16 results on '"Michikawa C"'
Search Results
2. Classification of extracapsular spread of the lymph node metastasis in oral cancer
- Author
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Michikawa, C., Uzawa, N., Izumo, T., Yamaguchi, A., and Harada, K.
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- 2013
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3. Clinical significance of lymphatic and blood vessel invasion in oral tongue squamous cell carcinomas.
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Michikawa C, Uzawa N, Kayamori K, Sonoda I, Ohyama Y, Okada N, Yamaguchi A, and Amagasa T
- Abstract
Although vascular invasion (VI) is recognized as an important predictor of lymph node metastasis and a significant prognostic factor in head and neck squamous cell carcinoma (HNSCC), there is currently no common definition for the pathological evaluation of VI status. We reviewed the medical records of 63 consecutive resected primary oral tongue SCCs (OTSCCs) without preoperative treatment between June 1999 and April 2008, and evaluated VI status by investigating lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) by using immunohistochemistry (IHC) with monoclonal antibody D2-40 (D2-40) and Elastica van Gieson (EVG) staining, respectively. Subsequently, we analyzed their correlations with cervical lymph node metastasis and prognosis. LVI was found in 16 of the 63 tumors (25.4%) and BVI was in 32 tumors (50.8%). Univariate analysis revealed that the presence of LVI is statistically correlated with lymph node metastasis. Moreover, multivariate logistic regression analysis revealed that LVI is an independent risk factor of nodal metastasis (odds ratio=4.262, 95% confidence interval=1.262-14.397, p=0.020). In contrast, Kaplan-Meier survival analysis revealed that patients with BVI had a significantly shorter disease-free survival (DFS) and overall survival (OS) rates than those without BVI (68.6% versus 90.3%, p=0.028 and 68.6% versus 93.5%, p=0.013, respectively). The present study clearly demonstrated that LVI at primary OTSCC had significant correlation with lymph node metastasis, and that BVI was significantly associated with recurrence and poor prognosis. Evaluation of VI status, as LVI and BVI status separately, using IHC with D2-40 and EVG staining may be useful in predicting lymph node metastasis and poor prognosis in OTSCCs. [ABSTRACT FROM AUTHOR]
- Published
- 2012
4. Epidermal growth factor receptor gene copy number aberration at the primary tumour is significantly associated with extracapsular spread in oral cancer.
- Author
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Michikawa, C., Uzawa, N., Sato, H., Ohyama, Y., Okada, N., and Amagasa, T.
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EPIDERMAL growth factor , *ORAL cancer , *SQUAMOUS cell carcinoma , *FLUORESCENCE in situ hybridization , *LYMPH nodes - Abstract
Background: Extracapsular spread (ECS) of lymph node metastasis in head and neck cancers, including oral squamous cell carcinomas (OSCCs), is known to reflect tumour aggressiveness, and is significantly associated with high rates of loco-regional recurrence, distant metastasis, and poor outcome. The purpose of this study was to confirm ECS as an important prognostic indicator and to determine the significant factors associated with ECS in OSCCs.Methods: We investigated the incidence of ECS and impact of ECS on survival in 127 OSCC patients. To determine the factors significantly correlated with ECS, we examined many factors, including the clinicopathological features of primary tumours, lymph node metastasis, and copy number aberrations of the cyclin D1 gene (CCND1) and epidermal growth factor receptor gene (EGFR) at primary tumours, and evaluated the value of predicting the risk of ECS of the metastatic lymph node.Results: Kaplan-Meier and multivariate disease-free and overall survival analysis clearly demonstrated that ECS is an independent prognostic factor in OSCCs. Moreover, logistic regression analysis showed that the number of pathologically positive nodes and copy number aberrations of EGFR at the primary tumour are independent predictors of ECS.Conclusions: The findings suggest that ECS is an independent prognostic factor in OSCCs. Moreover, the number of pathologically positive lymph nodes and EGFR numerical aberrations of the primary tumour were also shown to be excellent predictors of ECS in OSCCs. Preoperative evaluation of EGFR numerical aberrations might therefore be a useful tool for selecting patients at high risk of ECS, who would benefit from targeted aggressive multimodality therapy. [ABSTRACT FROM AUTHOR]- Published
- 2011
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5. Chick Embryo Chorioallantoic Membrane as a Platform for Assessing the In Vivo Efficacy of Chimeric Antigen Receptor T-cell Therapy in Solid Tumors.
