Glycosylation of MUC6 by α1,4‐linked <i>N</i>‐acetylglucosamine enhances suppression of pancreatic cancer malignancy

Yuki, Atsuko; Fujii, Chifumi; Yamanoi, Kazuhiro; Matoba, Hisanori; Harumiya, Satoru; Kawakubo, Masatomo; Nakayama, Jun

doi:10.1111/cas.15209

Cited by 13 publications

(11 citation statements)

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“… 20 , 22 , 23 We recently showed that ectopic MUC6 expression attenuates malignant phenotypes in MIA PaCa‐2 and PANC‐1 pancreatic cancer cell lines, and that coexpression of α4GnT further attenuates these malignant phenotypes in vitro. 24 These findings strongly suggest that αGlcNAc binding to MUC6 has tumor suppressive effects. Here, we also observed that αGlcNAc overexpression attenuates cellular motility and invasiveness with cytoskeletal disruption of AGS cells (see Figures 2B–E,G , and S2B–E ).…”

Section: Discussionmentioning

confidence: 86%

“…Accumulating evidence indicates that αGlcNAc loss is an early event of cancer development in several gastric mucin‐producing tumors including stomach tumors, 6,9–12,18–23 and MUC6 expression is subsequently suppressed at late stages of tumor development 20,22,23 . We recently showed that ectopic MUC6 expression attenuates malignant phenotypes in MIA PaCa‐2 and PANC‐1 pancreatic cancer cell lines, and that coexpression of α4GnT further attenuates these malignant phenotypes in vitro 24 . These findings strongly suggest that αGlcNAc binding to MUC6 has tumor suppressive effects.…”

Section: Discussionmentioning

confidence: 96%

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α1,4‐Linked N‐acetylglucosamine suppresses gastric cancer development by inhibiting Mucin‐1‐mediated signaling

et al. 2022

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Gastric cancer is the second leading cause of cancer deaths worldwide, and more understanding of its molecular basis is urgently needed. Gastric gland mucin secreted from pyloric gland cells, mucous neck cells, and cardiac gland cells of the gastric mucosa harbors unique O-glycans carrying terminal α1,4-linked N-acetylglucosamine (αGlcNAc) residues. We previously reported that αGlcNAc loss correlated positively with poor outcomes for patients with differentiated-type gastric cancer. However, the molecular mechanisms underlying these outcomes remained poorly understood. Here, we examined the effects of upregulated αGlcNAc expression on malignant phenotypes of the differentiated-type gastric cancer cell lines, AGS and MKN7. Upregulation of αGlcNAc following ectopic expression of its biosynthetic enzyme attenuated cell proliferation, motility, and invasiveness of AGS and MKN7 cells in vitro. Moreover, AGS cell tumorigenicity was significantly suppressed by αGlcNAc overexpression in a xenograft model.To define the molecular mechanisms underlying these phenotypes, we investigated αGlcNAc binding proteins in AGS cells and identified Mucin-1 (MUC1) and podocalyxin.Both proteins were colocalized with αGlcNAc on human gastric cancer cells. We also found that αGlcNAc was bound to MUC1 in murine normal gastric mucosa. When we assessed the effects of αGlcNAc binding to MUC1, we found that αGlcNAc blocked galectin-3 binding to MUC1, phosphorylation of the MUC1 C-terminus, and recruitment of Src and β-catenin to that C-terminus. These results suggest that αGlcNAc regulates cancer cell phenotypes by dampening MUC1 signal transduction. K E Y W O R D S differentiated-type gastric cancer, invasion, malignant phenotype, tumor suppressor, αGlcNAcbinding protein 1 | INTRODUC TI ON Malignant neoplasms are leading causes of death in every country in the world and are important factors in decreasing life expectancy. 1 According to WHO estimates for 2019, malignant neoplasms are the leading or second highest cause of death before the age of 70 in 112 of 183 countries, and rank as third or fourth in another 23 countries. 2 Among them, gastric cancer is the second leading cause of

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 96%

α1,4‐Linked N‐acetylglucosamine suppresses gastric cancer development by inhibiting Mucin‐1‐mediated signaling

et al. 2022

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“…Although the importance of MUC6 in cancer is well recognized, its exact role in tumorigenesis remains a controversial topic, as both oncogenic and inhibitory effects have been demonstrated 16 , 25 , 26 . For example, MUC6 is highly expressed at early noninvasive stages of pancreatic tumor progression and then suppressed or lost at invasive stages 27 , 28 .…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Analysis of MUC6 Genetic Variants on the Clinicopathologic Characteristics of Patients with Hepatocellular Carcinoma

