Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells

Hur, Eun‐Hye; Goo, Bon-Kwan; Moon, Jiwon; Choi, Yunsuk; Hwang, Jung Jin; Kim, Choung‐Soo; Bae, Kyun‐Seop; Choi, Jeongyong; Cho, Suk Young; Yang, Sanghwa; Seo, Jeongbeob; Lee, Gilnam; Lee, Je‐Hwan

doi:10.18632/oncotarget.17866

Cited by 9 publications

(9 citation statements)

References 49 publications

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“…Additionally, reliability of the top enriched pathway associated with GC resistance, Transcriptional misregulation in cancer, is further supported by studies reporting that BCL2A1, PAX5, and CXCL8 play important roles in GC‐resistant ALL . Moreover, Pathways in cancer (map05200 on KEGG website) comprised various oncogenesis signaling pathways including MAPK, JAT/STAT, and PI3K‐AKT signaling pathways, which were confirmed to promote development of GC resistance in leukemia by multiple independent studies . Collectively, results of enriched KEGG pathway analysis were positively correlated with experimental findings.…”

Section: Discussionmentioning

confidence: 67%

Integrated bioinformatics analysis of the crucial candidate genes and pathways associated with glucocorticoid resistance in acute lymphoblastic leukemia

et al. 2020

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Glucocorticoids (GC) are the foundation of the chemotherapy regimen in acute lymphoblastic leukemia (ALL). However, resistance to GC is observed more frequently than resistance to other chemotherapy agents in patients with ALL relapse.Moreover, the mechanism underlying the development of GC resistance in ALL has not yet been fully uncovered. In this study, we used bioinformatic analysis methods to integrate the candidate genes and pathways participating in GC resistance in ALL and subsequently verified the bioinformatics findings with in vitro cell experiments.Ninety-nine significant common differentially expressed genes (DEGs) associated with GC resistance were determined by integrating two gene profile datasets, including GC-sensitive and -resistant samples. Using Kyoto Encyclopedia of Genes and Genomes (KEGG) and REACTOME pathways analysis, the signaling pathways in which DEGs were significantly enriched were clustered. The GC resistance-related biologically functional interactions were visualized as DEG-associated Protein-Protein Interaction (PPI) network complexes, with 98 nodes and 127 edges. MYC, a node which displayed the highest connectivity in all edges, was highlighted as the core gene in the PPI network. Increased C-MYC expression was observed in adriamycin-resistant BALL-1/ADR cells, which we demonstrated was also resistant to dexamethasone. These results outlined a panorama in which the solitary and scattered experimental results were integrated and expanded. The potential promising target of the candidate pathways and genes involved in GC resistance of ALL was concomitantly revealed. K E Y W O R D S acute lymphoblastic leukemia, bioinformatic analysis, glucocorticoid resistance, MYC, signaling pathway | 2919 CHEN Et al.

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Section: Discussionmentioning

confidence: 67%

Integrated bioinformatics analysis of the crucial candidate genes and pathways associated with glucocorticoid resistance in acute lymphoblastic leukemia

et al. 2020

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“…It was previously reported that activation of Wnt/β‐catenin signaling pathway is associated with chemoresistance in several cancers . Hur et al showed that in melanoma cells, β‐catenin activation indirectly contributed to resistance to MEK inhibitor by upregulating immunoglobulin transcription factor‐2 . Wang et al showed enhanced resistance of miR‐214 expressing non‐small–cell lung cancers to gefitinib .…”

Section: Discussionmentioning

confidence: 97%

“…[52][53][54] Hur et al showed that in melanoma cells, β-catenin activation indirectly contributed to resistance to MEK inhibitor by upregulating immunoglobulin transcription factor-2. 55 Wang et al showed enhanced resistance of miR-214 expressing non-small-cell lung cancers to gefitinib. 56 In this study, employing a MAPKi-sensitive BRAF(V600E) mutant melanoma cell line and MAPKi-resistant cell lines derived from this line, we show that overexpression of miR-214 not only decreased the sensitivity of both drug-sensitive and resistant cell lines but knockdown of miR-214 enhanced the resistance to MAPK inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Role of miR‐214 in regulation of β‐catenin and the malignant phenotype of melanoma

