Interplay between MAPK/ERK signaling pathway and MicroRNAs: A crucial mechanism regulating cancer cell metabolism and tumor progression

Asl, Elmira Roshani; Amini, Mohammad; Najafi, Souzan; Mansoori, Behzad; Mokhtarzadeh, Ahad; Mohammadi, Ali; Lotfinejad, Parisa; Bagheri, Minoo; Shirjang, Solmaz; Lotfi, Ziba; Rasmi, Yousef; Baradaran, Behzad

doi:10.1016/j.lfs.2021.119499

Cited by 95 publications

(46 citation statements)

References 62 publications

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“…To further explore the mechanism of the biological function, we studied the changes in important signaling pathways related to proliferation, metabolism and autophagy in AML cell lines. Mitogen-activated protein kinase (MAPK) is one of the main signaling pathways mediating the growth and survival of tumor cells and plays important roles in regulating cell proliferation, cell cycle, apoptosis, migration and invasion (27)(28)(29). Our results revealed that the phosphorylated P38 MAPK was significantly reduced in the GNA15-KD cells, while the phosphorylated ERK, AMPKa, Smad3, Akt and LC3 A/B showed no change.…”

Section: Discussionmentioning

confidence: 69%

Downregulation of GNA15 Inhibits Cell Proliferation via P38 MAPK Pathway and Correlates with Prognosis of Adult Acute Myeloid Leukemia With Normal Karyotype

Liu

et al. 2021

Front. Oncol.

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BackgroundThe prognosis of acute myeloid leukemia (AML) with a normal karyotype is highly heterogonous, and the current risk stratification is still insufficient to differentiate patients from high-risk to standard-risk. Changes in some genetic profiles may contribute to the poor prognosis of AML. Although the prognostic value of G protein subunit alpha 15 (GNA15) in AML has been reported based on the GEO (Gene Expression Omnibus) database, the prognostic significance of GNA15 has not been verified in clinical samples. The biological functions of GNA15 in AML development remain open to investigation. This study explored the clinical significance, biological effects and molecular mechanism of GNA15 in AML.MethodsReverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA expression level of GNA15 in blasts of bone marrow specimens from 154 newly diagnosed adult AML patients and 26 healthy volunteers. AML cell lines, Kasumi-1 and SKNO-1, were used for lentiviral transfection. Cell Counting Kit-8 (CCK8) and colony formation assays were used to determine cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. The relevant signaling pathways were evaluated by Western blot. The Log-Rank test and Kaplan-Meier were used to evaluate survival rate, and the Cox regression model was used to analyze multivariate analysis. Xenograft tumor mouse model was used for in vivo experiments.ResultsThe expression of GNA15 in adult AML was significantly higher than that in healthy individuals. Subjects with high GNA15 expression showed lower overall survival and relapse-free survival in adult AML with normal karyotype. High GNA15 expression was independently correlated with a worse prognosis in multivariate analysis. Knockdown of GNA15 inhibited cell proliferation and cell cycle progression, and induced cell apoptosis in AML cells. GNA15-knockdown induced down-regulation of p-P38 MAPK and its downstream p-MAPKAPK2 and p-CREB. Rescue assays confirmed that P38 MAPK signaling pathway was involved in the inhibition of proliferation mediated by GNA15 knockdown.ConclusionsIn summary, GNA15 was highly expressed in adult AML, and high GNA15 expression was independently correlated with a worse prognosis in adult AML with normal karyotype. Knockdown of GNA15 inhibited the proliferation of AML regulated by the P38 MAPK signaling pathway. Therefore, GNA15 may serve as a potential prognostic marker and a therapeutic target for AML in the future.

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Section: Discussionmentioning

confidence: 69%

Downregulation of GNA15 Inhibits Cell Proliferation via P38 MAPK Pathway and Correlates with Prognosis of Adult Acute Myeloid Leukemia With Normal Karyotype

Liu

et al. 2021

Front. Oncol.

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“…Considerable evidence has demonstrated that the deregulation of YAP/TAZ signaling may play a key role in intrinsic and acquired resistance to various chemotherapies [ 25 ]. Regarding the enrichment in MAPK binding, emerging evidence suggests that this event can modulate drug resistance and sensitivity in various cancers [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Quantitative phosphoproteomic analysis reveals chemoresistance-related proteins and signaling pathways induced by rhIL-6 in human osteosarcoma cells

