Truncated O-Glycan-Bearing MUC16 Enhances Pancreatic Cancer Cells Aggressiveness via α4β1 Integrin Complexes and FAK Signaling

Rajesh, Christabelle; Sagar, Satish; Rathinavel, Ashok Kumar; Chemparathy, Divya Thomas; Peng, Xianlu L.; Yeh, Jen Jen; Hollingsworth, Michael A.; Radhakrishnan, Prakash

doi:10.3390/ijms23105459

Cited by 14 publications

(5 citation statements)

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“…Deletion of MUC16 decreases tumor cell migration in pancreatic ductal adenocarcinoma cells [46], which is in line with the decrease in proliferation and migratory ability in MUC16silenced YTS-1 cells. MUC16 bearing truncated O-glycans exacerbates malignancy by FAK activation through interactions with integrins on cell membranes [46], indicating that O-glycans might regulate the localization and turnover of target proteins and be involved in cancer progression.…”

Section: Discussionsupporting

confidence: 75%

Dysregulation and prometastatic function of glycosyltransferase C1GALT1 modulated by cHP1BP3/ miR-1-3p axis in bladder cancer

Tan

Jiang

Liang

et al. 2022

J Exp Clin Cancer Res

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Background Abnormal glycosylation in a variety of cancer types is involved in tumor progression and chemoresistance. Glycosyltransferase C1GALT1, the key enzyme in conversion of Tn antigen to T antigen, is involved in both physiological and pathological conditions. However, the mechanisms of C1GALT1 in enhancing oncogenic phenotypes and its regulatory effects via non-coding RNA are unclear. Methods Abnormal expression of C1GALT1 and its products T antigen in human bladder cancer (BLCA) were evaluated with BLCA tissue, plasma samples and cell lines. Effects of C1GALT1 on migratory ability and proliferation were assessed in YTS-1 cells by transwell, CCK8 and colony formation assay in vitro and by mouse subcutaneous xenograft and trans-splenic metastasis models in vivo. Dysregulated circular RNAs (circRNAs) and microRNAs (miRNAs) were profiled in 3 pairs of bladder cancer tissues by RNA-seq. Effects of miR-1-3p and cHP1BP3 (circRNA derived from HP1BP3) on modulating C1GALT1 expression were investigated by target prediction program, correlation analysis and luciferase reporter assay. Functional roles of miR-1-3p and cHP1BP3 on migratory ability and proliferation in BLCA were also investigated by in vitro and in vivo experiments. Additionally, glycoproteomic analysis was employed to identify the target glycoproteins of C1GALT1. Results In this study, we demonstrated upregulation of C1GALT1 and its product T antigen in BLCA. C1GALT1 silencing suppressed migratory ability and proliferation of BLCA YTS-1 cells in vitro and in vivo. Subsets of circRNAs and miRNAs were dysregulated in BLCA tissues. miR-1-3p, which is reduced in BLCA tissues, inhibited transcription of C1GALT1 by binding directly to its 3′-untranslated region (3′-UTR). miR-1-3p overexpression resulted in decreased migratory ability and proliferation of YTS-1 cells. cHP1BP3 was upregulated in BLCA tissues, and served as an miR-1-3p “sponge”. cHP1BP3 was shown to modulate migratory ability, proliferation, and colony formation of YTS-1 cells, and displayed tumor-suppressing activity in BLCA. Target glycoproteins of C1GALT1, including integrins and MUC16, were identified. Conclusions This study reveals the pro-metastatic and proliferative function of upregulated glycosyltransferase C1GLAT1, and provides preliminary data on mechanisms underlying dysregulation of C1GALT1 via miR-1-3p / cHP1BP3 axis in BLCA.

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Section: Discussionsupporting

confidence: 75%

Dysregulation and prometastatic function of glycosyltransferase C1GALT1 modulated by cHP1BP3/ miR-1-3p axis in bladder cancer

Tan

Jiang

Liang

et al. 2022

J Exp Clin Cancer Res

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“…In breast cancer metastasis, DKK1 is a serum marker that promotes breast cancer bone metastasis by Frontiers in Pharmacology frontiersin.org regulating the WNT signaling pathway (Zhuang et al, 2017). Moreover, MUC16 is associated with PDAC malignant progression, and that truncated O-glycans containing MUC16 activate FAK signaling through specific interactions with α4 and β1 integrin complexes on cancer cell membranes, contributing to PDAC malignancy progress (Rajesh et al, 2022). Frontiers in Pharmacology frontiersin.org…”

Section: Discussionmentioning

confidence: 99%

Characterization of tumor microenvironment and programmed death-related genes to identify molecular subtypes and drug resistance in pancreatic cancer

Cui

2023

Front. Pharmacol.

