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#1由 EVKVLIN 在 二, 05/12/2015 – 10:08 發表。
2014/04/23 Seminar2014/04/23 Seminar AnnouncementTopic: A Paracrinal Ineterleukin-6-Mediated Epigenetic Regulation of MiR142-3p Promotes Tumor Initiation in Malignant Glioma Speaker: Dr.Shih-Hwa Chiou 陽明邱世華 醫師
Professor, The Institute of Pharmacology, National Yang-Ming University
Physcian Attending, Department of Medical Research and Education, Taipei Veterans General Hospital
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#2由 EVKVLIN 在 二, 05/12/2015 – 09:44 發表。
張書銘老師部分2014/5/5
PLoS One. 2014 May 5;9(5):e96507. doi: 10.1371/journal.pone.0096507. eCollection 2014.
Huang CC1, Lee WT1, Tsai ST1, Ou CY1, Lo HI1, Wong TY2, Fang SY1, Chen KC2, Huang JS2, Wu JL1, Yen CJ3, Hsueh WT4, Wu YH4, Yang MW4, Lin FC4, Chang JY5, Chang KY5, Wu SY3, Hsiao JR1, Lin CL6, Wang YH7, Weng YL7, Yang HC7, Chang JS7.
Author information 1Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
2Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 3Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 4Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 5Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan. 6Department of Nursing, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 7National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan. Abstract
BACKGROUND:
The current study evaluated the association between tea consumption and head and neck cancer (HNC) in Taiwan, where tea is a major agricultural product and a popular beverage.
METHODS:
Interviews regarding tea consumption (frequency, duration, and types) were conducted with 396 HNC cases and 413 controls. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with tea drinking, adjusted for sex, age, education, cigarette smoking, betel quid chewing, and alcohol drinking.
RESULTS:
A reduced HNC risk associated with tea drinking (OR for every cup per day = 0.96, 95% CI: 0.93-0.99; OR for ≧5 cups per day = 0.60, 95% CI: 0.39-0.94) was observed. The association was especially significant for pharyngeal cancer (OR for every cup per day = 0.93, 95% CI: 0.88-0.98; OR for ≧5 cups per day = 0.32, 95% CI: 0.16-0.66). A significant inverse association between HNC and tea consumption was observed particularly for green tea.
CONCLUSIONS:
This study suggests that tea drinking may reduce the risk of HNC. The anticancer property of tea, if proven, may offer a natural chemopreventive measure to reduce the occurrence of HNC. PMID:24796481
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#3由 EVKVLIN 在 二, 05/12/2015 – 09:38 發表。
2014/11 楊順發老師新作!PLoS One. 2014 Nov 25;9(11):e113129. doi: 10.1371/journal.pone.0113129. eCollection 2014. |
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#4由 EVKVLIN 在 二, 05/12/2015 – 09:35 發表。
2014/10 夏興國老師實驗室Cancer Research新作!Cancer Res. 2014 Oct 28. pii: canres.0978.2014. [Epub ahead of print] Downregulated miR-329 and miR-410 promote the proliferation and invasion of oral squamous cell carcinoma by targeting Wnt-7b. Author information MicroRNA (miRNA) dysregulation contributes widely to human cancer but has not been fully assessed in oral cancers. In this study, we conducted a global microarray analysis of miRNA expression in 40 pairs of betel quid-associated oral squamous cell carcinoma (OSCC) specimens and their matched non-tumorous epithelial counterparts. Eighty-four miRNAs were differentially expressed in the OSCC specimens compared to the matched tissue. Among these downregulated miRNAs, 19 miRNAs were found and mapped to the chromosome 14q32.2 miRNA cluster region, which resides within a parentally imprinted region designated Dlk-Dio3 and known to be important in development and growth. Bioinformatic analysis predicted two miRNAs from the cluster region, miR-329 and miR-410, which could potentially target Wnt-7b, an activator of the Wnt/β-catenin pathway, thereby attenuating the Wnt/β-catenin signaling pathway in OSCC. Stable ectopic expression of Wnt-7b in OSCC cells overexpressing miR-329 or miR-410 restored proliferation and invasion capabilities abolished by these miRNA. Combining a demethylation agent and a histone deacetylase inhibitor was sufficient to re-express miR-329, miR-410 and Meg3 consistent with epigenetic regulation of these miRNA in human OSCC. Specifically, arecoline, a major betel nut alkaloid, reduced miR-329, miR-410 and Meg3 gene expression. Overall, our results provide novel molecular insights into how betel quid contribute to oral carcinogenesis through epigenetic silencing of tumor suppressor miRNA which target Wnt/β-catenin signaling. PMID: 25351956 |
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#5由 sufang 在 一, 02/16/2015 – 16:07 發表。
