Isoforms of MUC16 activate oncogenic signaling through EGF receptors to enhance the progression of pancreatic cancer.

Aberrant expression of CA125/MUC16 is associated with pancreatic ductal adenocarcinoma (PDAC) progression and metastasis. However, knowledge of the contribution of MUC16 to pancreatic tumorigenesis is limited. Here, we show that MUC16 expression is associated with disease progression, basal-like and squamous tumor subtypes, increased tumor metastasis, and short-term survival of PDAC patients. MUC16 enhanced tumor malignancy through the activation of AKT and GSK3ß oncogenic signaling pathways. Activation of these oncogenic signaling pathways resulted in part from increased interactions between MUC16 and epidermal growth factor (EGF)-type receptors, which were enhanced for aberrant glycoforms of MUC16. Treatment of PDAC cells with monoclonal antibody (mAb) AR9.6 significantly reduced MUC16-induced oncogenic signaling. mAb AR9.6 binds to a unique conformational epitope on MUC16, which is influenced by O-glycosylation. Additionally, treatment of PDAC tumor-bearing mice with either mAb AR9.6 alone or in combination with gemcitabine significantly reduced tumor growth and metastasis. We conclude that the aberrant expression of MUC16 enhances PDAC progression to an aggressive phenotype by modulating oncogenic signaling through ErbB receptors. Anti-MUC16 mAb AR9.6 blocks oncogenic activities and tumor growth and could be a novel immunotherapeutic agent against MUC16-mediated PDAC tumor malignancy.

Invasive phenotype induced by low extracellular pH requires mitochondria dependent metabolic flexibility.

Metabolic reprogramming is required for tumors to meet the bioenergetic and biosynthetic demands of malignant progression. Numerous studies have established a causal relationship between oncogenic drivers and altered metabolism, most prominently aerobic glycolysis, which supports rapid growth and affects the tumor microenvironment. Less is known about how the microenvironment modulates cancer metabolism. In the present study, we found that low extracellular pH, a common feature of solid tumors, provoked PDAC cells to decrease glycolysis and become resistant to glucose starvation. This was accompanied by increased dependency on mitochondrial metabolism, in which long-chain fatty acids became a primary fuel source. Consistent with previous reports, low pH enhanced tumor cell invasiveness. A novel finding was that limiting PDAC metabolic flexibility by either suppression of oxidative phosphorylation capacity or the pharmacological inhibition of fatty-acid oxidation prevented invasion induced by low extracellular pH. Altogether, our results suggest for the first time that targeting fatty-acid oxidation may be a viable adjunct strategy for preventing metastatic progression of pancreatic cancer mediated by the acidic tumor compartment.

Pancreatic Stellate Cells: The Key Orchestrator of The Pancreatic Tumor Microenvironment.

Pancreatic cancer is one of the most challenging adenocarcinomas due to its hostile molecular behavior and complex tumor microenvironment. It has been recently postulated that pancreatic stellate cells (PSCs), the resident lipid-storing cells of the pancreas, are important components of the tumor microenvironment as they can transdifferentiate into highly proliferative myofibroblasts in the context of tissue injury. Targeting tumor-stromal crosstalk in the tumor microenvironment has emerged as a promising therapeutic strategy against pancreatic cancer progression and metastasis. This chapter brings a broad view on the biological and pathological role of PSCs in the pancreas, activated stellate cells in the onset of tissue fibrosis, and tumor progression with particular emphasis on the bidirectional interactions between tumor cells and PSCs. Further, potential therapeutic regimens targeting activated PSCs in the pre-clinical and clinical trials are discussed.

Truncated O-glycans promote epithelial-to-mesenchymal transition and stemness properties of pancreatic cancer cells.