Lee¹,

Chien²,

Wang³

et al. 2022

J. Cancer

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Hepatocellular carcinoma (HCC) is the leading malignancy associated with cancer-related deaths worldwide. Many studies have indicated that mucin (MUC) expression plays an important role in cancer metastasis and recurrence. MUC6 expression is observed in gastric and oncocytic phenotypes and may play an important role during cancer progression. We found the level of MUC6 is lower in HCC patients but did not affect the survival of HCC patients. Therefore, in this study, we investigated the combined effect of MUC6 polymorphisms and exposure to environmental carcinogens on the susceptibility to and clinicopathological characteristics of HCC. Three single-nucleotide polymorphisms (SNPs) of MUC6 (rs61869016, rs6597947, and rs7481521) from 1197 healthy controls and 423 HCC patients were analyzed using real-time PCR. After adjusting for other co-variants, we found that carrying a CC genotype at MUC6 rs61869016 had a lower risk of developing HCC than wildtype carriers. Moreover, patients with a smoking habit who carried the C allele of rs61869016 and T allele of rs7481521 had a higher (B or C) Child-Pugh score than other genotypes, suggesting significant functional compromise and decompensated disease. Therefore, our findings suggest that genetic variations in MUC6 may corelate to HCC and indicate progression in HCC patients.

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“…WB is a traditional protein analysis method to identify and quantify specific proteins in biological samples ( 48 ). Tumor biomarkers such as MUC1 ( 52 ), MUC6 ( 53 ), CD82 ( 54 ), EGFR ( 55 ), PSA ( 56 ), and other glycosylated proteins ( 71 ) have been extensively studied with WB. These methods are very sensitive, capable of detecting up to 0.1 nanograms of proteins in a sample ( 72 ).…”

Section: Recent Advances In Glycomics-based Biomarker Discoverymentioning

confidence: 99%

Cancer glycomics offers potential biomarkers and therapeutic targets in the framework of 3P medicine

et al. 2022

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Glycosylation is one of the most important post-translational modifications (PTMs) in a protein, and is the most abundant and diverse biopolymer in nature. Glycans are involved in multiple biological processes of cancer initiation and progression, including cell-cell interactions, cell-extracellular matrix interactions, tumor invasion and metastasis, tumor angiogenesis, and immune regulation. As an important biomarker, tumor-associated glycosylation changes have been extensively studied. This article reviews recent advances in glycosylation-based biomarker research, which is useful for cancer diagnosis and prognostic assessment. Truncated O-glycans, sialylation, fucosylation, and complex branched structures have been found to be the most common structural patterns in malignant tumors. In recent years, immunochemical methods, lectin recognition-based methods, mass spectrometry (MS)-related methods, and fluorescence imaging-based in situ methods have greatly promoted the discovery and application potentials of glycomic and glycoprotein biomarkers in various cancers. In particular, MS-based proteomics has significantly facilitated the comprehensive research of extracellular glycoproteins, increasing our understanding of their critical roles in regulating cellular activities. Predictive, preventive and personalized medicine (PPPM; 3P medicine) is an effective approach of early prediction, prevention and personalized treatment for different patients, and it is known as the new direction of medical development in the 21st century and represents the ultimate goal and highest stage of medical development. Glycosylation has been revealed to have new diagnostic, prognostic, and even therapeutic potentials. The purpose of glycosylation analysis and utilization of biology is to make a fundamental change in health care and medical practice, so as to lead medical research and practice into a new era of 3P medicine.

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Glycosylation of MUC6 by α1,4‐linked N‐acetylglucosamine enhances suppression of pancreatic cancer malignancy

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 13 publications

References 40 publications

α1,4‐Linked N‐acetylglucosamine suppresses gastric cancer development by inhibiting Mucin‐1‐mediated signaling

α1,4‐Linked N‐acetylglucosamine suppresses gastric cancer development by inhibiting Mucin‐1‐mediated signaling

Analysis of MUC6 Genetic Variants on the Clinicopathologic Characteristics of Patients with Hepatocellular Carcinoma

Cancer glycomics offers potential biomarkers and therapeutic targets in the framework of 3P medicine

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