MMP8

Gene Summary

Gene:MMP8; matrix metallopeptidase 8
Aliases: HNC, CLG1, MMP-8, PMNL-CL
Location:11q22.3
Summary:This gene encodes a member of the matrix metalloproteinase (MMP) family of proteins. These proteins are involved in the breakdown of extracellular matrix in embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Proteolysis at different sites on this protein results in multiple active forms of the enzyme with distinct N-termini. This protein functions in the degradation of type I, II and III collagens. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:neutrophil collagenase
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
Show (13)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MMP8 (cancer-related)

Wang PW, Abedini MR, Yang LX, et al.
Gelsolin regulates cisplatin sensitivity in human head-and-neck cancer.
Int J Cancer. 2014; 135(12):2760-9 [PubMed] Related Publications
Chemoresistance is a major challenge in cancer therapy. Cisplatin is commonly used for chemotherapy in patients with head-and-neck cancer (HNC), but it increases control of the disease by only 10-15%. Downregulation of proapoptotic pathways is a key determinant for chemoresistance in which gelsolin (GSN) is critically involved. We analyzed the association between GSN expression and cisplatin resistance in HNC cell lines, animals with HNC and cancer tissue samples from 58 cisplatin-treated patients with HNC. GSN expression levels were positively associated with chemoresistance in vitro and in vivo. Cisplatin-induced GSN downregulation was associated with the cleavage of GSN and the promotion of apoptosis. GSN silencing facilitated cisplatin-induced apoptosis in chemoresistant cells. In contrast, intact gelsolin was prosurvival in the presence of cisplatin by interacting with X-linked inhibitor of apoptosis protein (XIAP). In chemosensitive cells, cisplatin suppressed GSN-XIAP interaction, promoted translocation of XIAP from the perinuclear region to the nucleus and induced apoptosis. In chemoresistant cells, GSN was highly expressed, and cisplatin had no significant effect on GSN-XIAP interaction and apoptosis. We conclude that GSN is important for chemoresistance in HNC and may be an appropriate therapeutic target in chemoresistant cancers.

Descamps G, Wattiez R, Saussez S
Proteomic study of HPV-positive head and neck cancers: preliminary results.
Biomed Res Int. 2014; 2014:430906 [PubMed] Free Access to Full Article Related Publications
Human papillomavirus (HPV) was recently recognized as a new risk factor for head and neck squamous cell carcinoma. For oropharyngeal cancers, an HPV+ status is associated with better prognosis in a subgroup of nonsmokers and nondrinkers. However, HPV infection is also involved in the biology of head and neck carcinoma (HNC) in patients with a history of tobacco use and/or alcohol consumption. Thus, the involvement of HPV infection in HN carcinogenesis remains unclear, and further studies are needed to identify and analyze HPV-specific pathways that are involved in this process. Using a quantitative proteomics-based approach, we compared the protein expression profiles of two HPV+ HNC cell lines and one HPV- HNC cell line. We identified 155 proteins that are differentially expressed (P < 0.01) in these three lines. Among the identified proteins, prostate stem cell antigen (PSCA) was upregulated and eukaryotic elongation factor 1 alpha (EEF1α) was downregulated in the HPV+ cell lines. Immunofluorescence and western blotting analyses confirmed these results. Moreover, PSCA and EEF1 α were differentially expressed in two clinical series of 50 HPV+ and 50 HPV- oral cavity carcinomas. Thus, our study reveals for the first time that PSCA and EEF1 α are associated with the HPV-status, suggesting that these proteins could be involved in HPV-associated carcinogenesis.

Tsai ST, Wong TY, Ou CY, et al.
The interplay between alcohol consumption, oral hygiene, ALDH2 and ADH1B in the risk of head and neck cancer.
Int J Cancer. 2014; 135(10):2424-36 [PubMed] Related Publications
Alcohol consumption is an established risk factor for head and neck cancer (HNC). The major carcinogen from alcohol is acetaldehyde, which may be produced by humans or by oral microorganisms through the metabolism of ethanol. To account for the different sources of acetaldehyde production, the current study examined the interplay between alcohol consumption, oral hygiene (as a proxy measure for the growth of oral microorganisms), and alcohol-metabolizing genes (ADH1B and ALDH2) in the risk of HNC. We found that both the fast (*2/*2) and the slow (*1/*1+ *1/*2) ADH1B genotypes increased the risk of HNC due to alcohol consumption, and this association differed according to the slow/non-functional ALDH2 genotypes (*1/*2+ *2/*2) or poor oral hygiene. In persons with the fast ADH1B genotype, the HNC risk associated with alcohol drinking was increased for those with the slow/non-functional ALDH2 genotypes. For those with the slow ADH1B genotypes, oral hygiene appeared to play an important role; the highest magnitude of an increased HNC risk in alcohol drinkers occurred among those with the worst oral hygiene. This is the first study to show that the association between alcohol drinking and HNC risk may be modified by the interplay between genetic polymorphisms of ADH1B and ALDH2 and oral hygiene. Although it is important to promote abstinence from or reduction of alcohol drinking to decrease the occurrence of HNC, improving oral hygiene practices may provide additional benefit.

Gresner P, Gromadzinska J, Twardowska E, et al.
Rad51C: a novel suppressor gene modulates the risk of head and neck cancer.
Mutat Res Fundam Mol Mech Mutagen. 2014; 762:47-54 [PubMed] Related Publications
We conducted a case-control study to investigate the possible association between the head and neck cancer (HNC) and genetic variability of Rad51C tumor suppressor gene. Eight polymorphic sites spanning over non-coding regions of Rad51C promoter, exon 1 and intron 1 were genotyped in 81 HNC cases and 156 healthy controls using the real-time PCR technique. One investigated site turned out to be not polymorphic, while among the remaining seven sites a significant HNC risk-increasing effect was found for rs16943176 (c.-118G>A), rs12946397 (c.-26C>T) and rs17222691 (c.145+947C>T) on both allelic (OR=1.8; p<0.05) and genotypic (OR=2.0; p<0.05) level. Furthermore, our data seem to provide marginal evidence, that this effect might possibly be confined to women only (OR=2.8; p=0.05 for allelic and OR=3.7; p=0.05 for genotypic comparisons). These SNPs were found to co-segregate together forming two distinct, HNC risk-modulating haplotypes. The genetic variability of Rad51C might thus be of relevance with respect to HNC risk.

