advanced maternal age was associated with a significantly increased TGF-ß1 concentration in colostrum, and caesarean delivery was significantly associated with an increased MUC1 concentration in colostrum. Finally, a high concentration of TGF-ß1 in colostrum was significantly associated with a higher risk of infantile diarrhea within the first 3 months after giving birth, and infantile upper respiratory infection (URI) within the first 6 months after giving birth. Conclusions: To the best of our knowledge, we for the first time showed that a high concentration of TGF-ß1 in human breast milk was significantly associated with an increased risk of infantile diarrhea and URI, which helps to give a better understanding of the relationship between the TGF-ß1 in human breast milk and infantile diseases.

Distinct sulfated glycans expressed in intrahepatic cholangiocarcinoma: a potential target for new therapy.

Cholangiocytes exhibit morphological and functional heterogeneity, depending on their anatomical localization; however, like other ductal organs, their mucosal surface is covered with mucin, which functions to prevent the entry of foreign substances, lubricate and prevent clogging by bile. Recently, the authors discovered that distinct sulfated glycans recognized by a series of antisulfated glycan antibodies are expressed not only in normal intrahepatic bile ducts but also in intrahepatic cholangiocarcinoma (iCCA). In this review, the authors first describe the anatomy of bile ducts and the biochemical characteristics of bile-duct-associated mucins, and then describe differences in structure and expression patterns of these sulfated glycans in physiological and pathological conditions. Finally, potential therapeutic strategies for iCCA using antisulfated glycan antibodies are discussed.

An electrochemical aptasensor based on intelligent walking DNA nanomachine with cascade signal amplification powered by nuclease for Mucin 1 assay.

Intelligently walking DNA nanomachines have sprung up an upsurge in various nucleic acid testing, but the rapid and sensitive test methods toward disease biomarker proteins based on the signal amplification strategy of DNA nanomachines were still ongoing development. In this work, an electrochemical aptasensor coupling the magnetic separation technique with the nuclease-powered walking DNA nanomachine was established for Mucin 1 (MUC1) detection. The magnetic beads (MBs) were modified by MUC1 aptamer hybridized with blocker DNA probe (BDP). After reacting with MUC1 proteins, the BDP was released from MBs to trigger the opening of capture hairpin DNA on Au nanoparticle (Au NPs)/MXene-modified electrode surface. In the presence of exonuclease III (Exo III), the BDP as a DNA walker is activated to autonomously move on the electrode. Then, lots of residual DNA fragments can still stay on electrode, further hybridizing with hairpin DNA, which can capture more UiO-66-NH2 metal-organic frameworks (MOFs). The amounts of ligands in MOFs can generate enhanced differential pulse voltammetry (DPV) signal probes. Furthermore, the concentrations of MUC1 can convert into the amplified DPV signals by introducing the signal amplification between the BDP as DNA walkers and Exo III as driven forces. This proposed electrochemical aptasensor achieved MUC1 detection ranging from 5 pg/mL to 50 ng/mL with detection limit of 0.72 pg/mL. Consequently, the designed and nuclease-powered walking DNA nanomachine provided an efficient strategy for the quantitative analysis of proteins by the interconversion between protein and BDP as a walker, which exhibited practical applicability of MUC1 detection in human serum.

MUC1 detection and in situ imaging method based on aptamer conformational switch and hybridization chain reaction.

Mucin 1 (MUC1) overexpression in tumor cells is related to various cancers, including breast, stomach, and lung cancer. MUC1 detection and imaging are important for cancer localization in tissue sections to support histopathological diagnosis. In this study, we developed a simple, enzyme-free MUC1 detection and in situ imaging method. Three hairpin probes, Apt-trigger, HP1-FAM, and HP2, were designed for MUC1 recognition and hybridization chain reaction (HCR). The Apt-trigger probe was composed of two sequences: the MUC1 aptamer and HCR trigger sequence. The 5' end of the HP1-FAM probe was modified with a FAM signal molecule. In the presence of MUC1, the aptamer sequence is activated and bound to MUC1, which opens the hairpin structure. Then, the trigger sequence gets exposed and, complementary to HP1-FAM, triggers a continuous HCR process. This method was successfully used to detect MUC1 of 200 pM-25 nM and MUC1 in situ imaging in specific cells, such as human breast carcinoma (MCF-7) and human colon cancer (HT-29) cells.

