miR-130-3p Promotes MTX-Induced Immune Killing of Hepatocellular Carcinoma Cells by Targeting EPHB4

The vast majority of primary hepatocellular cancer is hepatocellular carcinomas (HCCs). Currently, HCC is one of the more common cancers in humans, and it has a high mortality and disability rate. Mitoxantrone (MTX) is an antitumor drug that can block type II topoisomerase. It has been reported that immunogenic cell death evoked by MTX can induce the discharge of damage associated with molecular patterns (DAMPs) and subsequently influence immune cell infiltration in the tumor microenvironment. High mobilities aggregation box 1 (HMGB1) is the prototypical extracellular DAMP. Many cellular processes have been reported to involve EPHB4 receptor tyrosine kinases, but the relation of DAMP and EPHB4 is uncertain. In this research, we assessed the impact of miR-130-3p by Edu incorporation test on cell proliferation, and we have proven its impact on HCC cell migration through Transwell and wound healing tests. Flow cytometry was applied to study its influence on apoptosis. Luciferase report test was integrated in detecting the miR-130-3p target gene. The influence of miR-130-3p on the manifestation of classical DAMPs was studied, such as HMGB1, ATP, and Calreticulin. A coculture experiment was carried out to further confirm its effects on immune cell infiltration. The result displayed that miR-130-3p overexpression considerably facilitates apoptosis and suppresses the migration or proliferation of HCC cells. EPHB4 was confirmed as the target gene of miR-130-3p. Overexpression of this target gene promotes emission of Calreticulin, ATP, and HMGB1 and subsequently promotes DCs maturation and proliferation of CD4+ T cells. In summary, our results demonstrated that miR-130-3p inhibits HCC cell proliferation and migration by targeting EPHB4 and promotes drug-induced immunogenic cell death.

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WISP1 modulates immune cell infiltration upon drug-induced liver injury (DILI)

Zeitschrift für Gastroenterologie ◽

10.1055/s-0035-1567970 ◽

2015 ◽

Vol 53 (12) ◽

Author(s):

AB Widera ◽

L Pütter ◽

S Leserer ◽

G Campos ◽

K Rochlitz ◽

...

Keyword(s):

Liver Injury ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Drug Induced ◽

Drug Induced Liver Injury

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Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1804506115 ◽

2018 ◽

Vol 115 (50) ◽

pp. E11701-E11710 ◽

Cited By ~ 42

Author(s):

Yoong Wearn Lim ◽

Haiyin Chen-Harris ◽

Oleg Mayba ◽

Steve Lianoglou ◽

Arthur Wuster ◽

...

Keyword(s):

Gene Expression ◽

Cancer Immunotherapy ◽

Genetic Variants ◽

Immune Cell ◽

Response To Therapy ◽

Cell Infiltration ◽

Cancer Type ◽

Immune Cell Infiltration ◽

Durable Response ◽

The Impact

Cancer immunotherapy has emerged as an effective therapy in a variety of cancers. However, a key challenge in the field is that only a subset of patients who receive immunotherapy exhibit durable response. It has been hypothesized that host genetics influences the inherent immune profiles of patients and may underlie their differential response to immunotherapy. Herein, we systematically determined the association of common germline genetic variants with gene expression and immune cell infiltration of the tumor. We identified 64,094 expression quantitative trait loci (eQTLs) that associated with 18,210 genes (eGenes) across 24 human cancers. Overall, eGenes were enriched for their being involved in immune processes, suggesting that expression of immune genes can be shaped by hereditary genetic variants. We identified the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene as a pan-cancer type eGene whose expression levels stratified overall survival in a subset of patients with bladder cancer receiving anti–PD-L1 (atezolizumab) therapy. Finally, we identified 103 gene signature QTLs (gsQTLs) that were associated with predicted immune cell abundance within the tumor microenvironment. Our findings highlight the impact of germline SNPs on cancer-immune phenotypes and response to therapy; and these analyses provide a resource for integration of germline genetics as a component of personalized cancer immunotherapy.