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Nipper AJ, Warren EAK, Liao KS, Liu HC, Michikawa C, Porter CE, Wells GA, Villanueva M, Brasil da Costa FH, Veeramachaneni R, Villanueva H, Suzuki M, and Sikora AG
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- Animals, Chick Embryo, Humans, Cell Line, Tumor, Xenograft Model Antitumor Assays, T-Lymphocytes immunology, T-Lymphocytes metabolism, Mice, Neoplasms therapy, Neoplasms immunology, Female, Chorioallantoic Membrane, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen metabolism, Receptor, ErbB-2 metabolism, Immunotherapy, Adoptive methods
- Abstract
The fertilized chicken egg chorioallantoic membrane (CAM), a highly vascularized membrane nourishing the developing embryo, also supports rapid growth of three-dimensional vascularized tumors from engrafted cells and tumor explants. Because murine xenograft models suffer limitations of time, cost, and scalability, we propose CAM tumors as a rapid, efficient screening tool for assessing anti-tumor efficacy of chimeric Ag receptor (CAR) T cells against solid tumors. We tested the efficacy of human epidermal growth factor receptor 2 (HER2)-specific CAR T cells against luminescent, HER2-expressing (FaDu, SCC-47) or HER2-negative (MDA-MB-468) CAM-engrafted tumors. Three days after tumor engraftment, HER2-specific CAR T cells were applied to tumors grown on the CAM. Four days post-CAR T cell treatment, HER2-expressing FaDu and SCC-47 tumors treated with CAR T showed reduced viable cancer cells as assessed by luciferase activity. This reduction in viable tumor cells was confirmed by histology, with lower Ki-67 staining observed in CAR T cell-treated tumors relative to T cell-treated controls. Persistence of CAR T in CAM and tumor tissue 4 days post-treatment was confirmed by CD3 staining. Altogether, our findings support further development of the chick CAM as an in vivo system for rapid, scalable screening of CAR T cell efficacy against human solid tumors., (Copyright © 2024 The Authors.)
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- 2024
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6. Immune infiltration at the primary tumor is associated with clinical outcome of patients with extranodal extension of lymph node metastasis in oral cancer.
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Michikawa C, Gleber-Netto FO, Pickering CR, Rao X, Wang J, Sikora AG, Myers JN, and Frederick MJ
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- Humans, Male, Female, Middle Aged, Aged, Carcinoma, Squamous Cell immunology, Carcinoma, Squamous Cell pathology, Carcinoma, Squamous Cell mortality, Prognosis, Extranodal Extension pathology, Adult, Mouth Neoplasms pathology, Mouth Neoplasms immunology, Mouth Neoplasms mortality, Lymphatic Metastasis
- Abstract
Background: Extranodal extension (ENE) of lymph node metastasis is one of the most reliable prognostic indicators for patients with locally advanced oral cancer. Although multiple reports have found a close relationship between immune infiltration of tumors and patient clinical outcomes, its association with ENE is unknown., Methods: We identified 234 human papillomavirus-negative (HPV-) oral cavity squamous cell carcinoma (OSCC) patients in The Cancer Genome Atlas and investigated the immune infiltration profiles of primary tumors and their association with survival., Results: Hierarchical clustering analysis clearly classified the overall immune infiltration status in OSCC into high immune or low immune groups. The combination of ENE positivity and low immune infiltration was strongly associated with poor overall survival (OS) compared to the combination of ENE positivity and high immune infiltration [hazard ratio 2.04 (95 %CI, 1.08-3.83); p = 0.024]. The immune infiltration status was not associated with OS rates in patients with ENE-negative or node negative tumors., Conclusion: Overall Immune infiltration at the primary site was significantly associated with clinical outcome of OSCC patients with ENE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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7. TP53 gain-of-function mutation modulates the immunosuppressive microenvironment in non-HPV-associated oral squamous cell carcinoma.