Ong J, Salomon J, te Morsche RH, et al.
Polymorphisms in the insulin-like growth factor axis are associated with gastrointestinal cancer.
PLoS One. 2014; 9(3):e90916 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Numerous factors influence the development of gastrointestinal (GI) cancer. The insulin-like growth factor (IGF) axis plays a role in embryonic and postnatal growth and tissue repair. Elevated levels of IGFs, low levels of IGF binding proteins (IGFBPs) and over-expression of IGF receptor (IGFR-I) were associated with several stages of cancer. Here, the prevalence of the single nucleotide polymorphisms (SNPs) rs6214 in the IGF type I (IGF-I) gene and rs6898743 in the growth hormone receptor (GHR) gene in patients with GI cancer and controls was studied.
MATERIALS & METHODS: In this Dutch case-control study, DNA isolated from blood of 1,457 GI cancer patients; 438 patients with head and neck cancer (HNC), 475 with esophageal cancer (EC) and 544 with colorectal cancer (CRC) and 1,457 matched controls, was used to determine the rs6214 and rs6898743 genotypes by polymerase chain reaction. The association between these SNPs and GI cancer, HNC, esophageal adenocarcinoma (EAC), esophageal squamous-cell carcinoma (ESCC) and proximal or distal CRC was studied. Odds ratios (ORs) with 95% confidence interval (95% CI) were calculated via unconditional logistic regression.
RESULTS: Overall for GI cancer, the ORs for SNPs rs6214 and rs6898743 were approximately 1.0 (p-value>0.05), using the most common genotypes GG as reference. An OR of 1.54 (95% CI, 1.05-2.27) was found for EC for genotype AA of rs6214. The ORs for EAC were 1.45 (95% CI, 1.04-2.01) and 1.71 (95% CI, 1.10-2.68), for genotypes GA and AA, respectively. Genotype GC of rs6898743 showed an OR of 0.47 (95% CI, 0.26-0.86) for ESCC.
CONCLUSION: The A allele of SNP rs6214 in the IGF-I gene was associated with EAC, and with HNC in women. The GC genotype of rs6898743 in the GHR gene was negatively associated with ESCC.

Blitzer GC, Smith MA, Harris SL, Kimple RJ
Review of the clinical and biologic aspects of human papillomavirus-positive squamous cell carcinomas of the head and neck.
Int J Radiat Oncol Biol Phys. 2014; 88(4):761-70 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
Human papillomavirus (HPV), a known etiology of a subset of head-and-neck squamous cell carcinomas (HNCs), causes numerous alterations in normal cellular functions. This article reviews the biology, detection, and treatment of HPV-positive HNC. The role of HPV oncoproteins in tumor development, the natural history of HPV infection, and risk factors for and prevention of transmission of oral HPV are considered. Commonly used methods for detecting HPV infection, including limitations of these methods, are discussed to aid the practicing clinician in using these tests in their clinical practice. Clinical characteristics of HPV-positive HNC, including potential explanations for the improved outcomes seen in patients with HPV-positive HNC, are assessed. Ongoing clinical trials specific for patients with HPV-positive HNC are described, and areas in need of additional research are summarized. Until the results of ongoing trials are known, treatment of HPV-positive HNC should not differ in clinical practice from treatment of similar non-HPV related cancers.

Van Dyck E, Nazarov PV, Muller A, et al.
Bronchial airway gene expression in smokers with lung or head and neck cancer.
Cancer Med. 2014; 3(2):322-36 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
Cigarette smoking is the major cause of cancers of the respiratory tract, including non-small cell lung cancer (NSCLC) and head and neck cancer (HNC). In order to better understand carcinogenesis of the lung and upper airways, we have compared the gene expression profiles of tumor-distant, histologically normal bronchial biopsy specimens obtained from current smokers with NSCLC or HNC (SC, considered as a single group), as well as nonsmokers (NS) and smokers without cancer (SNC). RNA from a total of 97 biopsies was used for gene expression profiling (Affymetrix HG-U133 Plus 2.0 array). Differentially expressed genes were used to compare NS, SNC, and SC, and functional analysis was carried out using Ingenuity Pathway Analysis (IPA). Smoking-related cancer of the respiratory tract was found to affect the expression of genes encoding xenobiotic biotransformation proteins, as well as proteins associated with crucial inflammation/immunity pathways and other processes that protect the airway from the chemicals in cigarette smoke or contribute to carcinogenesis. Finally, we used the prediction analysis for microarray (PAM) method to identify gene signatures of cigarette smoking and cancer, and uncovered a 15-gene signature that distinguished between SNC and SC with an accuracy of 83%. Thus, gene profiling of histologically normal bronchial biopsy specimens provided insight into cigarette-induced carcinogenesis of the respiratory tract and gene signatures of cancer in smokers.

Wyss AB, Weissler MC, Avery CL, et al.
Single nucleotide polymorphisms in nucleotide excision repair genes, cancer treatment, and head and neck cancer survival.
Cancer Causes Control. 2014; 25(4):437-50 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
PURPOSE: Head and neck cancers (HNC) are commonly treated with radiation and platinum-based chemotherapy, which produce bulky DNA adducts to eradicate cancerous cells. Because nucleotide excision repair (NER) enzymes remove adducts, variants in NER genes may be associated with survival among HNC cases both independently and jointly with treatment.
METHODS: Cox proportional hazards models were used to estimate race-stratified (White, African American) hazard ratios (HRs) and 95 % confidence intervals for overall (OS) and disease-specific (DS) survival based on treatment (combinations of surgery, radiation, and chemotherapy) and 84 single nucleotide polymorphisms (SNPs) in 15 NER genes among 1,227 HNC cases from the Carolina Head and Neck Cancer Epidemiology Study.
RESULTS: None of the NER variants evaluated were associated with survival at a Bonferroni-corrected alpha of 0.0006. However, rs3136038 [OS HR = 0.79 (0.65, 0.97), DS HR = 0.69 (0.51, 0.93)] and rs3136130 [OS HR = 0.78 (0.64, 0.96), DS HR = 0.68 (0.50, 0.92)] of ERCC4 and rs50871 [OS HR = 0.80 (0.64, 1.00), DS HR = 0.67 (0.48, 0.92)] of ERCC2 among Whites, and rs2607755 [OS HR = 0.62 (0.45, 0.86), DS HR = 0.51 (0.30, 0.86)] of XPC among African Americans were suggestively associated with survival at an uncorrected alpha of 0.05. Three SNP-treatment joint effects showed possible departures from additivity among Whites.
CONCLUSIONS: Our study, a large and extensive evaluation of SNPs in NER genes and HNC survival, identified mostly null associations, though a few variants were suggestively associated with survival and potentially interacted additively with treatment.

