Genetic and tumor microenvironment differences between cell cycle progression pathway altered/non-altered patients with lung adenocarcinoma

Abstract Background Lung cancer is the leading cause of cancer-related death worldwide, among which lung adenocarcinoma (LUAD) is the most common type. Identified as a hallmark of cancer, the dysregulated cell cycle progression plays an important role in the promotion and progression of LUAD. This article aims to elucidate the heterogeneity between CDKN2A-CDK/cyclin-RB1 cell cycle progression pathway altered /non-altered patients with LUAD, thus helping us have a better understanding of the effect of the aberrant cell cycle. Material and Methods The data of this study were downloaded from The Cancer Genome Atlas (TCGA) data portal (https://portal.gdc.cancer.gov/) and UCSC Xena Browser (http://xena.ucsc.edu/), including simple nucleotide variation data, RNA-seq gene expression data, survival data, clinical data, and miRNA expression data. After matching the RNA-seq gene expression data, simple nucleotide variation data, miRNA expression data, and survival data with clinical data, 510 gene and long non-coding RNA expression data, 506 simple nucleotide variation data, 440 microRNA expression data, and 497 survival data were included in this study for further analysis. R software (version 4.0.3) was used for analysis. Results After dividing the patients into mutation (n = 57) and wild (n = 453) groups according to the cell cycle progression pathway status, we found no significant difference in survivorship between them. The mutation group had a higher mutational load and mutational rates of various genes such as tumor protein P53 (TP53) compared to the wild group. Subsequently, we analyzed the differentially expressed genes (DEGs) between the two groups. Among the 58387 genes analyzed, 302 were upregulated, and 354 were downregulated in the mutation group. Enrichment analysis indicated that these DEGs were closely related to metabolism items and cell cycle-related events. After performing immune cell infiltration analysis, we found the two groups have different patterns of immune cell profiling. Albeit the immune and stromal scores were higher in the wild group, we failed to find any significant difference between the two groups. Finally, we build a computational model to predict the cell cycle progression pathway-related gene mutation by LASSO-binary logistic regression analysis, the predictive accuracy of which is 0.88. Conclusion In summary, our study compared the genetic and microenvironment differences between cell cycle progression pathway altered /non-altered patients with LUAD by analyzing the data from TCGA datasets. We hope our findings could improve our understanding of the heterogeneity between the two kinds of patients, thus providing new insight into LUAD patients' treatments.

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Activated Sumoylation Is a Hallmark Of Burkitt's Lymphoma and MYC Driven Cancer Leading To Synthetic Lethal Interactions With Sumoylation Inhibitors

Blood ◽

10.1182/blood.v122.21.3783.3783 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3783-3783

Author(s):

Alexander Hoellein ◽

Sabine Steidle ◽

Mohammad Fellahi ◽

Stephanie Schoeffmann ◽

Martina Rudelius ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Cell Lines ◽