Aberrant expression of Sialyl-Tn (STn) antigen correlates with poor prognosis and reduced patient survival. We demonstrated that expression of Tn and STn in pancreatic ductal adenocarcinoma (PDAC) is due to hypermethylation of Core 1 synthase specific molecular chaperone (COSMC) and enhanced the malignant properties of PDAC cells with an unknown mechanism. To explore the mechanism, we have genetically deleted COSMC in PDAC cells to express truncated O-glycans (SimpleCells, SC) which enhanced cell migration and invasion. Since epithelial-to-mesenchymal transition (EMT) play a vital role in metastasis, we have analysed the induction of EMT in SC cells. Expressions of the mesenchymal markers were significantly high in SC cells as compared to WT cells. Equally, we found reduced expressions of the epithelial markers in SC cells. Re-expression of COSMC in SC cells reversed the induction of EMT. In addition to this, we also observed an increased cancer stem cell population in SC cells. Furthermore, orthotopic implantation of T3M4 SC cells into athymic nude mice resulted in significantly larger tumours and reduced animal survival. Altogether, these results suggest that aberrant expression of truncated O-glycans in PDAC cells enhances the tumour aggressiveness through the induction of EMT and stemness properties.

Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with high morbidity and mortality worldwide. To date, limited therapeutic achievements targeting cell proliferation and related mechanisms has led researchers to focus on the microenvironment where pancreatic cancers develop. The anomalous proliferation of stromal cells, such as pancreatic stellate cells, and an increased deposition of altered matrix proteins create an environment that facilitates tumor growth, metastasis and drug resistance. Here, we summarize our understanding of recent advances in research about the role of fibrosis in pancreatic cancer progression, with particular emphasize on the involvement of fibrotic machineries such as wound healing, extra cellular matrix degradation, and epithelial-to-mesenchymal transition. The precise influence of these mechanisms on the biological behaviors and growth of cancer cells has great impact on clinical therapy and therefore deserves more attention. We also discuss the role of various stromal components in conferring drug resistance to PDAC which further worsening the pessimistic disease prognosis. A more in depth understanding of cancer-stroma crosstalk within the tumor microenvironment and stroma based clinical and translational therapies may provide new therapeutic strategies for the prevention of pancreatic cancer progression.

A Polymeric Nanogel-Based Treatment Regimen for Enhanced Efficacy and Sequential Administration of Synergistic Drug Combination in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. A combination of cisplatin (CDDP) and gemcitabine (Gem) treatment has shown favorable clinical results for metastatic disease; both are limited by toxicities and nontargeted delivery. More than 80% of PDAC aberrantly expresses the sialyl Tn (STn) antigen due to the loss of function of the core 1ß3-Gal-T-specific molecular chaperone, a specific chaperone for the activity of core 1 ß3-galactosyltransferase or C1GalT. Here, we report the development of polymeric nanogels (NGs) loaded with CDDP and coated with an anti-STn antigen-specific antibody (TKH2 monoclonal antibody) for the targeted treatment of PDAC. TKH2-functionalized, CDDP-loaded NGs delivered a significantly higher amount of platinum into the cells and tumors expressing STn antigens. We also confirmed that a synergistic cytotoxic effect of sequential exposure of pancreatic cancer cells to Gem followed by CDDP can be mimicked by the codelivery of CDDP-loaded NGs (NG/CDDP) and free Gem. In a murine orthotopic model of PDAC, combined simultaneous treatment with Gem and targeted NG/CDDP significantly attenuated tumor growth with no detectable acute toxicity. Altogether, these results suggest that combination therapy consisting of Gem followed by TKH2-conjugated CDDP NGs induces highly synergistic therapeutic efficacy against pancreatic cancer. Our results offer the basis for development of combination drug regimens using targeted nanomedicines to increase treatment effectiveness and improve outcomes of PDAC therapy.

A New Fluorescent Sensor Based on Bisindolizine Derivative.

A fluorescent sensor based on 1,2,1',2'- Tetra(methoxycarbonyl)- 3,3'- bis(p-methylbenzoyl)- 7,7'-bisindolizine (MBI) showing excellent selectivity towards Fe(3+) ions was developed. Under optimized experimental conditions, the fluorescence intensity of 1,2,1',2'- Tetramethoxycarbonyl- 3,3'- bis(p-methylbenzoyl)- 7,7'-bisindolizine was quenched linearly by Fe(3+) ions in the range of 2.00 × 10(-2) to 4.76 × 10(-3) M. The limit of detection was found to be 3.17 × 10(-3) M. The mechanism for quenching was investigated. The developed sensor was applied for the determination of Fe(3+) in pharmaceutical samples.

Inherited metabolic disorders: prenatal diagnosis of lysosomal storage disorders.

