Subcellular localization of beta‐catenin in malignant cell lines and squamous cell carcinomas of the oral cavity

Gasparoni, A; Chaves, Aline Lauda Freitas; Fonzi, L; Johnson, Georgia K.; Schneider, Galen B.; Squier, Christopher A.

doi:10.1034/j.1600-0714.2002.00108.x

Cited by 32 publications

(34 citation statements)

References 38 publications

(60 reference statements)

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“…Although activating mutations in the ␤-catenin pathway are only found in a subset of hLSCC, [33][34][35] nuclear localization of ␤-catenin and hence increased transcriptional activity are regularly found at the invasive front of hLSCC ( Figure 5). Nuclear ␤-catenin increased with tumor progression, which was reported also for carcinoma of other origin, and to be independent of mutational activation.…”

Section: Discussionmentioning

confidence: 99%

Sonic Hedgehog Acts as a Negative Regulator of β-Catenin Signaling in the Adult Tongue Epithelium

Schneider

Schänzer

Czupalla

et al. 2010

The American Journal of Pathology

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Wnt/␤-catenin signaling has been implicated in taste papilla development; however , its role in epithelial maintenance and tumor progression in the adult tongue remains elusive. We show Wnt/␤-catenin pathway activation in reporter mice and by nuclear ␤-catenin staining in the epithelium and taste papilla of adult mouse and human tongues. ␤-Catenin activation in APC min/؉ mice , which carry a mutation in adenomatous poliposis coli (APC), up-regulates Sonic hedgehog (Shh) and Jagged-2 (JAG2) in the tongue epithelium without formation of squamous cell carcinoma (SCC). We demonstrate that Shh suppresses ␤-catenin transcriptional activity in a signaling-dependent manner in vitro and in vivo. A similar regulation and function was observed for JAG2, suggesting that both pathways negatively regulate ␤-catenin, thereby preventing SCC formation in the tongue. This was supported by reduced nuclear ␤-catenin in the tongue epithelium of Patched ؉/؊ mice , exhibiting dominant active Shh signaling. At the invasive front of human tongue cancer , nuclear ␤-catenin and Shh were increased , suggesting their participation in tumor progression. Interestingly , Shh but not JAG2 was able to reduce ␤-catenin signaling in SCC cells , arguing for a partial loss of negative feedback on ␤-catenin transcription in tongue cancer. We show for the first time that the putative Wnt/␤-catenin targets Shh and JAG2 control ␤-catenin signaling in the adult tongue epithelium, a function that is partially lost in lingual SCC. (Am J

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Section: Discussionmentioning

confidence: 99%

Sonic Hedgehog Acts as a Negative Regulator of β-Catenin Signaling in the Adult Tongue Epithelium

Schneider

Schänzer

Czupalla

et al. 2010

The American Journal of Pathology

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“…Similar findings were reported by Tanaka et al (38), who investigated the immunohistochemical expression of h-catenin in 159 oral squamous cell cancers. Gasparoni et al (39) analyzed the subcellular localization of h-catenin in cultures of human oral normal and malignant keratinocytes and in 24 frozen samples of oral squamous cell carcinomas by a double-staining technique for nucleic acids and h-catenin. The authors found that nuclear h-catenin is a rare finding in oral squamous cell cancers.…”

Section: Discussionmentioning

confidence: 99%

β-Catenin Functions Mainly as an Adhesion Molecule in Patients with Squamous Cell Cancer of the Head and Neck