Cell Cycle Progression ◽

Burkitt’S Lymphoma ◽

Expression Data ◽

Lymphoma Cells ◽

Cycle Progression ◽

E3 Ligases ◽

Oncogenic Pathway

Abstract Myc oncoproteins (c-Myc, N-Myc and L-Myc) are transcription factors that regulate cell growth, cell division and metabolism under physiologic conditions. Myc overexpression is a hallmark of cancer, present in most advanced tumors, and associated with poor prognosis. We have previously shown that Myc overexpression results in specific cancer cell liabilities, e.g. during cell cycle progression, that constitute therapeutic targets for synthetic lethality approaches. Small Ubiquitin-like Modifier (SUMO) proteins covalently bind to other proteins to modify their function. SUMOylation is involved in various cellular processes including transcription and cell cycle progression. Hierarchical cluster analysis comparing RNA expression data in murine normal control, pre-malignant and lymphoma Eµ-Myc B cells identified a Myc-induced SUMOylation-related gene expression signature. This signature was present in pre-malignant and Eµ-Myc lymphoma cells and involved the up-regulation of various critical components of the SUMOylation machinery, including the E1 ligases SAE1 and SAE2, the E2 ligase Ube2i and the E3 ligases Ranbp2 and PIAS2. Moreover this translated into elevated protein expression of the whole SUMOylation pathway and ubiquitous hyper-SUMOylation of proteins in Eµ-Myc lymphoma cells. For cross-species validation we analyzed human gene expression data and found that the Myc-induced regulation of SUMOylation-associated genes was also present in human IG/MYC Burkitt lymphomas, in contrast to Non-IG/MYC B-cell lymphomas. What is more analysis of ChIP-on-chip experiments revealed direct binding of Myc to regulatory genomic regions of almost all SUMOylation regulators (SUMO2, SUMO3 and E1, E2 and E3 ligases). The characteristic of cancer cells to depend on certain intact physiologic mechanisms is known as non-oncogene addiction. Since SUMOylation of proteins is involved in essential metabolic, survival and proliferation pathways we reasoned that intact SUMOylation is a non-oncogenic pathway that Myc-driven cells rely upon. We thus hypothesized that Myc-dependent cells could be specifically susceptible when interfering with SUMOylation by pharmacological means. We found that Eµ-Myc lymphoma cells were highly sensitive to the SUMOylation inhibitors ginkolic acid and anarcardic acid. In particular, inhibition of SUMOylation lead to cell cycle arrest, polyploidy, and subsequent cell death. This therapeutic effect was Myc-specific as shown by use of genetically defined cell lines and conditional Myc-overexpression systems. Specifically human Burkitt lymphoma cell lines were strikingly more sensitive to inhibition of SUMOylation than non-Myc-transformed lymphoma samples. Taken together, we provide correlative and experimental evidence that the Myc-associated expression of genes involved in SUMOylation is a hallmark of Burkitt’s lymphoma and constitutes a non oncogenic pathway which is therapeutically exploitable in lymphoma and other Myc-driven cancers. Disclosures: No relevant conflicts of interest to declare.

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5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis

Journal of Radiation Research ◽

10.1093/jrr/rrs060 ◽

2012 ◽

Vol 53 (6) ◽

pp. 840-853 ◽

Cited By ~ 32

Author(s):

Marcy B. Grace ◽

Vijay K. Singh ◽

Juong G. Rhee ◽

William E. Jackson ◽

Tzu-Cheg Kao ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Progression ◽

Cell Function ◽

Immune Cell ◽

Innate Immune ◽

Dependent Manner ◽

Immune Cell Function ◽

Cycle Progression ◽

Radiation Induced

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A Cell Cycle Progression-Derived Gene Signature to Predict Prognosis and Therapeutic Response in Hepatocellular Carcinoma

Disease Markers ◽

10.1155/2021/1986159 ◽

2021 ◽

Vol 2021 ◽

pp. 1-36

Author(s):

Yongfeng Hui ◽

Junzhi Leng ◽

Dong Jin ◽

Di Liu ◽

Genwang Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Cycle Progression ◽

Immune Cell ◽

Gene Signature ◽

Cancer Genome ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Hallmarks Of Cancer ◽

Cycle Progression

Objective. Dysregulation of cell cycle progression (CCP) is one of the hallmarks of cancer. Here, our study is aimed at developing a CCP-derived gene signature for predicting high-risk population of hepatocellular carcinoma (HCC). Methods. Our study retrospectively analyzed the transcriptome profiling and clinical information of HCC patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) projects. Uni- and multivariate cox regression models were conducted for identifying which hallmarks of cancer were risk factors of HCC. CCP-derived gene signature was developed with LASSO method. The predictive efficacy was verified by ROC curves and subgroup analyses. A nomogram was then generated and validated by ROC, calibration, and decisive curves. Immune cell infiltration was estimated with ssGSEA method. Potential small molecular compounds were predicted via CTRP and CMap analyses. The response to chemotherapeutic agents was evaluated based on the GDSC project. Results. Among hallmarks of cancer, CCP was identified as a dominant risk factor for HCC prognosis. CCP-derived gene signature displayed the favorable predictive efficacy in HCC prognosis independent of other clinicopathological parameters. A nomogram was generated for optimizing risk stratification and quantifying risk evaluation. CCP-derived signature was in relation to immune cell infiltration, HLA, and immune checkpoint expression. Combining CTRP and CMap analyses, fluvastatin was identified as a promising therapeutic agent against HCC. Furthermore, CCP-derived signature might be applied for predicting the response to doxorubicin and gemcitabine. Conclusion. Collectively, CCP-derived gene signature was a promising marker in prediction of survival outcomes and therapeutic responses for HCC patients.

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