Orthotopic non-metastatic and metastatic oral cancer mouse modelOral Oncol. 2015 Feb 11. pii: S1368-8375(15)00024-X. doi: 10.1016/j.oraloncology.2015.01.012. [Epub ahead of print]
Orthotopic non-metastatic and metastatic oral cancer mouse models.Abstract |
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#6由 sufang 在 一, 02/16/2015 – 09:29 發表。
NEJM EditorialOne of the greatest challenges in the study and treatment of cancer has been that the disease is too heterogeneous: too many tissue types, too many etiologic factors, too much genetic diversity. After the discovery of oncogenes, it was thought that a limited number of genes, the proto-oncogenes, might turn a normal cell into a cancerous one. But soon it was discovered that tumor-suppressor genes antagonize the action of oncogenes, thus increasing genetic diversity in the context of cancer pathogenesis. To date, about 140 genes have been identified that can drive cancer growth when genetically altered.1 The discovery that driver genes can be classified into 1 or more of 12 pathways led to one of the greatest achievements in drug development and the establishment of targeted therapy in cancer. Recently, whole-genome sequencing revealed a surprising fact: every tumor contains hundreds to thousands of somatic mutations, which are obtained throughout life, and their number is directly correlated with age. Certain types of tumors display many more or many fewer mutations. Melanomas and lung cancers are the outliers and contain approximately 200 nonsynchronous mutations per tumor. It has been hypothesized that this large number of mutations reflects the effect of potent mutagens (e.g., ultraviolet light and cigarette smoking).5 The unique genetic fingerprint of almost every tumor raises the concern that treatments might be destined to fail owing to tumor heterogeneity and the continuous development of mutations. Despite the long debate about the ability of T cells to destroy tumors,6 the unprecedented recent success of immunotherapy in malignant disorders has provided evidence that the patient’s endogenous immune system can be altered to attack established tumors. A major hurdle in tumor immunotherapy is the fact that mechanisms of self-tolerance that prevent autoimmunity also impair T-cell responses against tumors, which do not differ substantially from self. Blockade of the major checkpoint inhibitors cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) has resulted in durable responses in many patients.7,8 However, why other patients have only transient responses or no responses at all remains unclear. It is also unclear how patients should be identified as appropriate candidates for immunotherapy. In a study now reported in the Journal, Snyder and colleagues9 asked whether the genetic landscape of melanoma might affect clinical benefit from immunotherapy with CTLA-4 blockade. The investigators analyzed tumor DNA using whole-exome sequencing and, as expected, detected a large number of somatic mutations. Mutational burden was higher in patients with a sustained clinical benefit than in those without a sustained benefit. Specific tumor neoepitopes encoded by these mutations were identified, and, after translation of missense mutations into mutant and nonmutant peptides, their ability to initiate major histocompatibility complex (MHC) class I–mediated responses in T cells was assessed by means of a bioinformatics algorithm incorporating prediction for MHC class I binding, T-cell receptor binding, and patient-specific HLA type. Mutant peptides were predicted to bind MHC class I molecules with higher affinity than the corresponding nonmutant peptides. Moreover, it was determined that a number of tetrapeptide sequences corresponding to mutation-derived neoepitopes were shared by patients with a long-term clinical benefit but were completely absent from patients with a minimal benefit or no benefit. These neoepitopes defined a signature that could predict long-term clinical benefit from CTLA-4 blockade. The quality — not the number — of mutations had the strongest predictive value. Strikingly, many neoepitopes that were common to patients who had a sustained clinical benefit were homologous to viral and bacterial antigens. These findings are exciting for two main reasons. First, these data provide convincing evidence that in order for a CTLA-4 checkpoint blockade to mediate clinical benefit, T cells must be activated in the context of tumor-associated antigens. In unstimulated T cells, a small amount of CTLA-4 resides in intracellular vesicles of the endosomal and trans-Golgi network and recycles continuously to the cell surface, followed by rapid endocytosis