Correlation between protein expression and epigenetic and mutation changes of Wnt pathway-related genes in oral cancer

Yeh, Kun Tu; Chang, Jui‐Hsing; Lin, Ting Hsu; Wang, Yu Fen; Shih, Mu‐Chin; Lin, Cheng Chieh

doi:10.3892/ijo.23.4.1001

Cited by 30 publications

(43 citation statements)

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“…4, AϪC). This finding is supported by a recent report (34) that showed no ␤-catenin and AXIN1 gene mutations and no methylation of the CpG island of ␤-catenin, AXIN1, and GSK3␤ genes in oral cancer cells. Suzui et al (35) also demonstrated that no ␤-catenin gene mutations were found in rat oral tumors induced by 4-nitroquinoline 1-oxide treatment.…”

Section: ␤-Trcpsupporting

confidence: 86%

Invasion and Metastasis of Oral Cancer Cells Require Methylation of E-Cadherin and/or Degradation of Membranous β-Catenin

Kudo

Kitajima

Ogawa

et al. 2004

Clinical Cancer Research

181

143

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The extent of lymph node metastasis is a major determinant in the prognosis of oral squamous cell carcinoma (OSCC). Abnormalities of cell adhesion molecules are known to play an important role in invasion and metastasis of cancer cells through the loss of cell-to-cell adhesion. In this study, we isolated highly invasive clones from an OSCC cell line established from a lymph node metastasis by using an in vitro invasion assay method and compared the abnormalities of cell adhesion molecule E-cadherin and ␤-catenin in these cells. The isolated, highly invasive clones showed significant invasive capacity and reduction of E-cadherin and membranous ␤-catenin protein in comparison with parent cells. We found that reduced expression of E-cadherin was due to methylation of its promoter region. In fact, most invasive and metastatic area of OSCCs showed reduced expression and methylation of E-cadherin. Moreover, we found that reduced expression of membranous ␤-catenin was due to its protein degradation. Reduced expression of membranous ␤-catenin was also found frequently in invasive and metastatic areas of OSCCs. In summary, invasion and metastasis of OSCC cells require methylation of Ecadherin and/or degradation of membranous ␤-catenin. In addition, we suggest that the method of isolation of highly invasive clones may be useful for studies aimed at discovering novel genes involved in invasion and metastasis.

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Section: ␤-Trcpsupporting

confidence: 86%

Invasion and Metastasis of Oral Cancer Cells Require Methylation of E-Cadherin and/or Degradation of Membranous β-Catenin

Kudo

Kitajima

Ogawa

et al. 2004

Clinical Cancer Research

181

143

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“…Many studies have demonstrated a reduction in or loss of cell surface desmosomal cadherin expression, β-catenin membranous expression, and β-catenin mutation, which correlated with esophageal carcinoma [23], oral carcinoma [37,18], and other carcinomas in systemic organs [29,19,1]. It was also shown that downregulation of desmosomal protein and abnormal β-catenin expression was associated with invasion and cell proliferation in pharyngeal [9], oral [9,34], hepatocellular [7], and pancreatic [31] carcinomas.…”

Section: Introductionmentioning

confidence: 93%

Altered expression of desmocollin 3, desmoglein 3, and β-catenin in oral squamous cell carcinoma: correlation with lymph node metastasis and cell proliferation

et al. 2007

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Desmocollin 3 (Dsc3) and desmoglein 3 (Dsg3) are both transmembrane glycoproteins that belong to the cadherin family of calcium-dependent cell adhesion molecules. beta-Catenin is a member of the cadherin-catenin complex that mediates homotypic cell-cell adhesion and is also an important molecule in the wnt signaling pathway. In this study, we examined the simultaneous expression level of Dsc3, Dsg3, and beta-catenin in oral squamous cell carcinomas (OSCCs) and normal oral epithelia using immunohistochemistry. There was a significant correlation (p < 0.05) among the following variables in OSCCs: reduced or loss of expression of Dsc3, Dsg3, and beta-catenin compared to normal oral epithelium, reduced or loss of expression of Dsc3 and histological grade (moderately or poorly differentiated), and reduced or loss of expression of beta-catenin and lymph node metastasis. Furthermore, a positive correlation was found between reduced or loss of beta-catenin staining and reduced or loss of Dsc3 staining in lymph node metastatic cancer tissue (r = 0.734, p < 0.05). These results suggest an abnormal expression of Dsc3, Dsg3, and beta-catenin induced in the progression of oral carcinomas and that the Dsc3 expression level might be related to the regulation of beta-catenin in lymph node metastasis and cell proliferation in OSCCs.