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Background: Immunotherapy has been a key option for the treatment of many types of cancer. A positive response to immunotherapy is heavily dependent on tumor microenvironment (TME) interaction. However, in pancreatic adenocarcinoma (PAAD), the association between TME mode of action and immune cell infiltration and immunotherapy, clinical outcome remained unknown.Methods: We systematically evaluated 29 TME genes in PAAD signature. Molecular subtypes of distinct TME signatures in PAAD were characterized by consensus clustering. After this, we comprehensively analyzed their clinical features, prognosis, and immunotherapy/chemotherapy response using correlation analysis, Kaplan-Meier curves analysis, ssGSEA analysis. 12 programmed cell death (PCD) patterns were acquired from previous study. Differentially expressed genes (DEGs) were acquired based on differential analysis. Key genes affecting overall survival (OS) of PAAD were screened by COX regression analysis and used to develop a RiskScore evaluation model. Finally, we assessed the value of RiskScore in predicting prognosis and treatment response in PAAD.Results: We identified 3 patterns of TME-associated molecular subtypes (C1, C2, C3), and observed that clinicopathological characteristics, prognosis, pathway features and immune features, immunotherapy/chemosensitivity of patients were correlated with the TME related subtypes. C1 subtype was more sensitive to the four chemotherapeutic drugs. PCD patterns were more likely to occur at C2 or C3. At the same time, we also detected 6 key genes that could affect the prognosis of PAAD, and 5 genes expressions were closely associated to methylation level. Low-risk patients with high immunocompetence had favorable prognostic results and high immunotherapy benefit. Patients in the high-risk group were more sensitive to chemotherapeutic drugs. RiskScore related to TME was an independent prognostic factor for PAAD.Conclusion: Collectively, we identified a prognostic signature of TME in PAAD patients, which could help elucidate the specific mechanism of action of TME in tumors and help to explore more effective immunotherapy strategies.

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“…Rajesh et al. revealed that in PDAC, truncated O-glycan forms of MUC16 interact with the α4β1 integrin complex, activating the ILK/FAK signaling pathway and enhancing tumor invasiveness ( 68 ). Muniyan et al.…”

Section: The Relevance Of Muc1 and Muc16 To Tumor Development And Pro...mentioning

confidence: 99%

MUC1 and MUC16: critical for immune modulation in cancer therapeutics

Chen,

Sandrine,

Yang

et al. 2024

Front. Immunol.

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The Mucin (MUC) family, a range of highly glycosylated macromolecules, is ubiquitously expressed in mammalian epithelial cells. Such molecules are pivotal in establishing protective mucosal barriers, serving as defenses against pathogenic assaults. Intriguingly, the aberrant expression of specific MUC proteins, notably Mucin 1 (MUC1) and Mucin 16 (MUC16), within tumor cells, is intimately associated with oncogenesis, proliferation, and metastasis. This association involves various mechanisms, including cellular proliferation, viability, apoptosis resistance, chemotherapeutic resilience, metabolic shifts, and immune surveillance evasion. Due to their distinctive biological roles and structural features in oncology, MUC proteins have attracted considerable attention as prospective targets and biomarkers in cancer therapy. The current review offers an exhaustive exploration of the roles of MUC1 and MUC16 in the context of cancer biomarkers, elucidating their critical contributions to the mechanisms of cellular signal transduction, regulation of immune responses, and the modulation of the tumor microenvironment. Additionally, the article evaluates the latest advances in therapeutic strategies targeting these mucins, focusing on innovations in immunotherapies and targeted drugs, aiming to enhance customization and accuracy in cancer treatments.

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Truncated O-Glycan-Bearing MUC16 Enhances Pancreatic Cancer Cells Aggressiveness via α4β1 Integrin Complexes and FAK Signaling

Cited by 14 publications

References 43 publications

Dysregulation and prometastatic function of glycosyltransferase C1GALT1 modulated by cHP1BP3/ miR-1-3p axis in bladder cancer

Dysregulation and prometastatic function of glycosyltransferase C1GALT1 modulated by cHP1BP3/ miR-1-3p axis in bladder cancer

Characterization of tumor microenvironment and programmed death-related genes to identify molecular subtypes and drug resistance in pancreatic cancer

MUC1 and MUC16: critical for immune modulation in cancer therapeutics

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