TGF-α antisense gene therapy inhibits head and neck squamous cell carcinoma growth in vivo

Endo, Sohei; Zeng, Qing; Burke, Nancy A.; He, Yukai; Melhem, Mona F.; Watkins, S.; Lango, Miriam; Drenning, Stephanie D.; Huang, Leaf; Grandis, Jennifer R.

doi:10.1038/sj.gt.3301315

Cited by 39 publications

(26 citation statements)

References 45 publications

(46 reference statements)

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“…This not only reveals the possibility for using comethylation for improved diagnosis but also suggests that the candidates described in this study may be involved in a similar pathway that is disrupted and epigenetically silenced in HNSCC. TGF-h signaling has been found to be disrupted in HNSCC progression; therefore, this pathway has been targeted for therapy (14). Aberrant expression of hypoxia-induced proteins has also been shown to have relevance for HNSCC progression and prognosis prediction (15).…”

Section: Discussionmentioning

confidence: 99%

Frequently Methylated Tumor Suppressor Genes in Head and Neck Squamous Cell Carcinoma

et al. 2008

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Head and neck squamous cell carcinoma (HNSCC) is a very aggressive cancer. In advanced stages, the patient has poor chances of receiving effective treatment, and survival rates are low. To facilitate timely diagnosis and improve treatment, elucidation of early detection markers is crucial. DNA methylation markers are particularly advantageous because DNA methylation is an early event in tumorigenesis, and the epigenetic modification, 5-methylcytosine, is a stable mark. A genome-wide screen using Restriction Landmark Genomic Scanning found a set of genes that are most commonly methylated in head and neck cancers. Five candidate genes: septin 9 (SEPT9), sodium-coupled monocarboxylate transporter 1 (SLC5A8), functional smad-suppressing element on chromosome 18 (FUSSEL18), early B-cell factor 3 (EBF3), and iroquois homeobox 1 (IRX1) were methylated in 27% to 67% of the HNSCC patient samples tested. Furthermore, f50% of the methylated tumor samples shared methylation between two of the five genes (most commonly between EBF3 and IRX1), and 15% shared methylation between three of the five genes. Expression analysis revealed candidate gene down-regulation in 25% to 93% of the HNSCC samples, and 5-aza-2 ¶-deoxycytidine treatment was able to restore expression in at least 2 of 5 HNSCC cell lines for all of the genes tested. Overexpression of the three most frequently down-regulated candidates, SLC5A8, IRX1, and EBF3, validated their tumor suppressor potential by growth curve analysis and colony formation assay. Interestingly, all of the candidates identified may be involved in the transforming growth factor B signaling pathway, which is often disrupted in HNSCC. [Cancer Res 2008;68(12):4494-9]

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Section: Discussionmentioning

confidence: 99%

Frequently Methylated Tumor Suppressor Genes in Head and Neck Squamous Cell Carcinoma

et al. 2008

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“…The TGF-β pathway has been shown to be commonly disrupted in HNSCC progression and can be targeted in therapy (19). Aberrant expression of hypoxia-induced proteins has been shown to have relevance to HNSCC progression and prognosis prediction (20).…”

Section: Discussionmentioning

confidence: 99%

Disruption of Transforming Growth Factor-β Signaling by Five Frequently Methylated Genes Leads to Head and Neck Squamous Cell Carcinoma Pathogenesis

2009

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Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with low survival rates in advanced stages. To facilitate timely diagnosis and improve outcome, early detection markers (e.g., DNA methylation) are crucial for timely cancer diagnosis. In a recent publication, an epigenomewide screen revealed a set of genes that are commonly methylated and downregulated in head and neck cancers (SEPT9, SLC5A8, FUSSEL18, EBF3, and IRX1). Interestingly, these candidates are potentially involved in the transforming growth factor-β (TGF-β) signaling pathway, which is often disrupted in HNSCC. Therefore, we sought to determine coordinated epigenetic silencing of these candidate genes in HNSCC as potential key disruptors of TGF-β signaling, which could ultimately result in HNSCC progression. Through immunoprecipitation studies, all five of the investigated candidate genes were found to interact with components of the TGF-β pathway. Overexpression of SLC5A8, EBF3, and IRX1 resulted in decreased mitotic activity and increased apoptosis. In addition, EBF3 was found to increase p21 promoter activity, and SMAD2 significantly increased IRX1 promoter activity. These findings are significant because they reveal a set of genes that interact with components of the TGF-β pathway, and their silencing via methylation in HNSCC results in coordinated decrease in apoptosis, increased proliferation, and decreased differentiation. [Cancer Res 2009;69(24):9301-5]

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“…As pointed out, above MMPs can directly or indirectly induce tumor angiogenesis through degradation of ECM and release or activation of growth factors, like TNF-␣ and TGF-␤. Moreover, the release and/or activation of growth factors, such as IGF and TGF-␣, might also lead to tumor growth independent of angiogenesis [110][111][112][113][114].…”

Section: The Role Of Mmps In Tumor Angiogenesis and Tumor Growthmentioning

confidence: 99%

The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia

Klein

Vellenga

Fraaije

et al. 2004

Critical Reviews in Oncology/Hematology

310

170

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TGF-α antisense gene therapy inhibits head and neck squamous cell carcinoma growth in vivo

Cited by 39 publications

References 45 publications

Frequently Methylated Tumor Suppressor Genes in Head and Neck Squamous Cell Carcinoma

Frequently Methylated Tumor Suppressor Genes in Head and Neck Squamous Cell Carcinoma

Disruption of Transforming Growth Factor-β Signaling by Five Frequently Methylated Genes Leads to Head and Neck Squamous Cell Carcinoma Pathogenesis

The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia

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