Mucin 1 downregulation decreases the anti-tumor effects of melanoma vaccine.

Background: Immunotherapy-based approaches are important breakthroughs with potential treatment benefits for melanoma patients. Mucin 1 (MUC1) is significantly upregulated in melanoma relative to normal cells. It has been reported that MUC1 influences cancer cell proliferation, apoptosis, invasion, and metastasis.The study aimed to explore the effect of MUC1 knockdown on the biological characteristics of the melanoma cell line B16F10 and evaluate whether MUC1 is an effective candidate target antigen for melanoma vaccine development. Methods: First, lentiviral vector-mediated short hairpin RNA (shRNA) was used to knockdown MUC1 in B16F10 cells (shMUC1-B16F10 cells). Next, we examined epithelial-mesenchymal transition (EMT), migration, proliferative capacity, clone formation, and distribution of cell cycle in shMUC1-B16F10 cells. Finally, the vaccine was prepared by repeated freeze-thawing of the shMUC1-B16F10 cells and used to subcutaneously immunize C57BL/6 mice, which were then challenged using B16F10 cells 10 days after the final vaccination. Results: It was revealed that shMUC1 suppressed B16F10 proliferative and colony formation capacity, induced the arrest of cell cycle in the G0/G1 phase, and adjusted the expression of EMT-associated factors. MUC1 downregulation markedly suppressed the effect of B16F10 vaccine against melanoma in a mouse model. As compared with B16F10-vaccinated mice, B16F10-vaccinated mice in which MUC1 was silenced had reduced natural killer (NK) cytotoxicity, lower production of interferon-γ (IFN-γ), anti-MUC1 antibodies, perforin, granzyme B, and elevated tumor growth factor-ß (TGF-ß) level. Conclusions: MUC1 has strong melanoma vaccine immunogenicity, and induces the host's anti-tumor reaction. MUC1 knockdown inhibits the immune activity of B16F10 cell vaccine and anti-melanoma effect, suggesting the MUC1 is an important candidate target antigen of the melanoma vaccine.

Adjuvant MUC vaccination with tecemotide after resection of colorectal liver metastases: a randomized, double-blind, placebo-controlled, multicenter AIO phase II trial (LICC).

Resection of colorectal liver metastases (CRLM) is a potential curative treatment for patients with metastatic colorectal cancer (mCRC) with liver-limited disease (LLD). Although long-term survival improved considerably within the last decades, high recurrence rates of 50-75% after resection remain a major challenge.Tecemotide (L-BLP25) is an antigen-specific cancer vaccine inducing immunity against mucin-1 (MUC1). The LICC trial aimed to improve survival in patients with mCRC after R0/R1 resection of CRLM. LICC was a binational, randomized, double-blind, placebo-controlled, multicenter phase 2 study including patients with R0/R1 resected CRLM without evidence of metastatic disease outside the liver. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS) rate, secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. In total, 121 patients were 2:1 randomized between Oct 2011 and Dec 2014to receive tecemotide (N=79) or placebo (N=42). Baseline characteristics were well balanced. Median RFS was 6.1 months (95% CI 4.5-8.9) and 11.4 months (95% CI 3.7-21.2) (P = .1754), 3-year OS rate 69.1% and 79.1%, median OS 62.8 months and not reached in the tecemotide vs. placebo arm (P = .2141), respectively. Cox regression models revealed no dependence of RFS or OS on MUC1 expression. The most common tecemotide-related grade 3/4 adverse events were diarrhea, injection site reaction, intestinal perforation, peritonitis and tinnitus (1.3% each). The LICC trial failed to meet its primary endpoints of significantly improving RFS and OS with tecemotide. However, both arms showed unexpectedly long OS. MUC1 expression was not associated with outcome.EudraCT No: 2011-000218-20Clinical Trial Information: NCT01462513Financial Support: Merck KGaA, Darmstadt, Germany. Abbreviations: AE: adverse event; CP: cyclophosphamide; CRC: colorectal cancer; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; FU: follow-up; HR: hazard ratio; IHC: immunohistochemical staining; ITT: intention-to-treat; DSMB: Data Safety Monitoring Board; LLD: liver-limited disease; mCRC: metastatic colorectal cancer; MPLA: monophosphoryl lipid; AMRI: magnetic resonance imaging; MUC1: mucin 1; NA: not applicable; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; NS: normal saline; NSCLC: non-small-cell lung carcinoma; OS: overall surviva; lPP: per protocol; RAS: Rat sarcoma; RFS: recurrence-free survival; TEAE: treatment-emergent adverse event; UICC: Union for International Cancer Control; US: ultrasound; vs.: versus.

