According to GLOBOCAN 2022, female breast cancer accounts for an estimated 11.6% of all cancer cases worldwide, making it the second most common cause of cancer incidence
[1]
. Breast cancer most commonly originates from the epithelial cells lining the milk ducts and is of 4 main subtypes: Luminal A, Luminal B, Her2-enriched, and Basal-like
[2]
[3]
. Post-transcriptional regulation influences cell-specific expression patterns by controlling RNA processing, localization, translation, and destruction
[4]
[5]
. MicroRNAs are small, non-coding RNAs that have a length of about 21 nucleotides. They play a major role in regulating gene expression post-transcriptionally. Depending on the degree of complementarity with target mRNA sequences in the 3’UTR, the miRNA/mRNA interaction results in either repression of translation or degradation of mRNA
[6]
. It has been reported that dysregulation of miRNA expression is linked to breast cancer. Tumor suppressor miRNA (tsmiR) or oncogenic miRNA (oncomiR) regulates different biological processes involved in the development of breast cancer, including apoptosis, metastasis, cancer recurrence, and cell proliferation
[7]
[8]
.
Luminal B breast cancers are an aggressive and highly proliferative subtype of breast cancer
[9]
. The miR-99a/let-7c/miR-125b cluster has been identified to be a marker for distinguishing luminal A from luminal B subtype, with a lower expression of this cluster of miRNAs in luminal B breast cancer
[10]
. Also, the luminal B subtype showed a distinct expression pattern of miR-182-5p, miR-200b-3p, miR-15b-3p, miR-149-5p, miR-193b-3p and miR-342-3p, 5p
[11]
. While there are a few miRNA-based studies on the luminal B breast cancer subtype, there aren’t a lot of studies that analyze both the miRNA and the mRNA expression data together. Comprehending the regulation of gene expression through miRNAs plays a pivotal role in understanding the unique expression patterns observed in breast cancers. Our earlier analysis concentrated on identifying luminal B specific expression patterns
[12]
. In this study, we investigated the post-transcriptional regulation of gene expression by analyzing both miRNA and mRNA expression data together to identify critical miRNA-target gene pairs in luminal B breast cancer.
2. Methods2.1. Data Collection
Luminal B breast cancer sample expression data and clinical data were obtained from TCGA (The Cancer Genome Atlas). Both miRNA and mRNA expression data of 164 inflammatory ductal carcinoma luminal B breast cancer samples, including 16 paired normal samples, were retrieved. The samples that had both mRNA expression data and miRNA expression data were only included. cBioPortal was used to obtain the PAM50 subtype classification data (cBioportal.
https://www.cbioportal.org/
).
2.2. Differential Expression of mRNA and miRNA in Luminal B Breast Cancer
The miRNA and mRNA expression data retrieved were used for differential expression analysis. The differential expression of miRNA and mRNA between the
luminal B tumor samples and corresponding normal samples was analyzed using DEseq2, a tool that tests for differential expression by use of negative binomial generalized linear models
[13]
. The count data was imported into DEseq2, normalized, and the differential expression was quantified as log2 fold change (logFC) values. The wald test was used to assess the statistical significance and corrected for by Benjamini & Hochberg method. The miRNA and mRNA that were differentially expressed with a |logFC| ≥ 1 and FDR < 0.05 were considered significant. Principal component analysis (PCA) was carried out in R. Heatmaps of top 100 differentially expressed miRNA and mRNA was generated using pheatmap function. Volcano plots were generated using ggplot2.
2.3. Identification of Dysregulated miRNA-Target Gene Pairs in Luminal B Breast Cancer
Firstly, miRTarBase, a database that contains experimentally validated target sites of miRNAs, was used to identify all the target mRNAs of miRNAs differentially expressed in luminal B breast cancer
[14]
. The target mRNAs that were identified to be differentially expressed in luminal B breast cancer in our analysis were only retained. The differentially expressed miRNA and mRNA that showed opposite trends of expression were used to identify miRNA-target gene pairs. These miRNA-mRNA pairs were further analyzed for correlation between normalized mRNA expression values and normalized miRNA expression values using the Spearman correlation method. The miRNA-target gene pairs that showed a negative correlation were only considered. A cutoff of Spearman’s correlation coefficient (R) < −0.2 and p < 0.05 was used to identify significant pairs.
2.4. Functional Annotation and miRNA-Target Gene Pair Visualization
The differentially expressed target genes were functionally enriched using Enrichr in R. Enrichr is a web-based tool that is used for functional enrichment analysis of gene sets
[15]
. The genes were enriched for Gene Ontology (GO) terms and Kyto Encyclopedia of Genes and Genomes (KEGG) pathways. A cut-off of p-value < 0.05 was used to identify the significant pathways enriched. Also, the significant miRNA-target gene pairs were visualized using cytoscape, a tool for visualization and integration of molecular interaction networks with gene expression data
[16]
.
2.5. Survival Analysis
Kaplan-Meier survival method was used to investigate the correlation between gene expression and overall survival (OS). Survival analysis was carried out in R. Based on median expression value, the samples were divided into high and low expression groups and the log-rank test was used to assess the statistical significance of difference in survival probabilities between the survival curves of low and high expression groups. A p value of <0.05 was used as cut-off to identify the significant associations.
3. Results3.1. Data Used in the Analysis
The mRNA and miRNA expression data of 164 inflammatory ductal carcinoma luminal B breast cancer samples, including 16 paired normal samples, were retrieved from TCGA. The clinical details of the patients are shown in
Table 1
.
3.2. Differential mRNA Expression in Luminal B Breast Cancer
Differential expression of mRNA between 164 luminal B breast cancer and 16 paired normal tissue samples identified 5951 significant differentially expressed mRNAs (|logFC| ≥ 1 and FDR < 0.05). Of the 5951 differentially expressed mRNAs, 2972 were down-regulated and 2979 were up-regulated between luminal B breast cancer and corresponding surrounding normal tissue samples. PCA analysis using mRNA expression data showed differential clustering of tumor and normal samples. PCA analysis was carried out on the log2 transformed gene expression data, where the principal component 1 (PC1) accounted for 14% of the total variance and principal component 2 (PC2) accounted for 9% the total variance (
Figure 1(a)
). Heatmap of top 100 differentially expressed genes between luminal B breast cancer tissues and paired normal tissue samples was generated using pheatmap (
Figure 1(b)
) and a volcano plot of differentially expressed mRNAs between the tumor tissue and paired normal tissue samples is shown in
Figure 1(c)
.
Figure 1. Differential expression of mRNA in luminal B breast cancer. (a) Principal component analysis using mRNA expression data. Blue dots represent luminal B tumor samples; Red dots represent paired normal samples; PC1 represents principal component 1; PC2 represents principal component 2. (b) Heatmap of top 100 differentially expressed genes. LumB represents Luminal B subtype. (c) Volcano plot of differentially expressed mRNA. X axis represents log2 (fold change); Y axis represents −log10 (FDR); Red dots represent genes with significantly differential expression.
3.3. Differential miRNA Expression in Luminal B Breast Cancer
Differential miRNA expression analysis between 164 luminal B breast cancer and 16 paired normal tissue samples identified 266 significant differentially expressed miRNAs. Of the 266 differentially expressed miRNAs, 117 were down-regulated and 149 were up-regulated between luminal B breast cancer and the corresponding surrounding normal tissue samples (Supplementary
Table S1
). PCA analysis using miRNA expression data showed differential clustering of tumor and normal samples. PCA analysis was carried out on the log2 transformed miRNA expression data, where the PC1 accounted for 12% of the total variance and PC2 accounted for 5% the total variance (
Figure 2(a)
). Heatmap of top 100 differentially expressed miRNA between luminal B breast cancer tissues and paired normal tissue samples was generated using pheatmap (
Figure 2(b)
) and a volcano plot of differentially expressed miRNAs between the tumor tissue and paired normal tissue samples is shown in
Figure 2(c)
.
The miRTarBase, containing experimentally validated miRNA target sites, was searched for the identification of target sites of differentially expressed miRNAs. Differentially expressed miRNAs and mRNAs that showed opposite trends of expression were used for identifying the miRNA-mRNA pairs. Further, these
Figure 2. Differential expression of miRNA in luminal B breast cancer. (a) Principal component analysis using miRNA expression data. The Blue dots represent luminal B tumor samples; Red dots represent paired normal samples; PC1 represents principal component 1; PC2 represents principal component 2. (b) Heatmap of top 100 differentially expressed miRNAs. LumB represents Luminal B subtype. (c) Volcano plot of differentially expressed miRNA. X axis represents log<sub>2</sub> (fold change); Y axis represents −log<sub>10</sub> (FDR); Red dots represent genes with significantly differential expression.
miRNAs and targets were analyzed for correlation using the Spearman correlation method. The miRNA-target gene pairs that showed a negative correlation with Spearman’s correlation coefficient R < −0.2 and p-value < 0.05 were considered significant. This led to the identification of 164 significant miRNA-target gene pairs, which include 31 miRNAs and 154 mRNAs (Supplementary
Table S2
; Supplementary
Table S3
). The miRNA-mRNA regulatory pairs were visualized using cytoscape (
Figure 3
).
