ISG15 induction is required during L1-mediated colon cancer progression and metastasis

Cheriyamundath, Sanith; Basu, Sayon; Haase, Gal; Doernberg, Harry; Gavert, Nancy; Brabletz, Thomas; Ben-Ze’ev, Avri

doi:10.18632/oncotarget.27390

Cited by 13 publications

(14 citation statements)

References 25 publications

(42 reference statements)

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“…In previous studies, we have shown that the increase in the expression of various genes in CRC cells following L1 transfection operates by a mechanism that involves cooperation between ezrin and NF-κB signaling [ 7 , 10 , 12 , 13 ]. Since the induction of PLOD2 by L1 depends on ezrin ( Supplementary Table S1 ), we wished to determine the downstream effectors of the ezrin-mediated increase in PLOD2.…”

Section: Resultsmentioning

confidence: 99%

“…The analysis of genes induced by L1 expression in CRC cells revealed a number of genes known as intestinal stem cell signature genes [ 5 , 6 , 7 , 8 , 9 ]. We identified also additional L1-induced genes [ 10 , 11 , 12 ] that were all shown to be necessary for promoting the tumorigenesis and metastasis of CRC cells by L1 expression. A common signaling pathway activating these genes by L1 overexpression involves the cytoskeletal actin-binding protein ezrin and the NF-κB pathway [ 7 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression

Cheriyamundath

Kumar

Gavert

et al. 2021

IJMS

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The overactivation of Wnt/b-catenin signaling is a hallmark of colorectal cancer (CRC) development. We identified the cell adhesion molecule L1CAM (L1) as a target of b-catenin-TCF transactivation in CRC cells. The overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis and liver metastasis, and L1 is exclusively localized in the invasive areas of human CRC tissue. A number of genes are induced after L1 transfection into CRC cells by a mechanism involving the cytoskeletal protein ezrin and the NF-kB pathway. When studying the changes in gene expression in CRC cells overexpressing L1 in which ezrin levels were suppressed by shRNA to ezrin, we discovered the collagen-modifying enzyme lysyl hydroxylase 2 (PLOD2) among these genes. We found that increased PLOD2 expression was required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis and liver metastasis, since the suppression of endogenous PLOD2 expression, or its enzymatic activity, blocked the enhanced tumorigenic properties conferred by L1. The mechanism involved in increased PLOD2 expression by L1 involves ezrin signaling and PLOD2 that affect the SMAD2/3 pathway. We found that PLOD2 is localized in the colonic crypts in the stem cell compartment of the normal mucosa and is found at increased levels in invasive areas of the tumor and, in some cases, throughout the tumor tissue. The therapeutic strategies to target PLOD2 expression might provide a useful approach for CRC treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression

Cheriyamundath

Kumar

Gavert

et al. 2021

IJMS

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“…Another protein whose level is elevated in the secretome of CRC cells is the ubiquitin-like interferon induced gene 15 (ISG15), which operates much like ubiquitin by conjugating to target proteins (ISGylation) [ 63 ]. We found that increased ISG15 levels were required for L1-mediated CRC progression because suppression of ISG15 expression blocked the L1-mediated increase in CRC cell motility, tumorigenesis, and metastasis [ 63 ]. The induction of ISG15 was dependent on proper L1–L1 mediated adhesions, as point mutations in the L1 ectodomain abolished its ability to induce the expression of ISG15 [ 63 ].…”

Section: Secreted Factors That Promote the Tumorigenesis Induced Bmentioning

confidence: 99%

“…We found that increased ISG15 levels were required for L1-mediated CRC progression because suppression of ISG15 expression blocked the L1-mediated increase in CRC cell motility, tumorigenesis, and metastasis [ 63 ]. The induction of ISG15 was dependent on proper L1–L1 mediated adhesions, as point mutations in the L1 ectodomain abolished its ability to induce the expression of ISG15 [ 63 ]. The induction in ISG15 by L1 was dependent on the NF-κB pathway and ISG15 was detected in CRC tumor tissue and in the adjacent stroma, but not in normal colonic mucosa, suggesting that ISG15 could serve as a therapeutic target for CRC treatment [ 63 ].…”

