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1.  Site disparities in apoptotic variants as predictors of risk for second primary malignancy in patients with squamous cell carcinoma of the head and neck 
BMC Cancer  2016;16:70.
Background
FAS/FASL promoter variants are considered in altering transcriptional activity of those genes and consequently alter regulation of cell death. However, no studies have investigated whether tumor sites contribute to the association between FAS/FASL polymorphisms and risk for second primary malignancy (SPM).
Method
In this study, FAS670 A > G, FAS1377 G > A, FASL124 A > G, and FASL844C > T polymorphisms were genotyped in 752 OPC and 777 non-OPC patients. Both univariate and multivariable cox proportional hazard models were used to assess the associations.
Results
The univariate and multivariable analyses showed that patients with index OPC and FASL844 CT/TT genotype had significantly increased risk of SPM (cHR, 2.5; 95 % CI, 1.1–5.8, P = 0.043 and aHR, 2.7; 95 % CI, 1.2–6.0, P = 0.032) compared with those with FASL844 CC genotype as the reference group, while index non-OPC patients with FAS670 AG/GG and FasL844 CT/TT genotypes had significantly increased risk of SPM (cHR, 2.2 and 1.8; 95 % CI, 1.2–5.7 and 1.1–3.2; and P = 0.04 and 0.041, respectively and aHR, 2.4 and 1.7; 95 % CI, 1.1–5.1 and 1.0-3.0; and P = 0.043 and 0.049, respectively) compared with their corresponding AA and CC genotypes . Moreover, patients carrying more FAS/FASL variants significantly increased risk of SPM among index non-OPC patients. The stratified analysis showed that smoking status differently modified the associations between FAS/FASL polymorphisms and risk of SPM among index non-OPC from OPC patients.
Conclusion
These results suggested that FAS/FASL polymorphisms might significantly modify SPM risk among patients with SCCHN in a tumor site-specific manner.
doi:10.1186/s12885-016-2110-y
PMCID: PMC4746789  PMID: 26858129
FAS/FASLG; Squamous cell carcinoma of head and neck; Second primary malignancy; Susceptibility; Polymorphism; Oropharyngeal cancer; Nonoropharyngeal cancer
2.  Integrative enrichment analysis: a new computational method to detect dysregulated pathways in heterogeneous samples 
BMC Genomics  2015;16:918.
Background
Pathway enrichment analysis is a useful tool to study biology and biomedicine, due to its functional screening on well-defined biological procedures rather than separate molecules. The measurement of malfunctions of pathways with a phenotype change, e.g., from normal to diseased, is the key issue when applying enrichment analysis on a pathway. The differentially expressed genes (DEGs) are widely focused in conventional analysis, which is based on the great purity of samples. However, the disease samples are usually heterogeneous, so that, the genes with great differential expression variance (DEVGs) are becoming attractive and important to indicate the specific state of a biological system. In the context of differential expression variance, it is still a challenge to measure the enrichment or status of a pathway. To address this issue, we proposed Integrative Enrichment Analysis (IEA) based on a novel enrichment measurement.
Results
The main competitive ability of IEA is to identify dysregulated pathways containing DEGs and DEVGs simultaneously, which are usually under-scored by other methods. Next, IEA provides two additional assistant approaches to investigate such dysregulated pathways. One is to infer the association among identified dysregulated pathways and expected target pathways by estimating pathway crosstalks. The other one is to recognize subtype-factors as dysregulated pathways associated to particular clinical indices according to the DEVGs’ relative expressions rather than conventional raw expressions. Based on a previously established evaluation scheme, we found that, in particular cohorts (i.e., a group of real gene expression datasets from human patients), a few target disease pathways can be significantly high-ranked by IEA, which is more effective than other state-of-the-art methods. Furthermore, we present a proof-of-concept study on Diabetes to indicate: IEA rather than conventional ORA or GSEA can capture the under-estimated dysregulated pathways full of DEVGs and DEGs; these newly identified pathways could be significantly linked to prior-known disease pathways by estimated crosstalks; and many candidate subtype-factors recognized by IEA also have significant relation with the risk of subtypes of genotype-phenotype associations.
Conclusions
Totally, IEA supplies a new tool to carry on enrichment analysis in the complicate context of clinical application (i.e., heterogeneity of disease), as a necessary complementary and cooperative approach to conventional ones.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-2188-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-2188-7
PMCID: PMC4641376  PMID: 26556243
3.  Significance of MMP11 and P14ARF expressions in clinical outcomes of patients with laryngeal cancer 
Background: To evaluate the association of MMP11 and P14ARF expression in laryngeal squamous cell carcinoma (LSCC) with clinical pathological characteristics and survival. Methods: The mRNA and protein levels for both genes were determined in 65 LSCC patients. A log-rank test and Cox models were used to compare survival among different groups. Results: The mRNA expressions of MMP11 and P14ARF were significantly different between LSCC and their corresponding adjacent tissues (All P < 0.001). The expressions of MMP11 and P14ARF were correlated with several clinical characteristics (All P < 0.05). Patients with low MMP11 and high P14ARF expression had significantly better survival compared with those with high MMP11 and low P14ARF expression, respectively (All P < 0.05). The patients with surgery only had significantly better survival than those with chemoradiotherapy (log rank: P = 0.016), particularly in patients with low MMP11 and high P14ARF expression (log rank: P = 0.006). Furthermore, multivariable analysis showed that patients with low MMP11 and high P14ARF expression alone had a significantly reduced risk of death compared with those with high MMP11 and low P14ARF expression. The reduced risk for overall death was pronounced for patients with low and high expression of both genes (HR, 0.2; 95% CI, 0.1-0.5) compared with any other co-expression status of both genes, particularly for patients with surgery only (HR, 0.1; 95% CI, 0.0-0.9). Conclusion: These results suggest that altered expression of MMP11 and P14ARF in tumors may individually, or in combination, predict poor prognosis of LSCC, particularly for patients with surgery only.