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Shi Y, Ren X, Cao S, Chen X, Yuan B, Brasil da Costa FH, Rodriguez Rosario AE, Corona A, Michikawa C, Veeramachaneni R, Osman AA, Xie T, Wang W, Sikora AG, Myers JN, and Rangel R
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- Animals, Humans, Mice, CD8-Positive T-Lymphocytes, Cytokines, Disease Models, Animal, Gain of Function Mutation, Mutation, Squamous Cell Carcinoma of Head and Neck genetics, Carcinoma, Squamous Cell genetics, Head and Neck Neoplasms, Mouth Neoplasms genetics, Tumor Microenvironment, Tumor Suppressor Protein p53 genetics
- Abstract
Background: TP53 , the most mutated gene in solid cancers, has a profound impact on most hallmarks of cancer. Somatic TP53 mutations occur in high frequencies in head and neck cancers, including oral squamous cell carcinoma (OSCC). Our study aims to understand the role of TP53 gain-of-function mutation in modulating the tumor immune microenvironment (TIME) in OSCC., Methods: Short hairpin RNA knockdown of mutant p53R172H in syngeneic oral tumors demonstrated changes in tumor growth between immunocompetent and immunodeficient mice. HTG EdgeSeq targeted messenger RNA sequencing was used to analyze cytokine and immune cell markers in tumors with inactivated mutant p53R172H . Flow cytometry and multiplex immunofluorescence (mIF) confirmed the role of mutant p53R172H in the TIME. The gene expression of patients with OSCC was analyzed by CIBERSORT and mIF was used to validate the immune landscape at the protein level., Results: Mutant p53R172H contributes to a cytokine transcriptome network that inhibits the infiltration of cytotoxic CD8
+ T cells and promotes intratumoral recruitment of regulatory T cells and M2 macrophages. Moreover, p53R172H also regulates the spatial distribution of immunocyte populations, and their distribution between central and peripheral intratumoral locations. Interestingly, p53R172H -mutated tumors are infiltrated with CD8+ and CD4+ T cells expressing programmed cell death protein 1, and these tumors responded to immune checkpoint inhibitor and stimulator of interferon gene 1 agonist therapy. CIBERSORT analysis of human OSCC samples revealed associations between immune cell populations and the TP53R175H mutation, which paralleled the findings from our syngeneic mouse tumor model., Conclusions: These findings demonstrate that syngeneic tumors bearing the TP53R172H gain-of-function mutation modulate the TIME to evade tumor immunity, leading to tumor progression and decreased survival., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2023
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8. Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma.
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Osman AA, Arslan E, Bartels M, Michikawa C, Lindemann A, Tomczak K, Yu W, Sandulache V, Ma W, Shen L, Wang J, Singh AK, Frederick MJ, Spencer ND, Kovacs J, Heffernan T, Symmans WF, Rai K, and Myers JN
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- Animals, Humans, Mice, Cell Line, Tumor, Cisplatin pharmacology, Cisplatin therapeutic use, Drug Resistance, Neoplasm genetics, Epigenesis, Genetic, Epigenomics, Kelch-Like ECH-Associated Protein 1 genetics, Kelch-Like ECH-Associated Protein 1 metabolism, Mice, Nude, Signal Transduction, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms genetics, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Squamous Cell Carcinoma of Head and Neck drug therapy, Squamous Cell Carcinoma of Head and Neck genetics
- Abstract
Purpose: Cisplatin (CDDP)-based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCC), despite a high rate of treatment failures, acquired resistance, and subsequent aggressive behavior. The purpose of this study was to study the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC., Experimental Design: Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF2 activation in vitro and in vivo on CDDP sensitivity and development of metastasis. Western blotting, immunostaining, whole-exome sequencing, single-cell transcriptomic and epigenomic profiling platforms were performed to dissect clonal evolution and molecular mechanisms., Results: Implantation of CDDP-resistant HNSCC cells into the tongues of nude mice resulted in a very high rate of distant metastases. The CDDP-resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wild-type KEAP1 genes resensitized resistant cells to CDDP and decreased distant metastasis (DM). Finally, treatment with inhibitor of glutaminase-1, a NRF2 target gene, alleviated CDDP resistance., Conclusions: CDDP resistance and development of DM are associated with dysregulated and epigenetically reprogrammed KEAP1-NRF2 signaling pathway. A strategy targeting KEAP1/NRF2 pathway or glutamine metabolism deserves further clinical investigation in patients with CDDP-resistant head and neck tumors., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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9. Fusobacterium is enriched in oral cancer and promotes induction of programmed death-ligand 1 (PD-L1).
