L1, a novel target of β-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers

Gavert, Nancy; Conacci‐Sorrell, Maralice; Gast, Daniela; Schneider, Annette; Altevogt, Peter; Brabletz, Thomas; Ben-Ze’ev, Avri

doi:10.1083/jcb.200408051

Cited by 334 publications

(416 citation statements)

References 49 publications

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“…L1CAM family members L1, CHL1, and NrCAM have been annotated roles in cancer progression and metastasis, and are involved in the regulation of proliferation and migration of diverse cancer types 5, 7, 11, 18, 19, 20, 23, 28…”

Section: Discussionmentioning

confidence: 99%

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Copy number variation, increased gene expression, and molecular mechanisms of neurofascin in lung cancer

Erdem

Arnoldussen

Skaug

et al. 2017

Molecular Carcinogenesis

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Metastasis and cell adhesion are key aspects of cancer progression. Neurofascin (NFASC) is a member of the immunoglobulin superfamily of adhesion molecules and, while studies on NFASC are inadequate, other members have been indicated pivotal roles in cancer progression and metastasis. This study aimed at increasing the knowledge on the involvement of adhesion molecules in lung cancer progression by studying the regulation and role of NFASC in non‐small cell lung cancer (NSCLC). Here, copy number variations in the NFASC gene were analyzed in tumor and non‐tumorous lung tissues of 204 NSCLC patients. Frequent gene amplifications (OR = 4.50, 95%CI: 2.27‐8.92, P ≤ 0.001) and increased expression of NFASC (P = 0.034) were identified in tumors of NSCLC patients. Furthermore, molecular mechanisms of NFASC in lung cancer progression were evaluated by investigating the effects of NFASC silencing on cell proliferation, viability, migration, and invasion using siRNA technology in four NSCLC cell lines. Silencing of NFASC did not affect cell proliferation or viability but rather decreased NSCLC cell migration (P ≤ 0.001) and led to morphological changes, rearrangements in the actin cytoskeleton and changes in F‐actin networks in migrating NSCLC cell lines. This study is the first to report frequent copy number gain and increased expression of NFASC in NSCLC. Moreover, these data suggest that NFASC is a novel regulator of NSCLC cell motility and support a role of NFASC in the regulation of NSCLC progression.

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Section: Discussionmentioning

confidence: 99%

“…However, copy number gain and increased expression of L1 have been demonstrated in breast cancer 36, 7, 8, 9, 10, 11…”

Section: Discussionmentioning

confidence: 99%

Copy number variation, increased gene expression, and molecular mechanisms of neurofascin in lung cancer

Erdem

Arnoldussen

Skaug

et al. 2017

Molecular Carcinogenesis

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“…Examples include BIRC7, L1CAM, PLAUR and FGF18, which are all downstream targets of Wnt/bcatenin signaling (Mann et al, 1999;Shimokawa et al, 2003;Gavert et al, 2005;Yuan et al, 2007). PLAUR and SERPINE1 are components of the urokinase plasminogen activator system, and the overexpression of these genes has been correlated with a high-grade tumor and poor survival outcomes in RCC (Swiercz et al, 1998;Ohba et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

et al. 2008

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The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P ¼ 0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P ¼ 0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of b-catenin. Knockdown of CXXC4 induced the nuclear translocation of b-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

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“…Among genes upregulated by CagA, those that were not induced by serum starvation were selected. Selected genes included p21 and cyclin D1 and also b-catenin-dependent genes such as L1 cell adhesion molecule, cyclin D2 and cdx1 (Lickert et al, 2000;Kioussi et al, 2002;Gavert et al, 2005) (Table 1). Transactivation of the cdx1 promoter by CagA was also confirmed by a luciferase reporter assay (Supplementary Figure S4).…”

Section: Induction Of Intestinal Transdifferentiation In Gastric Epitmentioning

confidence: 99%

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

et al. 2007

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Infection with Helicobacter pylori cagA-positive strains is associated with gastric adenocarcinoma. Intestinal metaplasia is a precancerous lesion of the stomach characterized by transdifferentiation of the gastric mucosa to an intestinal phenotype. The H. pylori cagA gene product, CagA, is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases. Tyrosine-phosphorylated CagA specifically binds to and activates SHP-2 phosphatase, thereby inducing cell-morphological transformation. We report here that CagA physically interacts with E-cadherin independently of CagA tyrosine phosphorylation. The CagA/E-cadherin interaction impairs the complex formation between E-cadherin and b-catenin, causing cytoplasmic and nuclear accumulation of b-catenin. CagA-deregulated b-catenin then transactivates b-catenin-dependent genes such as cdx1, which encodes intestinal specific CDX1 transcription factor. In addition to b-catenin signal, CagA also transactivates p21 WAF1/Cip1 , again, in a phosphorylation-independent manner. Consequently, CagA induces aberrant expression of an intestinal-differentiation marker, goblet-cell mucin MUC2, in gastric epithelial cells that have been arrested in G1 by p21 WAF1/Cip1 . These results indicate that perturbation of the E-cadherin/b-catenin complex by H. pylori CagA plays an important role in the development of intestinal metaplasia, a premalignant transdifferentiation of gastric epithelial cells from which intestinal-type gastric adenocarcinoma arises.

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L1, a novel target of β-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers

Cited by 334 publications

References 49 publications

Copy number variation, increased gene expression, and molecular mechanisms of neurofascin in lung cancer

Copy number variation, increased gene expression, and molecular mechanisms of neurofascin in lung cancer

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

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