and degradation. T-cell activation leads to an increase in CTLA-4, translocation of CTLA-4–containing vesicles to the immunologic synapse, and the release and expression of CTLA-4 on the cell surface. The stronger the T-cell–receptor signal, the more CTLA-4 accumulates at the immunologic synapse.10 It is conceivable that in patients with melanomas expressing immunogenic neoepitopes, mutant peptides capable of binding MHC class I molecules with high affinity induce T-cell activation, leading to relocalization of CTLA-4–containing intracellular vesicles to the immunologic synapse, release of CTLA-4, and up-regulation of CTLA-4 on the cell surface. Under these conditions, anti–CTLA-4 antibodies reverse the inhibitory effect of CTLA-4, which is mediated by B7-1 and B7-2 ligation, and induce long-term antitumor responses (Figure 1A) In contrast, in patients lacking such mutations, nonmutant peptides corresponding to the nonmutated counterparts of immunogenic neoepitopes have lower affinity for MHC class I molecules and do not induce T-cell activation. Under these conditions, CTLA-4 remains in the intracellular vesicles and is not up-regulated on the cell surface. Consequently, anti–CTLA-4 antibodies yield no clinical benefit (Figure 1B). Second, these findings indicate that clinical benefit from CTLA-4 blockade depends on responses against epitopes that T cells are likely to recognize, such as those present on viral and bacterial pathogens. It is tempting to speculate that development of these antitumor responses might also be mediated by memory T cells generated during prior exposure to such antigens that were foreign to the host and happened to be homologous to neoepitopes induced by somatic mutations in melanomas. Importantly, a high mutational burden increased the likelihood of the development of specific neoepitopes that would confer clinical benefit from CTLA-4 blockade. In the era of immunotherapy, genetic diversity of cancer may, in fact, be a good thing. FIGURE 1 Somatic Neoepitopes of Melanomas and Benefit from CTLA-4 Blockade.
Recognition of epitopes by T-cell receptors can be mediated by consensus tetrapeptides in immunogenic peptides. As shown in Panel A, mutant tetrapeptides that bind major histocompatibility complex (MHC) class I molecules with high affinity induce activation of antigen-specific naive or memory T cells that recognize this tumor-specific antigen, leading to translocation of cytotoxic T-lymphocyte antigen 4 (CTLA-4)–containing vesicles to the immunologic synapse and up-regulation of CTLA-4 expression on the cell surface. Ligation of CTLA-4 by B7-1 and B7-2 mediates an inhibitory signal in these tumor-specific T cells. Under these conditions, anti–CTLA-4 antibodies prevent CTLA-4 ligation and CTLA-4–mediated inhibition, resulting in the generation of functional tumor-specific effector T cells, which induce antitumor responses. As shown in Panel B, in the absence of such mutations, nonmutant tetrapeptides corresponding to the nonmutated counterparts of immunogenic somatic neoepitopes have lower affinity for MHC class I molecules and do not induce activation of antigen-specific naive or memory T cells that recognize this tumor-specific antigen. Under these conditions, CTLA-4–containing vesicles do not translocate to the immunologic synapse, CTLA-4 expression is not up-regulated, and anti–CTLA-4 antibodies confer no clinical benefit. REFERENCES1 CrossRef | Web of Science | Medline 2 Free Full Text | Web of Science | Medline 3 Free Full Text | Web of Science | Medline 4 Free Full Text | Web of Science | Medline 5 CrossRef | Web of Science | Medline 6 CrossRef | Web of Science | Medline 7 Free Full Text | Web of Science | Medline 8 Free Full Text | Web of Science | Medline 9 10 |
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#7由 sufang 在 日, 01/11/2015 – 21:01 發表。
Gene expression profiling reveals biological pathwaysOral Oncol. 2015 Jan 2. pii: S1368-8375(14)00376-5. doi: 10.1016/j.oraloncology.2014.12.004. [Epub ahead of print] pdf: 4269 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/25560800 Saeed AA1, Sims AH2, Prime SS3, Paterson I4, Murray PG5, Lopes VR6. Abstract
OBJECTIVES
It is well recognized that oral squamous cell carcinoma (OSCC) cases from Asia that are associated with betel quid chewing are phenotypically distinct to those from Western countries that are predominantly caused by smoking/drinking, but the molecular basis of these differences are largely unknown. The aim of this study is to examine gene expression, related carcinogenic pathways and molecular processes that might be responsible for the phenotypic heterogeneity of OSCC between UK and Sri Lankan population groups.
