A prospective study revealing the role of an immune-related eRNA, WAKMAR2, in breast cancer

AbstractEnhancer RNAs (eRNAs) are a subclass of non-coding RNAs that are generated during the transcription of enhancer regions and play an important role in tumourigenesis. In this study, we focused on the crucial eRNAs that participate in immune responses in invasive breast cancer (IBC). We first used The Cancer Genome Atlas and Human enhancer RNA Atlas to screen for tissue-specific eRNAs and their target genes. Through Pearson correlation analysis with immune genes, the eRNA WAKMAR2 was identified as a key candidate involved in IBC. Our further research suggested that WAKMAR2 is crucial in regulating the tumour microenvironment and may function by regulating immune-related genes, including IL27RA, RAC2, FABP7, IGLV1-51, IGHA1, and IGHD. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of WAKMAR2 in IBC and normal tissues, and the effect of WAKMAR2 on the regulation of downstream genes in MB-231 and MCF7 cells was studied in vitro. WAKMAR2 was found to be highly involved in tumour immunity and was downregulated in IBC tissues. Furthermore, the expression of WAKMAR2 and its target genes was observed at the pan-cancer level. This study provides evidence to suggest new potential targets for the treatment of breast cancer.

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The human intermediate prolactin receptor is a mammary proto-oncogene

npj Breast Cancer ◽

10.1038/s41523-021-00243-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Jacqueline M. Grible ◽

Patricija Zot ◽

Amy L. Olex ◽

Shannon E. Hedrick ◽

J. Chuck Harrell ◽

...

Keyword(s):

Breast Cancer ◽

Prolactin Receptor ◽

The Cancer Genome Atlas ◽

Cancer Tissue ◽

Mcf7 Cells ◽

Cancer Pathogenesis ◽

Cancer Genome Atlas ◽

Alternatively Spliced

AbstractThe hormone prolactin (PRL) and its receptor (hPRLr) are significantly involved in breast cancer pathogenesis. The intermediate hPRLr (hPRLrI) is an alternatively-spliced isoform, capable of stimulating cellular viability and proliferation. An analogous truncated mouse PRLr (mPRLr) was recently found to be oncogenic when co-expressed with wild-type mPRLr. The goal of this study was to determine if a similar transforming event occurs with the hPRLr in human breast epithelial cells and to better understand the mechanism behind such transformation. hPRLrL+I co-expression in MCF10AT cells resulted in robust in vivo and in vitro transformation, while hPRLrI knock-down in MCF7 cells significantly decreased in vitro malignant potential. hPRLrL+I heterodimers displayed greater stability than hPRLrL homodimers, and while being capable of activating Jak2, Ras, and MAPK, they were unable to induce Stat5a tyrosine phosphorylation. Both immunohistochemical breast cancer tissue microarray data and RNA sequencing analyses using The Cancer Genome Atlas (TCGA) identified that higher hPRLrI expression associates with triple-negative breast cancer. These studies indicate the hPRLrI, when expressed alongside hPRLrL, participates in mammary transformation, and represents a novel oncogenic mechanism.

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Identification of novel cell glycolysis related gene signature predicting survival in patients with breast cancer

Scientific Reports ◽

10.1038/s41598-021-83628-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Feng Jiang ◽

