Differential glycosylation of collagen modulates lung cancer stem cell subsets through β1 integrin‐mediated interactions

Gardelli, Cecilia; Russo, Laura; Cipolla, Laura; Moro, Massimo; Andriani, Francesca; Rondinone, Ornella; Nicotra, Francesco; Sozzi, Gabriella; Bertolini, Giulia; Roz, Luca

doi:10.1111/cas.14700

Cited by 27 publications

(13 citation statements)

References 50 publications

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“…In this study, CLDN4 showed approximately 40% of the affinity of CLDN7 for integrin β1. Integrin β1 is known to promote stemness through downstream FAK activation [ 34 , 35 ]. Alterations in the association of cancer cells with the stroma [ 36 ] and Notch signaling have been reported as the underlying mechanisms [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Hypomethylation of CLDN4 Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer

Maesaka

Kuwada

Horii

et al. 2022

IJMS

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The tight junction (TJ) protein claudin-4 (CLDN4) is overexpressed in bladder urothelial carcinoma (BUC) and correlates with cancer progression. However, the mechanism of CLDN4 upregulation and promotion of malignant phenotype is not clear. Here, we analyzed 157 cases of BUC and investigated the hypomethylation of CpG island in the CLDN4 promoter DNA and its correlation with cancer progression. In hypomethylated cases, CLDN4 expression, cell proliferation, stemness, and epithelial-mesenchymal transition were increased. Treatment of three human BUC cell lines with the demethylating agent aza-2′-deoxycytidine (AZA) led to excessive CLDN4 expression, and, specifically, to an increase in CLDN4 monomer that is not integrated into the TJ. The TJ-unintegrated CLDN4 was found to bind integrin β1 and increase stemness, drug resistance, and metastatic ability of the cells as well as show an anti-apoptosis effect likely via FAK phosphorylation, which reduces upon knockdown of CLDN4. Thus, CLDN4 is overexpressed in BUC by an epigenetic mechanism and the high expression enhances the malignant phenotype of BUC via increased levels of TJ-unintegrated CLDN4. CLDN4 promoter DNA methylation is expected to be a novel indicator of BUC malignant phenotype and a new therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Hypomethylation of CLDN4 Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer

Maesaka

Kuwada

Horii

et al. 2022

IJMS

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“…It can physically shield CSCs from therapeutic agents and modulate CSCs [ 160 ]. Integrins are prominent ECM surface receptor proteins that mediate cell-to-cell interactions and communication with the ECM [ 161 ], which are critical for the function of CSC [ 162 , 163 ]. The role of integrin depends a lot on lipid raft to transmit signals.…”

Section: Csc Niche and Lipid Raftmentioning

confidence: 99%

The lipid rafts in cancer stem cell: a target to eradicate cancer

Zhang

Zhu

et al. 2022

Stem Cell Res Ther

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Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem cell properties that sustain cancers, which may be responsible for cancer metastasis or recurrence. Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in the plasma membrane that mediate various intracellular signaling. The occurrence and progression of cancer are closely related to lipid rafts. Emerging evidence indicates that lipid raft levels are significantly enriched in CSCs compared to cancer cells and that most CSC markers such as CD24, CD44, and CD133 are located in lipid rafts. Furthermore, lipid rafts play an essential role in CSCs, specifically in CSC self-renewal, epithelial-mesenchymal transition, drug resistance, and CSC niche. Therefore, lipid rafts are critical regulatory platforms for CSCs and promising therapeutic targets for cancer therapy.

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“…CD133 is encoded by PROM1 gene composed of 8 N-linked glycosylation sites (93), and the glycosylation plays important roles in maintaining CSC properties (94,95). In fact, glycosylation of CD133 has been suggested as a secondary indicator of CSCs (96)(97)(98). In particular, sialylation of CD133 N-glycan terminal via a2,3-site was found in the CSC of glioma (54), which was augmented in hypoxic conditions, correlating with the migration and survival of brain CSCs (99).…”

Section: Glycosylation Of Csc Markersmentioning

confidence: 99%

Abnormal Glycosylation of Cancer Stem Cells and Targeting Strategies

Khan

Cabral

2021

Front. Oncol.

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Cancer stem cell (CSCs) are deemed as one of the main reasons of tumor relapse due to their resistance to standard therapies. Numerous intracellular signaling pathways along with extracellular features are crucial in regulating CSCs properties, such as heterogeneity, plasticity and differentiation. Aberrant glycosylation of these cellular signaling pathways and markers of CSCs have been directly correlated with maintaining survival, self-renewal and extravasation properties. In this review, we highlight the importance of glycosylation in promoting stemness character of CSCs, and present strategies for targeting abnormal glycosylation to eliminate the resistant CSC population.

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Differential glycosylation of collagen modulates lung cancer stem cell subsets through β1 integrin‐mediated interactions

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 27 publications

References 50 publications

Hypomethylation of CLDN4 Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer

Hypomethylation of CLDN4 Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer

The lipid rafts in cancer stem cell: a target to eradicate cancer

Abnormal Glycosylation of Cancer Stem Cells and Targeting Strategies

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