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Identification of plasma microRNA profiles for primary resistance to EGFR-TKIs in advanced non-small cell lung cancer (NSCLC) patients with EGFR activating mutation.

Wang S, Su X, Bai H, Zhao J, Duan J, An T, Zhuo M, Wang Z, Wu M, Li Z, Zhu J, Wang J - J Hematol Oncol (2015)

Bottom Line: Training group: 153 miRNAs were found to be differentially expressed between the sensitive and resistant groups.Training group: three out of the 12 miRNAs (miR-21, AmiR-27a, and miR-218) were verified to have significantly higher expression (P miR-21 = 0.004, P miR-27a = 0.009, P miR-218 = 0.041, respectively) in the resistant group compared to the sensitive group.These findings need to be further confirmed in a study with a larger sample size.

View Article: PubMed Central - PubMed

Affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.

ABSTRACT

Background: EGFR mutation is a strong predictor of efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) therapy in advanced non-small cell lung cancer (NSCLC). However, around 20-30 % of EGFR-mutated cases showed no response to EGFR-TKIs, suggesting that other determinants beyond EGFR mutation likely exist. This study analyzed the role of microRNAs (miRNAs) in primary resistance to EGFR-TKIs in advanced NSCLC patients with EGFR mutation.

Methods: Training group: 20 advanced NSCLC patients with EGFR 19 deletion treated with first-line EGFR-TKIs were enrolled; half of them had dramatic responses while the other half had primary resistance. Matched plasma samples were collected for miRNA profiling using TaqMan low-density array (TLDA). Bioinformatics analyses were used to identify related miRNAs possibly accounted for resistance. Testing group: Quantitative reverse transcriptase PCR (qRT-PCR) was employed to detect the level of miRNA with significant differential expression in the training set. Validation group: Another cohort with EGFR 19 deletion mutations, who had dramatically different responses to EGFR-TKI, was used to validate the difference of miRNA expression between the sensitive and resistant groups using RT-PCR.

Results: Training group: 153 miRNAs were found to be differentially expressed between the sensitive and resistant groups. Potential target genes were predicted with a target scan database. Twelve differentially expressed miRNAs were selected for the analysis because of their known roles in tumorigenesis of lung cancer, resistance to drugs, and regulation of EGFR pathway. Training group: three out of the 12 miRNAs (miR-21, AmiR-27a, and miR-218) were verified to have significantly higher expression (P miR-21 = 0.004, P miR-27a = 0.009, P miR-218 = 0.041, respectively) in the resistant group compared to the sensitive group. Validation group: The expression levels of these three miRNAs were validated to be significantly different (P = 0.011, 0.011, 0.026, respectively) in the validation cohort (n = 34).

Conclusions: Higher expression levels of miR-21, AmiR-27a, and miR-218 detected in this study suggest potential roles of these miRNAs in primary resistance to EGFR-TKI in advanced NSCLC patients with EGFR exon 19 deletion mutations. These findings need to be further confirmed in a study with a larger sample size.

No MeSH data available.


Related in: MedlinePlus

a miRNA up-regulated in the responsive training group and MiR-Gene Network. b miRNA up-regulated in the resistance training group and MiR-Gene Network. Green nodes represent up-regulated miRNAs; pink nodes represent targeted genes; and blue lines show the inhibitory effect of miRNAs on target mRNAs
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Fig1: a miRNA up-regulated in the responsive training group and MiR-Gene Network. b miRNA up-regulated in the resistance training group and MiR-Gene Network. Green nodes represent up-regulated miRNAs; pink nodes represent targeted genes; and blue lines show the inhibitory effect of miRNAs on target mRNAs

Mentions: To identify the candidates and investigate the cellular function, the signaling pathway and gene ontologies (GOs) of the target genes were analyzed. The results revealed a wide variety of miRNA involved in several signaling pathways (Fig. 1a, b), such as cancer, apoptosis, and EGFR signaling pathway. The miRNA-mRNA interaction network analysis integrated these miRNAs and GO terms by outlining the interactions of miRNA and GO-related genes (Fig. 2a). The targets of the 12 deregulated miRNAs (Table 2) were predicted by TargetScan. miR-448 and miR-605 were upregulated in the sensitive group, whereas miR-628-5p, miR-561, miR-520f, miR-409-3p, has-miR-138, miR-296-5p, miR-218,miR-1274B, miR-21, and miR-27a were upregulated in the resistance group.Fig. 1


Identification of plasma microRNA profiles for primary resistance to EGFR-TKIs in advanced non-small cell lung cancer (NSCLC) patients with EGFR activating mutation.