Yu CH, Yu CC
Photodynamic therapy with 5-aminolevulinic acid (ALA) impairs tumor initiating and chemo-resistance property in head and neck cancer-derived cancer stem cells.
PLoS One. 2014; 9(1):e87129 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
BACKGROUND: Head and neck cancer (HNC) ranks the fourth leading malignancy and cancer death in male population in Taiwan. Despite recent therapeutic advances, the prognosis for HNC patients is still dismal. New strategies are urgently needed to improve the chemosensitization to conventional chemotherapeutic drugs and clinical responses of HNC patients. Studies have demonstrated that topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is being used in the treatment of various human premalignant and malignant lesions with some encouraging clinical outcomes. However, the molecular mechanisms of ALA-PDT in the therapeutic effect in HNC tumorigenesis and whether ALA-PDT as chemosensitizer for HNC treatment remain unclear. Accumulating data support cancer stem cells (CSCs) contributes chemo-resistance in HNC. Based on the previous studies, the purpose of the study is to investigate the effect of ALA-PDT on CSCs and chemosensitization property in HNC.
METHODOLOGY/PRINCIPAL FINDING: CSCs marker ALDH1 activity of HNC cells with ALA-PDT treatment as assessed by the Aldefluor assay flow cytometry analysis. Secondary Sphere-forming self-renewal, stemness markers expression, and invasiveness of HNC-CSCs with ALA-PDT treatment were presented. We observed that the treatment of ALA-PDT significantly down-regulated the ALDH1 activity and CD44 positivity of HNC-CSCs. Moreover, ALA-PDT reduced self-renewal property and stemness signatures expression (Oct4 and Nanog) in sphere-forming HNC-CSCs. ALA-PDT sensitized highly tumorigenic HNC-CSCs to conventional chemotherapies. Lastly, synergistic effect of ALA-PDT and Cisplatin treatment attenuated invasiveness/colongenicity property in HNC-CSCs.
CONCLUSION/SIGNIFICANCE: Our results provide insights into the clinical prospect of ALA-PDT as a potential chemo-adjuvant therapy against head and neck cancer through eliminating CSCs property.

Khlifi R, Chakroun A, Hamza-Chaffai A, Rebai A
Association of CYP1A1 and CYP2D6 gene polymorphisms with head and neck cancer in Tunisian patients.
Mol Biol Rep. 2014; 41(4):2591-600 [PubMed] Related Publications
The purpose of this study was to investigate the relationship between head and neck cancer (HNC) and environmental agents and polymorphisms in CYP1A1, CYP2D6, NAT1 and NAT2 metabolic enzymes genes. To the best of our knowledge, this is the first report on polymorphisms in CYP1A1 6310C>T, CYP2D6 Arg365His, NAT1 52936A>T and NAT2 Arg268Lys (NAT2*12A) genes and susceptibility to HNC in Tunisian population. We study the prevalence of these polymorphisms in 169 patients with HNC and 261 control subjects using polymerase chain reaction based methods in a Tunisian population. We detected an association between HNC and CYP1A1 6310C>T (TT) and CYP2D6 Arg365His (His/His) variant carriers (OR 1.75, P = 0.008 and OR 1.66, P = 0.016, respectively). No association was found between the polymorphisms genotypes of NAT1 52936T>A and NAT2 Arg268Lys and risk of HNC. An association between HNC and CYP1A1 (TT) genotype was found among patients with smoking (P = 0.011) and drinking habit (P = 0.009). The combinations of NAT1 (AT or AA) and NAT2 (AA) at-risk genotypes increased HNC risk (OR 4.23, P = 0.005 and OR 3.60, P = 0.048, respectively). However, the combinations of CYP1A1 (AA) and CYP2D6 (CC) genotypes decreased risk of HNC (OR 0.20; P = 0.006). Genetic polymorphisms in CYP1A1 and CYP2D6 may significantly associate with HNC in the Tunisian population. The results of this study suggest a possible gene-environment interaction for certain carcinogen metabolizing enzymes, but larger studies that fully evaluate the interaction are needed.

Lin H, Lin D, Zheng C
Association of XPD Lys751Gln polymorphism with head and neck cancer susceptibility: evidence from 11,443 subjects.
Diagn Pathol. 2014; 9:15 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
BACKGROUND: Whether the single nucleotide polymorphism (SNP) Lys751Gln of xeroderma pigmentosum group D(XPD) gene increases susceptibility to head and neck cancer (HNC) is controversial and undetermined. Therefore, we conducted this meta-analysis to systematically assess the possible association between them.
METHODS: The OVID, Medline, Embase, Pubmed, Web of Science databases were searched to identify the eligible studies. The odds ratio (OR) with 95% confidence interval (95% CI) were used to assess the strength of association.
RESULTS: A total of 11,443 subjects from eighteen studies were subjected to meta-analysis. Overall, XPD Lys751Gln polymorphism had no association with increased HNC risk under all five genetic models (P > 0.05). In the subgroup analysis by ethnicity and source of controls, still no significant association was found under five genetic models (P > 0.05). In the subgroup analysis by cancer type, XPD Lys751Gln polymorphism had statistically significant association with elevated laryngeal cancer (LC) and nasopharyngeal cancer (NPC) risk under heterozygous comparison and dominant model (P<0.05) and borderline significantly increased risk was found under allele contrast for LC and NPC. Carriers of Lys allele and Lys/Lys genotype may be associated with elevated LC and NPC risk.
CONCLUSIONS: There is overall lack of association between XPD Lys751Gln polymorphism and HNC risk under all five genetic models and still no significant association was found in the subgroup analysis by ethnicity and source of controls. However, XPD Lys751Gln polymorphism was significantly associated with susceptibility to LC and NPC and the Lys allele and Lys/Lys genotype of XPD Lys751Gln polymorphism may be a risk factor for LC and NPC. However, relatively modest sample sizes were included in this meta-analysis and studies with large sample sizes and representative population are warranted to further clarify this finding.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5628716106316015.