- Author
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Michikawa C, Gopalakrishnan V, Harrandah AM, Karpinets TV, Garg RR, Chu RA, Park YP, Chukkapallia SS, Yadlapalli N, Erikson-Carter KC, Gleber-Netto FO, Sayour E, Progulske-Fox A, Chan EKL, Wu X, Zhang J, Jobin C, Wargo JA, Pickering CR, Myers JN, and Silver N
- Subjects
- B7-H1 Antigen genetics, Fusobacterium genetics, Fusobacterium metabolism, Humans, RNA, Messenger, RNA, Ribosomal, 16S genetics, Squamous Cell Carcinoma of Head and Neck genetics, Tumor Microenvironment genetics, Carcinoma, Squamous Cell, Head and Neck Neoplasms, Mouth Neoplasms genetics, Tongue Neoplasms genetics
- Abstract
Recently, increased number of studies have demonstrated a relationship between the oral microbiome and development of head and neck cancer, however, there are few studies to investigate the role of oral bacteria in the context of the tumor microenvironment in a single head and neck subsite. Here, paired tumor and adjacent normal tissues from thirty-seven oral tongue squamous cell carcinoma (SCC) patients were subjected to 16S rRNA gene sequencing and whole exome sequencing (WES), in addition to RNA sequencing for tumor samples. We observed that Fusobacterium was significantly enriched in oral tongue cancer and that Rothia and Streptococcus were enriched in adjacent normal tissues. A decrease in alpha diversity was found in tumor when compared to adjacent normal tissues. While increased Fusobacterium in tumor samples was not associated with changes in immune cell infiltration, it was associated with increased PD-L1 mRNA expression. Therefore, we examined the effects of Fusobacterium on PD-L1 expression in head and neck SCC cell lines. We demonstrated that infection with Fusobacterium species can increase both PD-L1 mRNA and surface PD-L1 protein expression on head and neck cancer cell lines. The correlation between Fusobacterium and PD-L1 expression in oral tongue SCC, in conjunction with the ability of the bacterium to induce PD-L1 expression in vitro suggests a potential role for Fusobacterium on modulation of the tumor immune microenvironment in head and neck cancer., Competing Interests: Declaration of Competing Interests VG has consulted for MicrobiomeDX and is currently employed by AstraZeneca. VG is an inventor on US patent (PCT/US17/53,717) relating to the microbiome. VG is inventor on a provisional US patent (WO2020106983A1). JAW is an inventor on a patents WO2018064165A2, WO2019191390A2, WO2020106983A1, WO2020150429A1 that covers methods to enhance immune checkpoint blockade responses and reduce associated toxicities by modulating the microbiome. JAW also reports compensation for speaker's bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune and Bristol-Myers Squibb and serves as a consultant / advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Biothera Pharmaceuticals. JAW also receives research support from GlaxoSmithKline, Roche/Genentech, Bristol-Myers Squibb, and Novartis. The remaining authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)
- Published
- 2022
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10. Evolutionary Action Score of TP53 Analysis in Pathologically High-Risk Human Papillomavirus-Negative Head and Neck Cancer From a Phase 2 Clinical Trial: NRG Oncology Radiation Therapy Oncology Group 0234.