OBJECTIVE: To offer accurate prenatal diagnosis of lysosomal storage disorders in early pregnancy. METHOD: Prenatal enzymatic diagnoses of Gaucher, Fabry, Pompe, Niemann Pick A/B, Tay Sach, Sandoff, GM1, mucoplysaccharidoses, Wolman, Krabbe, Metachromatic leukodystrophy and Batten diseases were made in uncultured chorionic villi samples by fluorometric/spectrophotometric methods. RESULTS: Of 331 prenatal enzymatic diagnosis, 207 fetuses (67%) were normal and 124 (37%) were affected. The interpretation of affected, normal and carrier fetuses was done using their respective reference ranges as well as % enzyme activity of normal mean. The prenatal molecular confirmation was feasible in 43 biochemically diagnosed fetuses. Of the 207 normal reported fetuses, post natal enzymatic confirmation was done in 23 babies, clinical status of another 165 babies was assessed as unaffected via questionnaire on telephone and 19 were lost to follow-up. In affected pregnancies, 123 opted for termination of which 44 were confirmed enzymatically after abortion. A single false positive was determined to be a carrier by prenatal mutation analysis and carried to term. CONCLUSION: We recommend uncultured chorionic villi for reliable prenatal enzymatic diagnosis of various lysosomal storage disorders on account of the low rate of false positive (0.5%) and false negative (2.2%) results.

Study of kinetic parameters and development of a voltammetric sensor for the determination of butylated hydroxyanisole (BHA) in oil samples.

Electrochemical behavior of artificial antioxidant, butylated hydroxyanisole (BHA), was investigated at a glassy carbon electrode modified with poly L- cysteine [poly (L- Cys/GCE)]. BHA exhibits a pair of well - defined redox peak on L- cysteine modified GCE with Epa = 69 mV and Epc = 4 mV. The modified electrode showed good electrocatalytic activity towards the oxidation of BHA under optimal conditions and exhibited a linear response in the range from 1.0 × 10(-5) to 1.0 × 10(-6) M with a correlation coefficient of 0.998. The limit of detection was found to be 4.1 × 10(-7) M. The kinetics parameters of the proposed sensor such as heterogeneous electron transfer rate, k s , and charge transfer coefficient,α, was calculated and found to be 1.20 s(-1) and 0.575 respectively. The average surface concentration of BHA on the surface of poly (L- Cys/GCE) was calculated to be 3.18 × 10(-4) mol cm(-2). The analytical utility of the proposed sensor was evaluated by the successful determination of BHA in coconut oil and sesame oil samples.

Quantum dots (QDs) based fluorescent sensor for the selective determination of nimesulide.

Fluorescent PET (Photoinduced Electron Transfer) has been of particular growth in recent times. A novel PET based fluorescent sensor using unmodified CdSe quantum dots (QDs) has been developed for the trace determination of Nimesulide (NIM). The sensor is based on the selective fluorescence quenching of quantum dots by NIM in presence of other NSAIDs and is found that intensity of quenching is linearly related to NIM concentration in the range 8.2 × 10(-7) - 4.01 × 10(-5) M. The mechanism of interaction is discussed. Finally, the potential application of the proposed method for the trace determination of NIM in pharmaceutical formulation is demonstrated.

Importance of Microminerals for Maintaining Antioxidant Function After COVID-19-induced Oxidative Stress.

Background: COVID-19 is caused by the Severe Acute Respiratory Distress Syndrome Coronavirus 2. Since the antioxidant mechanisms such as glutathione peroxidase or superoxide dismutase are downregulated during infection by the virus, there is an imbalance in the oxidant-antioxidant system. In this study we aimed to identify the effect of COVID-19 on the antioxidant defense mechanism by comparing the concentrations of antioxidants and microminerals in COVID-19 patients and healthy controls. Methods: This cross-sectional analytical study involved 200 patients at Kasturba Hospital, Manipal University. The serum concentrations of antioxidants and minerals were determined to establish the impact of COVID-19 on antioxidants mechanism and nutrient status in COVID-19 patients. Results: The serum concentrations of GPX (10.36 ± 2.70 ≥ 5.82 ± 1.64 mKAT/L, p < 0.0001) and copper (2192.5 ± 449.8 ≥ 782.15 ± 106.5 µg/dL, p < 0.0001) were significantly greater, and zinc (34.78 ± 4.5 ≤ 81.07 ± 10.13 µg/dL, p < 0.0001) was significantly less, in the study group than in controls. The Pearson correlation between serum SOD and zinc was significant (r = 0.491, p < 0.0001) indicating the importance of zinc in maintaining and improving SOD activity. No significant correlations were observed between copper and SOD (r = -0.089) or iron and CAT (r = -0.027). Conclusion: Our study demonstrated the expected increase in oxidant-radical production during COVID-19 by estimating the altered concentrations of antioxidants and the minerals required to neutralize the elevated ROS. This finding is not novel but adds to the existing literature, which recommends nutritional supplementation of microminerals and antioxidants.