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Analyzing the Impact of ATF3 in Tumorigenesis and Immune Cell Infiltration of Ovarian Tumor: A Bioinformatics Study

10.21203/rs.3.rs-471861/v1 ◽

2021 ◽

Author(s):

Xiujuan wu

Keyword(s):

Ovarian Tumor ◽

Immune Cell ◽

Interaction Network ◽

Critical Factor ◽

Gene Set Enrichment Analysis ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Transcription Activator ◽

Critical Pathways ◽

The Impact

Abstract ATF3 is an essential transcription activator in regulating cancer-related genetic expression. To identify the role of ATF3 in ovarian, we investigated the correlation between ATF3 expression and the clinicopathological properties using multiple database. The cBioPortal and GEPIA database displayed the clinical information of ovarian patients harboring or without harboring ATF3 mutation. Furthermore, we assessed the relationship between survival and ATF3 expression level using Kaplan-Meier plotter, which reveals that the ovarian patients with higher expression of ATF3 suffered the worse overall survival and progression-free survival. The differentially expressed genes were analyzed using Gene Ontology, protein-protein interaction network and gene set enrichment analysis to identify the hub gene and critical pathways, significantly affecting the tumorigenesis of ovarian tumor. Finally, we assessed the correlation between ATF3 and immune cell infiltration using Tumor Immunoassay Resource (TIMER) database. The results demonstrated that higher expression is positive correlation with macrophage infiltration, expression for M1 and M2 type macrophages. Our study suggests that ATF3 can regulate the cell cycle and heme-related oxidative phosphorylation process, and it may be a critical factor to regulate the macrophage cell to be infiltrated into ovarian cancer. ATF3 can be as a biomarker for diagnosis and therapy of ovarian.

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Opposite Roles of Tumor Cell Proliferation and Immune Cell Infiltration in Postoperative Liver Metastasis of PDAC

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.714718 ◽

2021 ◽

Vol 9 ◽

Author(s):

Guangfu Wang ◽

Shangnan Dai ◽

Hao Gao ◽

Yong Gao ◽

Lingdi Yin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Immune Response ◽

Cell Proliferation ◽

T Cells ◽

Liver Metastasis ◽

Tumor Cell ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Tumor Cell Proliferation

BackgroundRecurrence of liver metastasis after pancreatectomy is often a predictor of poor prognosis. Comprehensive genomic analysis may contribute to a better understanding of the molecular mechanisms of postoperative liver metastasis and provide new therapeutic targets.MethodsA total of 67 patients from The Cancer Genome Atlas (TCGA) were included in this study. We analyzed differentially expressed genes (DEGs) by R package “DESeq2.” Weighted gene co-expression network analysis (WGCNA) was applied to investigate the key modules and hub genes. Immunohistochemistry was used to analyze tumor cell proliferation index and CD4+ T cells infiltration.ResultsFunctional analysis of DEGs between the liver metastatic and recurrence-free groups was mainly concentrated in the immune response. The liver metastasis group had lower immune and stroma scores and a higher TP53 mutation rate. WGCNA showed that the genes in key modules related to disease-free survival (DFS) and overall survival (OS) were mainly enriched in the cell proliferation process and tumor immune response. Immunohistochemical analysis showed that the pancreatic cancer cells of patients with early postoperative liver metastasis had higher proliferative activity, while the infiltration of CD4+ T cells in tumor specimens was less.ConclusionOur study suggested that increased immune cell infiltration (especially CD4+ T cells) and tumor cell proliferation may play an opposite role in liver metastasis recurrence after pancreatic cancer.

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INHBA is A Novel Prognostic Biomarker And Correlated With Immune Infiltrates In Gastric Cancer

10.21203/rs.3.rs-877929/v1 ◽

2021 ◽

Author(s):

Weifeng Yu ◽

Zishao Zhong ◽

Guihua He ◽

Wang Zhang ◽

Zhenhao Ye ◽

...