Zhang

Wang

et al. 2021

Cancer Cell Int

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Background IL-6 plays a pivotal role in resistance to chemotherapeutics, including lobaplatin. However, the underlying mechanisms are still unclear. This study was to investigate the changes in phosphoproteins and their related signaling pathways in the process of IL-6-induced chemoresistance to lobaplain in osteosarcoma cells. Methods We performed a quantitative phosphoproteomic analysis of the response of SaOS-2 osteosarcoma cells to recombinant human IL-6 (rhIL-6) intervention prior to lobaplatin treatment. The cells were divided into the control group (Con), the lobaplatin group (Lob), and the rhIL-6-and-lobaplatin group (IL-6). Three biological replicates of each group were included. The differentially expressed phosphoproteins were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Netphos 3.1 was used for the prediction of kinases, and STRING was used for the visualization of protein–protein interactions. The conserved motifs surrounding the phosphorylated residues were analyzed using the motif-x algorithm. Western blot analysis was performed to verify the differential expression of p-FLNC, its predicted kinase and the related signaling pathway. The results of the bioinformatic analysis were validated by immunohistochemical staining of clinical specimens. Results In total, 3373 proteins and 12,183 peptides, including 3232 phosphorylated proteins and 11,358 phosphorylated peptides, were identified and quantified. Twenty-three significantly differentially expressed phosphoproteins were identified in the comparison between the IL-6 and Lob groups, and p-FLNC ranked second among these phosphoproteins. GO and KEGG analyses revealed the pivotal role of mitogen-activated protein kinase signaling in drug resistance induced by rhIL-6. Four motifs, namely, -SPxxK-, -RxxSP-, -SP-, and -SPK-, demonstrated higher expression in the IL-6 group than in the Lob group. The western blot analysis results verified the higher expression of p-FLNC, AKT1, and p-ERK and the lower expression of p-JNK in the IL-6 group than in the Con and Lob groups. The immunohistochemical staining results showed that p-FLNC, AKT1 and p-ERK1/2 were highly expressed in platinum-resistant clinical specimens but weakly expressed in platinum-sensitive specimens, and platinum-resistant osteosarcoma specimens demonstrated weak expression of p-JNK. Conclusions This phosphoproteomic study is the first to reveal the signature associated with rhIL-6 intervention before lobaplatin treatment in human osteosarcoma cells. p-FLNC, AKT1, and MAPK signaling contributes to resistance to lobaplatin in osteosarcoma SaOS-2 cells and may represent molecular targets to overcome osteosarcoma chemoresistance.

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“…MicroRNAs (miRNAs) are important regulatory factors of gene expression, which play a key role in the occurrence and development of tumors and can also regulate ERK signal, which is usually overexpressed in cancerous tissues. Study showed that the regulation of the ERK signaling pathway by miRNAs plays an important role in the development of cancer [25] . Venezuelan equine encephalitis virus (VEEV) can infect primary astrocytes by upregulation of Early Growth Response 1 (EGR1) induces cell apoptosis and viral transcription.…”

Section: Discussionmentioning

confidence: 99%

Seasonal Expression of Extracellular Signal Regulated Kinases in the Colon of Wild Ground Squirrels (Spermophilus Dauricus)

Song

Yang

Zhang

et al. 2021

Preprint

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Background: The aim of this study was to explore the localization and expression of extracellular signal regulated kinase/phospho-extracellular signal regulated kinases (ERK/pERK) in the colonic tissue of wild ground squirrels (Spermophilus dauricus) in the breeding season and the non-breeding season. Methods and Results: Hematoxylin-eosin staining, immunohistochemistry, real-time quantitative PCR and Western blot were used in this study. The histological results showed that the diameter of the colon lumen in the non-breeding season was larger than that in the breeding season, and the number of glandular cells in the non-breeding season was also more than those in the breeding season. The immunochemical results showed that ERK1/2 was expressed in the cytoplasm of goblet cells and intestinal epithelial cells, while pERK1/2 was expressed in the cytoplasm and nucleus of goblet cells and intestinal epithelial cells. The immunolocalization of ERK1/2 and pERK1/2 expression were more obvious in the non-breeding season, especially in intestinal epithelial cells. The results of real-time quantitative PCR and Western blot showed that the expression of ERK1/2 and pERK1/2 in the breeding season was significantly lower than that in the non-breeding season.Conclusions: The expression of ERK1/2 and pERK1/2 in the colons of the wild ground squirrels had seasonal changes, which had significant increases in the non-breeding season comparing to those in the breeding season. This study revealed the potential role of ERK1/2 in colon to the adaptation of seasonal changes in wild ground squirrel.

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Interplay between MAPK/ERK signaling pathway and MicroRNAs: A crucial mechanism regulating cancer cell metabolism and tumor progression

Cited by 95 publications

References 62 publications

Downregulation of GNA15 Inhibits Cell Proliferation via P38 MAPK Pathway and Correlates with Prognosis of Adult Acute Myeloid Leukemia With Normal Karyotype

Downregulation of GNA15 Inhibits Cell Proliferation via P38 MAPK Pathway and Correlates with Prognosis of Adult Acute Myeloid Leukemia With Normal Karyotype

Quantitative phosphoproteomic analysis reveals chemoresistance-related proteins and signaling pathways induced by rhIL-6 in human osteosarcoma cells

Seasonal Expression of Extracellular Signal Regulated Kinases in the Colon of Wild Ground Squirrels (Spermophilus Dauricus)

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