Frequent hypermethylation of <scp>WNT</scp> pathway genes in laryngeal squamous cell carcinomas

Paluszczak, Jarosław; Hemmerling, Dawid; Kostrzewska-Poczekaj, Magdalena; Jarmuż-Szymczak, Małgorzata; Grénman, Reidar; Wierzbicka, Małgorzata; Baer‐Dubowska, Wanda

doi:10.1111/jop.12178

Cited by 21 publications

(24 citation statements)

References 40 publications

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“…The dysregulation of sFRP2 has been reported in several malignancies, however the mechanisms by which it contributes to the biology of these cancers has been variable. For instance, sFRP2 is noted to be downregulated via epigenetic hypermethylation in human gastric cancer [16], colorectal cancer [17, 18], and oral squamous cell carcinoma [19, 20] suggesting a role as a tumor suppressor. However, overexpression of sFRP2 has been reported in renal cancer [8], human angiosarcoma, and breast cancer [21, 22], which leads to angiogenesis stimulation by activation of the calcineurin/NFATc3 pathway.…”

Section: Introductionmentioning

confidence: 99%

Secreted Frizzled-Related Protein 2 (sFRP2) promotes osteosarcoma invasion and metastatic potential

et al. 2016

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BackgroundOsteosarcoma (OS), which has a high potential for developing metastatic disease, is the most frequent malignant bone tumor in children and adolescents. Molecular analysis of a metastatic genetically engineered mouse model of osteosarcoma identified enhanced expression of Secreted Frizzled-Related Protein 2 (sFRP2), a putative regulator of Wnt signaling within metastatic tumors. Subsequent analysis correlated increased expression in the human disease, and within highly metastatic OS cells. However, the role of sFRP2 in osteosarcoma development and progression has not been well elucidated.MethodsStudies using stable gain or loss-of-function alterations of sFRP2 within human and mouse OS cells were performed to assess changes in cell proliferation, migration, and invasive ability in vitro, via both transwell and 3D matrigel assays. In additional, xenograft studies using overexpression of sFRP2 were used to assess effects on in vivo metastatic potential. ResultsFunctional studies revealed stable overexpression of sFRP2 within localized human and mouse OS cells significantly increased cell migration and invasive ability in vitro and enhanced metastatic potential in vivo. Additional studies exploiting knockdown of sFRP2 within metastatic human and mouse OS cells demonstrated decreased cell migration and invasion ability in vitro, thus corroborating a critical biological phenotype carried out by sFRP2. Interestingly, alterations in sFRP2 expression did not alter OS proliferation rates or primary tumor development.ConclusionsWhile future studies further investigating the molecular mechanisms contributing towards this sFRP2-dependent phenotype are needed, our studies clearly provide evidence that aberrant expression of sFRP2 can contribute to the invasive and metastatic potential for osteosarcoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2909-6) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Secreted Frizzled-Related Protein 2 (sFRP2) promotes osteosarcoma invasion and metastatic potential

et al. 2016

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“…In line with this model, epigenetic changes were observed not only in tumor sections but also in macroscopically normal surgical margin. The presence of epigenetic aberrations in surgical margin and distant mucosa in HNSCC is well documented [16, 60, 61]. These changes may constitute both part of the field of preneoplastic molecular alterations and be related to the presence of single neoplastic cells which are usually not detected under standard histopathological examination [61].…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of the methylation of Wnt pathway antagonists—CXXC4, DACT2, and the inhibitors of sonic hedgehog signaling—ZIC1, ZIC4, and HHIP in head and neck squamous cell carcinomas