Mass spectrometry for the identification and analysis of highly complex glycosylation of therapeutic or pathogenic proteins.

INTRODUCTION: Protein glycosylation influences characteristics such as folding, stability, protein interactions, and solubility. Therefore, glycan moieties of therapeutic proteins and proteins that are likely associated with disease pathogenesis should be analyzed in-depth, including glycan heterogeneity and modification sites. Recent advances in analytical methods and instrumentation have enabled comprehensive characterization of highly complex glycosylated proteins. AREA COVERED: The following aspects should be considered when analyzing glycosylated proteins: sample preparation, chromatographic separation, mass spectrometry (MS) and fragmentation methods, and bioinformatics, such as software solutions for data analyses. Notably, analysis of glycoproteins with heavily sialylated glycans or multiple glycosylation sites requires special considerations. Here, we discuss recent methodological advances in MS that provide detailed characterization of heterogeneous glycoproteins. EXPERT OPINION: As characterization of complex glycosylated proteins is still analytically challenging, the function or pathophysiological significance of these proteins is not fully understood. To reproducibly produce desired forms of therapeutic glycoproteins or to fully elucidate disease-specific patterns of protein glycosylation, a highly reproducible and robust analytical platform(s) should be established. In addition to advances in MS instrumentation, optimization of analytical and bioinformatics methods and utilization of glycoprotein/glycopeptide standards is desirable. Ultimately, we envision that an automated high-throughput MS analysis will provide additional power to clinical studies and precision medicine.

Codelivery of Genistein and miRNA-29b to A549 Cells Using Aptamer-Hybrid Nanoparticle Bioconjugates.

This study aimed to evaluate the anti-cancer effect of a combination therapy of miRNA-29b and genistein loaded in mucin-1 (MUC 1)-aptamer functionalized hybrid nanoparticles in non-small cell lung cancer (NSCLC) A549 cell line. Genistein-miRNA-29b-loaded hybrid nanoparticles (GMLHN) was prepared and characterized. Particle size and zeta potential were measured using photon correlation spectroscopy (PCS). Encapsulation efficiency and loading efficiency were determined using HPLC. Preferential internalization of MUC 1-aptamer functionalized GMLHN by A549 cells was evaluated and compared to normal MRC-5 cells. The ability of GMLHN to downregulate targeted oncoproteins Phosphorylated protein kinase, strain AK, Thymoma (Phosphorylated protein kinase B) (pAKT), Phosphorylated phosphoinositide 3-kinase (p-PI3K), DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) and Myeloid Cell Leukemia Sequence 1 (MCL 1) was evaluated using western blot, while antiproliferative effect and ability to initiate apoptosis was also assessed in A549 cells. MUC 1-aptamer functionalized GMLHN nanoparticles were prepared. These nanoparticles were preferentially internalized by A549 cells but less so, in MRC-5 cells. pAKT, p-PI3K, DNMT3B and MCL 1 were efficiently downregulated by these nanoparticles without affecting the levels of AKT and PI3K in A549 cells. GMLHN demonstrated a superior antiproliferative effect compared to individual genistein and miRNA-29b-loaded nanoparticles. Results generated were able to demonstrate that genistein-miRNA-29b-loaded hybrid nanoparticles (GMLHN) could be a potential treatment modality for NSCLC because of the ability of the payloads to attack multiple targets.

Combined Detection of CA19-9 and MUC1 Using a Colorimetric Immunosensor Based on Magnetic Gold Nanorods for Ultrasensitive Risk Assessment of Pancreatic Cancer.

