ErbB2 Glycomic Data from WT and ST6GAL1 K.O. Gastric Cancer Cells
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ABSTRACT: Glycomic analysis of total N-glycan species released from ErbB2 isolated from WT and ST6GAL1 K.O. ErbB2-positive gastric cancer cells (NCI-N87)
Project description:The clinical performance of trastuzumab in the treatment of ErbB2-positive gastric cancer is severely hampered by the emergence of molecular resistance. The glycosylation landscape of ErbB2’s extracellular domain, and the molecular mechanisms through which it tunes gastric cell malignancy, including the acquisition of trastuzumab resistance, remain elusive. We show that the expression of ErbB2 sialylated glycoforms holds clinical utility in the prediction of clinical outcome and stratification of gastric cancer patients. In-depth glycoproteomic and glycomic analysis of ErbB2 extracellular region disclosed a site-specific profile in gastric cancer cells. We further demonstrate that ST6Gal1 sialyltransferase specifically targets ErbB2 N-glycosylation sites within the trastuzumab binding domain. Moreover, the abrogation of ST6Gal1-mediated α2,6-sialylation reshapes ErbB2 glycome and sensitizes gastric cancer cells to trastuzumab-induced cytotoxicity through receptor membrane stabilization and a downregulation of ErbB2 activation. Overall, this data demonstrates that aberrant sialylation tunes the molecular resistance of ErbB2-driven gastric cancer cells to trastuzumab.
Project description:To discover potential biomarkers of melanoma development and progression, we embarked on studies comparing the glycomic gene profiles of normal human epidermal melanocytes with human metastatic melanoma (MM) cells represented by A375 and G361 cell lines. Glycomic features embody all of those enzymatic, membranous and regulatory proteins that influence glycan ‘sugar’ formation/degradation on a cell. Comparative expression profiling of glycomic genes indicated that several genes were differentially expressed between normal melanocytes and MM cells. We speculate that glycome genes differentially expressed in MM cells help drive malignant and metastatic behavior of MM cells and could potentially serve as a biomarker(s) of melanoma progression.
Project description:People with HIV (PWH) experience an increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors that contribute to or are associated with this vulnerability remain uncertain. In the general population, alterations in the glycomes of circulating IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG glycomes of cross-sectional and longitudinal samples from 1,216 women and men, both living with virally suppressed HIV and those without HIV. Our glycan-based machine learning models indicate that living with chronic HIV significantly accelerates the accumulation of pro-aging associated glycomic alterations. Consistently, PWH exhibit heightened expression of senescence associated glycan-degrading enzymes compared to their controls. These glycomic alterations correlate with elevated markers of inflammatory aging and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit reduced anti-HIV IgG-mediated innate immune functions. These findings hold significant potential for the development of glycomic based biomarkers and tools to identify and prevent premature aging and comorbidities in people living with chronic viral infections.
Project description:Downregulation or gene mutation of MUC6, a major component of gastric mucin, is often identified in human gastric cancers. However, the mechanistic role of MUC6 alteration in gastric carcinogenesis remains unclear. Here, using Muc6-deficient mice, we revealed that dysregulated glycosylation in Muc6-deficient gastric epithelium causes aberrant golgi stress responses, resulting in spontaneous gastric cancer development. Muc6-deficient tumor growth is dependent on MAPK activation, which is mediated by golgi stress-induced golph3 upregulation. Glycomic analysis and lectin-binding assays revealed abnormal expression of mannose-rich N-type glycans in Muc6-deficient gastric tumors. Banana lectin-drug conjugates, which bind to mannose-rich glycans, dramatically suppress mannose-rich murine and human gastric cancer growth. Thus, we propose golgi stress responses and aberrant sugar chains as promising therapeutic targets in gastric cancers accompanied with mucin expression disorder.