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Michikawa C, Torres-Saavedra PA, Silver NL, Harari PM, Kies MS, Rosenthal DI, Le QT, Jordan RC, Duose DY, Mallampati S, Trivedi S, Luthra R, Wistuba II, Osman AA, Lichtarge O, Foote RL, Parvathaneni U, Hayes DN, Pickering CR, and Myers JN
- Abstract
Purpose: An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations stratifies patients with head and neck squamous cell carcinoma (HNSCC) bearing TP53 missense mutations as high-risk, associated with poor outcomes, or low-risk, with similar outcomes as TP53 wild-type, and has been validated as a reliable prognostic marker. We performed this study to further validate prior findings demonstrating that EAp53 is a prognostic marker for patients with locally advanced HNSCC and explored its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy., Methods and Materials: Eighty-one resection samples from patients treated surgically for stage III or IV human papillomavirus-negative HNSCC with high-risk pathologic features, who received either radiation therapy + cetuximab + cisplatin (cisplatin) or radiation therapy + cetuximab + docetaxel (docetaxel) as adjuvant treatment in a phase 2 study were subjected to TP53 targeted sequencing and EAp53 scoring to correlate with clinical outcomes. Due to the limited sample size, patients were combined into 2 EAp53 groups: (1) wild-type or low-risk; and (2) high-risk or other., Results: At a median follow-up of 9.8 years, there was a significant interaction between EAp53 group and treatment for overall survival ( P = .008), disease-free survival ( P = .05), and distant metastasis (DM; P = .004). In wild-type or low-risk group, the docetaxel arm showed significantly better overall survival (hazard ratio [HR] 0.11, [0.03-0.36]), disease-free survival (HR 0.24, [0.09-0.61]), and less DM (HR 0.04, [0.01-0.31]) than the cisplatin arm. In high-risk or other group, differences between treatments were not statistically significant., Conclusions: The docetaxel arm was associated with better survival than the cisplatin arm for patients with wild-type or low-risk EAp53. These benefits appear to be largely driven by a reduction in DM., (© 2022 NRG Oncology.)
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- 2022
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11. High-Risk TP53 Mutations Are Associated with Extranodal Extension in Oral Cavity Squamous Cell Carcinoma.
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Sandulache VC, Michikawa C, Kataria P, Gleber-Netto FO, Bell D, Trivedi S, Rao X, Wang J, Zhao M, Jasser S, Myers JN, and Pickering CR
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- Cohort Studies, Disease-Free Survival, Female, Humans, Lymph Nodes pathology, Lymphatic Metastasis genetics, Lymphatic Metastasis pathology, Male, Prognosis, Retrospective Studies, Carcinoma, Squamous Cell genetics, Mouth pathology, Mouth Neoplasms genetics, Mutation genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Purpose: Development of extranodal extension (ENE) has been associated with poor survival in patients with oral cavity squamous cell carcinoma (OSCC). Here, we sought to confirm the role of ENE as a poor prognostic factor, and identify genomic and epigenetic markers of ENE in order to develop a predictive model and improve treatment selection. Experimental Design: An institutional cohort (The University of Texas MD Anderson Cancer Center) was utilized to confirm the impact of ENE on clinical outcomes and evaluate the genomic signature of primary and ENE containing tissue. OSCC data from The Cancer Genome Atlas (TCGA) were analyzed for the presence of molecular events associated with nodal and ENE status. Results: ENE was associated with decreased overall and disease-free survival. Mutation of the TP53 gene was the most common event in ENE
+ OSCC. The frequency of TP53 mutation in ENE+ tumors was higher compared with ENE- tumors and wild-type (WT) TP53 was highly represented in pN0 tumors. pN+ ENE+ patients had the highest proportion of high-risk TP53 mutations. Both primary tumors (PT) and lymph nodes with ENE (LN) exhibited a high rate of TP53 mutations (58.8% and 58.8%, respectively) with no significant change in allele frequency between the two tissue sites. Conclusions: ENE is one of the most significant markers of OSCC OS and DFS. There is a shift toward a more aggressive biological phenotype associated with high-risk mutations of the TP53 gene. Prospective clinical trials are required to determine whether TP53 mutational status can be used for personalized treatment decisions. Clin Cancer Res; 24(7); 1727-33. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
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12. Characterizing Genetic Transitions of Copy Number Alterations and Allelic Imbalances in Oral Tongue Carcinoma Metastasis.
