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DNA methylation cancer immune response

Man Liu, Jingying Zhou, Zhiwei Chen, Alfred Sze-Lok Cheng
The tumour microenvironment plays an instrumental role in cancer development, progression and treatment response/resistance. Accumulating evidence underscores the fundamental importance of epigenetic regulation in tumour immune evasion. Following many pioneering discoveries demonstrating malignant transformation through epigenetic anomalies ("epimutations"), there is also growing emphasis on elucidating aberrant epigenetic mechanisms that reprogramme the milieu of tumour-associated immune and stromal cells toward an immunosuppressive state...
October 22, 2016: Journal of Pathology
David L Marks, Rachel Lo Olson, Martin E Fernandez-Zapico
Stromal cells of the tumor microenvironment have been shown to play important roles in both supporting and limiting cancer growth. The altered phenotype of tumor-associated stromal cells (fibroblasts, immune cells, endothelial cells etc.) is proposed to be mainly due to epigenetic dysregulation of gene expression; however, only limited studies have probed the roles of epigenetic mechanisms in the regulation of stromal cell function. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation and histone post-translational modification-based gene expression regulation, and miRNA-mediated translational regulation) drive aspects of stromal cell phenotype, and discuss the implications of these findings for treatment of malignancies...
October 4, 2016: Epigenomics
Ferenc Sipos, Gábor Firneisz, Györgyi Műzes
Colonic inflammation is required to heal infections, wounds, and maintain tissue homeostasis. As the seventh hallmark of cancer, however, it may affect all phases of tumor development, including tumor initiation, promotion, invasion and metastatic dissemination, and also evasion immune surveillance. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability, and, further, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation...
September 21, 2016: World Journal of Gastroenterology: WJG
Maciej Tarnowski, Michał Czerewaty, Anna Deskur, Krzysztof Safranow, Wojciech Marlicz, Elżbieta Urasińska, Mariusz Z Ratajczak, Teresa Starzyńska
Background. While cancer/testis antigens (CTAs) are restricted in postnatal tissues to testes and germ line-derived cells, their role in cancer development and the clinical significance of their expression still remain to be better defined. Objective. The aim of this study was to investigate the level of CTA expression in colon samples from patients with colorectal cancer (CRC) in relation to patient clinical status. Methods. Forty-five patients with newly diagnosed colorectal cancer were included in the study...
2016: Disease Markers
Zhen Cao, Shihua Zhang
To investigate the commonalities and specificities across tumor lineages, we perform a systematic pan-cancer transcriptomic study across 6744 specimens. We find six pan-cancer subnetwork signatures which relate to cell cycle, immune response, Sp1 regulation, collagen, muscle system and angiogenesis. Moreover, four pan-cancer subnetwork signatures demonstrate strong prognostic potential. We also characterize 16 cancer type-specific subnetwork signatures which show diverse implications to somatic mutations, somatic copy number aberrations, DNA methylation alterations and clinical outcomes...
2016: Scientific Reports
Layale Yaghi, Isabelle Poras, Renata T Simoes, Eduardo A Donadi, Jörg Tost, Antoine Daunay, Bibiana Sgorla de Almeida, Edgardo D Carosella, Philippe Moreau
HLA-G is an immune checkpoint molecule with specific relevance in cancer immunotherapy. It was first identified in cytotrophoblasts, protecting the fetus from maternal rejection. HLA-G tissue expression is very restricted but induced in numerous malignant tumors such as glioblastoma, contributing to their immune escape. Hypoxia occurs during placenta and tumor development and was shown to activate HLA-G. We aimed to elucidate the mechanisms of HLA-G activation under conditions combining hypoxia-mimicking treatment and 5-aza-2'deoxycytidine, a DNA demethylating agent used in anti-cancer therapy which also induces HLA-G...
August 26, 2016: Oncotarget
Reiner Strick, Pamela L Strissel, Stephen B Baylin, Katherine B Chiappinelli
Loss of DNA methylation can activate endogenous retroviral expression and dsRNA in cancer cells. This leads to induction of toll-like receptor signaling stimulating an antiviral interferon response. Recent findings provide a therapeutic rationale for combining DNA methylation inhibitors with blockage of immune checkpoint proteins to fight cancer.