PMCID: PMC4658941  PMID: 26629052
P14ARF; MMP11; LSCC; survival; biomarker
4.  Influence of Smoking History on Imaging Characteristics among HPV-Positive Oropharyngeal Cancer Patients: A Blinded Matched-Pair Analysis 
Background and Purpose
Human papillomavirus (HPV)-positive oropharyngeal cancers represent a distinct clinical entity with more favorable prognosis than HPV-negative oropharyngeal cancers. However, among patients with HPV-positive oropharyngeal carcinomas, those with a significant smoking history have a much worse prognosis. Recently, imaging characteristics of oropharyngeal cancers were identified as markers of poor prognosis. The purpose of this study was to determine whether nodal imaging characteristics differ between smokers and never/light smokers with HPV-positive oropharyngeal cancer.
Materials and Methods
Review of 130 pretreatment CT examinations of HPV-positive oropharyngeal cancers in smokers (>10 pack-years) and never/light smokers (≤10 pack-years) matched for T stage and tumor subsite was performed with the reviewing radiologist blinded to HPV status, smoking history, and clinical stage. An additional 24 pretreatment CT examinations of patients with HPV-negative oropharyngeal cancers were also reviewed in a blinded fashion. Imaging characteristics of metastatic nodal disease were compared using chi-square testing (Fisher exact testing where appropriate) and McNemar chi-square testing for the matched-pair analysis.
Results
As expected, those with HPV-positive oropharyngeal cancer were more likely to be younger, male, non-Hispanic white, never/former smokers, and never drinkers than those with HPV-negative oropharyngeal cancer. Furthermore, the HPV-positive oropharyngeal cancers were more likely to be in the tonsil, smaller T-category, higher N-category, poorly differentiated, tonsil primaries, smaller T-category, higher N-category, and poorly differentiated than HPV-negative oropharyngeal cancers. However, among the HPV-positive oropharyngeal cancers, we could identify no obvious difference in the pretreatment imaging characteristics of paired smokers and never/light smokers.
Conclusions
Among patients with HPV-positive oropharyngeal cancer, no imaging characteristics were identified to correlate with the critical prognostic feature smoking status. Cystic and necrotic nodal metastases, as described previously, were more common among patients with HPV-positive than HPV-negative oropharyngeal cancers. While cystic nodal metastases were more common among never/light smokers with HPV-positive oropharyngeal cancer than smokers with HPV-positive oropharyngeal cancer; however, because these results did not reach statistical significance, we conclude that imaging results cannot serve as a surrogate for an HPV-driven phenotype.
doi:10.1097/RCT.0000000000000100
PMCID: PMC4318505  PMID: 24943254
5.  Expression of purinergic receptor P2Y4 in Schwann cell following nerve regeneration 
Objective: Emerging evidences suggested an important role of purinergic receptor P2Y4 in nerve system. The present study aims to investigate the localization and possible function of P2Y4 receptor in recurrent laryngeal nerve (RLN) following regeneration. Methods: Right RLN of fifty Sprague-Dawley rats was cut and immediately repaired with PLGA/chitosan nerve conduit. Immunofluorescence, real-time qPCR and Western blot were used to detect the expression alterations of P2Y4 receptor. Results: Weak immunostaining signals of P2Y4 receptor were located on the plasmalemma of Schwann cell (SC) with regular arrangement of axons in normal RLN. On the post-injury 4th day, the sprouting axons regrowed along the degenerated SCs intensively expressing P2Y4 receptor. On the post-injury 7th day, the regenerating axons existed in multicellular cords of P2Y4 receptor-positive SCs occupying the nerve gap. On the post-injury 14th day, the axons grew along the bands of P2Y4 receptor-positive SCs exhibiting the regularly parallel distribution. On the post-injury 30th day, mild immunostaining signals of P2Y4 receptor still existed on SC surface, and the regenerated axons were located inside the remodeled endoneurium tube. In accordance with immunofluorescence findings, the transcription and protein expression levels of P2Y4 were significantly increased after the injury and the peak value appeared on the post-injury 7th day, compared to control group (P < 0.05). Conclusion: Data from the present study suggested a potential role of P2Y4 receptors in functional modulation of SCs in the regeneration of RLN.
PMCID: PMC4612929  PMID: 26550244
Purinergic receptor; Schwann cell; nerve regeneration; recurrent laryngeal nerve
6.  Laryngeal Neuroendocrine Carcinomas: A Retrospective Study of 14 Cases 
BioMed Research International  2015;2015:832194.