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Morita T, Uzawa N, Mogushi K, Sumino J, Michikawa C, Takahashi KI, Myo K, Izumo T, and Harada K
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- Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell secondary, Case-Control Studies, DNA, Neoplasm genetics, Female, Follow-Up Studies, Humans, Loss of Heterozygosity, Lymphatic Metastasis, Male, Middle Aged, Mouth Neoplasms pathology, Prognosis, Tongue Neoplasms pathology, Allelic Imbalance genetics, Biomarkers, Tumor genetics, Carcinoma, Squamous Cell genetics, Chromosome Aberrations, DNA Copy Number Variations genetics, Mouth Neoplasms genetics, Tongue Neoplasms genetics
- Abstract
Primary tumor (PT) heterogeneity can significantly affect the genetic profile of clones at metastatic sites. To understand the mechanisms underlying metastasis, we compared the genetic profile of paired PT and metastatic lymph node (MLN) samples obtained from patients with oral tongue squamous cell carcinoma (OTSCC). Large-scale genetic profiling was performed on paired PT-MLN samples obtained from 10 OTSCC patients using high-density single-nucleotide polymorphism microarrays. We compared the genetic profile of PT and MLN OTSCC samples to identify common and specific copy number alterations and copy-neutral loss-of-heterozygosity (CN-LOH). Unsupervised hierarchical clustering analysis indicated that 8 of the 10 PT-MLN sample pairs formed clusters, indicating that the primary and metastatic tumors were composed of predominantly genetically similar tumor cells. In 6 of the 10 pairs, 8q11.21, 8q12.2-3, and 8q21.3 gains, and 22q11.23 loss were detected in both the PT and MLN. In addition, 16p11.2 CN-LOH was identified in 9 of the 10 pairs. Conversely, 20q11.2 gain was only observed in the MLNs of 5 of the 10 sample pairs, indicating that genes in this chromosomal region may play a significant role in OTSCC lymph node metastasis. To confirm this, we investigated the expression of two candidate 20q11.2 genes in a separate patient cohort. The expression of one of these genes, E2F1, was significantly increased during the process of metastasis. This study indicates that additional genetic changes, such as 20q11.2 gain, which encodes the E2F1 gene, can be acquired through clonal evolution, and may be required for the metastatic process. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
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- 2016
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13. The high-temperature requirement factor A3 (HtrA3) is associated with acquisition of the invasive phenotype in oral squamous cell carcinoma cells.
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Moriya Y, Uzawa N, Morita T, Mogushi K, Miyaguchi K, Takahashi K, Michikawa C, Sumino J, Tanaka H, and Harada K
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- Base Sequence, Carcinoma, Squamous Cell genetics, Cell Line, Tumor, DNA Primers, Humans, Mouth Neoplasms genetics, Phenotype, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Serine Endopeptidases genetics, Biomarkers, Tumor metabolism, Carcinoma, Squamous Cell pathology, Hot Temperature, Mouth Neoplasms pathology, Serine Endopeptidases physiology
- Abstract
Objectives: Previous studies have identified several genes involved in the carcinogenesis of oral cancer; however, the detailed mechanisms underlying this process have not been elucidated. Previously, we established a database of the transcriptional progression profile of oral carcinogenesis and identified 15 candidate genes with continuously increasing or decreasing expression (Sumino et al., 2013)., Materials and Methods: In the present study, using this database, we attempted to identify genes that may specifically contribute to progression from oral dysplastic lesions to invasive tumours., Results: We identified 4 candidate genes. Using a literature survey, we narrowed down the candidates and focused on the high-temperature requirement factor A3 (HtrA3). Quantitative real-time reverse transcription polymerase chain reaction and immunohistochemical analysis confirmed that HtrA3 expression significantly increased during this process. In addition, high HtrA3 expression was significantly associated with decreased disease-free survival (P=0.045) and overall survival (P=0.003). Multivariate Cox proportional hazards analysis found that high HtrA3 expression significantly correlated with overall survival (P=0.018)., Conclusion: The findings of this study demonstrated that the HtrA3 is likely to be associated with the acquisition of the invasive phenotype in oral squamous cell carcinoma cells and may be a potential prognostic marker for oral cancer., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
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- 2015
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14. Gene expression changes in initiation and progression of oral squamous cell carcinomas revealed by laser microdissection and oligonucleotide microarray analysis.