METHODS: We have compared the gene expression profiles of OSCCs and normal oral mucosal tissues from both Sri Lankan and UK individuals using Affymetrix gene expression arrays. The generated data was interrogated using significance analysis of microarrays and Ingenuity Pathway Analysis (IPA). RESULTS: The gene expression profiles of UK and Sri Lankan OSCC are similar in many respects to other oral cancer expression profiles reported in the literature and were mainly similar to each other.However, genes involved in tumor invasion, metastasis and recurrence were more obviously associated with UK tumors as opposed to those from Sri Lanka. CONCLUSION: The development of OSCCs in both UK and Sri Lankan populations appears largely mediated by similar biological pathways despite the differences related to race, ethnicity, lifestyle, and/or exposure to environmental carcinogens. However, IPA revealed a highly activated “Cell-mediated Immune Response” in Sri Lankan normal and tumor samples relative to UK cohorts. It seems likely, therefore, that any future attempts to personalize treatment for OSCC patients will need to be different in Western and Asian countries to reflect differences in gene expression and the immune status of the patients. |
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#8由 sufang 在 日, 01/11/2015 – 20:56 發表。
Common and complex Notch1 mutations in Chinese oral squamous celCommon and complex Notch1 mutations in Chinese oral squamous cell carcinoma.
Clin Cancer Res. 2014 Feb 1;20(3):701-10. doi: 10.1158/1078-0432.CCR-13-1050. Epub 2013 Nov 25.
Common and complex Notch1 mutations in Chinese oral squamous cell carcinoma.
Song X1, Xia R, Li J, Long Z, Ren H, Chen W, Mao L.
Author information
1Authors’ Affiliations: Department of Oral and Maxillofacial Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Stomatology, Shanghai, China; Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry; Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore; and Personal Diagnostix Inc., Gaithersburg, Maryland.
Abstract
This is a paper referred by 閻紫宸教授
PURPOSE:
To determine Notch1 mutation status in oral squamous cell carcinoma (OSCC) from Chinese population and its potential clinical implications.
EXPERIMENTAL DESIGN:
Surgically resected OSCC tissues from 51 Chinese patients and 13 head and neck squamous cell carcinoma (HNSCC) cell lines were sequenced for mutations in the entire coding regions of Notch1 and TP53 using a next-generation sequencing platform. Sequences of the genes were also determined in corresponding normal tissues from 46 of the 51 patients. Mutations and their association with clinical parameters were analyzed.
RESULTS:
Six mutations in Notch1 and 11 mutations in TP53 coding regions were detected in 4 (31%) and 10 (77%) of the 13 HNSCC cell lines, respectively. Forty-two somatic Notch1 mutations, including 7 nonsense mutations and 11 mutations within the domain commonly harboring potential activating mutations in acute lymphoblastic leukemia, were detected in 22 (43%) of the 51 Chinese OSCC tumors. In comparison, 25 somatic TP53 mutations were observed in 21 (41%) of the 51 tumors. Patients whose tumors carried Notch1 mutation had significantly shorter overall and disease-free survivals (P = 0.004 and P = 0.001, respectively, by log-rank test) compared with those whose tumors carried no Notch1 mutation. Multivariate analysis showed that both Notch1 mutation and lymph node metastasis are independent prognostic factors in the patient population (P = 0.001). All 15 patients with both Notch1 mutation and nodal metastasis recurred or metastasized within 2 years after surgery. PMID: 24277457
CONCLUSIONS:
Notch1 mutation is common in Chinese OSCC and associates with clinical outcomes. The complexity of the mutation spectrum warrants further investigation of Notch1 in Chinese patients with OSCC.