Clinical and Genetic Profile of Children With Short Stature Presenting to a Genetic Clinic in Northern India.

OBJECTIVE: To define the spectrum of genetic disorders in patients with short stature visiting the genetic out-patient department in a tertiary care hospital. METHODS: A chart review was done for 455 individuals (10 months-16 yrs) with short stature, who were evaluated at the genetic clinic from 1 January, 2017 upto 31 October, 2018. 226 patients who needed detailed evaluation, the spectrum of genetic diagnosis is presented. RESULTS: Proportionate short stature was identified in 63% individuals (n=142) of which 93 (65%) were recognizable syndromes such as Turner syndrome, and William syndrome, and RASopathies. In clinically undefined syndromes (39, 27%), a diagnosis could be made by karyotype (n=3/10), chromosomal microarray (6/12) and exome sequencing (1/6). In the 84 children in the disproportionate short stature group (37%), lysosomal storage disorders (LSDs) (45%, n=38) were identified by enzyme analysis in 86.8% and skeletal dysplasias (44%, n=37) identified by skeletal survey in 89% cases. CONCLUSIONS: In undefined syndromic short stature, chromosomal microarray may be the first investigation of choice if phenotyping is not suggestive of a specific genetic syndrome. Exome sequencing can be useful in identifying newer genes among idiopathic and familial short stature cohorts.

Altered glycosylation in cancer: A promising target for biomarkers and therapeutics.

Glycosylation is a well-regulated cell and microenvironment specific post-translational modification. Several glycosyltransferases and glycosidases orchestrate the addition of defined glycan structures on the proteins and lipids. Recent advances and systemic approaches in glycomics have significantly contributed to a better understanding of instrumental roles of glycans in health and diseases. Emerging research evidence recognized aberrantly glycosylated proteins as the modulators of the malignant phenotype of cancer cells. The Cancer Genome Atlas has identified alterations in the expressions of glycosylation-specific genes that are correlated with cancer progression. However, the mechanistic basis remains poorly explored. Recent researches have shown that specific changes in the glycan structures are associated with 'stemness' and epithelial-to-mesenchymal transition of cancer cells. Moreover, epigenetic changes in the glycosylation pattern make the tumor cells capable of escaping immunosurveillance mechanisms. The deciphering roles of glycans in cancer emphasize that glycans can serve as a source for the development of novel clinical biomarkers. The ability of glycans in intervening various stages of tumor progression and the biosynthetic pathways involved in glycan structures constitute a promising target for cancer therapy. Advances in the knowledge of innovative strategies for identifying the mechanisms of glycan-binding proteins are hoped to hold great potential in cancer therapy. This review discusses the fundamental role of glycans in regulating tumorigenesis and tumor progression and provides insights into the influence of glycans in the current tactics of targeted therapies in the clinical setting.

Levels of Lyso GL-1 in Gaucher and Lyso GL-3 in Fabry patients from India: Diagnostic aids for these lysosomal storage disorders.

BACKGROUND & AIMS: Lysosomal storage disorders (LSDs) remain a significant cause of morbidity in the Indian population and treatment is largely out of reach for most patients. Although data on enzymatic and molecular diagnosis of Gaucher disease (GD) and Fabry disease (FD) in Indian patients are available, the present study intended to establish the pathogenic levels of Lyso GL-1 and Lyso GL-3 in patients of GD and FD respectively as diagnostic aids. MATERIALS AND METHODS: From 2017 to 2019, ninety confirmed Gaucher cases (by enzymatic and molecular analysis) were tested for chitotriosidase (fluorometrically) and Lyso GL-1 (LC-MS/MS) and ten confirmed Fabry cases were analyzed for Lyso GL-3 (LC-MS/MS). RESULTS: Lyso GL-1 (median: 685.5 ng/mL, cut-off: 14) and Lyso GL-3 (median: 75.6 ng/mL, cut-off: 3.5) were found to be elevated in all enzymatically deficient patients of GD and FD respectively, however, no specific trend was observed between the levels of these biomarkers and the pathogenic variant(s) present in the patients of these disorders. CONCLUSIONS: This is the first report on Lyso GL-1 and Lyso GL-3 levels in Indian patients of GD and FD respectively. These results will be useful for early diagnosis to improve management of these LSDs.