3.5. Functional Enrichment of Target mRNAs
The differentially expressed target genes were enriched for pathways using Enrichr in R. Using a p value cut-off of 0.05, genes were enriched for GO terms and KEGG pathways (
Figure 4
). The top KEGG pathways enriched among the target genes were pathways in cancer, the Ras signaling pathway, focal adhesion, and the PI3K-Akt signaling pathway. The top GO molecular function terms enriched were transcription regulatory region DNA binding, regulatory region DNA binding, and transmembrane receptor protein kinase activity. The top GO biological process terms enriched were positive regulation of nucleic acid-templated transcription, regulation of transcription from the RNA polymerase II promoter, regulation of transcription, DNA templated, and positive regulation of gene expression.
Figure 3. Network of miRNA-target gene interactions in luminal B breast cancer. The circle nodes represent mRNAs. The triangle nodes represent miRNAs; Purple colour represents over-expression and green colour represents low expression; edges represent the correlation between the miRNA and mRNA expression.
(a)--(b)--(c)--Figure 4. Functional enrichment analysis of 154 target genes (a) KEGG pathway, (b) GO molecular function and (c) GO Biological process terms enriched.
(a)--(b)--(c)--Figure 4. Functional enrichment analysis of 154 target genes (a) KEGG pathway, (b) GO molecular function and (c) GO Biological process terms enriched.
(a)--(b)--(c)--Figure 4. Functional enrichment analysis of 154 target genes (a) KEGG pathway, (b) GO molecular function and (c) GO Biological process terms enriched.
3.6. Survival Analysis
To further elucidate the roles of 164 miRNA target gene pairs, the miRNAs and target genes identified were analyzed using the Kaplan-Meier method to investigate the association of expression with survival time. This resulted in the identification of five genes, including miR-421, DSN1 (DSN1 Component Of MIS12 Kinetochore Complex), SRP9 (Signal Recognition Particle 9), RACGAP1 (Rac GTPase Activating Protein 1), and SLC10A6 (Solute Carrier Family 10 Member 6), that had prognostic value. Expression of miRNA hsa-mir-421 was found to be up-regulated in luminal B breast cancers, and was negatively correlated with its target gene CBX7. Higher expression of this miRNA in luminal B breast cancers was associated with poor survival. Target genes DSN1, SRP9 and RACGAP1 were found to be overexpressed in luminal B breast cancers, and their expression was significantly negatively correlated with the expression of miRNA hsa-mir-5683. The upregulation of DSN1, SRP9 and RACGAP1 was found to be associated with poor survival. Expression of genes SLC10A6 was down-regulated in luminal B breast cancers, and was significantly negatively correlated with the expression of hsa-mir-940. Lower expression of this gene was found to be associated with poor survival. Survival plots showing survival curves of low and high expression groups, and scatter plots of Spearman correlation analysis for the prognostic genes are shown in
Figure 5
and
Figure 6
, respectively.
Figure 5. Survival analysis of luminal B breast cancer patients. Kaplan-Meier survival curves showing association between expression of (a) DSN1, (b) SRP9, (c) RACGAP1, (d) SLC10A6, (e) hsa-mir-421 and overall survival.
Figure 6. Spearman’s correlation analysis of miRNA-target gene pairs in luminal B breast cancer patients. Scatter plots showing correlation between prognostic target genes ((a)-(d)) and miRNAs that target them, (a) DSN1, (b) SRP9, (c) RACGAP1, and (d) SLC10A6. (e) Scatter plot showing correlation between prognostic microRNA hsa-mir-421 with its target gene CBX7. X axis represents normalized expression values of miRNA; Y axis represents normalized expression values of mRNA. R is Spearman’s correlation coefficient.
4. Discussion
Post-transcriptional regulation involves the binding of mature miRNAs mainly with the 3’UTR of target mRNAs at miRNA binding regions, resulting in the inhibition of translation or degradation of the transcript
[17]
. One miRNA is capable of targeting many genes, and multiple miRNAs can target the same gene
[18]
. Identifying the correct miRNA-mRNA pairs is necessary to understand the role of post-transcriptional regulation in the pathophysiology of luminal B breast cancer. In breast cancer, dysregulation of miRNAs is observed. In this study, we profiled differentially expressed mRNAs and miRNAs in luminal B breast cancers using TCGA data and identified significantly negatively regulated miRNA-target gene pairs.
The target genes were enriched for important pathways like the Ras signaling pathway and the PI3K-Akt signaling pathway. The PI3K/Akt pathway regulates cell growth, proliferation, and the cell cycle, and its dysregulation is associated with various cancers, including luminal B breast cancer. Aberrant post-transcriptional regulation by miRNA contributes to impairment of this pathway, promoting cancer and drug resistance in various cancers, including breast cancer
[19]
-
[21]
.
Further, miRNAs and corresponding target genes were investigated for the association of gene expression with survival, thus, identifying five genes, including miR-421, DSN1, SRP9, RACGAP1, and SLC10A6, with prognostic significance.
In our study, miR-421 was predicted to target Chromobox protein 7 (CBX7), and over-expression of miR-421 was significantly correlated with low expression of CBX7. According to Wang et al., the expression of miR-421 was found to be up-regulated in breast cancer tissues, and knockdown of miR-421 inhibited breast cancer cell proliferation, invasiveness, and migration
[22]
. Consistent with our findings, miR-421 was reported to directly target the 3’UTR of CBX7, leading to its downregulation in ovarian cancer cells
[23]
. Similarly, in gastric cancer, inhibition of miR-421 was found to correlate with upregulation of the CBX7 gene
[24]
.
In this study, the genes DSN1, SRP9 and RACGAP1 were predicted to be targeted by hsa-mir-5683. DSN1, a kinetochore protein, is a subunit of MTS12 kinetochore complex. It is involved in kinetochore assembly, accurate spindle microtubule attachment, and segregation of chromosomes during mitosis
[25]
[26]
. DSN1 was found to be overexpressed in breast cancer
[27]
. Overexpression of DSN1 was found to be oncogenic and acts as a driver in HER2 (human epidermal growth factor receptor 2) negative breast cancers
[28]
. SRP9 is a protein subunit of signal recognition particle (SRP) complex. SRP9, along with SRP14 (Signal Recognition Particle 14), is involved in pausing the elongation of secretory and membrane proteins, and the SRP complex then targets the nascent polypeptide to the endoplasmic reticulum, where the resumption of translation occurs
[29]
. The expression of SRP9 was found to be upregulated in breast cancer
[30]
. RACGAP1 was found to play a role in cytokinesis and cell proliferation
[31]
. In breast cancer cells, overexpression of RACGAP1 contributes to mitochondrial-induced metastasis
[32]
. Overall survival was found to be poor in breast cancer patients with high RACGAP1 expression
[33]
.
SLC10A6, also called SOAT (sodium-dependent organic anion transporter), is involved in the transport of all sulfated steroid hormones, including estrone-3-sulfate (E1S), and plays a role in fertility and the regulation of lipid metabolism
[34]
. In our study, we have observed that lower expression of SLC10A6 in luminal B breast cancer was strongly correlated with a lower probability of overall survival.
Overall, this work has resulted in identification of differential expressed miRNAs and associated pathways in luminal B breast cancers. It also resulted in identification of critical miRNA-target gene pairs and five genes of prognostic value in luminal B breast cancers. Further experimental analysis of these results may lead to better understanding of miRNA based post-transcriptional regulation in luminal B breast cancers.
Author Contributions
KU was associated with Conceptualization, Data curation, Formal Analysis, Investigation, Methodology and writing original draft of the study. RRA was associated with Formal Analysis. SRH was associated with Conceptualization, Project administration, Supervision and writing review & editing. All authors read and approved the final manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Publicly available datasets were analyzed in this study. This data can be found through
https://www.cancer.gov/ccg/research/genome-sequencing/tcga
.
Supplementary Materials
<xref ref-type="bibr" rid="scirp.136137-"></xref>Table S1. Differentially expressed miRNAs in luminal B breast cancers when compared to paired normal samples (|logFC| ≥ 1; FDR < 0.05).
