Comprehensive analysis of suppressor of cytokine signaling proteins in human breast Cancer

Abstract Background Abnormal expression of suppressor of cytokine signaling (SOCS) proteins regulates tumor angiogenesis and development in cancers. In this study, we aimed to perform a comprehensive bioinformatic analysis of SOCS proteins in breast invasive carcinoma (BRCA). Methods The gene expression, methylation level, copy number, protein expression and patient survival data related to SOCS family members in BRCA patients were obtained from the following databases: Oncomine, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), PCViz, cBioPortal and Kaplan-Meier plotter. Correlation analyses, identification of interacting genes and construction of regulatory networks were performed by functional and pathway enrichment analyses, weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA). Results Data related to 1109 BRCA tissues and 113 normal breast tissue samples were extracted from the TCGA database. SOCS2 and SOCS3 exhibited significantly lower mRNA expression levels in BRCA tissues than in normal tissues. BRCA patients with high mRNA levels of SOCS3 (p < 0.01) and SOCS4 (p < 0.05) were predicted to have significantly longer overall survival (OS) times. Multivariate analysis showed that SOCS3 was an independent prognostic factor for OS. High mRNA expression levels of SOCS2 (p < 0.001), SOCS3 (p < 0.001), and SOCS4 (p < 0.01), and a low expression level of SOCS5 (p < 0.001) were predicted to be significantly associated with better recurrence-free survival (RFS). Multivariate analysis showed that SOCS2 was an independent prognostic factor for RFS. Lower expression levels of SOCS2 and SOCS3 were observed in patients with tumors of more advanced clinical stage (p < 0.05). Functional and pathway enrichment analyses, together with WGCNA and GSEA, showed that SOCS3 and its interacting genes were significantly involved in the JAK-STAT signaling pathway, suggesting that JAK-STAT signaling might play a critical role in BRCA angiogenesis and development. Western blot results showed that overexpression of SOCS3 inhibited the activity of the JAK-STAT signaling pathway in vitro. Conclusions SOCS family proteins play a very important role in BRCA. SOCS3 may be a prognostic factor and SOCS2 may be a potential therapeutic target in breast cancer.

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Comprehensive Analysis of the Expression and Prognostic Significance of THBSs in Breast Cancer

10.21203/rs.3.rs-620437/v1 ◽

2021 ◽

Author(s):

Jun Wang ◽

Xuebing Zhan ◽

Qian Luo ◽

Yunshu Kuang ◽

Xiao Liang ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Protein Expression ◽

Cancer Patients ◽

Prognostic Value ◽

Breast Cancer Patients ◽

Free Survival ◽

Expression Levels ◽

Cancer Tissues ◽

Mrna Expression Levels

Abstract Background: Breast cancer is one of the most common tumors for women worldwide. Thrombospondins (THBSs) are reported to play important roles in various cellular processes and are involved in the occurrence and development of human cancers. However, the expression and prognostic value of THBSs family in breast cancer remain unclear.Methods: In this study, we examined the genes and protein expression levels of THBSs and their prognostic value by synthesizing several mainstream databases, including Oncomine, Human Protein Atlas (HPA), UALCAN, and KM Plotter. We also analyzed THBS interaction networks, genetic alterations, functional enrichment, and drug sensitivity with several publicly accessible databases, including GEPIA, GeneMANIA, STRING, cBioPortal, Metascape and NCI-60 database.Results: The results showed that the mRNA expression levels of THBS1, THBS2, THBS3, and THBS5 in breast cancer tissues were significantly higher than in normal tissues. The mRNA expression levels of THBS4 were different in different subtypes of breast cancer, and the protein expression levels of THBS1, THBS2, and THBS4 in breast cancer tissues were higher than in normal breast tissues. Survival analysis showed that breast cancer patients with high THBS1 gene expression showed worse overall survival (OS), relapse-free survival (RFS), and post-progression survival (PPS), and breast cancer patients with high THBS2 gene expression also showed worse RFS. Conversely, lower THBS3 levels predicted worse RFS, and lower THBS4 levels predicted worse OS, RFS, and distant metastasis-free survival (DMFS). Conclusions: These results suggest that THBSs may be potential biomarkers for breast cancer.