et al. 2016

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ObjectivesAberrations in Wnt and Shh signaling pathways are related to the pathogenesis of head and neck carcinomas, and their activation frequently results from epigenetic alterations. This study aimed to assess the frequency of methylation of negative regulators of Wnt signaling: CXXC4, DACT2, HDPR1, and FBXW11 and Shh signaling: HHIP, PTCH1, SUFU, ZIC1, and ZIC4 and correlate it with clinicopathological features in this group of patients.Materials and methodsMethylation-specific PCR was used to detect gene promoter methylation, and real-time PCR was used to assess gene expression level.ResultsThe analysis of the occurrence of gene promoter methylation in head and neck carcinoma cell lines indicated that CXXC4, DACT2, HHIP, ZIC1, and ZIC4 are methylated in these tumors. These genes were further analyzed in tumor sections from oral and laryngeal cancer patients. Gene methylation rate was higher in laryngeal tumors. The methylation index in tumor samples correlated with the overall survival in a subgroup of oral cancer patients who died of the disease. Moreover, ZIC4 methylation correlated with lymph node involvement in oral cancer patients.ConclusionsOur findings corroborate that the activation of Wnt signaling in head and neck squamous cell carcinoma (HNSCC) is related to epigenetic silencing of its negative regulators. Moreover, the results indicate that the same mechanism of activation may operate in the case of Shh signaling.Clinical relevanceThe methylation of ZIC4 may be considered a new prognostic marker in oral cavity and oropharyngeal tumors. Further investigations should determine the diagnostic significance of methylation of ZIC4, HHIP, and DACT2 in head and neck carcinomas.

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“…[33] Promoter hypermethylation of TSG WIF-1 is a common early event in a range of human tumors, such as laryngeal SCC, [34] adrenocortical tumor, [35] and gastric cardia AC. [36] Inconsistent and even controversial results existed concerning WIF-1 gene methylation frequencies in the promoter region in lung cancer cases, which ranged from 15.9% [22] to 84.6%.…”

Section: Discussionmentioning

confidence: 99%

Promoter hypermethylation of Wnt inhibitory factor-1 in patients with lung cancer

Zheng

Jiang

et al. 2016

Medicine

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Background:Promoter hypermethylation of Wnt inhibitory factor-1 (WIF-1)—a tumor suppressor gene—has been detected in several types of human tumors. However, the association between WIF-1 promoter hypermethylation and lung cancer remains to be elucidated. Therefore, we conducted this study to evaluate the clinical significance of WIF-1 promoter hypermethylation in lung cancer.Methods:A comprehensive literature search was conducted to obtain eligible studies. The combined odds ratios (ORs) or hazard ratios and 95% confidence intervals were used to estimate the strength of associations.Results:A total of 8 eligible publications with 626 cases and 512 controls were included in our study. The combined ORs revealed that WIF-1 promoter hypermethylation was significantly higher in lung cancer than in controls (OR 10.53, P < 0.001). Moreover, WIF-1 promoter hypermethylation was significantly associated with smoking behavior (OR 1.88, P = 0.002). No significant correlation was found between WIF-1 promoter hypermethylation and sex status, age status, tumor stage, and pathological types in cancer. Multivariate analysis results indicated the absence of correlation between WIF-1 promoter hypermethylation and with relapse-free survival and overall survival. Subgroup analysis by sample type demonstrated that promoter hypermethylation of WIF-1 was significantly associated with an increased risk of lung cancer in the tissue (OR 7.89, P < 0.001), blood (OR 21.83, P = 0.034), and pleural effusion subgroups (OR 157.43, P = 0.001).Conclusions:Promoter hypermethylation of WIF-1 may play a crucial role in lung cancer carcinogenesis. It may be a noninvasive biomarker using blood or pleural effusion detection. WIF-1 promoter hypermethylation is correlated with smoking behavior, but not with sex status, age status, tumor stage, pathological types, and the prognosis of lung cancer patients in terms of relapse-free survival and overall survival. More investigations, including a larger number of subjects, are required to further confirm the findings of our analysis.

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Frequent hypermethylation of WNT pathway genes in laryngeal squamous cell carcinomas

Abstract: Frequent hypermethylation of WNT pathway negative regulators is observed in laryngeal squamous cell carcinomas. The possible prognostic significance of the methylation of DKK1, PPP2R2B, and SFRP1 needs to be evaluated in further prospective studies.

Cited by 21 publications

References 40 publications

Secreted Frizzled-Related Protein 2 (sFRP2) promotes osteosarcoma invasion and metastatic potential

Secreted Frizzled-Related Protein 2 (sFRP2) promotes osteosarcoma invasion and metastatic potential

Prognostic significance of the methylation of Wnt pathway antagonists—CXXC4, DACT2, and the inhibitors of sonic hedgehog signaling—ZIC1, ZIC4, and HHIP in head and neck squamous cell carcinomas

Promoter hypermethylation of Wnt inhibitory factor-1 in patients with lung cancer

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