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“…Loss of heterozygosity at the APC locus has been observed in OSCC at frequencies ranging from 13% (4/31) (20) (21) analyzed CTNNB1 and AXIN1 mutations in 30 primary OSCCs, but found no mutations in any of the samples. In the present study, we analyzed exon 3 of CTNNB1 and the mutation cluster region of APC in 17 OSCC cell lines, but found no mutations of either gene.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas ß-catenin is localized exclusively to the membrane in normal oral mucosal epithelium (23), such membrane-bound ß-catenin is absent or diminished in OSCC, and there is a corresponding increase in cytoplasmic localization (20)(21)(22)(23)(24)(25). We also observed that membranebound ß-catenin is reduced or absent in more than half of the OSCC cell lines we tested, and the majority of those cell lines showed cytoplasmic and/or nuclear accumulation of ß-catenin.…”

Section: Discussionmentioning

confidence: 99%

“…In OSCC, loss of heterozygosity at the APC locus is reported at frequencies ranging from 13% to 72.7% (16)(17)(18)(19)(20), though mutations in APC, AXIN1 and CTNNB1 are rare (21,22). On the other hand, reduced levels of membrane-bound E-cadherin and/or ß-catenin and cytoplasmic accumulation of ß-catenin is often observed in OSCC, which indicates that Wnt signaling is activated in this disease (20)(21)(22)(23)(24)(25) and suggests that the activation is via an alternative pathway in OSCC.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma

Sogabe

Suzuki²,

Toyota³

et al. 2008

Int J Oncol

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Abstract. Although mutations of APC, CTNNB1 (ß-catenin) and AXIN1 are rare in oral squamous cell carcinoma (OSCC), activation of the Wnt signaling pathway is thought to play an important role in oral carcinogenesis. In the present study, we examined the relationship between Wnt signaling and epigenetic alteration of the secreted frizzled-related protein (SFRP) genes in OSCC. We frequently detected loss of membrane localization of ß-catenin and its cytoplasmic or nuclear accumulation in OSCC cell lines, although these cell lines showed no APC or CTNNB1 (ß-catenin) mutations and no methylation of CDH1 (E-cadherin). By contrast, we frequently detected methylation of SFRP1 (7/17, 41%) SFRP2 (16/17, 94%) and SFRP5 (14/17, 82%) in a panel of OSCC cell lines, as well as in specimens of primary tumors collected from 44 OSCC patients (SFRP1, 10/42, 24%; SFRP2, 16/44, 36%; SFRP5, 7/43, 16%). We also observed that OSCC cell lines express various Wnt ligands, and that ectopic expression of SFRPs inhibited cancer cell proliferation. Our results confirm the frequent methylation and silencing of SFRP genes in OSCC, and suggest that their loss of function contributes to activation of Wnt signaling that leads to cell proliferation during oral carcinogenesis.

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Correlation between protein expression and epigenetic and mutation changes of Wnt pathway-related genes in oral cancer

Cited by 30 publications

References 0 publications

Invasion and Metastasis of Oral Cancer Cells Require Methylation of E-Cadherin and/or Degradation of Membranous β-Catenin

Invasion and Metastasis of Oral Cancer Cells Require Methylation of E-Cadherin and/or Degradation of Membranous β-Catenin

Altered expression of desmocollin 3, desmoglein 3, and β-catenin in oral squamous cell carcinoma: correlation with lymph node metastasis and cell proliferation

Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma

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