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The BIRC Family Genes Expression in Patients with Triple Negative Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22041820 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1820

Author(s):

Anna Makuch-Kocka ◽

Janusz Kocki ◽

Anna Brzozowska ◽

Jacek Bogucki ◽

Przemysław Kołodziej ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Clinical Data ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Lymphatic Vessels ◽

The Cancer Genome Atlas ◽

Expression Level ◽

Cancer Tissue ◽

Expression Levels

The BIRC (baculoviral IAP repeat-containing; BIRC) family genes encode for Inhibitor of Apoptosis (IAP) proteins. The dysregulation of the expression levels of the genes in question in cancer tissue as compared to normal tissue suggests that the apoptosis process in cancer cells was disturbed, which may be associated with the development and chemoresistance of triple negative breast cancer (TNBC). In our study, we determined the expression level of eight genes from the BIRC family using the Real-Time PCR method in patients with TNBC and compared the obtained results with clinical data. Additionally, using bioinformatics tools (Ualcan and The Breast Cancer Gene-Expression Miner v4.5 (bc-GenExMiner v4.5)), we compared our data with the data in the Cancer Genome Atlas (TCGA) database. We observed diverse expression pattern among the studied genes in breast cancer tissue. Comparing the expression level of the studied genes with the clinical data, we found that in patients diagnosed with breast cancer under the age of 50, the expression levels of all studied genes were higher compared to patients diagnosed after the age of 50. We observed that in patients with invasion of neoplastic cells into lymphatic vessels and fat tissue, the expression levels of BIRC family genes were lower compared to patients in whom these features were not noted. Statistically significant differences in gene expression were also noted in patients classified into three groups depending on the basis of the Scarff-Bloom and Richardson (SBR) Grading System.

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Reduced mRNA expression levels of NFE2L2 are associated with poor outcome in breast cancer patients

BMC Cancer ◽

10.1186/s12885-016-2840-x ◽

2016 ◽

Vol 16 (1) ◽

Cited By ~ 11

Author(s):

Barbara Wolf ◽

Georg Goebel ◽

Hubert Hackl ◽

Heidi Fiegl

Keyword(s):

Breast Cancer ◽

Mrna Expression ◽

Cancer Patients ◽

Breast Cancer Patients ◽

Expression Levels ◽

Poor Outcome ◽

Mrna Expression Levels

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Suppressor of cytokine signaling (SOCS) genes are downregulated in breast cancer

World Journal of Surgical Oncology ◽

10.1186/s12957-018-1529-9 ◽

2018 ◽

Vol 16 (1) ◽

Cited By ~ 12

Author(s):

Soudeh Ghafouri-Fard ◽

Vahid Kholghi Oskooei ◽

Iman Azari ◽

Mohammad Taheri

Keyword(s):

Breast Cancer ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling

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Synaptotagmin 13 Is Highly Expressed in Estrogen Receptor-Positive Breast Cancer

Current Oncology ◽

10.3390/curroncol28050346 ◽

2021 ◽

Vol 28 (5) ◽

pp. 4080-4092

Author(s):

Takahiro Ichikawa ◽

Masahiro Shibata ◽

Takahiro Inaishi ◽

Ikumi Soeda ◽

Mitsuro Kanda ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Mrna Expression ◽

Cell Lines ◽

Mrna Levels ◽

Pcr Array ◽

Array Analysis ◽

Expression Levels ◽

Er Positive ◽

Mrna Expression Levels

Background: Accumulating evidence indicates tumor-promoting roles of synaptotagmin 13 (SYT13) in several cancers; however, no studies have investigated its expression in breast cancer (BC). This study aimed to clarify the significance of SYT13 in BC. Methods: SYT13 mRNA expression levels were evaluated in BC cell lines. Polymerase chain reaction (PCR) array analysis was conducted to determine the correlation between expression levels of SYT13 and other tumor-associated genes. Then, the association of SYT13 expression levels in the clinical BC specimens with patients’ clinicopathological factors was evaluated. These findings were subsequently validated using The Cancer Genome Atlas (TCGA) database. Results: Among 13 BC cell lines, estrogen receptor (ER)-positive cells showed higher SYT13 mRNA levels than ER-negative cells. PCR array analysis revealed positive correlations between SYT13 and several oncogenes predominantly expressed in ER-positive BC, such as estrogen receptor 1, AKT serine/threonine kinase 1, and cyclin-dependent kinases 4. In 165 patients, ER-positive specimens exhibited higher SYT13 mRNA expression levels than ER-negative specimens. The TCGA database analysis confirmed that patients with ER-positive BC expressed higher SYT13 levels than ER-negative patients. Conclusion: This study suggests that SYT13 is highly expressed in ER-positive BC cells and clinical specimens, and there is a positive association of SYT13 with the ER signaling pathways.

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Elevated mRNA expression levels of inflammation-related genes in triple-negative breast cancer: A pilot study from North East India

Annals of Oncology Research and Therapy ◽

10.4103/aort.aort_25_21 ◽

2021 ◽

Vol 1 (2) ◽

pp. 105

Author(s):

Rizwana Sultana ◽

SyedJaved Salman Chisty

Keyword(s):

Breast Cancer ◽

Pilot Study ◽

Mrna Expression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Expression Levels ◽

North East India ◽

North East ◽

Mrna Expression Levels

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Identification of differential gene expression related to epirubicin-induced cardiomyopathy in breast cancer patients

Human & Experimental Toxicology ◽

10.1177/0960327119893415 ◽

2019 ◽

Vol 39 (4) ◽

pp. 393-401 ◽

Cited By ~ 1

Author(s):

