p14ARF Protein Expression Is a Predictor of Both Relapse and Survival in Squamous Cell Carcinoma of the Anterior Tongue

Kwong, Rhonda A.; Kalish, Larry; Nguyen, Tuan Van; Kench, James G.; Bova, Ron; Cole, Ian; Musgrove, Elizabeth A.; Sutherland, Robert L.

doi:10.1158/1078-0432.ccr-04-2036

Cited by 32 publications

(27 citation statements)

References 38 publications

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“…Other strong indicators for a favorable prognosis in our study include tumor diameter o4 cm, low/no expression of cyclin D1, and low/no tobacco consumption. In accordance with most other studies on HPV-related oropharyngeal carcinomas, we also found a favorable disease-specific survival in patients with HPV16-positive tonsillar squamous cell carcinomas, 12,46,[60][61][62][63][64] and p14 ARF overexpression, 31 although with less significance than the indicators described above. We noticed that lymph node status, which is generally considered as the most important prognostic factor in head-and-neck squamous cell carcinomas, 23 had little value in our series of tonsillar squamous cell carcinomas, which is in concordance with other studies.…”

Section: Discussionsupporting

confidence: 92%

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

et al. 2009

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Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16 INK4A, cyclin D1, pRb, p14 ARF , MDM2, p53, p21 Cip1/WAF1 , and p27 KIP1 . Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16 INK4A overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14 ARF (Po0.0001) and p21 Cip1/WAF1 (P ¼ 0.001), and downregulation of pRb (Po0.0001) and cyclin D1 (P ¼ 0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers (P ¼ 0.006), as well as for patients with T1-2 tumors (Po0.0001) or tumors showing low expression of cyclin D1 (P ¼ 0.028), presence of human papillomavirus and overexpression of p16 INK4A (P ¼ 0.01), p14 ARF (P ¼ 0.02) or p21 Cip1/WAF1 (P ¼ 0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21 Cip1/WAF1 , were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21 Cip1/WAF1 and p14 ARF overexpression and downregulation of pRb and cyclin D1. In particular p21 Cip1/WAF1 overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas. Modern Pathology ( Head-and-neck squamous cell carcinoma is the sixth most prevalent malignancy in the world, contributing 6% of new cancer cases annually worldwide. 1,2 These tumors have a 5-year survival rate of approximately 50%, which has not improved in the last two decades. 3 Well-recognized risk factors in the etiology of head-and-neck squamous cell carcinomas are extensive tobacco and alcohol consumption in B90% of cases, as well as oncogenic human papillomaviruses (HPVs), predominantly HPV type 16. 3,4 Interestingly, the association of HPV is strongest for tonsillar squamous cell carcinoma with a prevalence up to 50%. [5][6][7][8]

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Section: Discussionsupporting

confidence: 92%

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

et al. 2009

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“…Similarly, overexpression of E2F1 and MCM7 has been observed (39), correlated with increased invasiveness (40,41) and more aggressive disease (42), and suggested to be predictive markers for nodal metastases (43). Our current study strongly suggests the biological significance of the miR-106b-25 cluster in HNSCC, indicating that overexpression of this cluster might play an oncogenic role, perhaps mediated by E2F1 activation and impaired TGF-β signaling, ultimately resulting in uncontrolled proliferation, dysregulated cell cycling, and increased invasiveness.…”

Section: Discussionmentioning

confidence: 92%

Comprehensive MicroRNA Profiling for Head and Neck Squamous Cell Carcinomas

Hui

Lenarduzzi

Krushel

et al. 2010

Clinical Cancer Research

343

295

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Purpose: The objective of this study is to investigate the significance of microRNAs (miRNA) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).Experimental Design: A global miRNA profiling was done on 51 formalin-fixed archival HNSCC samples using quantitative reverse transcription-PCR approach, correlated with patients' clinical parameters. Functional characterization of HNSCC-associated miRNAs was conducted on three HNSCC cell lines. Cell viability and proliferation were investigated using MTS and clonogenic assays, respectively; cell cycle analyses were assessed using flow cytometry.Results: Thirty-eight of the 117 (33%) consistently detected miRNAs were significantly differentially expressed between malignant versus normal tissues. Concordant with previous reports, overexpression of miR-21, miR-155, let-7i, and miR-142-3p and underexpression of miR-125b and miR-375 were detected. Upregulation of miR-423, miR-106b, miR-20a, and miR-16 as well as downregulation of miR-10a were newly observed. Exogenous overexpression of miR-375 in HNSCC cell lines reduced proliferation and clonogenicity and increased cells in sub-G 1 . Similar cellular effects were observed in knockdown studies of the miR-106b-25 cluster but with accumulation of cells in G 1 arrest. No major difference was detected in miRNA profiles among laryngeal, oropharyngeal, or hypopharyngeal cancers. miR-451 was found to be the only significantly overexpressed miRNA by 4.7-fold between nonrelapsed and relapsed patients.Conclusion: We have identified a group of aberrantly expressed miRNAs in HNSCC and showed that underexpression of miR-375 and overexpression of miR-106b-25 cluster might play oncogenic roles in this disease. Further detailed examinations of miRNAs will provide opportunities to dissect the complex molecular abnormalities driving HNSCC progression.

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“…Zhang et al (2000) found that overexpression of E2F transcription factor 1 (E2F-1) plays a positive role in cell cycle re-entry from quiescence and is associated with increased invasiveness in vivo. However, Kwong et al (2003) reported that overexpression of E2F-1 is associated with increased disease-free survival in squamous cell carcinoma of the anterior tongue. In addition, ETS domain-containing protein 1 (ELK1)is involved in the antiangiogenic and antitumor activities of insulin-like growth factor binding protein-3 (IGFBP-3) (Kim et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Critical genes in head and neck squamous cell carcinoma revealed by bioinformatic analysis of gene expression data

Wang

Wang²,

Cao

et al. 2015

Genet. Mol. Res.

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ABSTRACT. In this study, bioinformatic analysis of gene expression data of head and neck squamous cell carcinoma (HNSCC) was performed to identify critical genes. Gene expression data of HNSCC were downloaded from the Cancer Genome Atlas (TCGA) and differentially expressed genes were determined through significance analysis of microarrays. Protein-protein interaction networks were constructed and used to identify hub genes. Functional enrichment analysis was performed with DAVID. Relevant microRNAs, transcription factors, and small molecule drugs were predicted by the Fisher exact test. Survival analysis was performed with the Kaplan-Meier plot from a package for survival analysis in R. In the five groups of HNSCC patients, a total of 5946 DEGs were identified in group 1, 4575 DEGs in group 2, 5580 DEGs in group 3, 8017 DEGs in group 4, and 5469 DEGs in group 5. DEGs in the cell cycle and immune response were significantly over-represented. Five PPI networks were constructed from (2015) which hub genes were acquired, such as minichromosome maintenance complex component 7 (MCM7), MCM2, decorin (DCN), retinoblastoma 1 (RB1), and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG). No significant difference in survival was observed among the 5 groups; however, a significant difference existed between two combined groups (groups 1, 3, and 5 vs groups 2 and 4). Our study revealed critical genes in HNSCC, which could supplement the knowledge about the pathogenesis of HNSCC and provide clues for future therapy development.

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p14ARF Protein Expression Is a Predictor of Both Relapse and Survival in Squamous Cell Carcinoma of the Anterior Tongue

Cited by 32 publications

References 38 publications

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

Comprehensive MicroRNA Profiling for Head and Neck Squamous Cell Carcinomas

Critical genes in head and neck squamous cell carcinoma revealed by bioinformatic analysis of gene expression data

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