The Role of PI3K/AKT and MAPK Signaling Pathways in Erythropoietin Signalization

Tóthová, Zuzana; Šemeláková, Martina; Solárová, Zuzana; Tomc, Jana; Debeljak, Nataša; Solár, Peter

doi:10.3390/ijms22147682

Cited by 58 publications

(42 citation statements)

References 131 publications

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“…We also found that EPOR-interacting proteins include JAK2, EPO, and STAT5A/B, MAPK1/3, which fully suggests that EPOR interacts with EPO and is closely related to the activation of JAK2, STAT5, and MAPK (3,4,6). EPOR is associated with numerous diseases such as urological disorders, musculoskeletal or connective tissue disorders, immune system disorders, endocrine system disorders, hematologic disorders, cancer, or benign tumors, reflecting its broad distribution, and it plays a key role in the human body.…”

Section: Discussionsupporting

confidence: 62%

“…Upon EPO stimulation, binding to its homologous dimer receptor complex induces the activation of Janus kinase 2 (JAK2), a non-receptor tyrosine kinase ( 3 ). Activation of JAK2 results in the activation of specific downstream effectors, such as STAT1, STAT3, and STAT5 ( 4 ); the signal transducer and activator of transcription 5 (STAT5) usually refers to STAT5A and STAT5B proteins ( 5 ) and thus activates phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 (ERK1/2) ( 6 , 7 ). EPOR was originally discovered and described in erythroid progenitor cells, but it is also present in non-hematopoietic cells (tissues, organs) such as adipose tissue ( 8 ), bone progenitor cells ( 9 ), neurons ( 10 ), endothelial cells ( 11 ), and intestinal tract ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

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Pan-Cancer Analysis Based on EPOR Expression With Potential Value in Prognosis and Tumor Immunity in 33 Tumors

2022

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BackgroundErythropoietin receptor (EPOR), a member of the cytokine class I receptor family, mediates erythropoietin (EPO)-induced erythroblast proliferation and differentiation, but its significance goes beyond that. The expression and prognosis of EPOR in cancer remain unclear.MethodsThis study intended to perform a pan-cancer analysis of EPOR by bioinformatics methods. Several databases such as GTEx, TCGA, CCLE, and others were used to explore the overall situation of EPOR expression, and the correlation of EPOR expression with prognosis, microRNAs (miRNAs), immune infiltration, tumor microenvironment, immune checkpoint genes, chemokines, tumor mutation burden (TMB), microsatellite instability (MSI), methyltransferases, and DNA mismatch repair (MMR) genes in 33 tumors was analyzed. In addition, we compared the promoter methylation levels of EPOR in cancer tissues with those in normal tissues and performed protein–protein interaction network, gene–disease network, and genetic alteration analyses of EPOR, and finally enrichment analysis of EPOR-interacting proteins, co-expressed genes, and differentially expressed genes.ResultsThe TCGA database showed that EPOR expression was upregulated in BLCA, CHOL, HNSC, KIRC, LIHC, STAD, and THCA and downregulated in LUAD and LUSC. After combining the GTEx database, EPOR expression was found to be downregulated in 18 cancer tissues and upregulated in 6 cancer tissues. The CCLE database showed that EPOR expression was highest in LAML cell lines and lowest in HNSC cell lines. Survival analysis showed that high EPOR expression was positively correlated with OS in LUAD and PAAD and negatively correlated with OS in COAD, KIRC, and MESO. Moreover, EPOR had a good prognostic ability for COAD, LUAD, MESO, and PAAD and also influenced progression-free survival, disease-specific survival, disease-free survival, and progression-free interval in specific tumors. Further, EPOR was found to play a non-negligible role in tumor immunity, and a correlation of EPOR with miRNAs, TMB, MSI, and MMR genes and methyltransferases was confirmed to some extent. In addition, the enrichment analysis revealed that EPOR is involved in multiple cancer-related pathways.ConclusionThe general situation of EPOR expression in cancer provided a valuable clinical reference. EPOR may be target gene of hsa-miR-575, etc. A pan-cancer analysis of panoramic schema revealed that EPOR not only may play an important role in mediating EPO-induced erythroblast proliferation and differentiation but also has potential value in tumor immunity and is expected to be a prognostic marker for specific cancers.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Pan-Cancer Analysis Based on EPOR Expression With Potential Value in Prognosis and Tumor Immunity in 33 Tumors