J Peng ◽

Z Wang ◽

Y Li ◽

D Lv ◽

X Zhao ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Patients ◽

Enrichment Analysis ◽

Global Gene Expression ◽

Pathway Enrichment Analysis ◽

Breast Cancer Patients ◽

Chlorophyll Metabolism ◽

Pathway Enrichment ◽

Before And After

Background: Epirubicin is a potent chemotherapeutic agent for the treatment of breast cancer. However, it may lead to cardiotoxicity and cardiomyopathy, and no reliable biomarker was available for the early prediction of epirubicin-induced cardiomyopathy. Methods: Global gene expression changes of peripheral blood cells were studied using high-throughput RNA sequencing in three pair-matched breast cancer patients (patients who developed symptomatic cardiomyopathy paired with patients who did not) before and after the full session of epirubicin-based chemotherapy. Functional analysis was conducted using gene ontology and pathway enrichment analysis. Results: We identified 13 significantly differentially expressed genes between patients who developed symptomatic epirubicin-induced cardiomyopathy and their paired control who did not. Among them, the upregulated Bcl-associated X protein was related to “apoptosis,” while the downregulated 5′-aminolevulinate synthase 2 (ALAS2) was related to both “glycine, serine, and threonine metabolism” and “porphyrin and chlorophyll metabolism” in pathway enrichment analysis. Conclusions: ALAS2 and the metabolic pathways which were involved may play an important role in the development of epirubicin-induced cardiomyopathy. ALAS2 may be useful as an early biomarker for epirubicin-induced cardiotoxicity detection.

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Regulation and role of suppressor of cytokine signaling-3 in hypothalamic 4B cells

Journal of Endocrinology ◽

10.1677/joe-08-0506 ◽

2009 ◽

Vol 201 (3) ◽

pp. 369-376 ◽

Cited By ~ 3

Author(s):

Kazunori Kageyama ◽

Komaki Hanada ◽

Yasumasa Iwasaki ◽

Toshihiro Suda

Keyword(s):

Gene Expression ◽

Stress Responses ◽

Negative Regulator ◽

Cytokine Signaling ◽

Mrna Levels ◽

Suppressor Of Cytokine Signaling ◽

Hypothalamic Cells ◽

Parvocellular Neurons ◽

Response To Stress ◽

Inhibitory Signaling

Corticotropin-releasing factor (CRF) plays a central role in regulating stress responses. In the hypothalamic paraventricular nucleus (PVN), CRF, produced in response to stress, stimulates the release of ACTH from the anterior pituitary. ACTH then stimulates the release of glucocorticoids from the adrenal glands; circulating glucocorticoids are critical for recovery from stress conditions. Cytokines are also implicated in the regulation of CRF expression. Among them, interleukin (IL)-6 plays a role in the regulation of CRF. Factors other than glucocorticoids are likely to be involved in limiting the stimulation of CRF during stress. Suppressor of cytokine signaling (SOCS)-3 acts as a potent negative regulator of cytokine signaling. Little is known about the ability of the inhibitory signaling pathways to limit activation of the CRF gene in parvocellular PVN neurons. Hypothalamic 4B cells are useful for exploring the mechanisms, because these cells show characteristics of the parvocellular neurons of the PVN. In the present study, we examined whether SOCS-3 is regulated by IL-6 and cAMP in hypothalamic 4B cells. We also explored the involvement of SOCS-3 in the regulation of CRF gene expression. SOCS-3 was found to be regulated by IL-6 and via the cAMP/protein kinase A pathway in the hypothalamic cells. SOCS-3 knockdown increased IL-6- or forskolin-induced CRF gene transcription and mRNA levels. Therefore, SOCS-3, induced by a cAMP stimulant and IL-6, would be involved in the negative regulation of CRF gene expression in hypothalamic cells.

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Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2015-0036 ◽

2016 ◽

Vol 26 (1) ◽

Cited By ~ 5

Author(s):

Amira Alkharusi ◽

Mercedes Mirecki-Garrido ◽

Zuheng Ma ◽

Fahad Zadjali ◽

Amilcar Flores-Morales ◽

...

Keyword(s):

Type I Diabetes ◽

Janus Kinase ◽

Cytokine Signaling ◽

Type I ◽

Suppressor Of Cytokine Signaling ◽

Β Cell ◽

Diabetes In Mice ◽

Socs Proteins ◽

Stat Pathway

AbstractDiabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity.The elevated sensitivity of SOCS2We show that 6-month-old SOCS2Knockdown of SOCS2 makes mice less sensitive to MLDSTZ. These results are consistent with the proposal that elimination of SOCS2 in pancreatic islets creates a state of β-cell hypersensitivity to GH/PRL that mimics events in pregnancy, and which is protective against MLDSTZ-induced type I diabetes in mice. SOCS2-dependent control of β-cell survival may be of relevance to islet regeneration and survival in transplantation.

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