Laryngeal neuroendocrine carcinomas (LNECs) are rare and highly heterogeneous which present a wide spectrum of pathological and clinical manifestations. Fourteen patients with histologically demonstrated LNEC were collected and analyzed retrospectively. The 14 cases were classified into 3 subtypes: typical carcinoid in 2, atypical carcinoid in 5, and small cell neuroendocrine carcinoma in 7. The mean survival time of the 14 patients in this study was 112.5 months (95% CI, 81.5–143.6). Surgeries were performed for 2 patients of typical carcinoid, and they were alive with no evidence of recurrence after 24 and 47 months of follow-ups. Patients in the atypical carcinoid group were treated with surgeries and postoperative radiotherapy. After 58.4 months of follow-ups (range: 9–144), 2 patients showed no evidence of disease and 1 was lost to follow-up after 72 months. The other 2 patients died of other unrelated diseases. In the small cell neuroendocrine carcinoma group, a combination of chemotherapy and radiotherapy was applied. The mean survival time was 79.7 months (95% CI, 37.9–121.4), and the 5-year survival rate was 53.6%. In conclusion, the clinical behaviors, treatment protocols, and prognosis are different for each subtype of LNECs.
doi:10.1155/2015/832194
PMCID: PMC4518155  PMID: 26258144
7.  Unravelling personalized dysfunctional gene network of complex diseases based on differential network model 
In the conventional analysis of complex diseases, the control and case samples are assumed to be of great purity. However, due to the heterogeneity of disease samples, many disease genes are even not always consistently up-/down-regulated, leading to be under-estimated. This problem will seriously influence effective personalized diagnosis or treatment. The expression variance and expression covariance can address such a problem in a network manner. But, these analyses always require multiple samples rather than one sample, which is generally not available in clinical practice for each individual. To extract the common and specific network characteristics for individual patients in this paper, a novel differential network model, e.g. personalized dysfunctional gene network, is proposed to integrate those genes with different features, such as genes with the differential gene expression (DEG), genes with the differential expression variance (DEVG) and gene-pairs with the differential expression covariance (DECG) simultaneously, to construct personalized dysfunctional networks. This model uses a new statistic-like measurement on differential information, i.e., a differential score (DEVC), to reconstruct the differential expression network between groups of normal and diseased samples; and further quantitatively evaluate different feature genes in the patient-specific network for each individual. This DEVC-based differential expression network (DEVC-net) has been applied to the study of complex diseases for prostate cancer and diabetes. (1) Characterizing the global expression change between normal and diseased samples, the differential gene networks of those diseases were found to have a new bi-coloured topological structure, where their non hub-centred sub-networks are mainly composed of genes/proteins controlling various biological processes. (2) The differential expression variance/covariance rather than differential expression is new informative sources, and can be used to identify genes or gene-pairs with discriminative power, which are ignored by traditional methods. (3) More importantly, DEVC-net is effective to measure the expression state or activity of different feature genes and their network or modules in one sample for an individual. All of these results support that DEVC-net indeed has a clear advantage to effectively extract discriminatively interpretable features of gene/protein network of one sample (i.e. personalized dysfunctional network) even when disease samples are heterogeneous, and thus can provide new features like gene-pairs, in addition to the conventional individual genes, to the analysis of the personalized diagnosis and prognosis, and a better understanding on the underlying biological mechanisms.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0546-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0546-5
PMCID: PMC4467679  PMID: 26070628
Gene expression; Expression variance; Precision medicine; Gene network; Network biomarker; Disease heterogeneity; Edge biomarker
8.  Association of OPN overexpression with tumor stage, differentiation, metastasis and tumor progression in human laryngeal squamous cell carcinoma 
Background: Osteopontin (OPN) is overexpressed in many human tumors and involved in promotion of cancer cells by regulating various facets of tumor progression such as cell proliferation, invasion and metastasis. To understand roles of OPN in tumor progression of laryngeal squamous cell carcinoma (LSCC) or develop molecular marker for prognosis and treatment of LSCC, we thus explore biological function of OPN and correlation with p53 in LSCC. Methods: The expression of OPN and p53 in tumor tissues of LSCC was determined immunohistochemically in both LSCC and adjacent normal tissues. Lentivirus vector with RNAi small hairpin gene sequence of OPN (named LV-shOPN) was transfected into Hep-2 cells. OPN expression was detected by Western blotting assay and the viability and invasive ability of Hep-2 cells were examined by MTS and transwell assay. Results: We found that OPN and p53 protein expressions were significantly higher in LSCC tumor tissues than adjacent normal tissues (76.2% vs. 23.8% for OPN and 63.8% vs. 15.2% for p53, all P < 0.001). OPN expression was also significantly correlated with p53 expression, tumor stage, grade and the presence of lymph node. The constructed LV-shOPN effectively inhibited the OPN expression, viability and invasive ability of Hep-2 cells (all P < 0.050). Conclusion: Taken together, OPN is overexpressed in LSCC. OPN expression is correlated with p53 expression, tumor progression and lymph node metastasis. Additionally, RNAi silencing of OPN expression can significantly inhibit tumor viability and invasion ability of Hep-2 cells. Thus, OPN may be considered as a marker and potential gene targeting therapy in LSCC.