Lysosomal storage disorders: Novel and frequent pathogenic variants in a large cohort of Indian patients of Pompe, Fabry, Gaucher and Hurler disease.

OBJECTIVES: Diagnosis of lysosomal storage disorders (LSDs) remains challenging due to wide clinical, biochemical and molecular heterogeneity. The study applies a combined biochemical and genetic approach to diagnose symptomatic Indian patients of Pompe, Fabry, Gaucher and Hurler disease to generate a comprehensive dataset of pathogenic variants for these disorders. DESIGN & METHODS: Symptomatic patients were biochemically diagnosed by fluorometric methods and molecular confirmation was carried out by gene sequencing. Genetic variants were analyzed according to the ACMG/AMP 2015 variant interpretation guidelines. RESULTS: Amongst the 2181 suspected patients, 285 (13%) were biochemically diagnosed. Of these, 22.5% (64/285) diagnosed with Pompe disease harboured c.1933G>A, c.1A>G, c.1927G>A and c.2783G>C as common and 10 novel pathogenic variants while 7.4% (21/285) patients diagnosed with Fabry disease carried c.851T>C, c.902G>A, c.905A>C and c.1212_1234del as frequent disease-causing variants along with 7 novel pathogenic variants. As many as 48.4% (138/285) patients were diagnosed with Gaucher disease and had c.1448T>C as the most common pathogenic variant followed by c.1342G>C and c.754T>C with 7 previously unreported disease-causing variants and in the 21.7% (62/285) diagnosed cases of Hurler disease, c.1469T>C, c.754delC c.568_581del and c.1898C>T were identified as the most common causative variants along with 21 novel pathogenic variants. CONCLUSION: This comprehensive data set of disease-causing frequent and novel pathogenic variants reported for the first time in such a large patient cohort for each of these four LSDs from the Indian sub-continent, along with their biochemical and clinical spectrum will contribute towards providing definitive diagnosis and treatment, identifying carrier status, as well as in counselling prenatal cases to reduce the morbidity and mortality associated with these disorders.

MUC4 enhances gemcitabine resistance and malignant behaviour in pancreatic cancer cells expressing cancer-associated short O-glycans.

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal. MUC4 (mucin4) is a heavily glycosylated protein aberrantly expressed in PDAC and promotes tumorigenesis via an unknown mechanism. To assess this, we genetically knocked out (KO) MUC4 in PDAC cells that did not express and did express truncated O-glycans (Tn/STn) using CRISPR/Cas9 technology. We found that MUC4 knockout cells possess less tumorigenicity in vitro and in vivo, which was further reduced in PDAC cells that express aberrant overexpression of truncated O-glycans. Also, MUC4KO cells showed a further reduction of epidermal growth factor receptors (ErbB) and their downstream signaling pathways in truncated O-glycan expressing PDAC cells. Tn-MUC4 specific 3B11 antibody inhibited MUC4-induced ErbB receptor and its downstream signaling cascades. MUC4 knockout differentially regulates apoptosis and cell cycle arrest in branched and truncated O-glycan expressing PDAC cells. Additionally, MUC4KO cells were found to be more sensitive to gemcitabine treatment. They possessed the upregulated expression of hENT1 and hCNT3 compared to parental cells, which were further affected in cells with aberrant O-glycosylation. Taken together, our results indicate that MUC4 enhances the malignant properties and gemcitabine resistance in PDAC tumors that aberrantly overexpress truncated O-glycans via altering ErbB/AKT signaling cascades and expression of nucleoside transporters, respectively.

Late onset Pompe Disease in India - Beyond the Caucasian phenotype.