Chuyan Wu ◽

Ming Wang ◽

Ke Wei ◽

Jimei Wang

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Cox Regression ◽

Single Gene ◽

Prediction Method ◽

Gene Signature ◽

The Cancer Genome Atlas ◽

Cox Models ◽

Normal Tissues ◽

Predictive Risk

AbstractOne of the most frequently identified tumors and a contributing cause of death in women is breast cancer (BC). Many biomarkers associated with survival and prognosis were identified in previous studies through database mining. Nevertheless, the predictive capabilities of single-gene biomarkers are not accurate enough. Genetic signatures can be an enhanced prediction method. This research analyzed data from The Cancer Genome Atlas (TCGA) for the detection of a new genetic signature to predict BC prognosis. Profiling of mRNA expression was carried out in samples of patients with TCGA BC (n = 1222). Gene set enrichment research has been undertaken to classify gene sets that vary greatly between BC tissues and normal tissues. Cox models for additive hazards regression were used to classify genes that were strongly linked to overall survival. A subsequent Cox regression multivariate analysis was used to construct a predictive risk parameter model. Kaplan–Meier survival predictions and log-rank validation have been used to verify the value of risk prediction parameters. Seven genes (PGK1, CACNA1H, IL13RA1, SDC1, AK3, NUP43, SDC3) correlated with glycolysis were shown to be strongly linked to overall survival. Depending on the 7-gene-signature, 1222 BC patients were classified into subgroups of high/low-risk. Certain variables have not impaired the prognostic potential of the seven-gene signature. A seven-gene signature correlated with cellular glycolysis was developed to predict the survival of BC patients. The results include insight into cellular glycolysis mechanisms and the detection of patients with poor BC prognosis.

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Evaluation of the prognostic value of CBXs in gastric cancer patients

Scientific Reports ◽

10.1038/s41598-021-91649-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mengya He ◽

Limin Yue ◽

Haiyan Wang ◽

Feiyan Yu ◽

Mingyang Yu ◽

...

Keyword(s):

Gastric Cancer ◽

Target Genes ◽

Prognostic Significance ◽

Disease Free Survival ◽

Genetic Alterations ◽

Genetic Mutation ◽

The Cancer Genome Atlas ◽

Normal Tissues ◽

Interactive Analysis ◽

Gastric Cancer Patients

AbstractChromobox (CBX) proteins were suggested to exert epigenetic regulatory and transcriptionally repressing effects on target genes and might play key roles in the carcinogenesis of a variety of carcinomas. Nevertheless, the functions and prognostic significance of CBXs in gastric cancer (GC) remain unclear. The current study investigated the roles of CBXs in the prognosis of GC using the Oncomine, The Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, The Cancer Genome Atlas (TCGA), and cBioPortal databases. CBX1/2/3/4/5 were significantly upregulated in GC tissues compared with normal tissues, and CBX7 was downregulated. Multivariate analysis showed that high mRNA expression levels of CBX3/8 were independent prognostic factors for prolonged OS in GC patients. In addition, the genetic mutation rate of CBXs was 37% in GC patients, and genetic alterations in CBXs showed no association with OS or disease-free survival (DFS) in GC patients. These results indicated that CBX3/8 can be prognostic biomarkers for the survival of GC patients.

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YWHAZ interacts with DAAM1 to promote cell migration in breast cancer

Cell Death Discovery ◽

10.1038/s41420-021-00609-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Jie Mei ◽

Yan Liu ◽

Xinqian Yu ◽

Leiyu Hao ◽

Tao Ma ◽

...

Keyword(s):

Breast Cancer ◽

Poor Prognosis ◽

Molecular Mechanisms ◽

Transcriptional Regulator ◽

Expression Levels ◽

Functional Roles ◽

Normal Tissues ◽

Rhoa Activation ◽

Promote Cell Migration

AbstractDishevelled-associated activator of morphogenesis 1 (DAAM1) is a critical driver in facilitating metastasis in breast cancer (BrCa). However, molecular mechanisms for the regulation of DAAM1 activation are only partially elucidated. In this research, the expression levels of YWHAZ and DAAM1 were examined by immunohistochemistry (IHC) staining in BrCa tissues. The functional roles of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ)–DAAM1 axis and their regulator microRNA-613 (miR-613) in BrCa cells and associated molecular mechanisms were demonstrated in vitro. As results, the expression levels of DAAM1 and YWHAZ were significantly upregulated in BrCa tissues compared with normal tissues and remarkably associated with poor prognosis. Besides, DAAM1 and YWHAZ were positively correlated with each other in BrCa tissues. YWHAZ interacted and colocalized with DAAM1 in BrCa cells, which was essential for DAAM1-mediated microfilament remodeling and RhoA activation. Moreover, miR-613 directly targeted both YWHAZ and DAAM1, contributing to inhibiting BrCa cells migration via blocking the complex of YWHAZ–DAAM1. To sum up, these data reveal that YWHAZ regulates DAAM1 activation, and the YWHAZ–DAAM1 complex is directly targeted by the shared post-transcriptional regulator miR-613.