Brunotto M, Zarate AM, Bono A, et al.
Risk genes in head and neck cancer: a systematic review and meta-analysis of last 5 years.
Oral Oncol. 2014; 50(3):178-88 [PubMed] Related Publications
The aim of this work was to identify risk genes related to the development and progression of squamous cell carcinoma head and neck (SCCHN) and do a meta-analysis of available estimates. Eligible gene/polymorphism studies were identified by electronic searches. Individual participant data of 8540 patients with HNC and 9844 controls from 19 genetic studies were analyzed, yielding adjusted (tobacco, gender, age and alcohol) odds ratios (OR) and 95% confidence intervals (CIs) comparing cases with controls. A meta-analysis was done on the studies that applied fixed and random models. People have an increase of polymorphism expression related to inflammation (NFKB1-294-ATTG, TNFα308-A2A2/A2A1, and TNFβ252- B2B2/B2B1) or carcinogenic metabolism (GSTM1 null, and CYP1A1 m1/m1), representative of malignancy development. Furthermore, the increased expression of genes associated with the stabilization and repair of the cellular (OGG1-Asp267Asn, Ser279Gly Ile253Phe, 1578A>T, 1582C>T Ala399Glu (1542C>A) 1582insG 1543_1544delCT), and genes associated with the regulation of proliferation, apoptosis or tumor survival (miRNA499-CT/CC, CRYABC802G-CG/GG) are considered as risk factors. In this scheme, only the polymorphisms of ADH7A92G-GG and DEC1606-T/C genes are protective against malignancy transformation. The TP53, GSTM1 and CYPA1genes have been evaluated in more than one study and analyzed for homogeneity in each genotype. The meta-analysis showed no significant association between different allelic variants of Arg72Pro rs1042522 and SCCHN risk. In a model of tumorigenesis, an increased risk of SCCHN is associated with DNA repair and DNA stabilization genes. In addition, the polymorphisms involved in inflammation and carcinogenic metabolism processes represent an increased risk of SCCHN.

Succi M, de Castro TB, Galbiatti AL, et al.
DNMT3B C46359T and SHMT1 C1420T polymorphisms in the folate pathway in carcinogenesis of head and neck.
Mol Biol Rep. 2014; 41(2):581-9 [PubMed] Related Publications
Folate is an essential nutrient with important roles in the synthesis, repair, and DNA methylation. Polymorphisms in genes encoding enzymes involved in folate metabolism can change these processes and modulate cancer development. We investigated DNMT3B C46359T (rs2424913) and SHMT1 C1420T (rs1979277) polymorphisms related to folate pathway in head and neck cancer (HNC) risk and the association of the disease with gender, risk factors and clinical histopathological parameters. A case-control study was conducted in 725 individuals (237 patients with HNC and 488 control individuals). Real-time PCR technique was performed for genotyping. Chi square and multiple logistic regression tests were used for statistical analysis. Male gender (OR 1.80; 95 % CI 1.11-2.94; P < 0.02) and tobacco consumption (OR 6.14; 95 % CI 4.13-9.13; P < 0.001) were associated with increased risk for this neoplasia. There were no significant associations between the polymorphisms and risk of disease, however, the tobacco and alcohol habits together showed association with SHMT1 C1420T polymorphism (OR 1.48; 95 % CI 1.08-2.03; P = 0.014). SHMT1 C1420T polymorphism was associated with larynx tumor (OR 0.48; 95 % CI 0.27-0.86; P < 0.05). In conclusion, tobacco habit and male gender can be predictors for HNC risk. SHMT1 C1420T and DNMT3B C46359T polymorphisms are not associated with HNC development in Brazilian population, however, SHMT1 C1420T polymorphism is less frequent in patients with primary site of tumor in larynx and more frequent in individuals who consume tobacco and alcohol together. Further studies involving gene-gene interactions in folate pathway in different populations can contribute to the understanding of the polymorphisms effect on HNC risk.

Zhang Y, Li Z, Zhong Q, et al.
Polymorphisms of the XPC gene may contribute to the risk of head and neck cancer: a meta-analysis.
Tumour Biol. 2014; 35(4):3917-31 [PubMed] Related Publications
Polymorphisms of the XPC gene have been reported to be associated with an increased risk of head and neck cancer (HNC), though the exact biological effect is still unclear. Genetic association studies (GAS) investigating the associations between three common polymorphisms (PAT, Lys939Gln, and Ala499Val) of the XPC gene and HNC risk have produced contradictory and inconclusive results. The aim of this meta-analysis is to evaluate the contributions of these polymorphisms to the risk of HNC. A literature search was conducted in the PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure databases to indentify eligible studies. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to evaluate the strength of the associations under a fixed- or random-effect model according to heterogeneity test. Twelve case-control studies were included in this meta-analysis with a total of 3,078 HNC patients and 4,311 healthy controls. For XPC PAT, a significant overall association was found under all major genetic models. Stratified analyses further indicated significant associations in the Caucasian, population-based, non-PCR-RFLP, esophageal cancer and oral cancer subgroups. For XPC Lys939Gln, few significant results were found in either the overall analysis or stratified analyses. For XPC Ala499Val, the combined results revealed a significantly increased risk of HNC for carriers of the 499Val allele. This meta-analysis shows that the XPC PAT and Ala499Val polymorphisms may be associated with an increased risk of HNC, while XPC Lys939Gln may not be associated with HNC risk. Despite some limitations, this meta-analysis establishes solid statistical evidence for an association between XPC genetic polymorphisms and HNC risk that warrants further validation.