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Sumino J, Uzawa N, Okada N, Miyaguchi K, Mogushi K, Takahashi K, Sato H, Michikawa C, Nakata Y, Tanaka H, and Amagasa T
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- Biomarkers, Tumor genetics, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell mortality, Cytokines biosynthesis, Disease Progression, Female, Gene Expression Profiling, Humans, Laser Capture Microdissection, Male, Middle Aged, Mouth Neoplasms metabolism, Mouth Neoplasms mortality, Oligonucleotide Array Sequence Analysis, RNA, Messenger genetics, RNA, Messenger metabolism, Ubiquitins biosynthesis, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Cell Transformation, Neoplastic, Cytokines genetics, Gene Expression Regulation, Neoplastic, Mouth Neoplasms genetics, Mouth Neoplasms pathology, Ubiquitins genetics
- Abstract
Oral carcinogenesis is a complex process involving multiple genes. However, the genetic changes involved in this process are not apparent in identical oral squamous cell carcinomas (OSCCs). According to pathological characteristics, samples of normal tissue, oral dysplastic lesions (ODLs), and invasive cancers were obtained from identical OSCCs using laser microdissection (LMD). Large-scale gene expression profiling was carried out on 33 samples derived from 11 OSCCs. We analyzed genes differentially expressed in normal tissues vs. ODLs and in ODLs vs. invasive tumors and identified 15 candidate genes with continuously increasing or decreasing expression during oral carcinogenesis. One of these genes, ISG15, was chosen for further characterization. Real-time quantitative reverse transcription-polymerase chain reaction and immunohistochemical analysis confirmed that ISG15 expression consistently increased during oral tumorigenesis. An ISG15 high-expression level was significantly associated with poor prognosis (p = 0.027). In addition, patients with high-expression tumors had a poorer 5-year survival rate than patients with low expression levels (p = 0.019). In conclusion, we identified 15 genes with continuously increasing or decreasing expression during oral carcinogenesis. One of these, ISG15, is likely to be associated with both dysgenesis and tumorigenesis and may be a potential prognostic marker for oral cancer., (Copyright © 2012 UICC.)
- Published
- 2013
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15. Loss of NKX3-1 as a potential marker for an increased risk of occult lymph node metastasis and poor prognosis in oral squamous cell carcinoma.