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Hypermethylation of APC2 Is a Predictive Epigenetic Biomarker for Chinese Colorectal Cancer

Disease Markers ◽

10.1155/2018/8619462 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Yuan He ◽

Li-Yue Sun ◽

Jing Wang ◽

Rui Gong ◽

Qiong Shao ◽

...

Keyword(s):

Colorectal Cancer ◽

Cox Regression ◽

The Cancer Genome Atlas ◽

Sequencing Analysis ◽

Primary Tumors ◽

Protein Levels ◽

Normal Tissues ◽

Ffpe Tissues ◽

Epigenetic Biomarker

Objective. To investigate methylation of the adenomatosis polyposis coli homologue (APC2) promoter and its correlation with prognostic implications in Chinese colorectal cancer (CRC). Methods. The mRNA expression of APC2 in colorectal tissues was evaluated using the database of The Cancer Genome Atlas (TCGA). Methylation analysis of APC2 in tumor (n=66) and corresponding adjacent formalin-fixed and paraffin-embedded (FFPE) tissues (n=44) was performed by Sequenom EpiTYPER® and verified by cloning-based bisulfite sequencing analysis. Demethylation and retrieval of APC2 expression in cell lines HT29, HCT116, and SW480 were treated with 5-aza-2′-deoxycytidine (5-AZC). Results. Analysis of TCGA showed that APC2 mRNA was significantly downregulated in primary tumors when compared to normal tissues (p<0.05). APC2 methylation was upregulated (43.93% vs 7.31%, p<0.05) in tumors compared to adjacent FFPE tissues. In vitro experiments demonstrated that 5-AZC downregulated the methylation of APC2 and retrieved its expression of mRNA and protein levels (p<0.05). Multivariate Cox regression indicated that APC2_CPG_14 was an independent risk factor for overall survival (HR = 6.38, 95% CI: 1.59–25.64, p<0.05). Conclusion. This study indicates that APC2 is hypermethylated and may be a tumorigenesis biomarker for Chinese CRC patients.

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CTPS1 promotes malignant progression of triple-negative breast cancer with transcriptional activation by YBX1

Journal of Translational Medicine ◽

10.1186/s12967-021-03206-5 ◽

2022 ◽

Vol 20 (1) ◽

Author(s):

Yuxiang Lin ◽

Jie Zhang ◽

Yan Li ◽

Wenhui Guo ◽

Lili Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Triple Negative Breast Cancer ◽

Transcriptional Activation ◽

Triple Negative ◽

Pearson Correlation ◽

Disease Free Survival ◽

Luciferase Reporter

Abstract Background Cytidine nucleotide triphosphate synthase 1 (CTPS1) is a CTP synthase which play critical roles in DNA synthesis. However, its biological regulation and mechanism in triple-negative breast cancer (TNBC) has not been reported yet. Methods The expression of CTPS1 in TNBC tissues was determined by GEO, TCGA databases and immunohistochemistry (IHC). The effect of CTPS1 on TNBC cell proliferation, migration, invasion, apoptosis and tumorigenesis were explored in vivo and in vitro. In addition, the transcription factor Y-box binding protein 1 (YBX1) was identified by bioinformatics methods, dual luciferase reporter and chromatin immunoprecipitation (CHIP) assays. Pearson correlation analysis was utilized to assess the association between YBX1 and CTPS1 expression. Results CTPS1 expression was significantly upregulated in TNBC tissues and cell lines. Higher CTPS1 expression was correlated with a poorer disease-free survival (DFS) and overall survival (OS) in TNBC patients. Silencing of CTPS1 dramatically inhibited the proliferation, migration, invasion ability and induced apoptosis of MDA-MB-231 and HCC1937 cells. Xenograft tumor model also indicated that CTPS1 knockdown remarkably reduced tumor growth in mice. Mechanically, YBX1 could bind to the promoter of CTPS1 to promote its transcription. Furthermore, the expression of YBX1 was positively correlated with CTPS1 in TNBC tissues. Rescue experiments confirmed that the enhanced cell proliferation and invasion ability induced by YBX1 overexpression could be reversed by CTPS1 knockdown. Conclusion Our data demonstrate that YBX1/CTPS1 axis plays an important role in the progression of TNBC. CTPS1 might be a promising prognosis biomarker and potential therapeutic target for patients with triple-negative breast cancer.

