KEGG(Kyoto Encyclopedia of Genes and Genomes)〔和文〕 (特集 ゲノム医学の現在と未来--基礎と臨床) -- (データベース)

Epithelial-mesenchymal transitions (EMTs) are a key requirement for cancer cells to metastasize and colonize in a new environment. Epithelial-mesenchymal plasticity is mediated by master transcription factors and is also subject to complex epigenetic regulation. This Review outlines our current understanding of the interactions between EMT-inducing transcription factors and epigenetic modulators during cancer progression and the therapeutic implications of exploiting this intricate regulatory process. During the course of malignant cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, the extremes of which are defined by the expression of epithelial and mesenchymal phenotypes. This plasticity is enabled by underlying shifts in epigenetic regulation. A small cohort of pleiotropically acting transcription factors is widely recognized to effect these shifts by controlling the expression of a constituency of key target genes. These master regulators depend on complex epigenetic regulatory mechanisms, notably the induction of changes in the modifications of chromatin-associated histones, in order to achieve the widespread changes in gene expression observed during epithelial-mesenchymal transitions (EMTs). These associations indicate that an understanding of the functional interactions between such EMT-inducing transcription factors and the modulators of chromatin configuration will provide crucial insights into the fundamental mechanisms underlying cancer progression and may, in the longer term, generate new diagnostic and therapeutic modalities for treating high-grade malignancies.

The epigenetics of epithelial-mesenchymal plasticity in cancer

Targeting calcium signaling in cancer therapy.

Treatment of Asthma with Drugs Modifying the Leukotriene Pathway

BackgroundTumor-infiltrating immune cells have been linked to prognosis and response to immunotherapy; however, the levels of distinct immune cell subsets and the signals that draw them into a tumor, such as the expression of antigen presenting machinery genes, remain poorly characterized. Here, we employ a gene expression-based computational method to profile the infiltration levels of 24 immune cell populations in 19 cancer types.ResultsWe compare cancer types using an immune infiltration score and a T cell infiltration score and find that clear cell renal cell carcinoma (ccRCC) is among the highest for both scores. Using immune infiltration profiles as well as transcriptomic and proteomic datasets, we characterize three groups of ccRCC tumors: T cell enriched, heterogeneously infiltrated, and non-infiltrated. We observe that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM). We explore the prognostic value of distinct T cell subsets and show in two cohorts that Th17 cells and CD8+ T/Treg ratio are associated with improved survival, whereas Th2 cells and Tregs are associated with negative outcomes. Investigation of the association of immune infiltration patterns with the subclonal architecture of tumors shows that both APM and T cell levels are negatively associated with subclone number.ConclusionsOur analysis sheds light on the immune infiltration patterns of 19 human cancers and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ccRCC.

Additional file 1: Figures S1â S25. of Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures

Simvastatin is currently one of the most common drugs for old patients with hyperlipidemia, hypercholesterolemia and atherosclerotic diseases by reducing cholesterol level and anti-lipid properties. Importantly, simvastatin has also been reported to have anti-tumor effect, but the underlying mechanism is largely unknown. We collected several human bladder samples and performed microarray. Data analysis suggested bladder cancer (BCa) was significantly associated with fatty acid/lipid metabolism via PPAR signalling pathway. We observed simvastatin did not trigger BCa cell apoptosis, but reduced cell proliferation in a dose- and time-dependent manner, accompanied by PPARγ-activation. Moreover, flow cytometry analysis indicated that simvastatin induced cell cycle arrest at G0/G1 phase, suggested by downregulation of CDK4/6 and Cyclin D1. Furthermore, simvastatin suppressed BCa cell metastasis by inhibiting EMT and affecting AKT/GSK3β. More importantly, we found that the cell cycle arrest at G0/G1 phase and the alterations of CDK4/6 and Cyclin D1 triggered by simvastatin could be recovered by PPARγ-antagonist (GW9662), whereas the treatment of PPARα-antagonist (GW6471) shown no significant effects on the BCa cells. Taken together, our study for the first time revealed that simvastatin inhibited bladder cancer cell proliferation and induced cell cycle arrest at G1/G0 phase via PPARγ signalling pathway.

/pdf/simvastatin-induces-cell-cycle-arrest-and-inhibits-ce1ryybaz8.pdf

Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARγ signalling pathway.

The transition from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is detrimental to bladder cancer (BLCA) patients. Here, we aimed to study the underlying mechanism of the subtype transition. Gene set variation analysis (GSVA) revealed the epithelial-mesenchymal transition (EMT) signalling pathway with the most positive correlation in this transition. Then, we built a LASSO Cox regression model of an EMT-related gene signature in BLCA. The patients with high risk scores had significantly worse overall survival (OS) and disease-free survival (DFS) than those with low risk scores. The EMT-related gene signature also performed favourably in the accuracy of prognosis and in the subtype survival analysis. Univariate and multivariate Cox regression analyses demonstrated that the EMT-related gene signature, pathological N stage and age were independent prognostic factors for predicting survival in BLCA patients. Furthermore, the predictive nomogram model was able to effectively predict the outcome of BLCA patients by appropriately stratifying the risk score. In conclusion, we developed a novel EMT-related gene signature that has tumour-promoting effects, acts as a negative independent prognostic factor and might facilitate personalized counselling and treatment in BLCA.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.14767

An EMT-related gene signature for the prognosis of human bladder cancer.