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Miyaguchi K, Uzawa N, Mogushi K, Takahashi K, Michikawa C, Nakata Y, Sumino J, Okada N, Mizushima H, Fukuoka Y, and Tanaka H
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- Biomarkers, Tumor metabolism, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell mortality, Cluster Analysis, DNA Copy Number Variations, Female, Genome-Wide Association Study, Homeodomain Proteins metabolism, Humans, Kaplan-Meier Estimate, Lymphatic Metastasis, Male, Middle Aged, Mouth Neoplasms genetics, Mouth Neoplasms mortality, Prognosis, Risk Factors, Sequence Deletion, Statistics, Nonparametric, Transcription Factors metabolism, Transcription, Genetic, Vascular Endothelial Growth Factor C genetics, Vascular Endothelial Growth Factor C metabolism, Biomarkers, Tumor genetics, Carcinoma, Squamous Cell secondary, Homeodomain Proteins genetics, Mouth Neoplasms pathology, Transcription Factors genetics
- Abstract
The prognosis of oral squamous cell carcinoma (OSCC) is significantly dependent on the existence of cervical lymph node metastasis (LNM), with the overall survival rate being much lower in patients with LNM. Primary causes and molecular mechanisms of LNM are still largely unclear. We hypothesized that factors related with cancer progress and/or prognosis in OSCC are revealed by genome-wide investigation of DNA copy number aberrations (CNAs). In order to find biomarkers for occult LNM of OSCC, we comprehensively investigated genomic DNAs from 60 OSCC patients using Affymetrix mapping arrays and statistically analyzed correlations between CNAs of genes and the presence of occult LNM in the patients. The genome-wide CNA study indicated significant correlations between the presence of occult LNM and CNAs of certain genes. Through a literature survey, we narrowed down the candidates and focused on loss of NKX3-1, which is a homeodomain-containing transcription factor. NKX3-1 is known as a tumor suppressor gene in prostate cancer but has never been reported in OSCC. Quantitative RT-PCR and immunohistochemistry (IHC) analyses also showed significantly lower expression of NKX3-1 in the cases with occult LNM, which was further validated by IHC analysis in independent cases. The survival analyses indicated that NKX3-1 loss is a significant risk factor to decrease the disease-free survival (DFS) and the overall survival (OS) rates. This is the first time that the significant association of NKX3-1 loss and occult LNM was indicated in OSCC. The present results suggest that loss of NKX3-1 may be a potential biomarker for occult LNM of OSCC.
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- 2012
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16. EGFR gene copy number alteration is a better prognostic indicator than protein overexpression in oral tongue squamous cell carcinomas.
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Nakata Y, Uzawa N, Takahashi K, Sumino J, Michikawa C, Sato H, Sonoda I, Ohyama Y, Okada N, and Amagasa T
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- Biomarkers, Tumor analysis, Biopsy, Carcinoma, Squamous Cell chemistry, Carcinoma, Squamous Cell mortality, Carcinoma, Squamous Cell pathology, Carcinoma, Squamous Cell surgery, Disease-Free Survival, ErbB Receptors analysis, Female, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Japan, Kaplan-Meier Estimate, Male, Middle Aged, Predictive Value of Tests, Proportional Hazards Models, Risk Assessment, Risk Factors, Survival Rate, Time Factors, Tongue Neoplasms chemistry, Tongue Neoplasms mortality, Tongue Neoplasms pathology, Tongue Neoplasms surgery, Treatment Outcome, Biomarkers, Tumor genetics, Carcinoma, Squamous Cell genetics, ErbB Receptors genetics, Gene Dosage, Tongue Neoplasms genetics
- Abstract
Although epidermal growth factor receptor (EGFR) is particularly important in the pathogenesis of head and neck squamous cell carcinomas (HNSCCs), conflicting data have been reported on the correlation between EGFR copy number and survival and the association between EGFR copy number and protein expression. Anatomical site of the tumour in HNSCCs may likely contribute to the discordance of the above points as EGFR expression may differ between the sub-sites of HNSCCs. Thus, in this study, we focused on oral tongue squamous cell carcinomas (OTSCCs). To investigate the association between EGFR copy number alteration and overexpression and to determine which is the more reliable prognostic indicator, Fluorescence in situ hybridisation (FISH) and immunohistochemical staining (IHC) were performed at a single institution on samples from 89 patients with OTSCCs undergoing surgery as the primary treatment modality. Thirty-two (36%) of 89 cases demonstrated an EGFR copy number alteration. EGFR protein expression was found in all 89 cases, of which 82.0% showed overexpression. No significant correlation was found between gene copy number and protein overexpression. Gene copy number alteration was significantly associated with reduced disease-free survival (P=0.048) and overall survival (P=0.001). Multivariate Cox proportional hazards analysis demonstrated that EGFR copy number increase was significantly correlated with overall survival (P=0.001). EGFR copy number status is a more reliable indicator than protein overexpression of the survival rate in OTSCCs. FISH analysis of the EGFR status is useful in predicting poor prognosis in OTSCCs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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