We herein report a facile approach for developing an enzyme-free colorimetric immunosensor based on a magnetic iron oxide (IO)-coated gold nanorod (MGNR) nanocomposite with high electron transfer ability to accelerate the color bleaching reaction of methyl orange (MO) in the presence of NaBH4 for ultrasensitive detection of cancer antigens. In the case of MO, the reaction rate of MGNRs showed approximately 45.6-fold and 1520.8-fold higher than that of Cys-GNRs and NaBH4, respectively. The proposed colorimetric immunosensor was demonstrated to enable simple, cost-effective, sensitive, and specific carbohydrate antigen 19-9 (CA19-9) and mucin 1 (MUC1) detection for risk evaluation of pancreatic cancer (PC) with a small volume of serum sample without the use of any enhancing solutions or enzymes. By increasing the concentration of CA19-9 and MUC1, more MGNRs remained in the plate well to enhance the color bleaching of MO. As a proof-of-concept, the limit of detection (LOD) of 3.5 × 10-5 U/mL for CA19-9 and 5.2 × 10-6 U/mL for MUC1 was obtained with a wide linear quantification range from 8.6 × 10-5 U/mL to 1.4 × 10-2 U/mL for CA19-9 and 1.3 × 10-5 U/mL to 2.1 × 10-3 U/mL for MUC1, suggesting potential clinical applications for the early risk evaluation of PC.

Modified apple polysaccharide influences MUC-1 expression to prevent ICR mice from colitis-associated carcinogenesis.

The present study tried to assess the effects of modified apple polysaccharide (MAP) on colitis associated carcinogenesis and the expression of Mucin 1(MUC1). One hundred and twenty 5-week-old male ICR mice were used. The control mice were just administrated with saline, and the rest mice were injected intraperitoneally with 1, 2-dimethyl-hydrazine (DMH) and dextran sodium sulfate (DSS). In the 7th week, the mice in MAP-treated groups were bred with the basal diets mixed with different doses of MAP (w/w: 1.25%, 2.5% and 5%) for 13 weeks. The pathological findings demonstrated that: in the 20th week, adenocarcinoma and/or adenoma occurred in the colons of all the mice in model group. MAP treatment decreased the incidence of colorectal cancer significantly. In the early phase of inflammation, MUC1 expression in colonic mucosa had no significant changes. However, when the inflammation developed and tumor formed, MUC1 expression increased remarkably (P < 0.01). And the MAP treatment (especially at the dose of 5%) reduced MUC1 expression significantly. These data suggested that MAP could prevent against colitis associated colorectal cancer in ICR mice effectively, and MUC1 may be a potential therapeutic target in colorectal cancer prevention and treatment.

SMAD4-independent activation of TGF-ß signaling by MUC1 in a human pancreatic cancer cell line.

Pancreatic Ductal Adenocarcinoma (PDA) has a mortality rate that nearly matches its incidence rate. Transforming Growth Factor Beta (TGF-ß) is a cytokine with a dual role in tumor development switching from a tumor suppressor to a tumor promoter. There is limited knowledge of how TGF-ß function switches during tumorigenesis. Mucin 1 (MUC1) is an aberrantly glycosylated, membrane-bound, glycoprotein that is overexpressed in >80% of PDA cases and is associated with poor prognosis. In PDA, MUC1 promotes tumor progression and metastasis via signaling through its cytoplasmic tail (MUC1-CT) and interacting with other oncogenic signaling molecules. We hypothesize that high levels of MUC1 in PDA may be partly responsible for the TGF-ß functional switch during oncogenesis. We report that overexpression of MUC1 in BxPC3 human PDA cells (BxPC3.MUC1) enhances the induction of epithelial to mesenchymal transition leading to increased invasiveness in response to exogenous TGF-ß1. Simultaneously, these cells resist TGF-ß induced apoptosis by downregulating levels of cleaved caspases. We show that mutating the tyrosines in MUC1-CT to phenylalanine reverses the TGF-ß induced invasiveness. This suggests that the tyrosine residues in MUC1-CT are required for TGF-ß induced invasion. Some of these tyrosines are phosphorylated by the tyrosine kinase c-Src. Thus, treatment of BxPC3.MUC1 cells with a c-Src inhibitor (PP2) significantly reduces TGF-ß induced invasiveness. Similar observations were confirmed in the Chinese hamster ovarian (CHO) cell line. Data strongly suggests that MUC1 may regulate TGF-ß function in PDA cells and thus have potential clinical relevance in the use of TGF-ß inhibitors in clinical trials.

Sputum mucin 1 is increased during the acute phase of chronic obstructive pulmonary disease exacerbation.