baseMean
log2FoldChange
lfcSE
stat
p-value
padj
hsa-mir-486-1
402.09502
−5.5992831
0.4883122
−11.466605
1.94E−30
2.53E−28
hsa-mir-486-2
400.72936
−5.5963788
0.4931908
−11.347288
7.65E−30
8.56E−28
hsa-mir-4732
1.678313
−4.3656044
0.8544777
−5.1090911
3.24E−07
2.15E−06
hsa-mir-451a
1471.0801
−4.3519348
0.4736035
−9.1889838
3.97E−20
1.48E−18
hsa-mir-204
9.1679416
−4.3184841
0.4911169
−8.793189
1.45E−18
4.38E−17
hsa-mir-144
289.3198
−4.1317836
0.4001404
−10.325834
5.38E−25
3.01E−23
hsa-mir-139
178.06392
−3.4733478
0.2674525
−12.986786
1.45E−38
5.69E−36
hsa-mir-6507
0.36804
−3.3320522
0.934781
−3.564527
0.0003645
0.0012973
hsa-mir-5683
24.479438
−3.1356124
0.5105627
−6.1414837
8.18E−10
9.02E−09
hsa-mir-1258
3.7869247
−3.1064665
0.4651514
−6.6783994
2.42E−11
3.10E−10
hsa-mir-452
83.951499
−3.0661116
0.3200866
−9.5790076
9.80E−22
4.04E−20
hsa-mir-6499
0.2518401
−2.9955008
1.2792924
−2.3415294
0.0192049
0.0444895
hsa-mir-133b
1.0426853
−2.9345684
0.8467618
−3.4656364
0.000529
0.0018235
hsa-mir-6715a
0.8742895
−2.9269317
0.6853255
−4.2708636
1.95E−05
9.71E−05
hsa-mir-99a
1571.1035
−2.9236587
0.2716027
−10.764467
5.07E−27
3.61E−25
hsa-mir-145
4531.6336
−2.9218705
0.2174404
−13.437569
3.64E−41
2.85E−38
hsa-mir-125b-1
895.36333
−2.7080958
0.2410073
−11.236571
2.70E−29
2.35E−27
hsa-mir-125b-2
924.39469
−2.6946571
0.2386078
−11.293248
1.42E−29
1.39E−27
hsa-mir-337
95.814563
−2.6741037
0.2609667
−10.246915
1.22E−24
6.38E−23
hsa-let-7c
4563.8277
−2.6657936
0.2523765
−10.562765
4.43E−26
2.67E−24
hsa-mir-934
1.0848851
−2.6376624
0.6582157
−4.007292
6.14E−05
0.0002672
hsa-mir-511
22.988378
−2.6195397
0.31138
−8.4126788
4.01E−17
1.01E−15
hsa-mir-100
6770.8633
−2.5006717
0.2476823
−10.096287
5.74E−24
2.64E−22
hsa-mir-665
1.153046
−2.4735475
0.3456823
−7.1555522
8.33E−13
1.28E−11
hsa-mir-205
5452.1479
−2.4533337
0.5098277
−4.8120836
1.49E−06
8.60E−06
hsa-mir-607
0.9443823
−2.4485692
0.4933442
−4.9632068
6.93E−07
4.27E−06
hsa-mir-483
13.180753
−2.4249812
0.3313186
−7.3191827
2.49E−13
4.25E−12
hsa-mir-133a-2
7.5623179
−2.4024777
0.5595407
−4.2936603
1.76E−05
8.94E−05
hsa-mir-585
1.5288913
−2.3990911
0.44057
−5.4454259
5.17E−08
3.71E−07
hsa-mir-133a-1
8.3418292
−2.3776798
0.5605568
−4.2416398
2.22E−05
0.0001086
hsa-mir-551b
4.2851515
−2.3749172
0.3318399
−7.1568157
8.26E−13
1.28E−11
hsa-mir-584
85.565416
−2.3228587
0.2671677
−8.6943829
3.49E−18
1.01E−16
hsa-mir-6746
0.2895719
−2.2400447
0.7770778
−2.8826515
0.0039434
0.0113793
hsa-mir-378d-1
0.3647113
−2.2391925
0.5538497
−4.0429604
5.28E−05
0.0002348
hsa-mir-378a
637.23703
−2.2252757
0.2017619
−11.029217
2.76E−28
2.16E−26
hsa-mir-6513
0.3329167
−2.2215997
0.6615388
−3.3582307
0.0007844
0.0025807
hsa-mir-10b
221264.84
−2.2010546
0.2783316
−7.9080303
2.61E−15
5.12E−14
hsa-mir-1247
97.391629
−2.097876
0.4527959
−4.6331608
3.60E−06
1.97E−05
hsa-mir-378d-2
0.4306209
−2.0770332
0.5294013
−3.9233622
8.73E−05
0.0003716
hsa-mir-3199-1
0.7402999
−2.0500343
0.4003676
−5.1203803
3.05E−07
2.06E−06
hsa-mir-329-2
0.9684998
−2.0487001
0.3626569
−5.6491416
1.61E−08
1.34E−07
hsa-mir-378c
9.4502551
−2.046353
0.2267849
−9.023321
1.82E−19
6.21E−18
hsa-mir-224
69.355501
−2.0320418
0.4588992
−4.4280785
9.51E−06
5.06E−05
hsa-mir-329-1
0.6884448
−2.00735
0.4266703
−4.7046867
2.54E−06
1.43E−05
hsa-mir-7976
0.3503034
−2.0043497
0.6566987
−3.0521603
0.002272
0.006816
hsa-mir-3199-2
1.8436855
−1.9620287
0.2838771
−6.9115429
4.79E−12
6.95E−11
hsa-mir-6820
1.2918154
−1.9400861
0.3469019
−5.5926069
2.24E−08
1.79E−07
hsa-mir-4524a
0.3692785
−1.9289392
0.6824392
−2.8265362
0.0047054
0.0133009
hsa-mir-129-2
3.0914926
−1.925563
0.4468628
−4.30907
1.64E−05
8.39E−05
hsa-mir-495
15.76173
−1.9158719
0.212708
−9.0070513
2.12E−19
6.91E−18
hsa-mir-223
221.99261
−1.863759
0.2227777
−8.3660028
5.96E−17
1.46E−15
hsa-mir-140
1336.9093
−1.8556488
0.1535445
−12.085418
1.26E−33
2.47E−31
hsa-mir-6510
11.664277
−1.8492038
0.668622
−2.7656939
0.0056802
0.0156605
hsa-mir-433
2.4542096
−1.8293461
0.2649465
−6.9045865
5.03E−12
7.17E−11
hsa-mir-494
3.5821229
−1.8089136
0.2917317
−6.2006072
5.62E−10
6.29E−09
hsa-mir-376a-2
0.8098465
−1.8043181
0.4444626
−4.0595499
4.92E−05
0.0002225
hsa-mir-6720
0.7139041
−1.7782397
0.460535
−3.8612477
0.0001128
0.0004674
hsa-mir-432
11.798501
−1.7416987
0.2257058
−7.7166783
1.19E−14
2.12E−13
hsa-mir-1-1
6.8951249
−1.7410601
0.4923356
−3.536328
0.0004057
0.001431
hsa-mir-377
6.4125792
−1.7010712
0.2191166
−7.7633168
8.27E−15
1.51E−13
hsa-mir-1-2
7.744016
−1.6985119
0.4643349
−3.6579461
0.0002542
0.0009608
hsa-mir-335
277.84375
−1.6910593
0.2477821
−6.8247843
8.81E−12
1.21E−10
hsa-mir-944
2.277033
−1.684255
0.4457249
−3.7786872
0.0001577
0.0006235
hsa-mir-1262
1.3944442
−1.6426683
0.4491916
−3.6569433
0.0002552
0.0009608
hsa-mir-195
108.92029
−1.6165908
0.2033469
−7.9499176
1.87E−15
3.75E−14
hsa-mir-381
50.375039
−1.5681606
0.211392
−7.4182575
1.19E−13
2.06E−12
hsa-mir-365b
322.83769
−1.5668955
0.1951496
−8.0292026
9.81E−16
2.08E−14
hsa-mir-6892
8.2133205
−1.5639456
0.28462
−5.4948543
3.91E−08
2.94E−07
hsa-mir-365a
324.7972
−1.5558726
0.1953663
−7.9638746
1.67E−15
3.44E−14
hsa-mir-4491
0.6484421
−1.5528886
0.6117487
−2.5384419
0.0111347
0.0273307
hsa-mir-299
6.6797129
−1.5505203
0.2543703
−6.0955249
1.09E−09
1.17E−08
hsa-mir-654
40.960674
−1.5363505
0.2203801
−6.9713678
3.14E−12
4.64E−11
hsa-mir-1295a
1.9631271
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0.3939937
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0.0001476
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hsa-mir-379
1359.208
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3.46E−10
4.04E−09
hsa-mir-3926-1
1.4021725
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2.77E−05
0.0001309
hsa-mir-218-2
38.739212
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−8.3174274
8.99E−17
2.13E−15
hsa-mir-376c
9.5934551
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0.2358669
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1.06E−09
1.15E−08
hsa-mir-497
70.687982
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2.66E−10
3.16E−09
hsa-mir-6716
2.0471718
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1.03E−07
7.22E−07
hsa-mir-758
35.176244
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2.27E−08
1.79E−07
hsa-mir-143
85641.998
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1.05E−08
9.43E−08
hsa-mir-218-1
40.290029
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3.41E−15
6.51E−14
hsa-mir-675
109.78128
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hsa-mir-656
1.4412364
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hsa-mir-605
1.4451132
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hsa-mir-485
8.9037422
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1.62E−08
1.34E−07
hsa-mir-1468
14.817091
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5.18E−05
0.0002319
hsa-mir-487b
9.9815635
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4.80E−09
4.76E−08
hsa-mir-129-1
2.6944645
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hsa-mir-3926-2
1.8357309
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hsa-mir-326
36.906898
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hsa-mir-487a
2.7984448
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3.21E−06
1.77E−05
hsa-mir-6803
0.5734836
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hsa-mir-655
4.7897022
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7.50E−06
4.02E−05
hsa-mir-190a
9.8607254
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4.44E−08
3.25E−07
hsa-mir-411
11.03217
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2.88E−08
2.23E−07
hsa-mir-6802
1.4582584
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1.90E−05
9.56E−05
hsa-mir-676
1.9718384
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7.85E−05
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hsa-mir-130a
175.25575
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1.77E−07
1.23E−06
hsa-mir-154
14.672667