PMCID: PMC4509194  PMID: 26221249
Osteopontin; p53; RNA interference; laryngeal squamous cell carcinoma
9.  Genetic variants in TNF-α promoter are predictors of recurrence in patients with squamous cell carcinoma of oropharynx after definitive radiotherapy 
The promoter variants of TNF-α, a major regulator of immune and inflammation responses, have been implicated in cancer development and prognosis. Thus, we investigated associations between four TNF-α promoter variants and risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated associations of four TNF-α polymorphisms with risk of recurrence in a cohort of 846 patients with SCCOP. Log-rank test and multivariable Cox models were used to evaluate associations. Compared with patients with variant genotypes of the TNF-α −308 and TNF-α −863 polymorphisms, patients with common homozygous genotypes had worse disease-free survival (log-rank P = 0.0002 and P < 0.0001, respectively) and increased risk of SCCOP recurrence (HR, 1.9, 95% CI, 1.3–2.8 and HR, 1.9, 95% CI, 1.3–2.7, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of the TNF-α −308 and −863 polymorphisms had worse disease-free survival (log-rank P = 0.005 and P = 0.007, respectively) and higher recurrence risk than patients with variant genotypes of these polymorphisms (HR, 5.1, 95% CI, 1.4–18.4 and HR, 3.7, 95% CI, 1.5–9.1, respectively), while no such significant associations were found for TNF-α −857 or −1031 polymorphisms. Our findings suggest that TNF-α −308 and −863 polymorphisms may modulate the risk of SCCOP recurrence in patients with HPV16-positive tumors. However, larger studies are needed to validate these results.
doi:10.1002/ijc.28512
PMCID: PMC3947426  PMID: 24122460
TNF-α variant; recurrence; genetic polymorphisms; biomarkers; human papillomavirus; head and neck cancer; oropharyngeal cancer
10.  Gene microarray analysis of lncRNA and mRNA expression profiles in patients with hypopharyngeal squamous cell carcinoma 
Background: Studies have shown that long noncoding RNAs (lncRNAs) are involved in the development and progression of many types of cancer. However, the mechanisms by which lncRNAs influence development and progression of hypopharyngeal squamous cell carcinoma (HSCC) are unclear. Method: We investigated differences in lncRNA and mRNA expression profiles between 3 pairs of HSCC tissues and adjacent nontumor tissues by microarray analysis. Results: In HSCC tissues, 1299 lncRNAs were significantly upregulated (n=669) or downregulated (n=630) compared to levels in adjacent nontumor tissues. Moreover, 1432 mRNAs were significantly upregulated (n=684) or downregulated (n=748) in HSCC tissues. We randomly selected 2 differentially expressed lncRNAs (AB209630, AB019562) and 2 differentially expressed mRNAs (SPP1, TJP2) for confirmation of microarray results using qRT-PCR. The qRT-PCR results matched well with the microarray data. The differentially expressed lncRNAs and mRNAs were distributed on each of the chromosomes, including the X and Y chromosomes. Pathway analysis indicated that the biological functions of differentially expressed mRNAs were related to 48 cellular pathways that may be associated with HSCC development. GO analysis revealed that 593 mRNAs involved in biological processes, 50 mRNAs involved in cellular components, and 46 mRNAs involved in molecular functions were upregulated in the carcinomas; 280 mRNAs involved in biological processes, 58 mRNAs involved in cellular components, and 71 mRNAs involved in molecular functions were downregulated in the carcinomas. In addition, 8 enhancer-like lncRNAs and 21 intergenic lncRNAs with their adjacent mRNA pairs were identified as coregulated transcripts. Conclusion: These findings provide insight into the mechanisms underlying HSCC tumorigenesis and will facilitate identification of new therapeutic targets and diagnostic biomarkers for this disease.
PMCID: PMC4483811  PMID: 26131061
Hypopharyngeal squamous cell carcinoma; lncRNA; mRNA; microarray; expression profile
11.  Lateral tarsal artery flap: an option for hypopharyngeal reconstruction in patients with hypopharyngeal carcinomas after surgery 
Background: Hypopharyngeal reconstruction following resection of hypopharyngeal carcinoma has utilized local, regional and free tissue transfer flap options. No single surgical technique is currently in use for hypopharyngeal reconstruction that is applicable to all patients. In this article, we introduce the application of the lateral tarsal artery flap (LTA flap) as a reconstructive option following hypopharyngeal oncologic ablation. Methods: From June 2010 to January 2012, four patients of hypopharyngeal carcinomas underwent total laryngectomy and partial pharyngectomy followed by single-stage reconstruction with LTA flaps. After operation, patients were treated with radical radiotherapy within four weeks. All the patients were followed up. Results: All flaps survived, with an average size of 7.5 cm × 5.8 cm (range of 8.0-7.0 cm × 6.0-5.0 cm). There were no complications or contractures during the follow-up. Normal diets were adopted two weeks after operation. The follow-up ranged from 12-20 months (mean: 15 months). There were no distal stenosis or pharyngocutaneous fistula nor were there any donor-site complications. Conclusion: The LTA flap could be a viable option for hypopharyngeal reconstruction following head and neck oncologic resection. It seems that LTA flap would be a promising flap deserving extensively research.
PMCID: PMC4483898  PMID: 26131060
Lateral tarsal artery flap; free flaps; head and neck reconstruction; hypopharyngeal carcinoma
12.  Clinicopathologic significance and survival of TIP30 expression in laryngeal squamous cell carcinoma 
Background: The expression and clinical significance of TIP30 and p53 in laryngeal squamous cell carcinoma (LSCC) have not been investigated. Method: We determined immunohistochemically the expression of TIP30 and p53 in surgical specimens from 105 patients with LSCC. Survivals were estimated using the Kaplan-Meier method. Results: TIP30 protein expression in LSCC patients was significantly less in tumor tissues than that of adjacent normal tissues (46.7% vs. 79.0%), while p53 protein expression was significantly increased in LSCC (15.2% vs. 63.8%) compared with adjacent normal tissues. The TIP30 expression levels were also significantly correlated with tumor stage, differentiation, and the presence of lymph nodes. The expression of TIP30 was significantly negatively correlated with that of p53 (r = -0.249, P = 0.010). LSCC patients with lower expression level of TIP30 had a significantly higher recurrence and worse overall survival than those with elevated TIP30 expression (P = 0.014 and P = 0.040, respectively). Furthermore, multivariable analysis found that patients with high expression of TIP30 had a greater than approximately 2.2-fold increased risk for death overall or recurrence than those with low expression of TIP30, supporting that down-regulation of TIP30 expression in tumors may involve in development and progression and predict poor prognosis of patients with LSCC. Conclusion: Our results may suggest that down-expression of TIP30 is closely related to carcinogenesis, progression, biological behavior, and prognosis of LSCC.
