Bioinformatic and integrated analysis identifies an lncRNA–miRNA–mRNA interaction mechanism in gastric adenocarcinoma

As one of the most common malignant tumors worldwide, gastric adenocarcinoma (GC) and its prognosis are still poorly understood. Various genetic and epigenetic factors have been indicated in GC carcinogenesis. However, a comprehensive and in-depth investigation of epigenetic alteration in gastric cancer is still missing. In this study, we systematically investigated some key epigenetic features in GC, including DNA methylation and five core histone modifications. Data from The Cancer Genome Atlas Program and other studies (Gene Expression Omnibus) were collected, analyzed, and validated with multivariate statistical analysis methods. The landscape of epi-modifications in gastric cancer was described. Chromatin state transition analysis showed a histone marker shift in gastric cancer genome by employing a Hidden-Markov-Model based approach, indicated that histone marks tend to label different sets of genes in GC compared to control. An additive effect of these epigenetic marks was observed by integrated analysis with gene expression data, suggesting epigenetic modifications may cooperatively regulate gene expression. However, the effect of DNA methylation was found more significant without the presence of the five histone modifications in our study. By constructing a PPI network, key genes to distinguish GC from normal samples were identified, and distinct patterns of oncogenic pathways in GC were revealed. Some of these genes can also serve as potential biomarkers to classify various GC molecular subtypes. Our results provide important insights into the epigenetic regulation in gastric cancer and other cancers in general. This study describes the aberrant epigenetic variation pattern in GC and provides potential direction for epigenetic biomarker discovery.

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Integrated analysis and knockdown of RAB23 indicate the role of RAB23 in gastric adenocarcinoma

Annals of Translational Medicine ◽

10.21037/atm.2019.11.130 ◽

2019 ◽

Vol 7 (23) ◽

pp. 745-745

Author(s):

Hui Chen ◽

Dun Pan ◽

Zhihuang Yang ◽

Liangqing Li

Keyword(s):

Gastric Adenocarcinoma ◽

Integrated Analysis

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Network of “drug-target-SARS-CoV-2 Related Genes” Through Integrated Analysis of Pharmacology and Geo Database

10.21203/rs.3.rs-117894/v1 ◽

2020 ◽

Author(s):

Jin ping Hou ◽

Yong heng Wang ◽

Yu meng Chen ◽

Yi hao Chen ◽

Xiao Zhu ◽

...

Keyword(s):

Gene Therapy ◽

Molecular Docking ◽

Folic Acid ◽

Drug Target ◽

Drug Targets ◽

Interaction Mechanism ◽

Network Pharmacology ◽

Integrated Analysis ◽

Hub Genes ◽

Geo Database

Abstract BackgroundCoronavirus Disease 2019 (COVID-19) respiratory disease rapidly caused a global pandemic and social and economic disruption. The combination of Traditional Chinese medicine (TCM) and Conventional Western medicine (CWM) is more effective for COVID-19 treatment. Moreover, TCM and CWM are important data source for developing new drug targets and promote strategies treat SARS-CoV-2 infections. However, many studies have analyzed the therapeutic mechanism of CWM or TCM alone for COVID-19, it is still unclear the interaction mechanism between TCM and CWM on COVID-19.MethodsThis paper integrates network pharmacology and GEO database to mine and identify COVID-19 molecular therapeutic targets, providing potential targets and new ideas for COVID-19 gene therapy and new drug development. It includes: 1) using TCMSP, TTD, PubChem and CTD databases to analyze drug interactions and associated phenotypes for SARS-CoV-2, to correlate drug and disease interaction mechanisms to screen key drug targets; 2) using GEO database to correlate differential genes and drug targets to screen potential antiviral gene therapy targets, to construct regulatory network and key points of SARS-CoV-2 therapeutic drugs; 3) using computer simulation of molecular docking to screen virus-related proteins for new drugs. ResultsIntegrated analysis of network pharmacology discovered that baicalein, estrone and quercetin are the pivotal active ingredients in TCM and CWM. Combining drug target genes in pharmacology database and virus induced genes in GEO database, the result showed the core hub genes related to COVID-19: STAT1, IL1B, IL6, IL8, PTGS2 and NFKBIA, and these genes were significantly downregulated in A549 and NHBE cells by SARS-CoV-2 infection. Moreover, chemical interaction and molecular docking analysis of hub genes showed that folic acid might as be potential therapeutic drug for COVID-19 treatment, and SARS-CoV-2 nucleocapsid phosphoprotein was a potential drug target. The network of “drug-target-SARS-CoV-2 related genes” provide noval potential compounds and targets for further studies of SARS-CoV-2.ConclusionsIntegrated analysis of network pharmacology and big data mining provided noval potential compounds and targets for further studies of SARS-CoV-2. Our research implied folic acid and SARS-CoV-2 N as therapeutic target in TCM and CWM. Our research also suggests that targeting SARS-CoV-2 N protein is likely to be a common mechanism of TCM and CWM. On the one hand, the identification of pivotal genes provides a target for COVID-19 molecular therapy, on the other hand, it provides ideas for the analysis of interaction mechanism between virus and host.

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An integrated analysis of DNA promoter methylation, microRNA regulation, and gene expression in gastric adenocarcinoma

Annals of Translational Medicine ◽

10.21037/atm-21-3211 ◽

2021 ◽

Vol 0 (0) ◽

pp. 0-0

Author(s):

Hongyun Huang ◽

Lang Xie ◽

Xiaoxuan Feng ◽

Zheng Zheng ◽

Juntao Ouyang ◽

...