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2.10E−08
1.70E−07
hsa-mir-126
9214.6322
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6.23E−09
5.94E−08
hsa-mir-29a
9057.9605
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1.95E−11
2.59E−10
hsa-mir-431
22.95481
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2.92E−06
1.62E−05
hsa-mir-3157
0.8226011
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hsa-mir-550a-3
3.64957
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hsa-mir-376b
3.0911758
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hsa-mir-320c-1
1.1200069
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hsa-mir-6503
0.8519098
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hsa-mir-1228
3.2982382
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5.32E−05
0.000235
hsa-mir-323a
8.1561404
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3.63E−05
0.0001672
hsa-mir-376a-1
2.6338564
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hsa-mir-1271
8.4607772
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5.34E−05
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hsa-mir-5187
0.8577444
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hsa-mir-574
263.03563
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7.68E−08
5.47E−07
hsa-mir-193a
1275.3023
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4.29E−07
2.73E−06
hsa-mir-5010
1.8422211
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hsa-mir-369
18.336588
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1.37E−06
8.06E−06
hsa-mir-4746
8.5648571
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2.9258146
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hsa-mir-15b
781.52829
1.0136852
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3.6108926
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hsa-mir-3678
2.4604492
1.0315012
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2.3968982
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hsa-mir-181b-2
417.77498
1.0532627
0.2625167
4.0121738
6.02E−05
0.0002632
hsa-mir-128-2
125.36257
1.0799044
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5.3484082
8.87E−08
6.26E−07
hsa-mir-153-2
94.401054
1.0930262
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2.7522604
0.0059185
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hsa-mir-3917
3.2664687
1.1088028
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2.7258465
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hsa-mir-340
66.948502
1.1232094
0.1873446
5.9954198
2.03E−09
2.15E−08
hsa-mir-3200
15.729962
1.1397358
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3.2559816
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0.0036262
hsa-mir-3928
6.7152949
1.1475131
0.3404641
3.3704383
0.0007505
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hsa-mir-671
23.29653
1.1692315
0.1987674
5.8824113
4.04E−09
4.11E−08
hsa-mir-130b
70.490573
1.2067833
0.206822
5.8348875
5.38E−09
5.27E−08
hsa-mir-181b-1
486.95576
1.2155052
0.2589523
4.6939349
2.68E−06
1.50E−05
hsa-mir-548e
1.4325244
1.2284337
0.5098814
2.4092538
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0.0380438
hsa-mir-628
111.94896
1.2382649
0.2539657
4.8757173
1.08E−06
6.43E−06
hsa-mir-149
636.8323
1.2391683
0.3244591
3.8191818
0.0001339
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hsa-mir-659
3.8297918
1.2513507
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3.9376462
8.23E−05
0.000354
hsa-mir-493
26.163156
1.2575993
0.2451146
5.1306574
2.89E−07
1.97E−06
hsa-mir-4677
26.158883
1.2594943
0.2014037
6.2535813
4.01E−10
4.62E−09
hsa-mir-5003
1.7666079
1.2689819
0.5530758
2.2944085
0.021767
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hsa-mir-1180
37.177841
1.2749449
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3.6703202
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hsa-mir-92b
374.88802
1.2762793
0.3050507
4.1838261
2.87E−05
0.0001344
hsa-mir-3190
1.3821664
1.2775048
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2.3097706
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0.0479923
hsa-mir-32
68.37118
1.2864935
0.2194329
5.8628101
4.55E−09
4.57E−08
hsa-mir-191
3600.9051
1.294533
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5.6570012
1.54E−08
1.31E−07
hsa-mir-345
78.85085
1.2954632
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4.3958653
1.10E−05
5.84E−05
hsa-mir-7-1
116.64772
1.2994342
0.2548949
5.0979209
3.43E−07
2.26E−06
hsa-mir-421
6.821849
1.3280115
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4.217397
2.47E−05
0.000118
hsa-mir-651
6.5527581
1.3336776
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4.0756155
4.59E−05
0.0002089
hsa-mir-887
41.324838
1.3572844
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3.8967027
9.75E−05
0.0004083
hsa-mir-3150b
8.1362897
1.3596496
0.4644834
2.9272299
0.00342
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hsa-mir-1307
4081.0067
1.37424
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5.7910599
6.99E−09
6.52E−08
hsa-mir-142
6877.4725
1.3894628
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4.9928481
5.95E−07
3.70E−06
hsa-mir-1254-2
1.5203154
1.400673
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2.6217884
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hsa-mir-3940
3.442979
1.4236549
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3.3118608
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hsa-mir-6777
1.9191851
1.4297281
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2.6653068
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0.0197581
hsa-mir-188
7.2544601
1.4403146
0.3308722
4.353084
1.34E−05
6.91E−05
hsa-mir-454
40.813627
1.4518643
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6.97E−09
6.52E−08
hsa-mir-4728
12.1208
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2.9348198
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hsa-mir-3655
0.6146392
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hsa-mir-1254-1
1.5347473
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hsa-mir-4726
0.9534172
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hsa-mir-4791
1.172677
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2.781864
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hsa-mir-2277
3.4943187
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hsa-mir-200b
1624.7809
1.5567247
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6.324805
2.54E−10
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hsa-mir-192
1469.6734
1.5589765
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1.51E−08
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hsa-mir-508
28.949204
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hsa-mir-342
1466.4074
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3.99E−08
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hsa-mir-3150a
0.6304385
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hsa-mir-3174
0.7027517
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hsa-mir-3117
1.1553233
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hsa-mir-1284
1.1407519
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hsa-mir-5695
1.1546705
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hsa-mir-200c
29060.541
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8.581013
9.40E−18
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hsa-mir-4443
0.8817248
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hsa-mir-33a
55.270662
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2.01E−08
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hsa-mir-1537
0.737654
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hsa-mir-1276
0.5150502
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hsa-mir-3127
31.568717
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6.02E−09
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hsa-mir-514a-1
2.3547124