PMCID: PMC4484035  PMID: 26131199
Laryngeal squamous carcinoma; TIP30; p53; survival
13.  Bridger: a new framework for de novo transcriptome assembly using RNA-seq data 
Genome Biology  2015;16(1):30.
We present a new de novo transcriptome assembler, Bridger, which takes advantage of techniques employed in Cufflinks to overcome limitations of the existing de novo assemblers. When tested on dog, human, and mouse RNA-seq data, Bridger assembled more full-length reference transcripts while reporting considerably fewer candidate transcripts, hence greatly reducing false positive transcripts in comparison with the state-of-the-art assemblers. It runs substantially faster and requires much less memory space than most assemblers. More interestingly, Bridger reaches a comparable level of sensitivity and accuracy with Cufflinks. Bridger is available at https://sourceforge.net/projects/rnaseqassembly/files/?source=navbar.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-015-0596-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-015-0596-2
PMCID: PMC4342890  PMID: 25723335
14.  Functional characterization of OPN in human laryngeal squamous cell carcinoma and its xenograft model in nude mice 
Background: Osteopontin (OPN) is involved in promotion of cancer cells by regulating various facets of tumor progression such as cell proliferation, angiogenesis and metastasis. To understand the role of OPN in laryngeal squamous cell carcinoma (LSCC), we thus explored the biological function of OPN in LSCC after silencing OPN expression by RNA interference (RNAi). Method: The OPN expression in tumor tissues of LSCC was determined immunohistochemically in both LSCC and adjacent normal tissues. Lentivirus vector with RNAi small hairpin gene sequence of OPN (named LV-shOPN) was transfected into Hep-2 cells and transplanted into BALB/c-nu mice. After siRNA transfection, the viability of Hep-2 cells was examined by MTS, OPN expression was detected by Western blotting, and tumor angiogenesis was assessed by microvessel densities (MVD). Results: The difference of positive rate of OPN in 72 cases LSCC (54 cases, 75.0%) and adjacent normal tissues (15 cases, 20.8%) was statistically significant (P<0.001) and the OPN expression was also significantly correlated with tumor stage, grade and the presence of lymph node. Hep-2 cells infected with LV-shOPN significantly decreased OPN expression, in comparison to cells with LV-shNon transfection (as the control) (P<0.05). The constructed LV-shOPN effectively inhibited the viability of Hep-2 cell and growth of xenograft tumors in nude mice (all P<0.050). The expression of OPN and MVD was significantly decreased in xenograft tumors (all P<0.05). Conclusion: RNAi silencing of OPN expression can significantly inhibit tumor growth and angiogenesis of Hep-2 cells, and OPN may be considered as one of gene targeting therapy for LSCC.
PMCID: PMC4358440  PMID: 25784985
Osteopontin; RNA interference; laryngeal neoplasms; nude mice; laryngeal squamous cell carcinoma
15.  Potentially functional variants of p14 ARF are associated with HPV-positive oropharyngeal cancer patients and survival after definitive chemoradiotherapy 
Carcinogenesis  2013;35(1):62-68.
Since p14 ARF and human papillomavirus (HPV) 16 E6/E7 oncoproteins are important regulators participating in the p53/Rb pathways, genetic variations of p14 ARF may modify tumor HPV16 status and survival of HPV16-positive squamous cell carcinoma of the oropharynx (SCCOP) patients. We determined tumor HPV16 status and expression of p14/p53 and genotyped p14 ARF-rs3731217 and -rs3088440 polymorphisms in 552 incident SCCOP patients. We found that patients having variant genotypes for each p14 ARF polymorphism were approximately two or three times as likely to have HPV16-positive tumors compared with patients with corresponding common homozygous genotype, and such an association was particularly pronounced in patients with variant genotypes of both polymorphisms. After definitive chemoradiotherapy, patients having p14 ARF rs3731217 TG/GG variant genotypes had significantly better overall, disease-specific and disease-free survival than those having TT genotype, respectively. Multivariable analysis found that patients with p14 ARF-rs3731217 TT genotype had an ~7-, 11- and 3-fold increased risk for death overall, death due to SCCOP and recurrence than those with TG/GG variant genotypes, respectively. Furthermore, such significantly prognostic effect was also found when survival analysis was limited to HPV16-positive patients. Additionally, potentially functional relevance of the two variants was characterized to explore the genotype–phenotype correlation. Our findings indicate p14 ARF variants may predict tumor HPV16-positive SCCOP patients and survival.
doi:10.1093/carcin/bgt336
PMCID: PMC3871940  PMID: 24104554
16.  MicroRNA-503 Acts as a Tumor Suppressor in Osteosarcoma by Targeting L1CAM 
PLoS ONE  2014;9(12):e114585.
