γ-Catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth

Winn, Robert A.; Bremnes, Roy M.; Bemis, Lynne T.; Franklin, Wilbur A.; Miller, York E.; Heasley, Lynn E.

doi:10.1038/sj.onc.1205963

Cited by 102 publications

(97 citation statements)

References 39 publications

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“…Wnt signaling to date has been reported to be occasionally involved in lung carcinogenesis (Sunaga et al, 2001;Ueda et al, 2001;Hommura et al, 2002;Winn et al, 2002). Interestingly, a recent report identified Wnt signaling in lung cancer cell lines that corroborated active canonical Wnt signaling (Winn et al, 2002). Most of these reports, however, have focused on b-catenin activity only to evaluate the activity of Wnt signaling.…”

Section: Introduction Results and Discussionmentioning

confidence: 95%

“…We tested the function of Dvl in the lung cancer cell line H1703 by treatment with Dvl siRNA and control siRNA. We chose H1703, because it has Dvl-3 expression, and it has been also demonstrated to have Tcf-dependent transcriptional activity of bcatenin (Winn et al, 2002). After siRNA treatment, expression of dvl-3 was suppressed, while Dvl-1 and -2 remained unexpressed (Figure 2a).…”

Section: Introduction Results and Discussionmentioning

confidence: 99%

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Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression

et al. 2003

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Non small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States and worldwide. Unfortunately, standard therapies remain inadequate. An increased understanding of the molecular biology of lung cancer biology is required to develop more effective new therapies. In this report, we show that the Wnt pathway is activated through Dishevelled (Dvl) overexpression in NSCLC. Analysis of freshly resected tumors and lung cancer cell lines demonstrate that Dvl-3, a critical mediator of Wnt signaling, is overexpressed. Specifically, Dvl-3 was overexpressed significantly in 75% of fresh NSCLC microdissected samples compared to control paired matched normal lung samples. To evaluate the biological significance of Wnt signaling and, in particular, Dvl function in lung cancer, we transfected siRNA (designed to inhibit selectively human Dvl-1, -2, and -3), to the NSCLC cell line H1703, which is known to have bcatenin-mediated Tcf-dependent transcriptional activity. Here, we demonstrate that Dvl-specific siRNA treatment in H1703 decreases significantly Dvl and b-catenin expression, resulting in reduction of Tcf-dependent transcriptional activity, and, importantly, growth inhibition. Taken together, these data support the novel hypothesis that Dvl overexpression is critical to Wnt signaling activation and cell growth in NSCLC.

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Section: Introduction Results and Discussionmentioning

confidence: 95%

Section: Introduction Results and Discussionmentioning

confidence: 99%

Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression

et al. 2003

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“…Plakoglobin has often been associated with tumorsuppressor activity, although the mechanisms behind this activity remain unclear (Simcha et al, 1996;Pantel et al, 1998;Parker et al, 1998;Winn et al, 2002;Reiger-Christ et al, 2005). More recently, downregulation of plakoglobin was also shown to increase the risk of pulmonary metastasis in soft tissue sarcomas (Kanazawa et al, 2008) and was associated with poor differentiation of oral squamous cell carcinoma and with lymph node metastases (Narkio-Makela et al, 2009), further supporting the idea that plakoglobin functions to suppress metastasis in addition to tumor formation.…”

Section: Plakoglobin Interacts With and Regulates Nm23mentioning

confidence: 95%

“…In contrast, plakoglobin has typically been associated with tumor/metastasis-suppressor activity, although the mechanism behind this activity is not understood (Simcha et al, 1996;Pantel et al, 1998;Parker et al, 1998;Winn et al, 2002;Reiger-Christ et al, 2005;Kanazawa et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

et al. 2010

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Plakoglobin (c-catenin) is a homolog of b-catenin with similar dual adhesive and signaling functions. The adhesive function of these proteins is mediated by their interactions with cadherins, whereas their signaling activity is regulated by association with various intracellular partners. In this respect, b-catenin has a well-defined oncogenic activity through its role in the Wnt signaling pathway, whereas plakoglobin acts as a tumor/metastasis suppressor through mechanisms that remain unclear. We previously expressed plakoglobin in SCC9 squamous carcinoma cells (SCC9-P) and observed a mesenchymalto-epidermoid transition. Comparison of the protein and RNA profiles of parental SCC9 cells and SCC9-P transfectants identified various differentially expressed proteins and transcripts, including the nonmetastatic protein 23 (Nm23). In this study, we show that Nm23-H1 mRNA and Nm23-H2 protein are increased after plakoglobin expression. Coimmunoprecipitation and confocal microscopy studies using SCC9-P and various epithelial cell lines with endogenous plakoglobin expression revealed that Nm23 interacts with plakoglobin, cadherins and a-catenin. Furthermore, Nm23-H2 is the primary isoform involved in these interactions, which occur prominently in the cytoskeleton-associated pool of cellular proteins. In addition, we show that plakoglobinNm23 interaction requires the N-terminal (a-catenin interacting) domain of plakoglobin. Our data suggest that by increasing the expression and stability of Nm23, plakoglobin has a role in regulating the metastasis suppressor activity of Nm23, which may further provide a potential mechanism for the tumor/metastasis suppressor function of plakoglobin itself.

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“…Methylation of the PLAKOGLOBIN gene has also been reported to be associated with a poor prognosis in renal cell carcinoma . CpG hypermethylation of the plakoglobin promoter has also been demonstrated to be responsible for the loss of plakoglobin expression in thyroid and lung cancer (Potter et al, 2001;Winn et al, 2002). Increased expression of DNMT1, DNMT3A and DNMT3B has been reported in many cancers (el-Deiry et al, 1991;Belinsky et al, 1996;Robertson et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells

et al. 2007

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Directed by microarray analyses, we report that autocrine human growth hormone (hGH) increased the mRNA and protein expression of DNA methyltransferase 1 (DNMT1), DNMT3A and DNMT3B in mammary carcinoma cells. Autocrine hGH stimulation of DNMT3A and DNMT3B expression was mediated by JAK2 and Src kinases, and treatment of mammary carcinoma cells with the DNMT inhibitor, 5 0 -aza-2 0 -deoxycytidine (AZA), abrogated autocrine hGH-stimulated cellular proliferation, apoptosis and anchorage-independent growth. AZA reversed the epitheliomesenchymal transition of mammary carcinoma cells induced by autocrine hGH, to an epithelioid morphology and abrogated cell migration stimulated by autocrine hGH. Autocrine hGH-stimulated hypermethylation of the first exon of the PLAKOGLOBIN gene and AZA abrogated the ability of autocrine hGH to repress plakoglobin gene transcription. Small interfering RNA (siRNA)-mediated depletion of the individual DNMT molecules did not release autocrine hGH repression of PLAKOGLOBIN promoter activity nor did individual DNMT depletion affect autocrine hGH-stimulated migration. However, concomitant siRNA-mediated depletion of both DNMT3A and DNMT3B abrogated hypermethylation of the PLAKO-GLOBIN gene stimulated by autocrine hGH and subsequent repression of plakoglobin gene transcription and increased cell migration. Thus, the autocrine hGHstimulated increases in DNMT3A and DNMT3B expression mediate repression of plakoglobin gene transcription by direct hypermethylation of its promoter and consequent phenotypic conversion of mammary carcinoma cells. Autocrine hGH, therefore, utilizes DNA methylation as a mechanism to exert its oncogenic effects in mammary carcinoma cells.

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γ-Catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth

Cited by 102 publications

References 39 publications

Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression

Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells

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