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Identification and Validation of an Immune-Related eRNA Prognostic Signature for Hepatocellular Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.657051 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shenglan Cai ◽

Xingwang Hu ◽

Ruochan Chen ◽

Yiya Zhang

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Cells ◽

Cox Regression ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Roc Curves ◽

The Cancer Genome Atlas ◽

Immune Checkpoints ◽

Immune Genes ◽

Normal Tissues

BackgroundEnhancer RNAs (eRNAs) are intergenic long non-coding RNAs (lncRNAs) that participate in the progression of malignancies by targeting tumor-related genes and immune checkpoints. However, the potential role of eRNAs in hepatocellular carcinoma (HCC) is unclear. In this study, we aimed to construct an immune-related eRNA prognostic model that could be used to prospectively assess the prognosis of patients with HCC.MethodsGene expression profiles of patients with HCC were downloaded from The Cancer Genome Atlas (TCGA). The eRNAs co-expressed from immune genes were identified as immune-related eRNAs. Cox regression analyses were applied in a training cohort to construct an immune-related eRNA signature (IReRS), that was subsequently used to analyze a testing cohort and combination of the two cohorts. Kaplan-Meier and receiver operating characteristic (ROC) curves were used to validate the predictive effect in the three cohorts. Gene Set Enrishment Analysis (GSEA) computation was used to identify an IReRS-related signaling pathway. A web-based cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) computation was used to evaluate the relationship between the IReRS and infiltrating immune cells.ResultsA total of sixty-four immune-related eRNAs (IReRNAs) was identified in HCC, and 14 IReRNAs were associated with overall survival (OS). Five IReRNAs were used for constructing an immune-related eRNA signature (IReRS), which was shown to correlate with poor survival and to be an independent prognostic biomarker for HCC. The GSEA results showed that the IReRS was correlated to cancer-related and immune-related pathways. Moreover, we found that IReRS was correlated to infiltrating immune cells, including CD8+ T cells and M0 macrophages. Finally, differential expressions of the five risk IReRNAs in tumor tissues vs. adjacent normal tissues and their prognostic values were verified, in which the AL445524.1 may function as an oncogene that affects prognosis partly by regulating CD4-CLTA4 related genes.ConclusionOur results suggest that the IReRS could serve as a biomarker for predicting prognosis in patients with HCC. Additionally, it may be correlated to the tumor immune microenvironment and could also be used as a biomarker in immunotherapy for HCC.

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The glycobiological landscape of breast cancer: insights into galectins and O-GlcNAc homeostasis-related genes

10.21203/rs.3.rs-898135/v1 ◽

2021 ◽

Author(s):

Rada Tazhitdinova ◽

Alexander V Timoshenko

Keyword(s):

Breast Cancer ◽

Cancer Biology ◽

Breast Cancer Subtype ◽

The Cancer Genome Atlas ◽

Correlation Relationship ◽

Cancer Data ◽

Normal Tissues ◽

Genes Encoding ◽

Genetic Landscape ◽

Cancer Tissues

Abstract Purpose This study aimed to assess the functional associations between genes of the glycobiological landscape encoding galectins and O-GlcNAc cycle enzymes in the context of breast cancer biology and clinical applications. Methods An in silico analysis of the breast cancer data from The Cancer Genome Atlas was conducted comparing expression, pairwise correlations, and prognostic value for 17 genes encoding galectins, O-GlcNAc cycle enzymes, and cell stemness-related transcription factors. Results Multiple general and breast cancer subtype-specific differences in galectin/O-GlcNAc genetic landscape markers were observed and classified. Specifically, LGALS12 was found to be significantly downregulated in breast cancer tissues across all subtypes while LGALS2 and GFPT1 showed potential as prognostic markers. Remarkably, there was an overall loss of both correlation strength and correlation relationship between expression of galectin/O-GlcNAc landscape genes in the breast cancer samples versus normal tissues. Six gene pairs (GFPT1/LGALS1, GFPT1/LGALS3, GFPT1/LGALS12, GFPT1/KLF4, OGT/LGALS12, and OGT/KLF4) were found to be potential diagnostic markers for breast cancer. Conclusions These findings indicate that the glycobiological landscape of breast cancer underwent significant remodeling, which might be associated with switching galectin gene regulation within a framework of O-GlcNAc homeostasis.