Deregulated microRNAs and their roles in tumorigenesis have attracted much attention in recent years. Although miR-503 was shown to be important in tumorigenesis, its role in osteosarcoma remains unknown. In this study, we focused on the expression and mechanisms of miR-503 in osteosarcoma development. We found that miR-503 was down-regulated in osteosarcoma cell lines and primary tumor samples, and the restoration of miR-503 reduced cell proliferation, migration and invasion. Low level of miR-503 in patients with osteosarcoma was associated with considerably shortened disease-free survival. Furthermore, bioinformatic prediction and experimental validation revealed that the anti-tumor effect of miR-503 was probably exerted through targeting and repressing of L1CAM expression. L1CAM was up-regulated in osteosarcoma cell lines and primary tumor samples and the expression level of L1CAM were negatively correlated with miR-503 levels in osteosarcoma tissues. Collectively, our data identify the important roles of miR-503 in osteosarcoma pathogenesis, indicating its potential application in cancer therapy.
doi:10.1371/journal.pone.0114585
PMCID: PMC4275157  PMID: 25536034
17.  Association of TBX2 and P21 expression with clinicopathological features and survival of laryngeal squamous cell carcinoma 
Background: The expression of P21 and TBX2 in laryngeal squamous cell carcinoma (LSCC) and their corresponding adjacent normal laryngeal tissues, as well as their association with clinical pathological features and survival remain unclear. Method: we used the RT-PCR and immunohistochemistry to detect their mRNA and protein levels in 75 LSCC patients. We also use log-rank test and Cox models to compare survival among different groups. Results: The mRNA expression level of TBX2 was up-regulated, while P21 was down-regulated in LSCC compared with their matched adjacent laryngeal tissues (All P < 0.001). The expression of P21 was correlated with tumor stage, lymph node metastasis and smoking; and TBX2 expression was associated with lymph node metastasis, differentiation degree and smoking (All P < 0.05). Patients with high TBX2 and low P21 expression had significantly worse survival than those with low TBX2 and high P21 expression, respectively (All P < 0.05). A significant correlation between expression of TBX2 and P21 (Pearson, P < 0.05) was observed. Furthermore, multivariable analysis showed that patients with low TBX2 and high P21 expression alone had a significantly reduced risk for overall death compared with those with low TBX2 and high P21 expression. The risk for overall death was even lower for patients with both low and high expression of both genes than any other co-expression status of both genes (HR, 0.1; 95% CI, 0.0-0.9). Conclusion: These results suggest that abnormal expression of P21 and TBX2 in tumors may jointly, or individually, predict poor prognosis of LSCC.
PMCID: PMC4307495  PMID: 25664048
P21; TBX2; LSCC; survival
18.  Mechanisms of methotrexate resistance in osteosarcoma cell lines and strategies for overcoming this resistance 
Oncology Letters  2014;9(2):940-944.
The aim of the present study was to investigate the underlying mechanisms of methotrexate (MTX) resistance in the human osteosarcoma cell line, Saos-2/MTX4.4, and to evaluate various methods of overcoming the resistance to this chemotherapeutic agent. MMT assays were performed to determine the resistance of the primary (Saos-2) and resistant (Saos-2/MTX4.4) cell lines to MTX, cisplatin [cis-diamminedichloroplatinum II (DDP)], ifosfamide (IFO), Adriamycin (ADM), epirubicin (EPI) and theprubicin (THP). The Saos-2/MTX4.4 cells exhibited a low resistance to IFO, ADM, EPI and THP; however, no resistance to DDP was identified. Overall, the Saos-2/MTX4.4 cells exhibited a greater resistance to all the chemotherapeutic agents investigated compared with the Saos-2 cells. Rhodamine 123 (R123) fluorescence was measured in the Saos-2/MTX4.4 and Saos-2 cells 30 and 60 min after the addition of R123, and R123 plus verapamil (VER). VER administration increased the intracellular accumulation of R123. In addition, reverse transcription-quantitative polymerase chain reaction was performed to determine the mRNA expression levels of multidrug resistance gene 1 (MDR1) in the two cell lines. Although the Saos-2/MTX4.4 cells were more resistant to the chemotherapeutic agents than the Saos-2 cells, no significant difference was identified between the relative mRNA expression levels of MDR1 in the Saos-2/MTX4.4 and Saos-2 cells (0.4350±0.0354 vs. 0.3886±0.0456; P>0.05).
doi:10.3892/ol.2014.2773
PMCID: PMC4301490  PMID: 25621072
osteosarcoma cell lines; drug resistance; methotrexate; overcoming resistance
19.  Human Papillomavirus and WHO Type I Nasopharyngeal Carcinoma 
The Laryngoscope  2010;120(10):1990-1997.
Objectives
Nasopharyngeal carcinoma (NPC) is a rare cancer in the United States. An association between NPC and Epstein-Barr virus (EBV) is well-established for World Health Organization (WHO) types II and III (WHO-II/III) NPC but less well-established for WHO type I (WHO-I) NPC. Given the rise in oropharyngeal tumors positive for high-risk human papillomavirus (HPV) and the unique biology of WHO-I NPC, we examined the relationship between HPV and WHO-I NPC.
Study Design
Retrospective case-comparison study.
Methods
A search of a large multidisciplinary cancer center tumor registry identified 183 patients seen from January 1999 to December 2008 with incident NPC and no prior cancer. Available paraffin-embedded tumor specimens (N=30) were analyzed for oncogenic HPV status by in-situ hybridization (ISH) and polymerase chain reaction (PCR) for HPV-16 and HPV-18; EBV status by ISH; and p16 expression by immunohistochemistry. Demographic parameters, including race and smoking, were obtained from the medical records.