Keyword(s):

Gene Expression ◽

Gastric Adenocarcinoma ◽

Promoter Methylation ◽

Integrated Analysis ◽

Microrna Regulation

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Proteogenomic Landscape of Gastric Adenocarcinoma Peritoneal Metastases

10.21203/rs.3.rs-81037/v1 ◽

2020 ◽

Author(s):

Jaffer Ajani ◽

Shuangtao Zhao ◽

Ruiping Wang ◽

Shumei Song ◽

Makoto Kobayashi ◽

...

Keyword(s):

Protein Expression ◽

Gastric Adenocarcinoma ◽

Immune Cell ◽

Expression Patterns ◽

Integrated Analysis ◽

Cancer Genes ◽

Cell Extracts ◽

Cancer Testis Antigens ◽

Poor Outcomes ◽

Cancer Testis

Abstract Advanced gastric adenocarcinoma (GAC) often leads to peritoneal carcinomatosis (PC) and is associated with very poor outcomes. Therapeutic are limited and effective. Here we report the first proteogenomic study of PC cells from a prospective GAC cohort (n = 26 patients). A total of 16,449 proteins were detected from whole cell extracts (TCEs). PC cells could be classified based on the protein profiles alone into three distinct unsupervised clusters (tumor cell enriched, immune cell enriched and tumor-immune mixed) that differed in expression of oncogene/immune-related proteins. Integrated analysis revealed enriched biological pathways and notably, novel druggable targets (cancer-testis antigens, kinases, and receptors) that could be exploited to develop effective therapies and/or tumor stratifications. Systematic comparison of expression levels of proteins and mRNAs revealed novel expression patterns of key cancer genes notably high mRNA and low protein expression of HAVCR2, low mRNA but high protein expression of cancer testis antigens CTAGE1 and CTNNA2. These results inform strategies to target GAC vulnerabilities.

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Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response

Gut ◽

10.1136/gutjnl-2018-318070 ◽

2019 ◽

Vol 69 (1) ◽

pp. 18-31 ◽

Cited By ~ 13

Author(s):

Ruiping Wang ◽

Shumei Song ◽

Kazuto Harada ◽

Fatemeh Ghazanfari Amlashi ◽

Brian Badgwell ◽

...

Keyword(s):

T Cell ◽

Gastric Adenocarcinoma ◽

T Cell Activation ◽

Immune Checkpoint ◽

Copy Number ◽

Molecular Subtypes ◽

Integrated Analysis ◽

Rna Seq ◽

Response To Chemotherapy ◽

Novel Targets

ObjectivePeritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC’s development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets.DesignWe performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs.ResultsWe identified distinct alterations in PC versus primary GACs, such as more frequentCDH1 and TAF1mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations inTP53, CDH1, TAF1andKMT2C, higher level of ‘clock-like’ mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: ‘mesenchymal-like’ and ‘epithelial-like’ with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive ‘mesenchymal-like’ subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-β as potential therapeutic immune targets.ConclusionsWe have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.

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Genome-Wide Integrated Analysis Revealed Functions of lncRNA–miRNA–mRNA Interaction in Growth of Intermuscular Bones in Megalobrama amblycephala

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.603815 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yulong Chen ◽

Shiming Wan ◽

Qing Li ◽

Xiaoru Dong ◽

Jinghan Diao ◽

...

Keyword(s):

Growth Mechanism ◽

Messenger Rna ◽

Expression Profiles ◽

Economic Value ◽

Draft Genome ◽

Interaction Mechanism ◽

Cellular Level ◽

Megalobrama Amblycephala ◽

Integrated Analysis ◽

Growth Stages

Intermuscular bone (IB) occurs in the myosepta of teleosts. Its existence has an adverse influence on the edible and economic value of fish, especially for aquaculture species belonging to Cypriniformes. The growth mechanism of IBs is quite lacking. In this study, we firstly used single molecular real-time sequencing (SMRT) technology to improve the draft genome annotation and full characterization of the transcriptome for one typical aquaculture species, blunt snout bream (Megalobrama amblycephala). The long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) expression profiles in two IB growth stages (1 and 3 years old) were compared through transcriptome and degradome analyses. A total of 126 miRNAs, 403 mRNAs, and 353 lncRNAs were found to be differentially expressed between the two stages. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the significantly upregulated map2k6 and cytc in the MAPK/p53 signaling pathway and the significantly downregulated lama3 and thbs4b in the extracellular matrix (ECM)–receptor pathway may play a key regulatory role in IB growth. Bioinformatics analysis subsequently revealed 14 competing endogenous RNA (ceRNA) pairs related to the growth of IBs, consisting of 10 lncRNAs, 7 miRNAs, and 10 mRNAs. Of these, dre-miR-24b-3p and dre-miR-193b-3p are core regulatory factors interacting with four lncRNAs and three mRNAs, the interaction mechanism of which was also revealed by subsequent experiments at the cellular level. In conclusion, our data showed that IBs had higher activity of cell apoptosis and lower mineralization activity in IB_III compared to IB_I via interaction of MAPK/p53 and ECM–receptor signaling pathways. The downregulated zip1 interacted with miR-24a-3p and lnc017705, decreased osteoblast differentiation and Ca2+ deposition in the IB_III stage. Our identified functional mRNAs, lncRNAs, and miRNAs provide a data basis for in-depth elucidation of the growth mechanism of teleost IB.

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