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hsa-mir-4442
0.7940265
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hsa-mir-639
1.5173041
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hsa-mir-615
49.520772
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7.44E−06
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hsa-mir-148b
649.33419
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1.02E−17
2.66E−16
hsa-mir-935
20.572243
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hsa-mir-3652
2.092463
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hsa-mir-877
5.973361
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2.36E−05
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hsa-mir-4444-2
1.8782265
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hsa-mir-6501
1.4267307
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hsa-mir-4784
1.5369185
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hsa-mir-6798
1.1108443
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hsa-mir-7-2
4.0426703
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hsa-mir-4638
4.7189462
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1.15E−05
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hsa-mir-940
19.49345
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2.60E−07
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hsa-mir-203a
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hsa-mir-7974
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hsa-mir-1224
6.1559971
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hsa-mir-3690-1
1.4211261
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hsa-mir-1301
49.23123
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5.31E−15
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hsa-mir-9-2
1710.1567
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hsa-mir-3609
1.2756874
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hsa-mir-9-1
1711.192
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hsa-mir-9-3
1723.3757
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hsa-mir-4326
25.497004
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1.42E−06
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hsa-mir-5684
2.0404031
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hsa-mir-4668
17.931526
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3.16E−08
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hsa-mir-556
2.2265754
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hsa-mir-7706
6.2067987
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1.20E−08
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hsa-mir-6854
2.3788626
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hsa-mir-3187
1.2252649
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hsa-mir-1277
3.5964211
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9.83E−07
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hsa-mir-301a
71.189087
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6.850193
7.38E−12
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hsa-mir-3614
16.609324
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5.42E−07
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hsa-mir-4640
0.8494643
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hsa-mir-21
580260.95
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10.656383
1.63E−26
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hsa-mir-4675
1.1349113
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hsa-mir-200a
2259.243
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4.36E−18
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hsa-mir-182
104572.93
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9.17E−19
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hsa-mir-3619
1.6264388
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hsa-mir-4714
2.4291421
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hsa-mir-3176
0.81665
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hsa-mir-503
55.723256
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6.2468427
4.19E−10
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hsa-mir-2114
2.5871486
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3.2819263
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hsa-mir-4680
1.0308286
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hsa-mir-3677
52.426063
2.2994318
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6.5964942
4.21E−11
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hsa-mir-5694
3.4974724
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3.4398967
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hsa-mir-4758
0.9944876
2.376604
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3.696034
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hsa-mir-1910
1.5046284
2.4076585
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3.705191
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hsa-mir-429
287.81234
2.4460055
0.2710352
9.0246777
1.80E−19
6.21E−18
hsa-mir-203b
136.27092
2.4541576
0.5605937
4.3777828
1.20E−05
6.22E−05
hsa-mir-187
63.910204
2.4625125
0.5773194
4.2654249
2.00E−05
9.89E−05
hsa-mir-141
4904.4781
2.4695679
0.2117873
11.660604
2.03E−31
3.17E−29
hsa-mir-3156-2
1.0068944
2.469967
1.0124368
2.4396258
0.0147025
0.035531
hsa-mir-3065
194.1868
2.6722265
0.466008
5.7342932
9.79E−09
9.02E−08
hsa-mir-7156
2.9362456
2.6897926
0.8438436
3.1875486
0.0014348
0.004476
hsa-mir-3662
2.1014578
2.6983715
0.656894
4.1077734
3.99E−05
0.0001829
hsa-mir-4446
2.0919794
2.7451863
0.6566598
4.1805306
2.91E−05
0.0001355
hsa-mir-96
94.122746
2.8487537
0.2984195
9.5461382
1.35E−21
5.27E−20
hsa-mir-3664
3.0183011
2.925689
0.5991985
4.8826711
1.05E−06
6.26E−06
hsa-mir-4756
1.5154464
2.9370098
0.7484983
3.9238697
8.71E−05
0.0003716
hsa-mir-33b
27.096283
2.9473853
0.4101897
7.1854199
6.70E−13
1.07E−11
hsa-mir-301b
5.4643352
2.9940638
0.5238337
5.7156768
1.09E−08
9.72E−08
hsa-mir-760
14.67738
3.0452155
0.4764883
6.3909557
1.65E−10
2.02E−09
hsa-mir-3610
3.5277704
3.0726743
0.5606211
5.4808395
4.23E−08
3.13E−07
hsa-mir-183
45458.422
3.0857932
0.2409641
12.806028
1.52E−37
3.96E−35
hsa-mir-937
14.601024
3.0987091
0.520384
5.9546584
2.61E−09
2.69E−08
hsa-mir-4664
3.5072935
3.1943344
0.5846401
5.4637616
4.66E−08
3.38E−07
hsa-mir-7-3
4.0323959
3.2720805
0.6805728
4.807833
1.53E−06
8.72E−06
hsa-mir-375
69032.074
3.3010072
0.3985204
8.2831571
1.20E−16
2.76E−15
hsa-mir-210
2316.5797
3.3420528
0.329561
10.140924
3.64E−24
1.78E−22
hsa-mir-196a-2
1498.9541
3.4204973
0.479967
7.1265261
1.03E−12
1.55E−11
hsa-mir-7705
3.6540236
3.5305883
0.5393149
6.5464314
5.89E−11
7.32E−10
hsa-mir-4652
2.1866127
3.5469799
0.9294273
3.8163069
0.0001355
0.0005439
hsa-mir-190b
74.86657
3.5515278
0.3619959
9.8109614
1.01E−22
4.39E−21
hsa-mir-196a-1
1287.1559
3.5550906
0.4884056
7.2789722
3.36E−13
5.49E−12
hsa-mir-147b
3.4595148
3.8580574
0.6738046
5.7257808
1.03E−08
9.37E−08
hsa-mir-4501
5.3061953
3.8741146
0.7602908
5.0955696
3.48E−07
2.27E−06
hsa-mir-449c
3.5868192
4.0610001
1.1560968
3.5126817
0.0004436
0.0015506
hsa-mir-592
14.645961
4.1646147
0.5088097
8.185014
2.72E−16
5.92E−15
hsa-mir-184
98.86697
4.1782731
0.7004144
5.9654304
2.44E−09
2.55E−08
hsa-mir-1251
5.2776275
4.1854343
0.9762677
4.2871788
1.81E−05
9.14E−05
hsa-mir-767
12.299696
4.5122213
1.2908321
3.4955912
0.000473
0.0016461
hsa-mir-4724
8.4668685
4.7239329
0.6955226
6.7919184
1.11E−11
1.49E−10
hsa-mir-449b
8.2158557
4.894992
0.9674178
5.0598531
4.20E−07
2.69E−06
hsa-mir-105-2
22.126731
5.666011
1.2381268
4.5762768
4.73E−06
2.57E−05
hsa-mir-105-1
22.393353
5.785696
1.132057
5.1107816
3.21E−07
2.15E−06
hsa-mir-1269b
11.678364
5.7910783
1.319335
4.3893917
1.14E−05
5.97E−05
hsa-mir-449a
23.345357
6.6957718
0.9186087
7.2890362
3.12E−13
5.20E−12
hsa-mir-1269a
201.18322
8.4834144
1.0283411
8.2496114
1.59E−16
3.56E−15