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RACK1 Acts as a Potential Tumor Promoter in Colorectal Cancer

Gastroenterology Research and Practice ◽

10.1155/2019/5625026 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8

Author(s):

Xue-Yang Li ◽

Yi Hu ◽

Nian-Shuang Li ◽

Jian-Hua Wan ◽

Yin Zhu ◽

...

Keyword(s):

Colorectal Cancer ◽

The Cancer Genome Atlas ◽

Biological Role ◽

Tumor Promoter ◽

Migration And Invasion ◽

Loss Of Function ◽

Normal Tissues ◽

Geo Dataset

Background. The receptor of activated protein kinase C 1 (RACK1) promotes the progression and invasion of several cancers. However, the role of RACK1 in the pathogenesis of colorectal cancer (CRC) has not been clearly defined. Herein, we aimed to investigate the biological role of RACK1 in CRC. Materials and Methods. The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset were searched, and the expression of RACK1 in CRC tissues and adjacent normal tissues was evaluated. Immunohistochemical staining was performed to detect the expression of RACK1 in human CRC, adenoma, and normal tissues. Western blotting was used to detect the expression of RACK1 in human CRC cell lines. Functional assays, such as BrdU, colony formation, and wound healing and transwell invasion assays, were used to explore the biological role of RACK1 in CRC. Results. RACK1 was upregulated in CRC tissues compared with its expression in adjacent normal tissues in TCGA and the GEO dataset (P<0.05). Moreover, RACK1 was significantly overexpressed in CRC and adenoma tissues compared with its expression in normal tissues (P<0.05). Loss-of-function experiments showed that RACK1 promoted cell proliferation, migration, and invasion in vitro. Conclusions. Our data indicated that RACK1, as an oncogene, markedly promoted the progression of CRC, which suggested that RACK1 is a potential therapeutic target for CRC management.

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In Vivo and In Vitro Evaluation of the Protective Effects of Hesperidin in Lipopolysaccharide-Induced Inflammation and Cytotoxicity of Cell

Molecules ◽

10.3390/molecules25030478 ◽

2020 ◽

Vol 25 (3) ◽

pp. 478 ◽

Cited By ~ 6

Author(s):

Rasha Al-Rikabi ◽

Hanady Al-Shmgani ◽

Yaser Hassan Dewir ◽

Salah El-Hendawy

Keyword(s):

Breast Cancer ◽

Chromatin Condensation ◽

Control Group ◽

Potential Candidate ◽

Dependent Manner ◽

Protective Effects ◽

Mcf7 Cells ◽

Tnf Α

(1) Background: Plant flavonoids are efficient in preventing and treating various diseases. This study aimed to evaluate the ability of hesperidin, a flavonoid found in citrus fruits, in inhibiting lipopolysaccharide (LPS) induced inflammation, which induced lethal toxicity in vivo, and to evaluate its importance as an antitumor agent in breast cancer. The in vivo experiments revealed the protective effects of hesperidin against the negative LPS effects on the liver and spleen of male mice. (2) Methods: In the liver, the antioxidant activity was measured by estimating the concentration of glutathione (GSH) and catalase (CAT), whereas in spleen, the concentration of cytokines including IL-33 and TNF-α was measured. The in vitro experiments including MTT assay, clonogenity test, and sulforhodamine 101 stain with DAPI (4′, 6-diamidino-2-phenylindole) were used to assess the morphological apoptosis in breast cancer cells. (3) Results: The results of this study revealed a significant increase in the IL-33 and TNF-α cytokine levels in LPS challenged mice along with a considerable elevation in glutathione (GSH); moreover, the catalase (CAT) level was higher compared to that of the control group. Cytotoxicity of the MCF-7 cell line revealed significant differences among the groups treated with different concentrations when compared to the control groups, in a concentration-dependent manner. Hesperidin significantly inhibited the colony formation of MCF7 cells when compared to that of control. Clear changes were observed in the cell shape, including cell shrinkage and chromatin condensation, which were associated with a later apoptotic stage. (4) Conclusion: The results indicate that hesperidin might be a potential candidate in preventing diseases.

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