Roh JL, Kim EH, Park HB, Park JY
The Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin increases cisplatin antitumor activity by inducing p53-mediated apoptosis in head and neck cancer.
Cell Death Dis. 2013; 4:e956 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
The tumor suppressor p53 is often inactivated in head and neck cancer (HNC) through TP53 mutations or overexpression of mouse double minute 2 or mouse double minute X. Restoration of p53 function by counteracting these p53 repressors is a promising strategy for cancer treatment. The present study assessed the ability of a heat shock protein 90 (Hsp90) inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), to induce apoptosis in HNC by restoring p53 function. The effect of 17AAG, alone or in combination with Nutlin-3a or cisplatin, was assessed in HNC cells using growth and apoptosis, immunoblotting, quantitative reverse transcription-polymerase chain reaction, and preclinical tumor xenograft models. 17AAG activated and stabilized p53 in HNC cells bearing wild-type TP53 by disrupting the p53-MDMX interaction. 17AAG upregulated p21 and proapoptotic gene expression, and promoted apoptosis in a concentration-dependent manner. Growth inhibition by 17AAG was highest in tumor cells with MDMX overexpression. The apoptotic response was blocked by inhibition of p53 expression, demonstrating that the effect of 17AAG depended on p53 and MDMX. 17AAG synergized in vitro with Nutlin-3a and in vitro and in vivo with cisplatin to induce p53-mediated apoptosis. 17AAG effectively induced p53-mediated apoptosis in HNC cells through MDMX inhibition and increased the antitumor activity of cisplatin synergistically, suggesting a promising strategy for treating HNC.

Wu X, Cao W, Wang X, et al.
TGM3, a candidate tumor suppressor gene, contributes to human head and neck cancer.
Mol Cancer. 2013; 12(1):151 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
BACKGROUND: In our previous study using oligonucleotide microarrays, we revealed that transglutaminase 3 (TGM3) was remarkably down-regulated in head and neck cancer (HNC). However, the potential of TGM3 as a useful biomarker or molecular target for HNC is unclear.
METHODS: The transcriptional and post-translational status of TGM3 in HNC cell lines and specimens was detected using real-time PCR and western blot analysis. Bisulfate-treated DNA sequencing was used to analyze the molecular mechanism of TGM3 gene silencing. In addition, the effects of TGM3 on the proliferation, colony formation and induction of apoptosis in vitro and tumorigenicity in vivo were investigated through exogenous expression of TGM3 in HNC cells. Immunohistochemistry was used to evaluate TGM3 expression in large HNC samples.
RESULTS: TGM3 was down-regulated in HNC samples and cell lines (P < 0.0001). The hypermethylation of a promoter CpG island was one of the mechanisms of silencing the TGM3 gene in HNC. Exogenous expression of TGM3 in HNC cells could inhibit the proliferation and enhance the apoptosis of HNC cells in vitro and suppress tumor growth in vivo. In addition, TGM3 protein levels were strongly associated with the pathological differentiation of HNC tissues (P = 0.0037). Survival analysis revealed that low TGM3 expression was associated with worse overall survival (P = 0.0002), and TGM3 expression level was an independent predictor in patients with HNC.
CONCLUSIONS: The studies prove that TGM3, as a candidate tumor suppressor, contributes to the carcinogenesis and development of HNC and may serve as a useful biomarker for patients with HNC.

Chiu CC, Lee LY, Li YC, et al.
Grp78 as a therapeutic target for refractory head-neck cancer with CD24(-)CD44(+) stemness phenotype.
Cancer Gene Ther. 2013; 20(11):606-15 [PubMed] Related Publications
Cancer stem cells are refractory to conventional therapy, which result to cancer metastasis and chemo-radioresistance. Grp78 is known to have important roles in cytoprotection and tumorigenesis in several cancers. We therefore examined whether Grp78 can serve as a therapeutic target for refractory stemness phenotype of head and neck cancer (HNC). Six HNC cell lines were used. Fluorescence-activated cell sorting (FACS) analysis was used to sort CD24(-)CD44(+) and Grp78(+) cells. The small interfering RNA (siRNA) knockdown and cDNA transfection were applied to examine the effects of Grp78 on cellular function. Western blot and confocol microscopy were used to determine the effects of downstream protein expressions. Xenografted mouse tumors and immunohistochemistry were used to validate the results. We found that Grp78 regulated the conversion of CD24(-)CD44(+) cells, a characteristic of HNC stem cells. The CD24(-)CD44(+)Grp78(+) cells showed superior chemo-radioresistance and invasion ability compared with CD24(-)CD44(+), Grp78(+) or the parental cells. Silencing Grp78 increased chemo-radiosensitivity, inhibited cell invasion, reverse epithelial-mesenchymal transition, suppressed cancer stemness, withdrew CD24(-)CD44(+) cell conversion and induced differentiated phenotype. Study in xenografted mice further showed that CD24(-)CD44(+)Grp78(+) cells exhibited highest tumorigenesis, compared with CD24(-)CD44(+) CD24(+)CD44(+) or the parental cells. Grp78 knockdown dramatically restrained tumor growth along with the inhibition of stem cell regulatory proteins Oct-4 and Slug. Grp78 may serve as a molecular target that can be further developed for eradication of refractory HNC with stemness phenotype.

Khlifi R, Messaoud O, Rebai A, Hamza-Chaffai A
Polymorphisms in the human cytochrome P450 and arylamine N-acetyltransferase: susceptibility to head and neck cancers.
Biomed Res Int. 2013; 2013:582768 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
The occurrence of head and neck cancer (HNC) is associated with smoking and alcohol drinking. Tobacco smoking exposes smokers to a series of carcinogenic chemicals. Cytochrome P450 enzymes (CYP450s), such as CYP1A1, CYP1B1, and CYP2D6, usually metabolize carcinogens to their inactive derivatives, but they occasionally convert the chemicals to more potent carcinogens. In addition, via CYP450 (CYP2E1) oxidase, alcohol is metabolized to acetaldehyde, a highly toxic compound, which plays an important role in carcinogenesis. Furthermore, two N-acetyltransferase isozymes (NATs), NAT1 and NAT2, are polymorphic and catalyze both N-acetylation and O-acetylation of aromatic and heterocyclic amine carcinogens. Genetic polymorphisms are associated with a number of enzymes involved in the metabolism of carcinogens important in the induction of HNC. It has been suggested that such polymorphisms may be linked to cancer susceptibility. In this paper, we select four cytochrome P450 enzymes (CYP1A1, CYP1BA1, CYP2D6, and CYP2E1), and two N-acetyltransferase isozymes (NAT1 and NAT2) in order to summarize and analyze findings from the literature related to HNC risk by focusing on (i) the interaction between these genes and the environment, (ii) the impact of genetic defect on protein activity and/or expression, and (iii) the eventual involvement of race in such associations.