<xref ref-type="bibr" rid="scirp.136137-"></xref>Table S2. Critical miRNA-target gene pairs identified by spearman’s correlation analysis (R < −0.2 and p-value < 0.05).
miRNA
miRNA-expression
Gene
Gene-expression
Spearman’s_correlation_coefficient (R)
p-value
hsa-mir-5683
down
SRP9
up
−0.3672128
3.97E−07
hsa-mir-665
down
PDCL3
up
−0.3642548
4.99E−07
hsa-mir-665
down
SPC24
up
−0.3608442
6.49E−07
hsa-mir-944
down
YWHAZ
up
−0.3440701
2.25E−06
hsa-mir-665
down
CALR
up
−0.3372896
3.66E−06
hsa-mir-665
down
SLC25A22
up
−0.3348415
4.34E−06
hsa-mir-5683
down
KIF21A
up
−0.3345275
4.44E−06
hsa-mir-665
down
SNRNP25
up
−0.3342616
4.52E−06
hsa-mir-665
down
CENPM
up
−0.3267832
7.56E−06
hsa-mir-5683
down
MTFR1
up
−0.3191654
1.26E−05
hsa-mir-934
down
PMAIP1
up
−0.3181198
1.35E−05
hsa-mir-665
down
NR2F6
up
−0.3124445
1.95E−05
hsa-mir-665
down
NACC1
up
−0.3033006
3.49E−05
hsa-mir-665
down
EIF4A3
up
−0.3022335
3.73E−05
hsa-mir-665
down
BCAS4
up
−0.3021408
3.75E−05
hsa-mir-665
down
PGAM5
up
−0.2998268
4.33E−05
hsa-mir-665
down
SYNGR2
up
−0.2995249
4.41E−05
hsa-mir-5683
down
CCNB1
up
−0.2957081
5.57E−05
hsa-mir-1258
down
PACSIN1
up
−0.2951285
5.77E−05
hsa-mir-665
down
NECAB3
up
−0.2947845
5.89E−05
hsa-mir-5683
down
DSN1
up
−0.2930242
6.55E−05
hsa-mir-665
down
TPM3
up
−0.2903635
7.69E−05
hsa-mir-665
down
SYAP1
up
−0.2864156
9.70E−05
hsa-mir-665
down
ZNF695
up
−0.281877
0.0001264
hsa-mir-665
down
HJURP
up
−0.2817984
0.0001269
hsa-mir-665
down
PTRH2
up
−0.2801275
0.0001397
hsa-mir-665
down
PSMC4
up
−0.2757109
0.0001796
hsa-mir-1258
down
ZNF281
up
−0.2698214
0.0002493
hsa-mir-934
down
ASB16
up
−0.2669101
0.0002924
hsa-mir-5683
down
GPR141
up
−0.2630908
0.0003594
hsa-mir-5683
down
MORF4L2
up
−0.2569629
0.0004974
hsa-mir-5683
down
POLQ
up
−0.2568022
0.0005016
hsa-mir-665
down
CENPN
up
−0.2508178
0.0006836
hsa-mir-665
down
RFC2
up
−0.2506172
0.0006906
hsa-mir-1262
down
CERS2
up
−0.2498418
0.0007185
hsa-mir-1262
down
AGMAT
up
−0.2425888
0.001034
hsa-mir-665
down
RRM2
up
−0.2414188
0.001095
hsa-mir-944
down
TSPAN13
up
−0.2407357
0.001133
hsa-mir-326
down
MAz
up
−0.2353943
0.001468
hsa-mir-665
down
GNG3
up
−0.2352009
0.001482
hsa-mir-5683
down
RACGAP1
up
−0.2330957
0.001638
hsa-mir-665
down
PRIM1
up
−0.2311795
0.001794
hsa-mir-665
down
RAD21
up
−0.2304525
0.001856
hsa-mir-665
down
TCEA3
up
−0.2293112
0.001958
hsa-mir-378c
down
DCTPP1
up
−0.2271472
0.002166
hsa-mir-5683
down
MTHFD2
up
−0.2251345
0.002377
hsa-mir-5683
down
PMAIP1
up
−0.2246175
0.002434
hsa-mir-665
down
DNA2
up
−0.2218089
0.002767
hsa-mir-665
down
AP1S3
up
−0.220575
0.002926
hsa-mir-665
down
BPNT1
up
−0.2185803
0.0032
hsa-mir-451a
down
HELLS
up
−0.2172289
0.00346
hsa-mir-665
down
BRI3BP
up
−0.2150804
0.003737
hsa-mir-326
down
RBM47
up
−0.2143822
0.003854
hsa-mir-1262
down
PTK6
up
−0.2137454
0.003963
hsa-mir-934
down
SERPINC1
up
−0.211244
0.004419
hsa-mir-665
down
ZNF623
up
−0.2062482
0.005473
hsa-mir-665
down
MRPL12
up
−0.2061883
0.005487
hsa-mir-326
down
PKM
up
−0.2058233
0.005573
hsa-mir-326
down
CD9
up
−0.203674
0.0061
hsa-mir-665
down
KCNK6
up
−0.2032562
0.006208
hsa-mir-429
up
QKI
down
−0.4347583
1.57E−09
hsa-mir-429
up
CDC14B
down
−0.4206447
5.82E−09
hsa-mir-375
up
EMP1
down
−0.4182187
7.23E−09
hsa-mir-190b
up
KLF6
down
−0.3900902
6.19E−08
hsa-mir-429
up
ACSL4
down
−0.3865243
1.07E−07
hsa-mir-429
up
ZEB2
down
−0.3733593
3.02E−07
hsa-mir-4501
up
ITGB8
down
−0.3670988
4.00E−07
hsa-mir-429
up
ZFPM2
down
−0.3607663
7.82E−07
hsa-mir-190b
up
DAB2
down
−0.3544191
1.05E−06
hsa-mir-190b
up
GPC5
down
−0.3523811
1.23E−06
hsa-mir-375
up
KIT
down
−0.3522784
1.46E−06
hsa-mir-421
up
CBX7
down
−0.3509502
1.36E−06
hsa-mir-429
up
ANKRD33B
down
−0.3479079
1.99E−06
hsa-mir-429
up
TCF7L2
down
−0.3466486
2.18E−06
hsa-mir-3662
up
MYOCD
down
−0.3430709
2.42E−06
hsa-mir-375
up
F3
down
−0.3416484
3.09E−06
hsa-mir-375
up
YAP1
down
−0.339243
3.66E−06
hsa-mir-375
up
MAP3K8
down
−0.3325843
5.77E−06
hsa-mir-429
up
IGF2
down
−0.3270286
8.37E−06
hsa-mir-429
up
TCF7L1
down
−0.3224606
1.13E−05
hsa-mir-190b
up
CYGB
down
−0.3167686
1.48E−05
hsa-mir-190b
up
IGF1
down
−0.3154332
1.61E−05
hsa-mir-4326
up
TXNIP
down
−0.3146926
1.69E−05
hsa-mir-375
up
ZFP36L2
down
−0.3126845
2.12E−05
hsa-mir-1269a
up
H6PD
down
−0.3117793
2.04E−05
hsa-mir-4784
up
HAP1
down
−0.3103257
2.24E−05
hsa-mir-940
up
PER2
down
−0.3036045
3.43E−05
hsa-mir-3652
up
PRKCA
down
−0.2999963
4.29E−05
hsa-mir-5694
up
ANTXR2
down
−0.2985284
4.69E−05
hsa-mir-375
up
CELF2
down
−0.293507
6.85E−05
hsa-mir-3662
up
PTPN14
down
−0.290054
7.83E−05
hsa-mir-375
up
TNS1
down
−0.2894266
8.70E−05
hsa-mir-375
up
SH3D19
down
−0.2888155
9.02E−05
hsa-miR-592
up
AKAP12
down
−0.2843705
0.0001094
hsa-mir-375
up
ACSL4
down
−0.2810766
0.0001405
hsa-mir-3609
up
ADAMTS9
down
−0.2807031
0.0001352
hsa-mir-429
up
AVPR1A
down
−0.2803296
0.0001465
hsa-mir-375
up
GATA6
down
−0.2760682
0.000186
hsa-mir-375
up
AKAP7
down
−0.2759715
0.000187
hsa-mir-429
up
KLF11
down
−0.2738521
0.0002102
hsa-mir-3652
up
SIK2
down
−0.2734481
0.0002039
hsa-mir-4784
up
WFIKKN2
down
−0.2719226
0.0002219
hsa-mir-449a
up
MET
down
−0.2714277
0.0002281
hsa-miR-592
up
CCL16
down
−0.2659841
0.0003075
hsa-mir-3662
up
ETS2
down
−0.2650204
0.0003239
hsa-mir-190b
up
PCDHB11
down
−0.2645826
0.0003317
hsa-mir-940
up
NPR1
down
−0.2634869
0.0003519
hsa-mir-940
up
OLFML2A
down
−0.262919
0.0003628
hsa-mir-3652
up
ABCA6
down
−0.2615974
0.0003893
hsa-mir-429
up
JUN
down
−0.2612797
0.0004134
hsa-mir-375
up
FAM89A
down
−0.2570923
0.0005141
hsa-mir-3652
up
PTGIS
down
−0.2557748
0.0005292
hsa-mir-3662
up
SLC35G2
down
−0.2545139
0.0005651
hsa-mir-375
up
SAMD4A
down
−0.2495571
0.0007548
hsa-mir-4326
up
TNS1
down
−0.2495448
0.0007294
hsa-mir-449a
up
TXNIP
down
−0.2463247
0.0008583
hsa-mir-7705
up
CYGB
down
−0.245438
0.0008973
hsa-mir-940
up
CDC14B
down
−0.2446813
0.0009318
hsa-mir-7705
up
KLHL3
down
−0.2409715
0.00112
hsa-mir-940
up
EPHA2
down
−0.2385039
0.001263
hsa-mir-1276
up
ACVR2A
down
−0.2379292
0.001299
hsa-mir-3609
up
KLF6
down
−0.2375235
0.001325
hsa-mir-5695
up
CHST3
down
−0.2370087
0.001358
hsa-mir-429
up
WASF3
down
−0.2364764
0.001432
hsa-miR-1284
up
RCAN2
down
−0.2360124
0.001425
hsa-mir-190b
up
PM20D2
down
−0.2353593
0.00147
hsa-mir-7705
up
CYP27C1
down
−0.2335649
0.001602
hsa-mir-375
up
PIK3IP1
down
−0.2328055
0.001703
hsa-mir-940
up
TLN1
down
−0.2312545
0.001788
hsa-mir-940
up
FOXC1
down
−0.2311928
0.001793
hsa-mir-940
up
SLC10A6
down
−0.2299449
0.001901
hsa-mir-5695
up
BACH2
down
−0.2288609
0.002
hsa-mir-375
up
LDHB
down
−0.2283033
0.0021
hsa-mir-5695
up
SOX17
down
−0.2277192
0.002109
hsa-mir-375
up
SYT15
down
−0.2276243
0.002167
hsa-mir-3662
up
ADAMTS1
down
−0.2240943
0.002493
hsa-mir-449a
up
FOXN3
down
−0.2239901
0.002505
hsa-mir-147b
up
MITF
down
−0.2232909
0.002587
hsa-mir-7705
up
LAMA4
down
−0.2226293
0.002666
hsa-mir-1269b
up
H6PD
down
−0.2213294
0.002828
hsa-mir-3652
up
MYH11
down
−0.2208941
0.002884
hsa-mir-3662
up
SH3TC2
down
−0.2203975
0.002949
hsa-mir-5695
up
SLC22A3
down
−0.2182073
0.003254
hsa-miR-592
up
EMCN
down
−0.2179502
0.003291
hsa-mir-449a
up
CLIC5
down
−0.2173743
0.003377
hsa-mir-449a
up
UST
down
−0.2173198
0.003385
hsa-mir-940
up
ADD2
down
−0.2168689
0.003453
hsa-mir-5695
up
ITGA9
down
−0.2160662
0.003578
hsa-mir-375
up
PRKCA
down
−0.2160478
0.003644
hsa-mir-3662
up
SEMA6D
down
−0.2141494
0.003893
hsa-mir-449a
up
NOTCH1
down
−0.2120725
0.004263
hsa-mir-4326
up
AMOTL1
down
−0.210992
0.004468
hsa-mir-3652
up
FBXO40
down
−0.2108282
0.004499
hsa-mir-3652
up
OMD
down
−0.2097977
0.004704
hsa-miR-1284
up
HOXA9
down
−0.2095338
0.004757
hsa-mir-1276
up
AKAP6
down
−0.2086087
0.00495
hsa-mir-3652
up
TSHZ2
down
−0.2082591
0.005025
hsa-mir-375
up
NCOA7
down
−0.2069097
0.005397
hsa-mir-940
up
PDE7B
down
−0.2058106
0.005576
hsa-mir-760
up
ETS1
down
−0.2053226
0.005692
hsa-mir-940
up
NPY4R
down
−0.2047089
0.005841
hsa-mir-3662
up
ACSL4
down
−0.2032589
0.006207
hsa-mir-5695
up
PDE1A
down
−0.2024794
0.006412
hsa-miR-592
up
EPHA4
down
−0.2005619
0.006943
<xref ref-type="bibr" rid="scirp.136137-"></xref>Table S3. Differentially expressed target genes in luminal B breast cancer.