Keyword(s):

Gastric Cancer ◽

Extracellular Matrix ◽

Immune Cell ◽

Prognostic Biomarker ◽

Curve Analysis ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Collagen Formation ◽

Matrix Organization ◽

The Impact

Abstract Background: Inhibin subunit beta A (INHBA) is reportedly a potential prognostic biomarker for a variety of cancers. However, its role in gastric cancer (GC) remains elusive. Methods: The expression of INHBA in GC and healthy tissues based on the data obtained from the UCSC Xena database. Logistic regression and Cox regression was performed to explore the correlation between clinical indicators and INHBA expression. Kaplan–Meier curve analysis was performed to assess the impact of INHBA expression on overall survival(OS). In addition, Received operating characteristic curve analysis was implied to clarify the diagnostic role of INHBA in GC. Functional analyses were conducted to explain the potential functions and enrichment pathways for INHBA. TIMER and GEPIA databases were used to calculate the confidence between INHBA and immune cell infiltration in GC. Results: INHBA was upregulated in GC(P < 0.001) and associated with a poor prognosis(P = 0.037). INHBA expression was an independent risk factor for OS(P = 0.004). Additionally, INHBA was a potential diagnostic marker in GC(AUC=0.961) and it was associated with extracellular matrix organization, response to growth factor, and cell-substrate adhesion. Tumor-associated signaling pathways, such as Wnt, Hippo, and p53, were associated with INHBA. Reactome pathways, such as collagen formation and extracellular matrix organization, were significantly enriched. Moreover, high INHBA expression displayed a strong correlation with immune cell infiltration, especially with macrophage infiltration in GC.Conclusions: INHBA could be a potential prognostic biomarker for GC and may drive the abnormal activity of critical cancer-associated pathways, potentially contributing to immune cell infiltration to promote GC development and becoming a new drug target for targeted GC therapies.

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Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats

10.1101/2021.10.21.465383 ◽

2021 ◽

Author(s):

Kaori Oka ◽

Shusuke Fujioka ◽

Yoshimi Kawamura ◽

Yoshihiro Komohara ◽

Takeshi Chujo ◽

...

Keyword(s):

Cell Death ◽

Inflammatory Response ◽

Immune Cell ◽

Resistance Mechanism ◽

Chemical Carcinogenesis ◽

Cell Infiltration ◽

Necrotic Cell Death ◽

Immune Cell Infiltration ◽

Cancer Resistance ◽

Necrotic Cell

Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted scientists to study their cancer resistance mechanisms in order to provide clues for human cancer prevention. Although cancer resistance in NMRs has been intensively investigated at the cellular level, it is still unknown how strongly resistant NMR individuals are to carcinogenesis and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration and reduced induction of inflammatory genes. NMRs harbor loss-of-function mutations in receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. A necroptosis-inducing stimulus did not increase death of NMR cells. After carcinogenic insults, leakage of the HMGB1, a marker of necrotic cell death, was not increased in NMR skin. In mice, inhibition or knockout of RIPK3 reduced immune cell infiltration and delayed the onset of chemical carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs. Further in vivo study of the unusual tissue immune system and carcinogenesis resistance of NMRs may lead to the development of new strategies to prevent carcinogenesis in humans.

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TAMI-17. RELATIONSHIP BETWEEN IRON METABOLISM, IMMUNE CELL INFILTRATION AND SEX-BASED SURVIVAL DIFFERENCES IN GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.906 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii216-ii216

Author(s):

Darya Nesterova ◽

Sang Lee ◽

Brad Zacharia ◽

Elizabeth Proctor ◽

Justin Lathia ◽

...