Lou Y, Peng WJ, Cao DS, et al.
DNA repair gene XRCC1 polymorphisms and head and neck cancer risk: an updated meta-analysis including 16344 subjects.
PLoS One. 2013; 8(9):e74059 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
BACKGROUND: DNA repair gene X-ray repair cross complementing group 1 (XRCC1) plays an important role in the maintenance of the genomic integrity and protection of cells from DNA damage. Sequence variation in XRCC1 gene may alter head and neck cancer (HNC) susceptibility. However, these results are inconclusive. To derive a more precise estimation of the relationship between XRCC1 polymorphism and HNC risk, we undertook a meta-analysis involving 16,344 subjects.
METHODS: A search of the literature by PubMed, Embase, Web of Science and China National Knowledge Infrastructure was performed to identify studies based on the predetermined inclusion criteria. The odds ratio (OR) with 95% confidence interval (CI) was combined using a random-effects model or a fixed-effects model.
RESULTS: Twenty-nine studies consisting of 6,719 cases and 9,627 controls were identified and analyzed. Overall, no evidence of significant association was observed between XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln genotypes and the risk of HNC in any genetic models. Subgroup analyses according to ethnicity, tumor site, publication year, genotyping method also detected no significant association in any subgroup, except that oral cancer was associated with Arg194Trp variant in recessive model. Furthermore, no significant effect of these polymorphisms interacted with smoking on HNC risk was detected but Arg194Trp homozygous variant.
CONCLUSION: In conclusion, this meta-analysis suggests that the XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphism may not involve in HNC susceptibility. Further studies about gene-gene and gene-environment interactions in different populations are required.

Gong L, Zhang W, Zhou J, et al.
Prognostic value of HIFs expression in head and neck cancer: a systematic review.
PLoS One. 2013; 8(9):e75094 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
BACKGROUND: Tumor hypoxia plays a fundamental role in resistance to therapy and disease progression. A number of studies have assessed the prognostic role of HIFs expression in head and neck cancer (HNC), but no consistent outcomes are reported.
METHODOLOGY: A systematical search was performed to search relevant literatures in PubMed, Web of Science and ISI Web of Knowledge databases. The patients' clinical characteristics and survival outcome were extracted. The correlation between HIFs expression and prognosis was analyzed.
PRINCIPAL FINDINGS: A total of 28 studies assessed the association between HIFs and HNC survival, the result showed that overexpressed HIFs was significantly associated with increase of mortality risk (HR = 2.12; 95% CI: 1.52-2.94; I(2) 74%). Subgroup analysis on different HIF isoforms with OS indicated that both HIF-1α and HIF-2α were associated with worse prognosis. The pooled HRs were 1.72(95% CI 1.34-2.20; I(2) 70.7%) and 1.79(95% CI: 1.42-2.27, I(2) 0%). Further subgroup analysis was performed by different geographical locations, disease subtype, stage, types of variate analysis and cut-off value. The results revealed that overexpressed HIF-1α was significantly associated with poor prognosis in Asian patients (HR = 2.34; 95% CI: 1.76-3.1; I(2) 48.9%), but not in European patients (HR = 1.13; 95% CI: 0.77-1.66; I(2) 78.3%). Furthermore, HIF-1α overexpression was significantly associated with worse OS in oral carcinoma (HR = 2.1; 95% CI: 1.11-3.97; I(2) 81.7%), nasopharyngeal carcinoma (HR = 2.07; 95% CI:1.23-3.49; I(2) 22.5%) and oropharynx carcinoma (HR = 1.76; 95% CI:1.05-2.97; I(2) 61%), but not in laryngeal carcinoma (HR = 1.38; 95% CI: 0.87-2.19; I(2) 62.5%). We also found that the prognostic value of HIF-1α overexpression existed only when using staining and percentage as positive definition (HR = 1.82; 95% CI 1.42-2.33; I(2) 9.9%).
CONCLUSIONS: This study showed that overexpressed HIFs were significantly associated with increase of mortality risk. Subgroup analysis revealed that overexpressed HIF-1α was significantly associated with worse prognosis of HNC in Asian countries. Additionally, HIF-1α had different prognostic value in different HNC disease subtypes.

Leng WD, He MN, Chen QL, et al.
Vascular endothelial growth factor (VEGF) gene polymorphisms and risk of head and neck cancer: a meta-analysis involving 2,444 individuals.
Mol Biol Rep. 2013; 40(10):5987-92 [PubMed] Related Publications
The association between vascular endothelial growth factor (VEGF) gene polymorphisms and risk of head and neck cancer (HNC) were investigated in many published studies; however, the currently available results are inconclusive. Therefore, we conducted this meta-analysis for deriving a more precise estimation of association between VEGF polymorphisms and the risk of HNC. Finally, we yield eight case-control studies involving six polymorphisms contain 2,444 individuals from PubMed, Embase, and CNKI up to January 30, 2013 (last updated on May 4, 2013). The results of meta-analysis showed that all the six polymorphisms of VEGF were not associated with risk of HNC [OR 1.25, 95 % CI (0.60-1.58) for TT vs. CC for 936 C/T; OR 1.41, 95 % CI (0.79-2.52) for GG vs. AA for -1,154 A/G; OR 0.97, 95 % CI (0.38-2.50) for CC vs. GG for 405 G/C; OR 1.44, 95 % CI (0.80-2.61) for AA vs. CC for 2,578 C/A; OR 1.27, 95 % CI (0.77-3.72) for TT vs. CC for -460 C/T; and OR 0.87, 95 % CI (0.37-2.06) for GG vs. CC for -634 G/C]. When performed subgroup analysis according to ethnicity for VEGF 936 C/T, the results suggested that it was not associated with the risk of HNC for either Asians [OR 0.84, 95 % CI (0.27-2.56) for TT vs. CC] or Caucasians [OR 2.10, 95 % CI (0.82-5.37) for TT vs. CC]. However, due to the limitations of this meta-analysis, more well designed, larger sample size, and adjusted risk factors studies are suggested to further assess the findings.