Wang S, Su X, Bai H, Zhao J, Duan J, An T, Zhuo M, Wang Z, Wu M, Li Z, Zhu J, Wang J - J Hematol Oncol (2015)

a miRNA up-regulated in the responsive training group and MiR-Gene Network. b miRNA up-regulated in the resistance training group and MiR-Gene Network. Green nodes represent up-regulated miRNAs; pink nodes represent targeted genes; and blue lines show the inhibitory effect of miRNAs on target mRNAs
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4643502&req=5

Fig1: a miRNA up-regulated in the responsive training group and MiR-Gene Network. b miRNA up-regulated in the resistance training group and MiR-Gene Network. Green nodes represent up-regulated miRNAs; pink nodes represent targeted genes; and blue lines show the inhibitory effect of miRNAs on target mRNAs
Mentions: To identify the candidates and investigate the cellular function, the signaling pathway and gene ontologies (GOs) of the target genes were analyzed. The results revealed a wide variety of miRNA involved in several signaling pathways (Fig. 1a, b), such as cancer, apoptosis, and EGFR signaling pathway. The miRNA-mRNA interaction network analysis integrated these miRNAs and GO terms by outlining the interactions of miRNA and GO-related genes (Fig. 2a). The targets of the 12 deregulated miRNAs (Table 2) were predicted by TargetScan. miR-448 and miR-605 were upregulated in the sensitive group, whereas miR-628-5p, miR-561, miR-520f, miR-409-3p, has-miR-138, miR-296-5p, miR-218,miR-1274B, miR-21, and miR-27a were upregulated in the resistance group.Fig. 1

Bottom Line: Training group: 153 miRNAs were found to be differentially expressed between the sensitive and resistant groups.Training group: three out of the 12 miRNAs (miR-21, AmiR-27a, and miR-218) were verified to have significantly higher expression (P miR-21 = 0.004, P miR-27a = 0.009, P miR-218 = 0.041, respectively) in the resistant group compared to the sensitive group.These findings need to be further confirmed in a study with a larger sample size.

View Article: PubMed Central - PubMed

Affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.

ABSTRACT

Background: EGFR mutation is a strong predictor of efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) therapy in advanced non-small cell lung cancer (NSCLC). However, around 20-30 % of EGFR-mutated cases showed no response to EGFR-TKIs, suggesting that other determinants beyond EGFR mutation likely exist. This study analyzed the role of microRNAs (miRNAs) in primary resistance to EGFR-TKIs in advanced NSCLC patients with EGFR mutation.

Methods: Training group: 20 advanced NSCLC patients with EGFR 19 deletion treated with first-line EGFR-TKIs were enrolled; half of them had dramatic responses while the other half had primary resistance. Matched plasma samples were collected for miRNA profiling using TaqMan low-density array (TLDA). Bioinformatics analyses were used to identify related miRNAs possibly accounted for resistance. Testing group: Quantitative reverse transcriptase PCR (qRT-PCR) was employed to detect the level of miRNA with significant differential expression in the training set. Validation group: Another cohort with EGFR 19 deletion mutations, who had dramatically different responses to EGFR-TKI, was used to validate the difference of miRNA expression between the sensitive and resistant groups using RT-PCR.

Results: Training group: 153 miRNAs were found to be differentially expressed between the sensitive and resistant groups. Potential target genes were predicted with a target scan database. Twelve differentially expressed miRNAs were selected for the analysis because of their known roles in tumorigenesis of lung cancer, resistance to drugs, and regulation of EGFR pathway. Training group: three out of the 12 miRNAs (miR-21, AmiR-27a, and miR-218) were verified to have significantly higher expression (P miR-21 = 0.004, P miR-27a = 0.009, P miR-218 = 0.041, respectively) in the resistant group compared to the sensitive group. Validation group: The expression levels of these three miRNAs were validated to be significantly different (P = 0.011, 0.011, 0.026, respectively) in the validation cohort (n = 34).

Conclusions: Higher expression levels of miR-21, AmiR-27a, and miR-218 detected in this study suggest potential roles of these miRNAs in primary resistance to EGFR-TKI in advanced NSCLC patients with EGFR exon 19 deletion mutations. These findings need to be further confirmed in a study with a larger sample size.

No MeSH data available.


Related in: MedlinePlus