Keyword(s):

Gene Expression ◽

Immune Cell ◽

Iron Regulation ◽

Cell Infiltration ◽

Low Grade ◽

Immune Cell Infiltration ◽

Male And Female ◽

Mitochondrial Aconitase ◽

Survival Differences ◽

The Impact

Abstract Iron plays a central role in cellular metabolism, both in normal cellular functioning and in tumorigenesis. Recent evidence has shown sex-based survival differences in glioblastoma (GBM) may be related to differential expression of metabolism genes. We previously reported the iron regulating gene, HFE, was shown to have a sex-based survival impact in both low-grade gliomas and GBM. We additionally found that females with low HFE expressing tumors have significantly higher survival than males in GBM. To evaluate the relationship between iron gene expression and sex-based survival differences in GBM, we analyzed TCGA GBM gene expression and clinical data. We first analyzed the impact of iron genes on sex-based survival. In addition to HFE, FTL, TFRC, TF, and SLC39A8 (ZIP8), also showed sex-based survival differences. We then compared correlations of HFE and other iron genes to identify whether male and female GBMs differ in iron regulation and metabolism. HFE expression is significantly positively correlated with HMOX1, SLC25A28, SLC11A2, FTH1, HAMP, and TFR2 only in females. Alternatively, HFE expression is negatively correlated with ACO2 (mitochondrial aconitase) in males and ACO1 (cytoplasmic aconitase) in females. We noted that the expression of certain iron genes was highly associated with immune cell infiltration based on sex. TFR2, LRP1, and XIST expression were negatively correlated with low immune cell infiltration in females, but not males. Alternatively, in males, SLC11A2, ACO2, FOXO1, HIF1a, and HAMP genes were negatively correlated with immune infiltration. This suggests that differences in iron regulation between males and females may be contributing to differences in immune function and subsequent survival in GBM. These data suggest that the iron signature of a tumor reflects and possibly drives the metabolic and immune landscape of the tumor microenvironment thereby directly impacting survival differences between male and female GBMs.

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ZBTB7A, a potential biomarker for prognosis and immune infiltrates, inhibits progression of endometrial cancer based on bioinformatics analysis and experiments

Cancer Cell International ◽

10.1186/s12935-020-01600-5 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Rong Geng ◽

Yuhua Zheng ◽

Donghua zhou ◽

Qingdong Li ◽

Ruiman Li ◽

...

Keyword(s):

Cell Proliferation ◽

Endometrial Cancer ◽

Zinc Finger Protein ◽

Immune Cell ◽

Vital Role ◽

Cell Infiltration ◽

Marker Genes ◽

Immune Cell Infiltration ◽

Potential Biomarker

Abstract Backgroud ZBTB protein is an important member of the C2H2 zinc finger protein family. As a transcription factor, it is widely involved in the transcriptional regulation of genes, cell proliferation, differentiation, and apoptosis. The ZBTB7A has been largely linked to different kinds of tumors due to its diverse function. However, the value for ZBTB7A in uterine corpus endometrial carcinoma (UCEC) is unclear. Methods In our work, we assessed the importance of ZBTB7A in UCEC. Firstly, Using Oncomine and Tumor Immunoassay Resource (TIMER) databases to evaluate the expression of ZBTB7A. Secondly, we explored the co-expression network of ZBTB7A through the cBioPortal online tool, Metascape, and LinkedOmics. TIMER was also used to explore the relationship between ZBTB7A and tumor immune invasion, and to detect the correlation between the ZBTB7A and the marker genes related to immune infiltration. Finally, CCK8, migration, ChIP assays were introduced to partly validate ZBTB7A function in endometrial cancer cells. Results We found the ZBTB7A expression in TIMER was associated with various cancers, especially UCEC. The decreased expression of ZBTB7A was markedly related to the stage and prognosis of UCEC. Furthermore, ZBTB7A was also related to the expression of various immune markers such as Neutrophils, Dendritic cell, T cell (general), Th1, Th2, and Treg. Finally, we verified that ZBTB7A repressed E2F4 transcription and inhibited cells proliferation and migration. These results indicate that ZBTB7A may play a vital role in regulating immune cell infiltration in UCEC, and is a valuable prognostic marker. Conclusions In summary, we demonstrate that ZBTB7A is notably downregulated in UCEC, plays a vital role in regulating immune cell infiltration, possesses diagnostic and prognostic values and attenuates E2F4 transcription and cell proliferation, migration in vitro.

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