Zhu X, Zhang F, Zhang W, et al.
Prognostic role of epidermal growth factor receptor in head and neck cancer: a meta-analysis.
J Surg Oncol. 2013; 108(6):387-97 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: To evaluate the predicting value of the epidermal growth factor receptor (EGFR) for survival in patients with head and neck cancer (HNC).
METHODS: Data were collected from studies comparing overall survival (OS) or progression-free survival (PFS) in patients with higher or lower EGFR levels. Studies were pooled and combined hazard ratios (HRs) of EGFR for survival were calculated.
RESULTS: A total of 68 studies involving 6,781 patients were included for meta-analysis. Either EGFR protein expression or gene copy number had prognostic value in HNC patients. EGFR overexpression could predict worse outcome, with HRs of 1.65 (95% CI: 1.45, 1.86) for OS and 1.27 (95% CI: 1.17, 1.37) for PFS. Increased EGFR copy number was also associated with reduced survival, with HRs of 1.5 (95% CI: 1.15, 1.96) for OS and 1.35 (95% CI: 1.14, 1.61) for PFS. Furthermore, EGFR overexpression could predict poorer OS in both eastern and western countries. Particularly, EGFR was considered a strong predictor in laryngeal squamous cell cancer (HR > 2).
CONCLUSION: Elevated EGFR expression and gene copy number could predict poor survival in HNC patients.

Giles KM, Kalinowski FC, Candy PA, et al.
Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib.
Mol Cancer Ther. 2013; 12(11):2541-58 [PubMed] Related Publications
Elevated expression and activity of the epidermal growth factor receptor (EGFR) is associated with development and progression of head and neck cancer (HNC) and a poor prognosis. Clinical trials with EGFR tyrosine kinase inhibitors (e.g., erlotinib) have been disappointing in HNC. To investigate the mechanisms mediating resistance to these agents, we developed an HNC cell line (HN5-ER) with acquired erlotinib resistance. In contrast to parental HN5 HNC cells, HN5-ER cells exhibited an epithelial-mesenchymal (EMT) phenotype with increased migratory potential, reduced E-cadherin and epithelial-associated microRNAs (miRNA), and elevated vimentin expression. Phosphorylated receptor tyrosine kinase profiling identified Axl activation in HN5-ER cells. Growth and migration of HN5-ER cells were blocked with a specific Axl inhibitor, R428, and R428 resensitized HN5-ER cells to erlotinib. Microarray analysis of HN5-ER cells confirmed the EMT phenotype associated with acquired erlotinib resistance, and identified activation of gene expression associated with cell migration and inflammation pathways. Moreover, increased expression and secretion of interleukin (IL)-6 and IL-8 in HN5-ER cells suggested a role for inflammatory cytokine signaling in EMT and erlotinib resistance. Expression of the tumor suppressor miR-34a was reduced in HN5-ER cells and increasing its expression abrogated Axl expression and reversed erlotinib resistance. Finally, analysis of 302 HNC patients revealed that high tumor Axl mRNA expression was associated with poorer survival (HR = 1.66, P = 0.007). In summary, our results identify Axl as a key mediator of acquired erlotinib resistance in HNC and suggest that therapeutic inhibition of Axl by small molecule drugs or specific miRNAs might overcome anti-EGFR therapy resistance.

Khlifi R, Kallel I, Hammami B, et al.
DNA repair gene polymorphisms and risk of head and neck cancer in the Tunisian population.
J Oral Pathol Med. 2014; 43(3):217-24 [PubMed] Related Publications
Altered activity of DNA repair enzymes may be involved in modulating cancer susceptibility and pathogenesis of head and neck cancer (HNC). We conducted a case-control study to test the association between three common single-nucleotide polymorphisms of XRCC1, ERCC2, and ERCC3 genes with HNC risk in Tunisian patients. To the best of our knowle dge, this is the first report on polymorphisms in XRCC1, ERCC2, and ERCC3 and susceptibility to HNC in our population. The genotype analyses of XRCC1 Arg399Gln, ERCC2 Lys751Gln, and ERCC3 7122 A>G polymorphisms for 169 HNC patients, and 261 controls were performed using the PCR-based restriction fragment length polymorphism. Stratification of the populations according to smoking and drinking habits and occupational exposure highlighted the importance of tobacco, alcohol, and toxic substance as three risk co-factors for the development of HNC. Our study suggests that only the XRCC1 Arg399Gln polymorphism was associated with the risk of HNC in the Tunisian population (OR = 2.04; P = 0.001). Furthermore, the risk of HNC was associated with XRCC1 Arg399Gln polymorphism stratified by occupational exposure status (OR = 2.29; P = 0.024). However, no statistically significant association was observed between the risk of developing HNC and the ERCC2 Lys751Gln and ERCC3 A>G polymorphisms. These data suggest that the XRCC1 Arg399Gln polymorphism is associated with an increased risk of developing HNC, because it correlates with occupational exposure in Tunisian population.

Saito K, Inagaki K, Kamimoto T, et al.
MicroRNA-196a is a putative diagnostic biomarker and therapeutic target for laryngeal cancer.
PLoS One. 2013; 8(8):e71480 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
BACKGROUND: MicroRNA (miRNA) is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue- or disease-specific nature. Head and neck cancer (HNC) is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary.
METHODOLOGY/PRINCIPAL FINDINGS: To explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR) on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model.
CONCLUSIONS/SIGNIFICANCE: Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.