Prabhakar

Rodríguez

Jayanthy

et al. 2019

Molecular Carcinogenesis

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Wnt/β‐catenin signaling plays an important role in melanocyte biology, especially in the early stages of melanocyte transformation and melanomagenesis. β‐catenin, encoded by the gene CTNNB1, is an intracellular signal transducer of Wnt signaling and activates transcription of genes important for cell proliferation and survival. Wnt/β‐catenin signaling is frequently activated in melanoma through oncogenic mutations of β‐catenin and elevated β‐catenin levels are positively correlated with melanoma aggressiveness. Molecular mechanisms that regulate β‐catenin expression in melanoma are not fully understood. MicroRNA‐214 is known to function as a tumor suppressor by targeting β‐catenin in several types of cancer cells. Here, we investigated the regulation of β‐catenin by miR‐214 and its role in melanoma. We show that β‐catenin mRNA levels are negatively correlated with miR‐214 in melanoma. However, overexpression of miR‐214 paradoxically increased β‐catenin protein levels and promoted malignant properties of melanoma cells including resistance to mitogen‐activated protein kinase inhibitors (MAPKi). RNA‐seq analysis revealed that melanoma cells predominantly express a β‐catenin mRNA isoform lacking miR‐214 target site. Using matched miRNA and mRNA‐seq and bioinformatics analysis, we identified novel miR‐214 targets, ankyrin repeat domain 6 (ANKRD6) and C‐terminal binding protein 1 (CTBP1), that are involved in negative regulation of Wnt signaling. Overexpression of miR‐214 or knockdown of the novel miR‐214 targets, ANKRD6 or CTBP1, increased melanoma cell proliferation, migration, and decreased sensitivity to MAPKi. Our data suggest that in melanoma cells β‐catenin is not regulated by miR‐214 and the functions of miR‐214 in melanoma are mediated partly by regulating proteins involved in attenuation of Wnt/β‐catenin signaling.

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“…In addition, activation of the STAT3 pathway has been associated with MEK inhibitor resistance through impairment of Bcl-2-like protein 11 (BIM), a member of the Bcl-2 family that is required for tumor suppression [ 98 ]. Increased expression of the immunoglobulin transcription factor 2 (ITF-2) gene, which codes for a transcription factor involved with lymphocyte development, has also been implicated as a mechanism of acquired MEK inhibitor resistance [ 99 ]. ITF-2 transcription is targeted by the Wnt signaling pathway, and ITF-2 expression was found to be significantly upregulated in MEK inhibitor-resistant melanoma cell lines [ 99 ].…”

Section: Mekmentioning

confidence: 99%

“…Increased expression of the immunoglobulin transcription factor 2 (ITF-2) gene, which codes for a transcription factor involved with lymphocyte development, has also been implicated as a mechanism of acquired MEK inhibitor resistance [ 99 ]. ITF-2 transcription is targeted by the Wnt signaling pathway, and ITF-2 expression was found to be significantly upregulated in MEK inhibitor-resistant melanoma cell lines [ 99 ]. Subsequent knockdown of ITF-2 resulted in increased sensitivity of resistant cells to selumetinib [ 99 ].…”

Section: Mekmentioning

confidence: 99%

Resistance to Molecularly Targeted Therapies in Melanoma

Patel

Eckburg

Gantiwala

et al. 2021

Cancers

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Malignant melanoma is the most aggressive type of skin cancer with invasive growth patterns. In 2021, 106,110 patients are projected to be diagnosed with melanoma, out of which 7180 are expected to die. Traditional methods like surgery, radiation therapy, and chemotherapy are not effective in the treatment of metastatic and advanced melanoma. Recent approaches to treat melanoma have focused on biomarkers that play significant roles in cell growth, proliferation, migration, and survival. Several FDA-approved molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) have been developed against genetic biomarkers whose overexpression is implicated in tumorigenesis. The use of targeted therapies as an alternative or supplement to immunotherapy has revolutionized the management of metastatic melanoma. Although this treatment strategy is more efficacious and less toxic in comparison to traditional therapies, targeted therapies are less effective after prolonged treatment due to acquired resistance caused by mutations and activation of alternative mechanisms in melanoma tumors. Recent studies focus on understanding the mechanisms of acquired resistance to these current therapies. Further research is needed for the development of better approaches to improve prognosis in melanoma patients. In this article, various melanoma biomarkers including BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K are described, and their potential mechanisms for drug resistance are discussed.

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Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells

Cited by 9 publications

References 49 publications

Integrated bioinformatics analysis of the crucial candidate genes and pathways associated with glucocorticoid resistance in acute lymphoblastic leukemia

Integrated bioinformatics analysis of the crucial candidate genes and pathways associated with glucocorticoid resistance in acute lymphoblastic leukemia

Role of miR‐214 in regulation of β‐catenin and the malignant phenotype of melanoma

Resistance to Molecularly Targeted Therapies in Melanoma

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