Section: Secreted Factors That Promote the Tumorigenesis Induced Bmentioning

confidence: 99%

“…The induction of ISG15 was dependent on proper L1–L1 mediated adhesions, as point mutations in the L1 ectodomain abolished its ability to induce the expression of ISG15 [ 63 ]. The induction in ISG15 by L1 was dependent on the NF-κB pathway and ISG15 was detected in CRC tumor tissue and in the adjacent stroma, but not in normal colonic mucosa, suggesting that ISG15 could serve as a therapeutic target for CRC treatment [ 63 ].…”

Section: Secreted Factors That Promote the Tumorigenesis Induced Bmentioning

confidence: 99%

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Wnt/β-Catenin Target Genes in Colon Cancer Metastasis: The Special Case of L1CAM

Cheriyamundath

Ben-Ze’ev

2020

Cancers

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Cell adhesion to neighboring cells is a fundamental biological process in multicellular organisms that is required for tissue morphogenesis. A tight coordination between cell–cell adhesion, signaling, and gene expression is a characteristic feature of normal tissues. Changes, and often disruption of this coordination, are common during invasive and metastatic cancer development. The Wnt/β-catenin signaling pathway is an excellent model for studying the role of adhesion-mediated signaling in colorectal cancer (CRC) invasion and metastasis, because β-catenin has a dual role in the cell; it is a major adhesion linker of cadherin transmembrane receptors to the cytoskeleton and, in addition, it is also a key transducer of Wnt signaling to the nucleus, where it acts as a co-transcriptional activator of Wnt target genes. Hyperactivation of Wnt/β-catenin signaling is a common feature in the majority of CRC patients. We found that the neural cell adhesion receptor L1CAM (L1) is a target gene of β-catenin signaling and is induced in carcinoma cells of CRC patients, where it plays an important role in CRC metastasis. In this review, we will discuss studies on β-catenin target genes activated during CRC development (in particular, L1), the signaling pathways affected by L1, and the role of downstream target genes activated by L1 overexpression, especially those that are also part of the intestinal stem cell gene signature. As intestinal stem cells are highly regulated by Wnt signaling and are believed to also play major roles in CRC progression, unravelling the mechanisms underlying the regulation of these genes will shed light on both normal intestinal homeostasis and the development of invasive and metastatic CRC.

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ISG15 as a prognostic biomarker in solitary fibrous tumour

Mondaza-Hernandez

Moura

López-Álvarez

et al. 2022

Cell. Mol. Life Sci.

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Background Solitary fibrous tumour (SFT) is a rare mesenchymal malignancy that lacks robust prognostic and predictive biomarkers. Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like modifier, associated with tumour progression, and with poor survival of SFT patients, as previous published by our group. Here, we describe the role of ISG15 in the biology of this rare tumour. Methods ISG15 expression was assessed by immunohistochemistry in tissue microarrays from SFT patients and tested for correlation with progression-free survival and overall survival (OS). The effects of ISG15 knockdown or induction were investigated for cancer stem cell (CSC) characteristics and for drug sensitivity in unique in vitro models of SFT. Results The prognostic value of ISG15 for OS was validated at protein level in malignant SFT patients, prospectively treated with pazopanib and enrolled in GEIS-32 trial. In SFT in vitro models, ISG15 knockdown lead to a decrease in the expression of CSC-related genes, including SOX2, NANOG, ALDH1A1, ABCB1 and ABCC1. Likewise, ISG15 downregulation decreased the clonogenic/ tumoursphere-forming ability of SFT cells, while enhancing apoptotic cell death after doxorubicin, pazopanib or trabectedin treatment in 3D cell cultures. The regulation of CSC-related genes by ISG15 was confirmed after inducing its expression with interferon-β1; ISG15 induction upregulated 1.28- to 451-fold the expression of CSC-associated genes. Conclusions ISG15 is a prognostic factor in malignant SFT, regulating the expression of CSC-related genes and CSCs maintenance. Our results suggest that ISG15 could be a novel therapeutic target in SFT, which could improve the efficacy of the currently available treatments.

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ISG15 induction is required during L1-mediated colon cancer progression and metastasis

Cited by 13 publications

References 25 publications

The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression

The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression

Wnt/β-Catenin Target Genes in Colon Cancer Metastasis: The Special Case of L1CAM

ISG15 as a prognostic biomarker in solitary fibrous tumour

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