BACKGROUND: Mucin 1 (MUC1) is a membrane tethered protein on airway epithelial cells. This protein is upregulated and plays an important anti-inflammatory role during acute lung inflammation. However, the relationship between sputum MUC1 level and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is unknown. METHODS: The levels of MUC1, IL-8, and TNF-α in induced sputum from 78 COPD patients were assessed by ELISA. The association between COPD exacerbation and MUC1 fragment levels was analyzed. An acute airway inflammation mouse model was established by intranasal LPS inhalation. The expression of Muc1 in lung and the levels of Muc1, TNF-α and KC in BAL fluid from mice were determined with western blotting and ELISA, respectively. RESULTS: Higher levels of MUC1 membrane-tethered (CT) and extracellular (EC) fragments, cytokines TNF-α and IL-8, more leucocyte and neutrophil counts were found in sputum from COPD patients in acute than in remission phase. Linear regression analysis confirmed that the level of sputum MUC1 CT fragment is positively correlated with sputum neutrophil number and patients' age; whereas the sputum EC fragment level is correlated inversely with FEV1/FVC value and positively with patients' age. Inhalation of lipopolysaccharide (LPS) induced acute lung inflammation in mice which exhibited increased levels of Muc1 CT fragment in lung and only Muc1 EC fragment increase in BAL fluid. CONCLUSIONS: Unlike pure bacterial induced lung inflammation, both sputum MUC1 CT and EC fragments are increased during acute exacerbation of COPD. The clinical benefits from measuring the changes of various sputum MUC1 fragments in AECOPD need to be elucidated in future studies.

Integrated signal probe based aptasensor for dual-analyte detection.

For the multi-analyte detection, although the sensitivity has commonly met the practical requirements, the reliability, reproducibility and stability need to be further improved. In this work, two different aptamer probes labeled with redox tags were used as signal probe1 (sP1) and signal probe2 (sP2), which were integrated into one unity DNA architecture to develop the integrated signal probe (ISP). Comparing with the conventional independent signal probes for the simultaneous multi-analyte detection, the proposed ISP was more reproducible and accurate. This can be due to that ISP in one DNA structure can ensure the completely same modification condition and an equal stoichiometric ratio between sP1 and sP2, and furthermore the cross interference between sP1 and sP2 can be successfully prevented by regulating the complementary position of sP1 and sP2. The ISP-based assay system would be a great progress for the dual-analyte detection. Combining with gold nanoparticles (AuNPs) signal amplification, the ISP/AuNPs-based aptasensor for the sensitive dual-analyte detection was explored. Based on DNA structural switching induced by targets binding to aptamer, the simultaneous dual-analyte detection was simply achieved by monitoring the electrochemical responses of methylene blue (MB) and ferrocene (Fc) This proposed detection system possesses such advantages as simplicity in design, easy operation, good reproducibility and accuracy, high sensitivity and selectivity, which indicates the excellent application of this aptasensor in the field of clinical diagnosis or other molecular sensors.

Superovulation at a specific stage of the estrous cycle determines the reproductive performance in mice.

Inconsistent reproductive performance has been reported in superovulated mice. Hence, the aim of this study was to analyze the effect and possible mechanism of superovulation timing on mouse reproductive performance. The results showed that mice superovulated at the metestrous (23.08±6.08%) and diestrous stages (33.33±11.45%) presented significantly lower pregnancy rates compared with those superovulated at the estrous stage (66.67±9.20%). After superovulation at the proestrous and estrous stages, mucin 1 (MUC1) and let-7a/let-7b microRNA (miRNA) expression levels were significantly attenuated and enhanced on embryonic day 3.5 (E3.5), respectively, whereas no significant differences in the expression level were found in mice superovulated at the other two stages. A higher number of developing and Graafian follicles was observed in the ovarian sections 48h after the administration of pregnant mare serum gonadotropin (PMSG) at the proestrous and estrous stages. The sections from mice treated at the metestrous and diestrous stages, however, presented more corpora lutea. Therefore, mice superovulated at the proestrous and estrous stages exhibited the best pregnancy rates. Furthermore, the disordered expression of MUC1 and let-7a/let-7b miRNA in mice superovulated at the metestrous and diestrous stages may impair reproduction performance.

Intra- and Extra-Cellular Events Related to Altered Glycosylation of MUC1 Promote Chronic Inflammation, Tumor Progression, Invasion, and Metastasis.