2022

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“…Two major cell survival pathways that are upregulated and activated in lung cancer tissues are mediated by Akt and ERK1/2, which are known to play a crucial role in the regulation of cellular proliferation, differentiation, and migration [22]. Hence, we performed a study of the possible role of lncCDH5-3:3 in the regulation of lung cancer cell proliferation via the Akt-and ERK1/2-mediated signaling pathways.…”

Section: Effects Of Lnccdh5-3:3 Overexpression On Cell Cycle Cell Pro...mentioning

confidence: 99%

LncCDH5-3:3 Regulates Apoptosis, Proliferation, and Aggressiveness in Human Lung Cancer Cells

Kwaśniak

Czarnik-Kwaśniak

Malysheva

et al. 2022

Cells

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(1) Lung cancer (both small cell and non-small cell) is the leading cause of new deaths associated with cancers globally in men and women. Long noncoding RNAs (lncRNAs) are associated with tumorigenesis in different types of tumors, including lung cancer. Herein, we discuss: (1) An examination of the expression profile of lncCDH5-3:3 in non-small cell lung cancer (NSCLC), and an evaluation of its functional role in lung cancer development and progression using in vitro models; (2) A quantitative real-time polymerase chain reaction assay that confirms lncCDH5-3:3 expression in tumor samples resected from 20 NSCLC patients, and that shows its statistically higher expression levels at stage III NSCLC, compared to stages I and II. Moreover, knockout (KO) and overexpression, as well as molecular and biochemical techniques, were used to investigate the biological functions of lncCDH5-3:3 in NSCLC cells, with a focus on the cells’ proliferation and migration; (3) The finding that lncCDH5-3:3 silencing promotes apoptosis and probably regulates the cell cycle and E-cadherin expression in adenocarcinoma cell lines. In comparison, lncCDH5-3:3 overexpression increases the expression levels of proliferation and epithelial-to-mesenchymal transition markers, such as EpCAM, Akt, and ERK1/2; however, at the same time, it also stimulates the expression of E-cadherin, which conversely inhibits the mobility capabilities of lung cancer cells; (4) The results of this study, which provide important insights into the role of lncRNAs in lung cancer. Our study shows that lncCDH5-3:3 affects important features of lung cancer cells, such as their viability and motility. The results support the idea that lncCDH5-3:3 is probably involved in the oncogenesis of NSCLC through the regulation of apoptosis and tumor cell metastasis formation.

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“…Tyrosine phosphorylation plays a pivotal role in EPOR signal transduction and the activation of downstream signaling cascades involved in erythropoiesis, including the signal transducer and activator of transcription 5 (STAT5), phosphatidylinositol 3-kinase (PI3K) and mitogenactivated protein kinase (MAPK/ERK) pathways [58][59][60]. The key players of EPO-EPOR signal transduction have been recently reviewed and are presented in Figure 2 [61,62]. Abnormally increased or prolonged activation of the three pathways is implicated in deregulated erythropoiesis and overproduction of red blood cells in polycythemia vera and congenital erythrocytosis [59], wherein inherited mutations in the EPOR itself (ECYT1), and acquired mutations in JAK2 (PV) are already well known genetic causes [1,63].…”

Section: Signal Transduction: Epo-epor Pathwaymentioning

confidence: 99%

“…Black line indicates transition (Figure was created using SMART servier medical art[18]. Figure adapted from[61,62]).…”

mentioning

confidence: 99%

Molecular Pathways Involved in the Development of Congenital Erythrocytosis

Tomc

Debeljak

2021

Genes

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Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis.

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The Role of PI3K/AKT and MAPK Signaling Pathways in Erythropoietin Signalization

Cited by 58 publications

References 131 publications

Pan-Cancer Analysis Based on EPOR Expression With Potential Value in Prognosis and Tumor Immunity in 33 Tumors

Pan-Cancer Analysis Based on EPOR Expression With Potential Value in Prognosis and Tumor Immunity in 33 Tumors

LncCDH5-3:3 Regulates Apoptosis, Proliferation, and Aggressiveness in Human Lung Cancer Cells

Molecular Pathways Involved in the Development of Congenital Erythrocytosis

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