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#9由 sufang 在 六, 01/10/2015 – 11:07 發表。
An eleven gene molecular signature for extra-capsular spread inOral Oncol. 2015 Jan 2. pii: S1368-8375(14)00384-4. doi: 10.1016/j.oraloncology.2014.12.012. [Epub ahead of print]
An eleven gene molecular signature for extra-capsular spread in oral squamous cell carcinoma serves as a prognosticator of outcome in patients without nodal metastases
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Wang W1, Lim WK2, Leong HS3, Chong FT3, Lim TK4, Tan DS5, Teh BT3, Iyer NG6.
Author information
Abstract
OBJECTIVES:
Extracapsular spread (ECS) is an important prognostic factor for oral squamous cell carcinoma (OSCC) and is used to guide management. In this study, we aimed to identify an expression profile signature for ECS in node-positive OSCC using data derived from two different sources: a cohort of OSCC patients from our institution (National Cancer Centre Singapore) and The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) cohort. We also sought to determine if this signature could serve as a prognostic factor in node negative cancers.
MATERIALS AND METHODS:
Patients with a histological diagnosis of OSCC were identified from an institutional database and fresh tumor samples were retrieved. RNA was extracted and gene expression profiling was performed using the Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray platform. RNA sequence data and corresponding clinical data for the TCGA HNSCC cohort were downloaded from the TCGA Data Portal. All data analyses were conducted using R package and SPSS.
RESULTS:
We identified an 11 gene signature (GGH, MTFR1 (哈哈 好可惜不是MTHFR), CDKN3, PSRC1, SMIM3, CA9, IRX4, CPA3, ZSCAN16, CBX7 (is this Tao’s baby?) and ZFP3) which was robust in segregating tumors by ECS status. In node negative patients, patients harboring this ECS signature had a significantly worse overall survival (p=0.04).
CONCLUSIONS:
An eleven gene signature for ECS was derived. Our results also suggest that this signature is prognostic in a separate subset of patients with no nodal metastasis Further validation of this signature on other datasets and immunohistochemical studies are required to establish utility of this signature in stratifying early stage OSCC patients.
Copyright © 2014 Elsevier Ltd. All rights reserved.
KEYWORDS:
Extracapsular spread; Gene molecular signature; Oral squamous cell carcinoma; Prognostic factor
PMID: 25560799
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#10由 sufang 在 四, 10/16/2014 – 14:12 發表。
Efficient replication of EBV in stratified epithelium in vitroProc Natl Acad Sci U S A. 2014 Oct 13. pii: 201400818. [Epub ahead of print] Epstein-Barr virus is a ubiquitous human herpesvirus associated with epithelial and lymphoid tumors. EBV is transmitted between human hosts in saliva and must cross the oral mucosal epithelium before infecting B lymphocytes, where it establishes a life-long infection. The latter process is well understood because it can be studied in vitro, but our knowledge of infection of epithelial cells has been limited by the inability to infect epithelial cells readily in vitro or to generate cell lines from EBV-infected epithelial tumors. Because epithelium exists as a stratified tissue in vivo, organotypic cultures may serve as a better model of EBV in epithelium than monolayer cultures. Here, we demonstrate that EBV is able to infect organotypic cultures of epithelial cells to establish a predominantly productive infection in the suprabasal layers of stratified epithelium, similar to that seen with Kaposi’s-associated herpesvirus. These cells did express latency-associated proteins in addition to productive-cycle proteins, but a population of cells that exclusively expressed latency-associated viral proteins could not be detected; however, an inability to infect the basal layer would be unlike other herpesviruses examined in organotypic cultures. Furthermore, infection did not induce cellular proliferation, as it does in B cells, but instead resulted in cytopathic effects more commonly associated with productive viral replication. These data suggest that infection of epithelial cells is an integral part of viral spread, which typically does not result in the immortalization or enhanced growth of infected epithelial cells but rather in efficient production of virus. PMID: 25313069
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