May 2016: Oncoimmunology
Dvir Netanely, Ayelet Avraham, Adit Ben-Baruch, Ella Evron, Ron Shamir
BACKGROUND: Breast cancer is a heterogeneous disease comprising several biologically different types, exhibiting diverse responses to treatment. In the past years, gene expression profiling has led to definition of several "intrinsic subtypes" of breast cancer (basal-like, HER2-enriched, luminal-A, luminal-B and normal-like), and microarray based predictors such as PAM50 have been developed. Despite their advantage over traditional histopathological classification, precise identification of breast cancer subtypes, especially within the largest and highly variable luminal-A class, remains a challenge...
2016: Breast Cancer Research: BCR
Yoshimasa Saito, Toshiaki Nakaoka, Kasumi Sakai, Toshihide Muramatsu, Kohta Toshimitsu, Masaki Kimura, Takanori Kanai, Toshiro Sato, Hidetsugu Saito
Recent studies have proposed that the major anti-tumor effect of DNA methylation inhibitors is induction of interferon-responsive genes via dsRNAs-containing endogenous retroviruses. Recently, a 3D culture system for stem cells known as organoid culture has been developed. Lgr5-positive stem cells form organoids that closely recapitulate the properties of original tissues. To investigate the effect of DNA demethylation on tumor organoids, we have established organoids from intestinal tumors of Apc(Min/+) (Min) mice and subjected them to 5-aza-2'-deoxycytidine (5-Aza-CdR) treatment and Dnmt1 knockdown...
2016: Scientific Reports
Baoping Cao, Nanxi Song, Meiying Zhang, Chao Di, Yang Yang, Youyong Lu, Runsheng Chen, Zhi John Lu, Mingzhou Guo
BACKGROUND: Recently, many lncRNAs were found to be deregulated in various human cancers and play important roles in carcinogenesis. MATERIAL AND METHODS: To investigate the association of lncRNAs to gastrointestinal cancers, 12 cases of esophageal cancer and hepatic cancer, 16 cases of gastric cancer and colorectal cancer and their matched adjacent tissue samples, 12 esophageal cancer cell lines, 7 gastric cancer cell lines, 10 colorectal cancer cell lines, and 11 hepatic cancer cell lines were examined...
March 2016: Discovery Medicine
Garima Sharma, Divya Tej Sowpati, Prakruti Singh, Mehak Zahoor Khan, Rakesh Ganji, Sandeep Upadhyay, Sharmistha Banerjee, Vinay Kumar Nandicoori, Sanjeev Khosla
A mammalian cell utilizes DNA methylation to modulate gene expression in response to environmental changes during development and differentiation. Aberrant DNA methylation changes as a correlate to diseased states like cancer, neurodegenerative conditions and cardiovascular diseases have been documented. Here we show genome-wide DNA methylation changes in macrophages infected with the pathogen M. tuberculosis. Majority of the affected genomic loci were hypermethylated in M. tuberculosis infected THP1 macrophages...
2016: Scientific Reports
Anja Reintjes, Julian E Fuchs, Leopold Kremser, Herbert H Lindner, Klaus R Liedl, Lukas A Huber, Taras Valovka
Nuclear factor kappa B (NF-κB) is an inducible transcription factor that plays critical roles in immune and stress responses and is often implicated in pathologies, including chronic inflammation and cancer. Although much has been learned about NF-κB-activating pathways, the specific repression of NF-κB is far less well understood. Here we identified the type I protein arginine methyltransferase 1 (PRMT1) as a restrictive factor controlling TNFα-induced activation of NF-κB. PRMT1 forms a cellular complex with NF-κB through direct interaction with the Rel homology domain of RelA...
April 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
C Richard Boland
Lynch syndrome is the inherited predisposition to cancer caused by a germline mutation in a DNA mismatch repair gene. The consequent tumors have a characteristic microsatellite instability (MSI) phenotype. Genomic sequencing of Lynch syndrome-associated colorectal cancers (CRCs) has demonstrated that these tumors have a substantially greater number of mutations than non-MSI CRCs, and that the target mutations driving tumor behavior are also different from what occurs in sporadic tumors. There are multiple non-Lynch syndrome entities that can create clinical confusion with that disease, including the acquired methylation of MLH1, Lynch-like syndrome, and Familial CRC-Type X...
July 2016: Familial Cancer
Alexander P R Bally, James W Austin, Jeremy M Boss
The inhibitory immune receptor programmed cell death-1 (PD-1) is intricately regulated. In T cells, PD-1 is expressed in response to most immune challenges, but it is rapidly downregulated in acute settings, allowing for normal immune responses. On chronically stimulated Ag-specific T cells, PD-1 expression remains high, leading to an impaired response to stimuli. Ab blockade of PD-1 interactions during chronic Ag settings partially restores immune function and is now used clinically to treat a variety of devastating cancers...