gene_id
gene_name
baseMean
log2FoldChange
lfcSE
stat
p-value
padj
ENSG00000133392.18
MYH11
4182.333
−4.73722
0.263733
−17.9622
3.85E−72
8.36E−70
ENSG00000169418.10
NPR1
994.8141
−4.40846
0.222879
−19.7796
4.46E−87
3.33E−84
ENSG00000157404.16
KIT
2759.348
−4.29016
0.382646
−11.2118
3.57E−29
1.05E−27
ENSG00000204174.8
NPY4R
1.131372
−4.24808
0.666555
−6.37318
1.85E−10
1.21E−09
ENSG00000275152.5
CCL16
6.107794
−3.6132
0.39113
−9.23786
2.51E−20
4.17E−19
ENSG00000154262.13
ABCA6
526.0594
−3.59807
0.267015
−13.4752
2.19E−41
1.25E−39
ENSG00000163833.8
FBXO40
2.115284
−3.53501
0.49209
−7.18366
6.79E−13
5.80E−12
ENSG00000182463.16
TSHZ2
1015.632
−3.46184
0.221596
−15.6223
5.13E−55
5.70E−53
ENSG00000017427.17
IGF1
146.2573
−3.43134
0.305261
−11.2407
2.57E−29
7.61E−28
ENSG00000079308.19
TNS1
13105.78
−3.42972
0.158007
−21.7062
1.79E−104
4.19E−101
ENSG00000146477.6
SLC22A3
125.967
−3.30656
0.394025
−8.39175
4.79E−17
5.97E−16
ENSG00000131016.17
AKAP12
2643.414
−3.26625
0.236728
−13.7975
2.64E−43
1.66E−41
ENSG00000154734.16
ADAMTS1
3428.261
−3.26333
0.3076
−10.609
2.71E−26
6.63E−25
ENSG00000164736.6
SOX17
205.1572
−3.12087
0.203069
−15.3686
2.66E−53
2.71E−51
ENSG00000054598.9
FOXC1
425.2381
−3.03671
0.232089
−13.0843
4.05E−39
2.07E−37
ENSG00000141052.18
MYOCD
49.80311
−2.95209
0.423622
−6.9687
3.20E−12
2.53E−11
ENSG00000164035.10
EMCN
1083.569
−2.80775
0.193672
−14.4974
1.26E−47
9.43E−46
ENSG00000105976.16
MET
1435.458
−2.77559
0.357854
−7.7562
8.75E−15
8.92E−14
ENSG00000170145.5
SIK2
3313.581
−2.77356
0.176112
−15.7488
7.00E−56
8.43E−54
ENSG00000134531.10
EMP1
11291.44
−2.74574
0.208157
−13.1907
9.93E−40
5.19E−38
ENSG00000124212.6
PTGIS
1898.959
−2.72032
0.337166
−8.06819
7.13E−16
8.00E−15
ENSG00000117525.14
F3
1222.6
−2.71613
0.312218
−8.69948
3.33E−18
4.59E−17
ENSG00000182118.8
FAM89A
394.7037
−2.71104
0.402906
−6.72871
1.71E−11
1.26E−10
ENSG00000145283.8
SLC10A6
41.70076
−2.64108
0.323546
−8.16293
3.27E−16
3.78E−15
ENSG00000137872.17
SEMA6D
476.5353
−2.61329
0.323742
−8.07216
6.91E−16
7.76E−15
ENSG00000169247.14
SH3TC2
102.764
−2.60906
0.271145
−9.62237
6.43E−22
1.19E−20
ENSG00000048740.18
CELF2
2009.801
−2.54104
0.237201
−10.7126
8.88E−27
2.24E−25
ENSG00000168917.9
SLC35G2
212.4747
−2.53843
0.226704
−11.1971
4.21E−29
1.23E−27
ENSG00000081377.17
CDC14B
722.5051
−2.49492
0.224796
−11.0986
1.27E−28
3.59E−27
ENSG00000132970.14
WASF3
391.7932
−2.46931
0.347207
−7.11193
1.14E−12
9.54E−12
ENSG00000122863.6
CHST3
1141.86
−2.41879
0.222482
−10.8718
1.57E−27
4.14E−26
ENSG00000265972.6
TXNIP
41624.99
−2.40691
0.221344
−10.8741
1.53E−27
4.05E−26
ENSG00000152284.5
TCF7L1
1180.151
−2.40503
0.277114
−8.67886
4.00E−18
5.45E−17
ENSG00000152104.12
PTPN14
3239.542
−2.3832
0.202184
−11.7873
4.54E−32
1.56E−30
ENSG00000173805.16
HAP1
77.31086
−2.36633
0.469786
−5.03704
4.73E−07
1.94E−06
ENSG00000020577.14
SAMD4A
944.5597
−2.32662
0.218535
−10.6464
1.81E−26
4.49E−25
ENSG00000112782.19
CLIC5
483.722
−2.32626
0.304194
−7.6473
2.05E−14
2.03E−13
ENSG00000204176.14
SYT15
21.12648
−2.30239
0.249285
−9.23597
2.56E−20
4.24E−19
ENSG00000112182.15
BACH2
257.1657
−2.26902
0.256459
−8.84749
8.95E−19
1.29E−17
ENSG00000177606.8
JUN
11479.81
−2.26689
0.228937
−9.90181
4.09E−23
8.22E−22
ENSG00000109686.19
SH3D19
4541.498
−2.24316
0.170627
−13.1466
1.78E−39
9.21E−38
ENSG00000171408.14
PDE7B
172.8577
−2.23779
0.204487
−10.9435
7.14E−28
1.93E−26
ENSG00000154229.12
PRKCA
429.3344
−2.17213
0.219209
−9.90898
3.81E−23
7.68E−22
ENSG00000163297.17
ANTXR2
2568.571
−2.17205
0.215654
−10.0719
7.35E−24
1.57E−22
ENSG00000142627.13
EPHA2
776.7399
−2.15179
0.190524
−11.2941
1.40E−29
4.21E−28
ENSG00000157557.13
ETS2
2737.954
−2.14215
0.169751
−12.6193
1.65E−36
7.13E−35
ENSG00000100307.13
CBX7
1545.103
−2.07287
0.209027
−9.91675
3.52E−23
7.15E−22
ENSG00000167244.21
IGF2
115.9528
−2.06731
0.319724
−6.46592
1.01E−10
6.80E−10
ENSG00000146281.6
PM20D2
570.7357
−2.05834
0.375368
−5.48351
4.17E−08
1.99E−07
ENSG00000166025.18
AMOTL1
2390.428
−2.04661
0.251772
−8.12879
4.34E−16
4.97E−15
ENSG00000163638.13
ADAMTS9
778.2113
−2.03456
0.186902
−10.8857
1.35E−27
3.59E−26
ENSG00000151320.11
AKAP6
264.7078
−2.01836
0.279149
−7.23039
4.82E−13
4.20E−12
ENSG00000161544.10
CYGB
603.7304
−2.01109
0.225797
−8.90663
5.26E−19
7.75E−18
ENSG00000111912.20
NCOA7
2513.176
−1.98953
0.209973
−9.47517
2.66E−21
4.71E−20
ENSG00000164236.12
ANKRD33B
267.3435
−1.95984
0.253401
−7.73414
1.04E−14
1.06E−13
ENSG00000144668.12
ITGA9
989.5649
−1.92159
0.213808
−8.98743
2.53E−19
3.83E−18
ENSG00000173714.8
WFIKKN2
5.471032
−1.91422
0.571935
−3.34692
0.000817
0.001955
ENSG00000169554.22
ZEB2
2546.417
−1.90165
0.199745
−9.52041
1.73E−21
3.09E−20
ENSG00000115252.18
PDE1A
234.1435
−1.89086
0.195606
−9.66667
4.18E−22
7.80E−21
ENSG00000152518.8
ZFP36L2
5244.958
−1.87946
0.223518
−8.40853
4.15E−17
5.21E−16
ENSG00000078399.19
HOXA9
138.6752
−1.87249
0.45164
−4.14598
3.38E−05
0.000104
ENSG00000053254.16
FOXN3
3115.684
−1.85297
0.175675
−10.5477
5.20E−26
1.26E−24
ENSG00000067082.15
KLF6
11675.17
−1.73614
0.171046
−10.1502
3.31E−24
7.22E−23
ENSG00000112769.20
LAMA4
6728.366
−1.72278
0.204349
−8.43058
3.44E−17
4.34E−16
ENSG00000148737.17
TCF7L2
1593.452
−1.70318
0.226376
−7.52366
5.33E−14
5.10E−13
ENSG00000111962.8
UST
607.7603
−1.68847
0.351058
−4.80965
1.51E−06
5.74E−06
ENSG00000172348.15
RCAN2
704.8905
−1.68334
0.185449
−9.0771
1.12E−19
1.74E−18
ENSG00000105855.10
ITGB8
1433.504
−1.66527
0.411121
−4.05055
5.11E−05
0.000152
ENSG00000127083.7
OMD
867.1152
−1.65735
0.412603
−4.01681
5.90E−05
0.000173
ENSG00000068366.20
ACSL4
2179.473
−1.65119
0.21483
−7.68603
1.52E−14
1.52E−13
ENSG00000107968.10
MAP3K8
790.9698
−1.62605
0.268341
−6.05964
1.36E−09
7.98E−09
ENSG00000172059.11
KLF11
1572.929
−1.62369
0.154556
−10.5055
8.15E−26
1.95E−24
ENSG00000169946.14
ZFPM2
457.4484
−1.59802
0.267775
−5.96777
2.41E−09
1.36E−08
ENSG00000146021.15
KLHL3
442.0001
−1.566
0.256042
−6.11618
9.58E−10
5.73E−09
ENSG00000112531.17
QKI
5172.184
−1.56491
0.17405
−8.99115
2.45E−19
3.72E−18
ENSG00000179399.15
GPC5
6.517002
−1.56448
0.48903
−3.19915
0.001378
0.003163
ENSG00000166148.4
AVPR1A
512.6131
−1.52204
0.329728
−4.61604
3.91E−06
1.39E−05