Project description:Downregulation or gene mutation of MUC6, a major component of gastric mucin, is often identified in human gastric cancers. However, the mechanistic role of MUC6 alteration in gastric carcinogenesis remains unclear. Here, using Muc6-deficient mice, we revealed that dysregulated glycosylation in Muc6-deficient gastric epithelium causes aberrant golgi stress responses, resulting in spontaneous gastric cancer development. Muc6-deficient tumor growth is dependent on MAPK activation, which is mediated by golgi stress-induced golph3 upregulation. Glycomic analysis and lectin-binding assays revealed abnormal expression of mannose-rich N-type glycans in Muc6-deficient gastric tumors. Banana lectin-drug conjugates, which bind to mannose-rich glycans, dramatically suppress mannose-rich murine and human gastric cancer growth. Thus, we propose golgi stress responses and aberrant sugar chains as promising therapeutic targets in gastric cancers accompanied with mucin expression disorder.
Project description:Downregulation or gene mutation of MUC6, a major component of gastric mucin, is often identified in human gastric cancers. However, the mechanistic role of MUC6 alteration in gastric carcinogenesis remains unclear. Here, using Muc6-deficient mice, we revealed that dysregulated glycosylation in Muc6-deficient gastric epithelium causes aberrant golgi stress responses, resulting in spontaneous gastric cancer development. Muc6-deficient tumor growth is dependent on MAPK activation, which is mediated by golgi stress-induced golph3 upregulation. Glycomic analysis and lectin-binding assays revealed abnormal expression of mannose-rich N-type glycans in Muc6-deficient gastric tumors. Banana lectin-drug conjugates, which bind to mannose-rich glycans, dramatically suppress mannose-rich murine and human gastric cancer growth. Thus, we propose golgi stress responses and aberrant sugar chains as promising therapeutic targets in gastric cancers accompanied with mucin expression disorder.
Project description:Background: Egl-9 family hypoxia inducible factor 3 (EGLN3) belongs to the family of 2-oxoglutarate (2-OG)- and ferrous iron (Fe 2+)-dependent dioxygenases, which play critical roles in all steps of tumorigenesis. Previous studies have found that EGLN3 regulates the malignant biological behavior of malignant tumors. However, its role and mechanism in the occurrence and development of gastric cancer (GC) are still unclear. This study aimed to investigate the role of EGLN3 in gastric carcinogenesis Methods:Bioinformatics analysis, qRT-PCR, western blot, CCK-8, and in vivo xenograft tumor model were used to examine the expression and function of EGLN3. Survival analysis was performed to determine the correlation between EGLN3 expression and prognosis of patients with GC. Genes modulated by EGLN3 in NCI-N87 cells were identified through RNA next generation sequence screening and further verified by qRT-PCR in NCI-N87 cells. Results: EGLN3 expression was markedly reduced in GC tissues as compared with that in normal tissues. Likewise, EGLN3 expression was also significantly reduced in a panel of GC cell lines . Forced expression of EGLN3 inhibited proliferation in NCI-N87 cells in vitro. Additionally, EGLN3 impaired growth of NCI-N87 cells in immunodeficient mice. Survival analysis showed that EGLN3 expression was positively associated with favorable outcome in patients with GC.
Project description:To develop a syngeneic mouse model of metastatic gastric cancer, we established the tumor organoids from gastric tumor arising in GAstric Neoplasia (GAN) mice (GAN-WT) which express Wnt1 and the PGE2 synthesis enzymes COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in the stomach epithelium. Furthemore, GAN-WT organoids were genetically manupilated into p53 knockout organoids (GAN-p53KO) and KrasG12V-expressing GAN-p53KO organoids (GAN-KP).
2021-06-15 | GSE178087 | GEO
Project description:Glycomic profiling of the gut microbiota by Glycan-seq
Project description:Gene expression profiling of ErbB2-engineered MCF10A and WT cells in 2D and 3D culture Gene expression profiling of ErbB2-engineered MCF10A and WT cells, 2D and 3D culture, 5 or 6 replicates