Clear cell renal cell carcinoma (ccRCC) is the most common solid lesion within kidney, and its prognostic is influenced by the progression covering a complex network of gene interactions. In current study, the microarray data GSE66272 containing ccRCC and adjacent normal tissues was analyzed to identify 4042 differentially expressed genes, on which weighted gene co-expression network analysis was performed. Then 12 co-expressed gene modules were identified. The highest association was found between blue module and pathological stage (r = -0.77) by Pearson's correlation analysis. Functional enrichment analysis revealed that biological processes of blue module focused on inflammatory response, immune response, chemotaxis (all p < 1e-10). In the significant module, a total of 38 network hub genes were identified, FCER1G exhibited the highest correlation (r = 0.95) with ccRCC progression. In addition, FCER1G was hub node in the protein-protein interaction network of the genes in blue module as well. Thus, FCER1G was subsequently selected for validation. In the test set GSE53757 and RNA-sequencing data, FCER1G expression was also positively correlated with four stages of ccRCC progression (p < 0.001). Receiver operating characteristic (ROC) curve indicated that FCER1G could distinguish localized (pathological stage I, II) from non-localized (pathological stage III, IV) ccRCC (AUC=0.74, p < 0.001). Besides, FCER1G could be a prognostic gene in clinical practice as well, revealed by survival analysis based on RNA-sequencing data (p < 0.05). In conclusion, using weighted gene co-expression analysis, FCER1G was identified and validated in association with ccRCC progression and prognosis, which might improve the prognosis by influencing immune-related pathways.

/pdf/co-expression-network-analysis-identified-fcer1g-in-40inzlkitu.pdf

Co-expression network analysis identified FCER1G in association with progression and prognosis in human clear cell renal cell carcinoma.

Tumour microenvironment (TME), which consists of widely diverse immune and stromal cells and the factors that they secrete, cultivates a chronic inflammatory, immunosuppressive, and pro-angiogenic intratumoural atmosphere, which has been reported to correlate with patient outcomes and treatment efficacy. In this study, we characterized TME pattern through the "Estimation of STromal and Immune cells in MAlignant Tumours using Expression data" (ESTIMATE) algorithm and build a TME-related signature (TMERS), which is serving as an independent prognostic factor in MIBC. Moreover, we found that the TMERS was highly positive correlated with immune infiltration, the expression of immune checkpoints and high malignancy molecular subtypes such as basal, infiltrated and basal/SCC-like. The value of the TMERS in assessing the immunotherapy response was evaluated using the tumour immune dysfunction and exclusion (TIDE) algorithm and confirmed in several cohorts treated with immune checkpoint inhibitors (ICIs). Furthermore, the TMERS had a negative correlation with the tumour mutation burden (TMB), which is a potential predictive biomarker of immunotherapy response. Remarkably, combining TMERS and TMB was more effective for survival and ICI response prediction. In conclusion, we established a novel TMERS which depicts the TME pattern and acts as a robust independent prognostic factor and predictive biomarker for the response to ICIs when combined with the TMB.

Tumour microenvironment (TME) characterization identified prognosis and immunotherapy response in muscle-invasive bladder cancer (MIBC)

// Rui Cao 1, * , Zhe Meng 1, * , Tongzu Liu 1 , Gang Wang 1 , Guofeng Qian 2 , Tingting Cao 3 , Xinyuan Guan 3 , Hancai Dan 4 , Yu Xiao 1, 5 , Xinghuan Wang 1 1 Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China 2 Department of Endocrinology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China 3 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong 4 Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD, USA 5 Center for Medical Science Research, Zhongnan Hospital of Wuhan University, Wuhan, China * These authors contributed equally to this work Correspondence to: Yu Xiao, email: yu.xiao@whu.edu.cn Xinghuan Wang, email: wangxinghuan@whu.edu.cn Keywords: TRPM7, bladder cancer, apoptosis, MAPK, AKT Received: March 29, 2016      Accepted: September 13, 2016      Published: September 20, 2016 ABSTRACT Transient receptor potential melastatin 7 (TRPM7) functions as a Mg 2+ /Ca 2+ -permeable channel fused with a kinase domain and regulates various physical processes and diseases. However, its effects on pathogenesis of human bladder cancer (BCa) has not been clarified yet. Our microarray analysis has suggested that calcium signaling pathway is connected with bladder cancer via MAPK pathway. Therefore, we aim to investigate the mechanism of TRPM7 in BCa tumorigenesis by using BCa tissues compared with normal bladder epithelium tissues, as well as using distinct BCa cell lines (EJ, 5637 and T24). We observed increased TRPM7 expression and dysregulation of proteins involved in Epithelial-Mesenchymal Transition (EMT) in BCa tissues. Moreover, knockdown of TRPM7 in BCa cells reversed the EMT status, accompanied by increase of reactive oxygen species (ROS). Furthermore, TRPM7 deficiency could inhibit BCa cell proliferation, migration and invasion, as well as induce p-ERK1/2 and suppress PI3K/AKT at the protein level. Downregulation of TRPM7 promoted cell cycle arrest at G0/G1 phase and apoptosis in vitro , which could be recovered by pre-treatment with U0126 to deactivate ERK1/2, suggesting a close correlation between TRPM7 and the MAPK signaling pathway. Furthermore, a NOD/SCID mouse model transplanted using the BCa cells was established, revealing delayed tumor growth by reduced protein activity and mRNA transcription of TRPM7 in vivo . Our results suggested TRPM7 might be essential for BCa tumorigenesis by interfering BCa cell proliferation, motility and apoptosis.

/pdf/decreased-trpm7-inhibits-activities-and-induces-apoptosis-of-2jz7qv35y6.pdf

Rui Cao

Papers

Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARγ signalling pathway.

An EMT-related gene signature for the prognosis of human bladder cancer.

Co-expression network analysis identified FCER1G in association with progression and prognosis in human clear cell renal cell carcinoma.

Tumour microenvironment (TME) characterization identified prognosis and immunotherapy response in muscle-invasive bladder cancer (MIBC)

Decreased TRPM7 inhibits activities and induces apoptosis of bladder cancer cells via ERK1/2 pathway.