ENSG00000187098.17
MITF
1058.335
−1.5204
0.239991
−6.33522
2.37E−10
1.53E−09
ENSG00000116106.12
EPHA4
743.7578
−1.48305
0.349354
−4.24512
2.18E−05
6.94E−05
ENSG00000075340.23
ADD2
227.8462
−1.45992
0.343043
−4.2558
2.08E−05
6.64E−05
ENSG00000132326.12
PER2
2618.643
−1.44958
0.144443
−10.0357
1.06E−23
2.24E−22
ENSG00000137693.14
YAP1
5476.509
−1.40184
0.199666
−7.02094
2.20E−12
1.77E−11
ENSG00000153071.15
DAB2
4863.07
−1.39153
0.207863
−6.69447
2.16E−11
1.58E−10
ENSG00000134954.14
ETS1
5635.614
−1.37916
0.191642
−7.19655
6.18E−13
5.31E−12
ENSG00000186684.14
CYP27C1
22.23172
−1.36
0.343668
−3.95732
7.58E−05
0.000218
ENSG00000197479.7
PCDHB11
122.8965
−1.33616
0.363511
−3.6757
0.000237
0.000626
ENSG00000049239.13
H6PD
5899.722
−1.30308
0.126274
−10.3195
5.76E−25
1.31E−23
ENSG00000185585.20
OLFML2A
3008.681
−1.29205
0.203804
−6.33965
2.30E−10
1.49E−09
ENSG00000141448.11
GATA6
252.49
−1.28394
0.247251
−5.19285
2.07E−07
8.96E−07
ENSG00000111716.14
LDHB
258.771
−1.25185
0.336054
−3.72514
0.000195
0.000525
ENSG00000148400.12
NOTCH1
2767.299
−1.21422
0.147763
−8.21738
2.08E−16
2.45E−15
ENSG00000100100.13
PIK3IP1
2570.633
−1.15021
0.157226
−7.31564
2.56E−13
2.31E−12
ENSG00000121989.15
ACVR2A
833.1735
−1.11146
0.176357
−6.30234
2.93E−10
1.87E−09
ENSG00000137076.21
TLN1
24040.19
−1.0122
0.142752
−7.09064
1.33E−12
1.11E−11
ENSG00000118507.17
AKAP7
442.2442
−1.00969
0.209109
−4.82852
1.38E−06
5.25E−06
ENSG00000067225.18
PKM
63589.19
1.003789
0.14141
7.098408
1.26E−12
1.05E−11
ENSG00000010278.15
CD9
27313.29
1.03073
0.174172
5.917889
3.26E−09
1.81E−08
ENSG00000162813.18
BPNT1
3818.101
1.032864
0.138539
7.455396
8.96E−14
8.46E−13
ENSG00000179218.14
CALR
47750.32
1.056944
0.159821
6.613301
3.76E−11
2.66E−10
ENSG00000162702.8
ZNF281
3935.303
1.056971
0.178739
5.913478
3.35E−09
1.85E−08
ENSG00000204219.11
TCEA3
4844.245
1.060776
0.194272
5.460249
4.75E−08
2.25E−07
ENSG00000013275.8
PSMC4
6371.815
1.073648
0.113419
9.466174
2.90E−21
5.11E−20
ENSG00000115539.14
PDCL3
1999.501
1.076507
0.122667
8.775874
1.70E−18
2.38E−17
ENSG00000163694.15
RBM47
10668.08
1.107651
0.148473
7.460285
8.63E−14
8.17E−13
ENSG00000143742.14
SRP9
17143.41
1.162208
0.147817
7.862505
3.77E−15
3.93E−14
ENSG00000247077.7
PGAM5
3686.237
1.162817
0.123098
9.446263
3.51E−21
6.13E−20
ENSG00000049541.11
RFC2
2610.376
1.18846
0.128301
9.263053
1.99E−20
3.32E−19
ENSG00000152056.17
AP1S3
382.8773
1.188634
0.195606
6.076678
1.23E−09
7.23E−09
ENSG00000141543.12
EIF4A3
9157.783
1.193752
0.143133
8.34013
7.42E−17
9.08E−16
ENSG00000123562.18
MORF4L2
25317.37
1.220208
0.165276
7.382856
1.55E−13
1.43E−12
ENSG00000198056.15
PRIM1
516.0286
1.253897
0.163747
7.657537
1.90E−14
1.88E−13
ENSG00000183309.12
ZNF623
5290.028
1.258205
0.178412
7.052244
1.76E−12
1.44E−11
ENSG00000164924.18
YWHAZ
97012.07
1.308363
0.190907
6.853413
7.21E−12
5.51E−11
ENSG00000169895.6
SYAP1
12361.49
1.323317
0.190062
6.96254
3.34E−12
2.64E−11
ENSG00000141378.15
PTRH2
2313.839
1.344021
0.234938
5.720745
1.06E−08
5.49E−08
ENSG00000139116.19
KIF21A
2617.672
1.371612
0.182837
7.501817
6.29E−14
6.00E−13
ENSG00000117601.14
SERPINC1
14.6167
1.380024
0.344103
4.010498
6.06E−05
0.000178
ENSG00000143549.21
TPM3
35311.88
1.394759
0.115391
12.08724
1.23E−33
4.62E−32
ENSG00000179958.10
DCTPP1
3178.149
1.480657
0.169935
8.713072
2.96E−18
4.08E−17
ENSG00000066855.16
MTFR1
3421.341
1.490422
0.209157
7.125854
1.03E−12
8.67E−12
ENSG00000160113.5
NR2F6
4102.62
1.508661
0.190579
7.916191
2.45E−15
2.61E−14
ENSG00000164754.15
RAD21
35872.35
1.521572
0.199188
7.638873
2.19E−14
2.17E−13
ENSG00000143418.20
CERS2
13470.45
1.53076
0.167388
9.144967
5.96E−20
9.50E−19
ENSG00000160877.6
NACC1
5695.161
1.571444
0.160161
9.811627
1.00E−22
1.96E−21
ENSG00000108639.8
SYNGR2
21865.43
1.573168
0.222722
7.063368
1.63E−12
1.33E−11
ENSG00000166451.13
CENPN
525.2235
1.582459
0.165603
9.555762
1.23E−21
2.23E−20
ENSG00000103495.14
MAZ
1324.477
1.584558
0.153138
10.34727
4.31E−25
9.90E−24
ENSG00000149636.16
DSN1
2614.142
1.608786
0.148041
10.86716
1.65E−27
4.34E−26
ENSG00000116771.6
AGMAT
199.9316
1.623433
0.269733
6.018662
1.76E−09
1.01E−08
ENSG00000184992.13
BRI3BP
3135.055
1.627688
0.138192
11.77842
5.04E−32
1.72E−30
ENSG00000262814.8
MRPL12
266.1392
1.630506
0.356902
4.568502
4.91E−06
1.72E−05
ENSG00000177542.11
SLC25A22
2302.414
1.642046
0.18744
8.760402
1.95E−18
2.72E−17
ENSG00000187037.8
GPR141
79.99273
1.700932
0.380754
4.46727
7.92E−06
2.70E−05
ENSG00000099337.5
KCNK6
4163.652
1.716541
0.229608
7.475959
7.66E−14
7.28E−13
ENSG00000161664.7
ASB16
156.6078
1.727263
0.299618
5.764878
8.17E−09
4.31E−08
ENSG00000065911.13
MTHFD2
5783.556
1.727698
0.17727
9.746149
1.92E−22
3.67E−21
ENSG00000161981.11
SNRNP25
3015.774
1.782309
0.174774
10.1978
2.03E−24
4.47E−23
ENSG00000125967.17
NECAB3
3696.475
1.989247
0.23244
8.558109
1.15E−17
1.51E−16
ENSG00000141682.12
PMAIP1
1307.21
2.065221
0.314488
6.566933
5.14E−11
3.58E−10
ENSG00000138346.15
DNA2
816.1066
2.106384
0.174439
12.07518
1.43E−33
5.34E−32
ENSG00000119969.15
HELLS
1568.739
2.154497
0.174916
12.31732
7.31E−35
2.89E−33
ENSG00000106537.8
TSPAN13
27275.54
2.184523
0.232017
9.415377
4.71E−21
8.18E−20
ENSG00000162188.6
GNG3
6.381731
2.274225
0.428108
5.312272
1.08E−07
4.87E−07
ENSG00000101213.7
PTK6
1491.814
2.443841
0.269593
9.064913
1.25E−19
1.93E−18
ENSG00000161800.13
RACGAP1
4784.994
2.580521
0.149218
17.29362
5.25E−67
8.61E−65
ENSG00000124243.17
BCAS4
2761.958
2.611711
0.240577
10.85604
1.87E−27
4.89E−26
ENSG00000134057.15
CCNB1
4642.506
3.105306
0.163561
18.98566
2.24E−80
9.30E−78
ENSG00000100162.15
CENPM
740.1221
3.221654
0.234838
13.71861
7.86E−43
4.76E−41
ENSG00000051341.14
POLQ
792.2459
3.224711
0.188866
17.07406
2.32E−65
3.66E−63
ENSG00000124507.11
PACSIN1
401.357
3.395711
0.328254
10.34476
4.42E−25
1.02E−23
ENSG00000161888.11
SPC24
910.7969
3.459886
0.198499
17.43026
4.86E−68
8.49E−66
ENSG00000197472.15
ZNF695
125.6736
3.480798
0.354153
9.828508
8.49E−23
1.66E−21
ENSG00000123485.12
HJURP
1205.887
4.037869
0.176764
22.8433
1.70E−115
7.95E−112
ENSG00000171848.16
RRM2
5165.332
4.254322
0.224536
18.94716
4.66E−80
1.85E−77
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