Results
Among the 18 WHO-I NPC patients, 66% (N=12) were smokers and 17% (N=3) Asian; among the 165 WHO-II/III NPC patients, 44% (N=73) were smokers and 24% (N=39) Asian. Eight WHO-I NPC patients had available paraffin blocks; 5 of 6 were HPV-16-positive by PCR and 4 of 8 were HPV-positive by ISH; only 2 of 8 (25%) were EBV-positive. Twenty-two WHO-II/III NPC patients had available paraffin blocks; only 1 was HPV-positive by ISH, and 13 of 22 (60%) were EBV-positive.
Conclusions
These results suggest that WHO-I NPC is associated with oncogenic HPV, though larger studies are needed to verify these findings.
doi:10.1002/lary.21089
PMCID: PMC4212520  PMID: 20824783
Human papillomavirus; Nasopharyngeal Carcinoma; WHO Type; In-situ hybridization; Polymerase chain reaction
20.  eMBI: Boosting Gene Expression-based Clustering for Cancer Subtypes 
Cancer Informatics  2014;13(Suppl 2):105-112.
Identifying clinically relevant subtypes of a cancer using gene expression data is a challenging and important problem in medicine, and is a necessary premise to provide specific and efficient treatments for patients of different subtypes. Matrix factorization provides a solution by finding checker-board patterns in the matrices of gene expression data. In the context of gene expression profiles of cancer patients, these checkerboard patterns correspond to genes that are up- or down-regulated in patients with particular cancer subtypes. Recently, a new matrix factorization framework for biclustering called Maximum Block Improvement (MBI) is proposed; however, it still suffers several problems when applied to cancer gene expression data analysis. In this study, we developed many effective strategies to improve MBI and designed a new program called enhanced MBI (eMBI), which is more effective and efficient to identify cancer subtypes. Our tests on several gene expression profiling datasets of cancer patients consistently indicate that eMBI achieves significant improvements in comparison with MBI, in terms of cancer subtype prediction accuracy, robustness, and running time. In addition, the performance of eMBI is much better than another widely used matrix factorization method called nonnegative matrix factorization (NMF) and the method of hierarchical clustering, which is often the first choice of clinical analysts in practice.
doi:10.4137/CIN.S13777
PMCID: PMC4213194  PMID: 25374455
matrix factorization; biclustering; microarray analysis; cancer classification; iterative method; consensus clustering
21.  Telomere length in peripheral blood lymphocytes contributes to the development of HPV-associated oropharyngeal carcinoma 
Cancer research  2013;73(19):5996-6003.
Sexual transmission of human papillomavirus, particularly HPV16, has been associated with an increasing incidence of oropharyngeal squamous cell carcinoma (OPC). Telomere shortening results in chromosomal instability, subsequently leading to cancer development. Given that HPV16 can affect telomerase activity and telomere length (TL), we conjectured that TL in peripheral blood lymphocytes (PBLs) may affect the risk of HPV16-associated OPC and tumor HPV16 status in patients. TL in PBLs and HPV16 serological status were measured in peripheral blood samples in 188 patients with OPC, 137 patients with oral cavity cancer (OCC) and 335 controls of non-Hispanic whites. Tumor HPV status was determined in 349 OPC cases. Odds ratios and 95% confidence intervals were calculated in univariate and multivariable logistic regression models. Overall, compared with long TL, short TL was associated significantly with a moderately increased risk of OPC but no increased risk of OCC. When we stratified the data by HPV16 serological status, using long TL and HPV16 seronegativity as the reference group, we found that the risk associated with HPV16 seropositivity was higher among OPC patients with short TL. Notably, such risk was particularly pronounced in never smokers, never drinkers and those >50 years of age. Furthermore, short TL was also associated significantly with tumor HPV-positive OPC. Together, our findings suggest that TL in PBLs may be associated with higher risk of HPV16-associated OPC and tumor HPV16 status, particularly in certain patient subgroups. Larger studies are needed to validate these findings.
doi:10.1158/0008-5472.CAN-13-0881
PMCID: PMC3790860  PMID: 23928994
telomere length; HPV; molecular epidemiology; oropharyngeal cancer
22.  Differences in Imaging Characteristics of HPV-Positive and HPV-Negative Oropharyngeal Cancers: A Blinded Matched-Pair Analysis 
BACKGROUND AND PURPOSE
Human papillomavirus–positive oropharyngeal cancers typically have younger age of onset, limited tobacco exposure, and more favorable prognosis than HPV-negative oropharyngeal cancers. We assessed whether HPV-positive and HPV-negative oropharyngeal cancers have consistent differences in pretreatment imaging characteristics.
MATERIALS AND METHODS
A retrospective review of 136 pretreatment CT examinations of paired HPV-positive and HPV-negative oropharyngeal cancers matched for T stage, tumor subsite, and smoking status was performed with the reviewing radiologist blinded to HPV status and clinical stage. Demographic/clinical characteristics and imaging characteristics of primary lesions and metastatic nodal disease were compared by use of Fisher exact testing. The McNemar χ2 test was used for the matched-pair analysis.
RESULTS
By imaging, HPV-negative tumors were more likely to demonstrate invasion of adjacent muscle (26% versus 6%, P = .013). HPV-positive primary tumors were more likely to be enhancing and exophytic with well-defined borders, whereas HPV-negative primary tumors were more likely to be isoattenuated and demonstrate ill-defined borders, though these results were not statistically significant. HPV-positive tumors were more likely to demonstrate cystic nodal metastases than HPV-negative tumors (36% versus 9%, P = .002).