Altered glycosylation of mucin 1 (MUC1) on tumor cells compared to normal epithelial cells was previously identified as an important antigenic modification recognized by the immune system in the process of tumor immunosurveillance. This tumor form of MUC1 is considered a viable target for cancer immunotherapy. The importance of altered MUC1 glycosylation extends also to its role as a promoter of chronic inflammatory conditions that lead to malignant transformation and cancer progression. We review here what is known about the role of specific cancer-associated glycans on MUC1 in protein-protein interactions and intracellular signaling in cancer cells and in their adhesion to each other and the tumor stroma. The tumor form of MUC1 also creates a different landscape of inflammatory cells in the tumor microenvironment by controlling the recruitment of inflammatory cells, establishing specific interactions with dendritic cells (DCs) and macrophages, and facilitating tumor escape from the immune system. Through multiple types of short glycans simultaneously present in tumors, MUC1 acquires multiple oncogenic properties that control tumor development, progression, and metastasis at different steps of the process of carcinogenesis.

Mucin1 expression in focal epidermal dysplasia of actinic keratosis.

BACKGROUND: Actinic keratoses (AKs) are generally considered as premalignant skin lesions that can progress into squamous cell carcinoma (SCC) in situ and invasive SCC. However, its progression to SCC is still matter of debate. A transmembrane glycoprotein that contributes to the progression of certain premalignant and malignant lesions is mucin1 (MUC1). Nevertheless, their functions in the skin lesions are not yet fully clear. Therefore, the aim of this study is to ascertain whether MUC1 is present in the focal epidermal dysplasia of AK. METHODS: Fourteen skin biopsies from patients diagnosed with AK were selected. They were classified according to the degree of dysplasia in keratinocyte intraepidermal neoplasia (KIN) I, KIN II, and KIN III. In five biopsies the three degrees were present, in two biopsies both KIN I and KIN II, in four biopsies only KIN I, and in three biopsies only KIN III. The presence of MUC1 was assessed by immunofluorescence staining using confocal laser scanning microscopy. RESULTS: Immunostaining revealed that MUC1 was present over the entire cell surface of only a few atypical basal keratinocytes confined to the lower third of the epidermis (KIN I). While in KIN II where atypical keratinocytes occupy the lower two thirds, MUC1 was localized at the apical surface of some atypical keratinocytes and over the entire cell surface of some of them. Interestingly, in KIN III where the atypical keratinocytes extend throughout the full thickness, MUC1 was localized at the apical surface and over the entire cell surface of many of these cells. Conversely, MUC1 expression was not detected in the epidermis of normal skin. CONCLUSIONS: Our findings suggest that the expression of MUC1 in AK would be induced by alteration of keratinocyte stratification and differentiation and associated to the degree of dysplasia rather than the thickness of the epidermis.

L-BLP25 as a peptide vaccine therapy in non-small cell lung cancer: a review.

Lung cancer is one of the most prevalent malignancies worldwide and the leading cause of cancer-related death. Most cases are non-small cell lung cancer (NSCLC). The median overall survival of patients with advanced stage undergoing current standard chemotherapy is approximately 10 months. The addition of new compounds, including targeted agents, to standard first-line cytotoxic doublets, which are administered concurrently and/or as maintenance therapy in patients who have not experienced disease progression after first-line treatment, has shown potential in improving the efficacy in patients with advanced disease. L-BLP25 is a mucin 1 (MUC1) antigen-specific immunotherapy induces a T-cell response to MUC1 in both a preclinical MUC1-transgenic lung cancer mouse model and patients. This review is aimed at introducing the mechanism by which L-BLP25 targets MUC1, summarizing the achievements gained in the completed clinical trials with L-BLP25 administered as maintenance therapy in the treatment of unresectable stage III/IV NSCLC, and discussing the research trends.

MUC1: a multifaceted oncoprotein with a key role in cancer progression.

The transmembrane glycoprotein Mucin 1 (MUC1) is aberrantly glycosylated and overexpressed in a variety of epithelial cancers, and plays a crucial role in progression of the disease. Tumor-associated MUC1 differs from the MUC1 expressed in normal cells with regard to its biochemical features, cellular distribution, and function. In cancer cells, MUC1 participates in intracellular signal transduction pathways and regulates the expression of its target genes at both the transcriptional and post-transcriptional levels. This review highlights the structural and functional differences that exist between normal and tumor-associated MUC1. We also discuss the recent advances made in the use of MUC1 as a biomarker and therapeutic target for cancer.