Chang JS, Lo HI, Wong TY, et al.
Investigating the association between oral hygiene and head and neck cancer.
Oral Oncol. 2013; 49(10):1010-7 [PubMed] Related Publications
OBJECTIVES: This analysis examined the association between oral hygiene and head and neck cancer (HNC) and whether this association differed by the consumption of alcohol, betel quid, or cigarette and by the genetic polymorphisms of inflammation-related genes.
MATERIALS AND METHODS: Interviews regarding dental care and oral health were conducted with 317 HNC cases and 296 controls. Genotyping was performed for 6 single nucleotide polymorphisms in IL6, IL10 and PTGS2.
RESULTS: A positive association was observed between HNC and no regular dental visits (odds ratio (OR)=2.86, 95% confidence interval (CI): 1.47-5.57), brushing teeth <2times/day (OR=1.51, 95% CI: 1.02-2.23), frequent gum bleeding (OR=3.15, 95% CI: 1.36-7.28), and loss of >20 teeth (OR=2.31, 95% CI: 1.05-5.07). Analysis with dental care score (range: 0-4, 4=worst dental care), which combined regular dental visits, toothbrushing, and use of dental floss and mouthwash, showed a positive trend with HNC risk, particularly among alcohol drinkers and cigarette smokers. Multifactor dimensionality reduction analysis divided the study subjects into high- and low-risk group based on combinations of dental care score and IL6 rs1800796 genotypes. Compared to the low-risk group, the high-risk group had an OR of HNC=2.16 (95% CI: 1.44-3.25).
CONCLUSIONS: This study observed a positive association between poor oral hygiene and HNC, which appeared to differ by alcohol or cigarette consumption and the genotypes of IL6 rs1800796. Further investigations are needed to determine whether poor oral hygiene is a cause for HNC or a surrogatemarker of an unhealthy lifestyle that increases the risk of HNC.

Soria-Valles C, Gutiérrez-Fernández A, Guiu M, et al.
The anti-metastatic activity of collagenase-2 in breast cancer cells is mediated by a signaling pathway involving decorin and miR-21.
Oncogene. 2014; 33(23):3054-63 [PubMed] Related Publications
Matrix metalloproteinases (MMPs) have been traditionally implicated in cancer progression because of their ability to degrade the extracellular matrix. However, some members of the MMP family have recently been identified as proteases with antitumor properties. Thus, it has been described that collagenase-2 (MMP-8) has a protective role in tumor and metastasis progression, but the molecular mechanisms underlying these effects are unknown. We show herein that Mmp8 expression causes a decrease in miR-21 levels that in turn leads to a reduction in tumor growth and lung metastasis formation by MDA-MB-231 (4175) breast cancer cells. By using both in vitro and in vivo models, we demonstrate that the mechanism responsible for these MMP-8 beneficial effects involves cleavage of decorin by MMP-8 and a subsequent reduction of transforming growth factor β (TGF-β) signaling that controls miR-21 levels. In addition, miR-21 downregulation induced by MMP-8 increases the levels of tumor suppressors such as programmed cell death 4, which may also contribute to the decrease in tumor formation and metastasis of breast cancer cells overexpressing this metalloproteinase. These findings reveal a new signaling pathway for cancer regulation controlled by MMP-8, and contribute to clarify the molecular mechanisms by which tumor-defying proteases may exert their protective function in cancer and metastasis.

Ekizoglu S, Dalay N, Karaman E, et al.
LKB1 downregulation may be independent of promoter methylation or FOXO3 expression in head and neck cancer.
Transl Res. 2013; 162(2):122-9 [PubMed] Related Publications
The serine/threonine kinase liver kinase B 1 (LKB1) is a multifunctional protein and has been associated with various cancer types. Although the tumor suppressor function of LKB1 is attributed mainly to its ability to phosphorylate directly different adenosine monophosphate-activated protein kinases, its regulation is still poorly understood. More recently, it has been shown that LKB1 expression can be regulated by forkhead box O transcription factors via cis-acting elements, which are found in the promoter region of the LKB1 gene. In this study, we investigated LKB1 messenger RNA expression levels in association with the promoter methylation of the gene and forkhead box O member 3 (FOXO3) messenger RNA expression in head and neck squamous cell carcinoma (HNSCC) tumor samples. Our results show that LKB1 expression is downregulated, especially in advanced-stage tumor samples, and this downregulation was not the result of promoter methylation or modulation by FOXO3 (P = 0.656). Despite observing a positive association between the LKB1 and FOXO3 expression levels in the tumors, this association was not statistically significant (P = 0.24). Our results indicate that downregulation of LKB1 is independent of FOXO3 and may be implicated in the progression of HNSCC.

Kimple RJ, Smith MA, Blitzer GC, et al.
Enhanced radiation sensitivity in HPV-positive head and neck cancer.
Cancer Res. 2013; 73(15):4791-800 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
Patients with human papillomavirus (HPV+)-associated head and neck cancer (HNC) show significantly improved survival outcome compared with those with HPV-negative (HPV-) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV- HNC cell lines using in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV-: 0.59 vs. HPV+: 0.22; P < 0.0001), corresponding with a prolonged G2-M cell-cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%; P = 0.002). A genome-wide microarray was used to compare gene expression 24 hours following radiation between HPV+ and HPV- cell lines. Multiple genes in TP53 pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6-fold increase in TP53 (P < 0.0001). Using immortalized human tonsillar epithelial (HTE) cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV- HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome.

Chen YJ, Lee LY, Chao YK, et al.
DSG3 facilitates cancer cell growth and invasion through the DSG3-plakoglobin-TCF/LEF-Myc/cyclin D1/MMP signaling pathway.
PLoS One. 2013; 8(5):e64088 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
Desmoglein 3 (DSG3) is a component of the desmosome, which confers strong cell-cell adhesion. Previously, an oncogenic function of DSG3 has been found in head neck cancer (HNC). Here, we investigated how this molecule contributes to the malignant phenotype. Because DSG3 is associated with plakoglobin, we examined whether these phenotypic alterations were mediated through the plakoglobin molecule. Immunoprecipitation and immunofluorescence staining revealed that DSG3 silencing disrupted its interaction with plakoglobin and induced plakoglobin translocation from the cytoplasm to the nucleus. Knockdown of DSG3 significantly increased the interaction of plakoglobin with the transcriptional factor TCF and suppressed the TCF/LEF transcriptional activity. These effects further conferred to reduced expression of the TCF/LEF downstream target genes, including c-myc, cyclin D1, and MMP-7. Functional analyses showed that DSG3 silencing reduced cell growth and arrested cells at G0/G1 phase. Besides, cell migration and invasion abilities were also decreased. These cellular results were confirmed using tumor xenografts in mice, as DSG3 silencing led to the suppressed tumor growth, plakoglobin translocation and reduced expression of TCF/LEF target genes in tumors. Therefore, our study shows that the desmosomal protein DSG3 additionally functions to regulate malignant phenotypes via nuclear signaling. In conclusion, we found that DSG3 functions as an oncogene and facilitates cancer growth and invasion in HNC cells through the DSG3-plakoglobin-TCF/LEF pathway.

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