March 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Jessamy Tiffen, Stephen Wilson, Stuart J Gallagher, Peter Hersey, Fabian V Filipp
The epigenetic modifier EZH2 is in the center of a repressive complex controlling differentiation of normal cells. In cancer EZH2 has been implicated in silencing tumor suppressor genes. Its role in melanoma as well as target genes affected by EZH2 are poorly understood. In view of this we have used an integrated systems biology approach to analyze 471 cases of skin cutaneous melanoma (SKCM) in The Cancer Genome Atlas (TCGA) for mutations and amplifications of EZH2. Identified changes in target genes were validated by interrogation of microarray data from melanoma cells treated with the EZH2 inhibitor GSK126...
February 2016: Neoplasia: An International Journal for Oncology Research
Bert Kindlund, Åsa Sjöling, Chakradhar Yakkala, Jenni Adamsson, Anders Janzon, Lars-Erik Hansson, Michael Hermansson, Peter Janson, Ola Winqvist, Samuel B Lundin
BACKGROUND: An increase of regulatory T cells, defined as CD25(high)- and/or FOXP3(+)-expressing CD4(+) T cells, within tumors has been reported in several studies. Tregs promote tumor growth by modulating the antitumor immune response, mainly through inhibition of T-cell-mediated tumor cell killing: this has been suggested to be dependent on IL-10 and/or TGF-β. In stomach cancer, the mechanisms behind the accumulation of Tregs in tumor tissue has not been fully elucidated, and neither has Treg gene expression in situ...
January 18, 2016: Gastric Cancer
Tae Woo Kim, Seon-Jin Lee, Byung Moo Oh, Heesoo Lee, Tae Gi Uhm, Jeong-Ki Min, Young-Jun Park, Suk Ran Yoon, Bo-Yeon Kim, Jong Wan Kim, Yong-Kyung Choe, Hee Gu Lee
Toll-like receptor 4 (TLR4) is important in promoting the immune response in various cancers. Recently, TLR4 is highly expressed in a stage-dependent manner in gastric cancer, but the regulatory mechanism of TLR4 expression has been not elucidated it. Here, we investigated the mechanism underlying regulation of TLR4 expression through promoter methylation and histone modification between transcriptional regulation and silencing of the TLR4 gene in gastric cancer cells. Chromatin immunoprecipitation was carried out to screen for factors related to TLR4 methylation such as MeCP2, HDAC1, and Sp1 on the TLR4 promoter...
January 26, 2016: Oncotarget
Zhongrun Qian, Qi Shen, Xi Yang, Yongming Qiu, Wenbin Zhang
Exosomes, microvesicles, and other extracellular vesicles are released by many cell types, including cancer cells and cancer-related immune cells. Extracellular vesicles can directly or indirectly facilitate the transfer of bioinformation to recipient cells or to the extracellular environment. In cancer, exosomes have been implicated in tumor initiation, proliferation, and metastasis. Extracellular vesicles can transmit proteins and nucleic acids that participate in DNA methylation, histone modification, and posttranscriptional regulation of RNA...
2015: BioMed Research International
Amanda Mickley, Olga Kovaleva, Julia Kzhyshkowska, Alexei Gratchev
Kidney cancer is one of the deadliest malignancies due to frequent late diagnosis (33 % or renal cell carcinoma are metastatic at diagnosis) and poor treatment options. There are two major subtypes of kidney cancer: renal cell carcinoma (RCC) and renal pelvis carcinoma. The risk factors for RCC, accounting for more than 90 % of all kidney cancers, are smoking, obesity, hypertension, misuse of pain medication, and some genetic diseases. The most common molecular markers of kidney cancer include mutations and epigenetic inactivation of von Hippel-Lindau (VHL) gene, genes of vascular endothelial growth factor (VEGF) pathway, and carbonic anhydrase IX (CIAX)...
2015: EPMA Journal
Diogo Libânio, Mário Dinis-Ribeiro, Pedro Pimentel-Nunes
The accepted paradigm for intestinal-type gastric cancer pathogenesis is a multistep progression from chronic gastritis induced by Helicobacter pylori (H. pylori) to gastric atrophy, intestinal metaplasia, dysplasia and ultimately gastric cancer. The genetic and molecular mechanisms underlying disease progression are still not completely understood as only a fraction of colonized individuals ever develop neoplasia suggesting that bacterial, host and environmental factors are involved. MicroRNAs are noncoding RNAs that may influence H...
October 10, 2015: World Journal of Clinical Oncology
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