Yang

Weinberger

Provost³

et al. 2005

Clinical Cancer Research

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Background: h-catenin, depending on subcellular localization, plays a dual role in carcinogenesis: as a signaling factor (in the nucleus) and as an adhesion molecule (in cell membrane). In this study, we sought to determine the role of h-catenin in head and neck carcinogenesis. Methods: First, we studied the incidence of mutations of h-catenin in a cohort of 60 head and neck squamous cell cancers (HNSCC).We subsequently evaluated the protein expression levels of h-catenin in a cohort of oropharyngeal squamous cell cancer tissue microarray using a novel in situ method of quantitative protein analysis and correlated those with cyclin D1levels and clinical and pathologic data. Results: The mean follow-up time for survivors was 45 months and for all patients was 35 months.We found no mutations in the cohort of 60 HNSCC. h-catenin displayed primarily membranous expression pattern. Patients with high tumor-node-metastasis stage were more likely to have high expression of h-catenin (P = 0.040). Patients with low h-catenin expression had a local recurrence rate of 79% compared with 29% for patients with high h-catenin tumors (P = 0.0021). Univariate Cox regression revealed a hazard ratio for low h-catenin tumors of 3.6 (P = 0.004). Kaplan-Meier analysis showed that patients with low h-catenin expressing tumors trended toward worse 5-year disease-free survival (P = 0.06). In multivariate analysis, only h-catenin expression status was an independent prognostic factor (P = 0.044) for local recurrence. Tumors with high h-catenin had low cyclin D1and vice versa (P = 0.007). Conclusions: The absence of activating h-catenin mutations combined with the inverse correlation between h-catenin levels with cyclin D1 levels and outcome suggest that h-catenin mainly functions as an adhesion and not signaling molecule in HNSCC.

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“…Catenin delocalization has been reported in pre-malignant lesions of the oral cavity and in OSCC (21)(22)(23). In previous studies, we have reported that the distribution of ß-catenin is different in OSCC cells than in normal mucosal cells.…”

Section: Discussionmentioning

confidence: 91%

“…Previous studies have shown that APC. CTNNB1 and Axin are frequently mutated in different types of human cancers (16), as well as colorectal cancer, gastric cancer, liver cancer and pancreatic neoplasia; however, mutations in APC or CTNNB1 are rarely found in OSCC cell lines and in OSCC (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

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WNT pathway in oral cancer: Epigenetic inactivation of WNT-inhibitors

Caraglia¹

2010

Oncol Rep

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Abstract. Epigenetic DNA methylations plays an important role in oral carcinogenesis. The soluble frizzled receptor protein (SFRP) family together with WIF-1 and DKK-3 encodes antagonists of the WNT pathway. Silencing of these genes leads to constitutive WNT signalling. Because aberrant expression of ß-catenin might be associated with the epigenetic inactivation of WNT inhibitors, we analyzed, in a collection of primary OSCC with matched normal oral mucosa, the methylation status of a complete panel of genes, SFRP-1, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3, that are involved directly and indirectly in WNT pathway, in order to demonstrate WNT-pathway activation in the absence of ß-catenin and/or APC/Axin mutations during oral carcinogenesis. Methylation-specific PCR (MSP) was performed to study inactivation of SFRP-1, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3 genes in 37 cases of paraffin embedded oral cancer. This study showed that the methylation is an important epigenetic alteration in oral cancer. In particular, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3 revealed methylation status of their promoter in OSCC, whereas SFRP-1 showed demethylation in cancer. Fisher's exact test revealed statistically significant results (p<0.05) for all genes. The Wald test confirmed the statistically significant association between SFRP2-4-5 gene methylation and OSCC (p<0.05). SFRP-1 was also characterized by a different statistically significant epigenetic behaviour, because of it was demethylated in cancer (p<0.05). Statistical regression test showed high levels of sensitivity, specificity and accuracy for SFRP genes, while WIF-1 and DKK-3 have reportedly high specificity, moderate accuracy but low sensitivity. This study suggests that a cause of catenin delocalization in oral cancer could be due to WNT pathway activation, by epigenetic alterations of SFRP, WIF-1 and DKK-3 genes.

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Subcellular localization of beta‐catenin in malignant cell lines and squamous cell carcinomas of the oral cavity

Cited by 32 publications

References 38 publications

Sonic Hedgehog Acts as a Negative Regulator of β-Catenin Signaling in the Adult Tongue Epithelium

Sonic Hedgehog Acts as a Negative Regulator of β-Catenin Signaling in the Adult Tongue Epithelium

β-Catenin Functions Mainly as an Adhesion Molecule in Patients with Squamous Cell Cancer of the Head and Neck

WNT pathway in oral cancer: Epigenetic inactivation of WNT-inhibitors

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