We evaluated the clinical histories, motor and pulmonary functions, cardiac phenotypes and GAA genotypes of an Indian cohort of twenty patients with late onset Pompe disease (LOPD) in this multi-centre study. A mean age at onset of symptoms and diagnosis of 9.9 ±â€¯9.7 years and 15.8 ±â€¯12.1 years respectively was identified. All patients had lower extremity limb-girdle muscle weakness. Seven required ventilatory support and seven used mobility assists. Of the four who used both assists, two received ventilatory support prior to wheelchair use. Cardiac involvement was seen in eight patients with various combinations of left ventricular hypertrophy, tricuspid regurgitation, cardiomyopathy, dilated ventricles with biventricular dysfunction and aortic regurgitation. Amongst 20 biochemically diagnosed patients (low residual GAA enzyme activity) GAA genotypes of 19 patients identified homozygous variants in eight and compound heterozygous in 11: 27 missense, 3 nonsense, 2 initiator codon, 3 splice site and one deletion. Nine variants in 7 patients were novel. The leaky Caucasian, splice site LOPD variant, c.-32-13T>G mutation was absent. This first study from India provides an insight into a more severe LOPD phenotype with earlier disease onset at 9.9 years compared to 33.3 years in Caucasian patients, and cardiac involvement more than previously reported. The need for improvement in awareness and diagnosis of LOPD in India is highlighted.

Role of Tumor and Stroma-Derived IGF/IGFBPs in Pancreatic Cancer.

Pancreatic cancer (PC) is the utmost stroma-rich cancer, which is accompanied by fibrotic reactions that stimulate interactions between tumor cells and stroma to promote tumor progression. Considerable research evidence denotes that insulin-like growth factor (IGF)/IGF binding proteins (IGFBP) signaling axis facilitate tumor growth, metastasis, drug resistance, and thereby facilitate PC into an advanced stage. The six members of IGFBPs were initially considered as passive carriers of free IGFs; however, current evidence revealed their functions beyond the endocrine role in IGF transport. Though numerous efforts have been made in blocking IGF/IGFBPs, the targeted therapies remain unsuccessful due to the complexity of tumor-stromal interactions in the pancreas. In this review, we explore the emerging evidence of the various roles of the tumor as well as stroma derived IGF/IGFBPs and highlight as a novel therapeutic target against PC progression.

Newborn Screening for Congenital Hypothyroidism, Congenital Adrenal Hyperplasia, and Glucose-6-Phosphate Dehydrogenase Deficiency for Improving Health Care in India.

Newborn screening (NBS) aims toward early detection of treatable congenital disorders. From January 2008 through December 2017, 13,376 newborns were screened for congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH), and glucose-6-phosphate dehydrogenase (G6PD) deficiency at Sir Ganga Ram Hospital, India, by measuring G6PD activity, thyroid-stimulating hormone, and 17-hydroxyprogesterone on dried blood specimens. The birth prevalence of 1:2,000 for CH, 1:2,500 for CAH, and 1:125 for G6PD deficiency indicates the latter as the most prevalent. Performance evaluation of testing reveals a robust screening program with 100% sensitivity and >99% specificity. Hence, we recommend NBS for early diagnosis and treatment to prevent adverse outcomes.

The glycoprotein mucin-1 negatively regulates GalNAc transferase 5 expression in pancreatic cancer.

Aberrant expression of the glycoprotein mucin-1 (MUC1) has been associated with pancreatic cancer progression and metastasis as a result of mediating the oncogenic transcriptional regulation of target genes. In the present study, we demonstrate that MUC1 downregulates the expression of the tumor suppressor polypeptide N-acetylgalactosaminyltransferase 5 in pancreatic cancer. ChIP-on-chip analysis revealed that the MUC1 cytoplasmic tail binds to regulatory elements in the GALNT5 gene. Additionally, MUC1 increases binding of p53 and c-Jun and decreases the binding of Sp1 to the proximal promoter and exonic regions of GALNT5. We also observed that expression of N-acetylgalactosaminyltransferase 5 is inversionally proportional to MUC1 expression in human pancreatic cancer. These results demonstrate that MUC1 downregulates the expression of N-acetylgalactosaminyltransferase 5 in pancreatic cancer by modifying the promoter occupancy of transcription factors through its cytoplasmic domain.