CONCLUSIONS
In this matched and blinded analysis of the imaging differences between HPV-positive and HPV-negative oropharyngeal cancers, HPV-positive carcinomas often had primary lesions with well-defined borders and cystic nodal metastases, whereas HPV-negative primaries more often had poorly defined borders and invasion of adjacent muscle.
doi:10.3174/ajnr.A3524
PMCID: PMC3951375  PMID: 23660291
23.  Surgical management of cervical esophageal carcinoma with larynx preservation and reconstruction 
Objectives: There is no generally accepted treatment strategy for cervical esophageal carcinoma. The purpose of this study was to evaluate the operative outcomes of reconstruction after resection of cervical esophageal and hypopharynx-esophagus junction carcinoma with larynx preservation. Methods: We retrospectively reviewed the data of 79 patients with carcinoma of the hypopharynx-esophagus junction and cervical esophagus. Transhiatal total esophagectomy without thoracotomy was carried out in 67 patients who underwent gastric pull-up (GP) or colon interposition (CI) techniques. Transcervical limited pharyngo-cervical esophagectomy was performed in the patients with the pectoralis major flap alone or combined with the split graft (PMF/CWSG) for reconstruction. Seventy-two patients received postoperative adjuvant therapy. Results: The 3-year and 5-year overall survival rates were 66.4% and 45.5%, respectively. The average time to resumption of oral feeding was 25.2 days. All patients had preserved laryngeal function. The overall incidence of complications was 29.1% (23/79), which included cervical fistula, abdominal wound dehiscence, liquefaction necrosis of abdominal fat, and pleural effusion. Conclusions: Surgical resection of cervical esophageal carcinoma and laryngeal preservation is possible. Complete esophagectomy should be performed when the resection extends below the thoracic inlet. The reconstruction methods we performed were safe and effective for the immediate restoration of alimentary continuity after resection of cervical esophageal and pharyngo-cervical esophageal carcinoma; and the patients with PMF/CWSG reconstruction had a better survival than those with GP or CI reconstruction. Combined with radiotherapy, the resectability rate and survival rate of cervical esophageal carcinoma can be improved.
PMCID: PMC4211788  PMID: 25356138
Carcinoma; cervical esophagus; gastric pull-up; colon interposition; larynx preservation; oral cancer
24.  Comparison of neuroendocrine differentiation and KRAS/NRAS/BRAF/PIK3CA/TP53 mutation status in primary and metastatic colorectal cancer 
Neuroendocrine differentiation of tumor tissue has been recognized as an important prerequisite for new targeted therapies. To evaluate the suitability of colorectal cancer (CRC) tissue for these treatment approaches and to find a possible link to pretherapeutic conditions of other targeted strategies, we compared neuroendocrine differentiation and KRAS/NRAS/BRAF/PIK3CA/TP53 mutational status in primary and metastatic CRC. Immunohistochemical expression analysis of neuroendocrine markers chromogranin A and synaptophysin was performed on archival CRC tissue, comprising 116 primary tumors, 258 lymph node metastases and 72 distant metastases from 115 patients. All CRC samples but 30 distant metastases were subjected to mutation analysis of KRAS, NRAS, BRAF, PIK3CA, and TP53. Neuroendocrine marker expression was found significantly less frequently in lymph node metastases compared to primary tumors and distant metastases (20%, 31%, 28%, respectively, P = 0.044). KRAS mutation rates increased significantly from primary tumors to lymph node metastases and distant metastases within the neuroendocrine negative CRC group (44%, 53%, 64%, respectively, P = 0.042). Neuroendocrine differentiation was significantly less concordant than KRAS/NRAS/BRAF/PIK3CA/TP53 mutational status in primary tumor/lymph node metastases pairs (65% versus 88%-99%; P < 0.0001) and primary tumor/distant metastases pairs (64% versus 83%-100%; P = 0.027 and P < 0.0001, respectively). According to these data, therapeutic targeting of neuroendocrine tumor cells can be considered only for a subset of CRC patients and biopsies from the metastatic site should be used to guide therapy. A possible importance of lacking neuroendocrine differentiation for progression of KRAS mutant CRC should be further investigated.
PMCID: PMC4203208  PMID: 25337237
Neuroendocrine differentiation; KRAS mutations; colorectal cancer
25.  Occupational Exposure to Welding Fume among Welders: Alterations of Manganese, Iron, Zinc, Copper, and Lead in Body Fluids and the Oxidative Stress Status 
Welders in this study were selected from a vehicle manufacturer; control subjects were from a nearby food factory. Airborne manganese levels in the breathing zones of welders and controls were 1.45 ± SD1.08 mg/m3 and 0.11 ± 0.07 μg/m3, respectively. Serum levels of manganese and iron in welders were 4.3-fold and 1.9-fold, respectively, higher than those of controls. Blood lead concentrations in welders increased 2.5-fold, whereas serum zinc levels decreased 1.2-fold, in comparison with controls. Linear regression revealed the lack of associations between blood levels of five metals and welder’s age. Furthermore, welders had erythrocytic superoxide dismutase activity and serum malondialdehyde levels 24% less and 78% higher, respectively, than those of controls. These findings suggest that occupational exposure to welding fumes among welders disturbs the homeostasis of trace elements in systemic circulation and induces oxidative stress.
PMCID: PMC4126160  PMID: 15091287

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