Results and discussion
Distinct miRNAs characterize progressive stages of CRC development
Distinct EphA2/EphB2-specific miRNAomes orchestrate cell proliferation/stemness/migration in progressive murine CRC stages
Establishment of two CRC EphA2/EphB2-specific signatures
Up-regulation of miRs-31 occurs at very early stages of hCRC development
Prognostic value of EphA2/EphB2-specific signatures
a.
| ||||||
GSE35982
FC (P value) |
GSE35834
FC (P value) |
TCGA-COAD
FC (P value) |
GSE4183
| |||
Adenoma
FC (P value) |
Carcinoma
FC (P value) |
IBD
FC (P value) | ||||
EPHA2
| -1.16 (0.35) |
1.18
(0.02)
| 1.27 (0.40) | 1.7 (0.07) | 1.67 (0.08) |
2.16
(0.003)
|
miR-423-5p
| -2.2 (0.30) | -1.26 (0.09) |
-8.82
(2.35e-142)
| - | - | - |
ARPC1A | -1.07 (0.20) | 1.12 (0.17) | -1.09 (0.35) | 1.14 (0.32) | 1.16 (0.24) | -1.13 (0.39) |
PAK1 | -1.01 (0.94) | -1.07 (0.25) | -1.21 (0.01) | -1.27 (0.02) | -1.49 (0.0006) | -1.63 (7.42e-05) |
GNG12 | 1.11 (0.46) | -1.63 (2.48e-08) | -1 (0.128) | -1.44 (0.005) | -1.28 (0.04) | -1.35 (0.02) |
CREB1
| -1.06 (0.40) | -1.04 (0.38) |
2.72
(2.85e-34)
| 1.16 (0.15) |
1.36
(0.005)
|
1.26
(0.04)
|
ADAMTS14
| -1.03 (0.67) | 1.03 (0.52) |
2.81
(0.0003)
| -1.05 (0.85) | 1.32 (0.21) |
1.52
(0.05)
|
EPHB2
| 1.19 (0.49) |
1.33
(0.0008)
|
1.75
(0.03)
|
3.39
(7.75e-06)
| 1.26 (0.16) | -1.13 (0.67) |
miR-31-5p
|
49.65
(0.02)
|
3.17
(0.03)
| 2.71 (0.41) | - | - | - |
miR-31-3p
|
14.73
(0.005)
| - | - | - | - | - |
RHOA | 1.10 (0.08) | -1.01 (0.71) | -1.08 (0.28) | 1.12 (0.06) | -1.29 (0.21) | 1.09 (0.13) |
CRKL | 1.07 (0.54) | 1.12 (0.002) | 1.18 (0.03) | 1.20 (0.139) | 1.13 (0.14) | -1.19 (0.22) |
CRK
| -1.11 (0.36) |
-1.25
(0.0008)
| -1.12 (0.10) |
-1.22
(0.02)
| -1.15 (0.09) | -1.13 (0.12) |
ITGA5 | 1.78 (0.30) | -1.08 (0.38) | -1.13 (0.64) | 1.88 (0.59) | 4.50 (0.03) | 4.56 (0.03) |
CXCL12
| -1.19 (0.69) |
-2.40
(9.44e-14)
|
-3.00
(6.55e-18)
|
-6.91
(9.80E-09)
|
-2.90
(2.95E-06)
|
-1.48
(0.01)
|
ARPC5
|
-1.18
(0.05)
| 1.01 (0.62) | 1.09 (0.36) | -1.33 (0.06) |
-1.36
(0.05)
|
-1.37
(0.05)
|
RASA1 | -1.03 (0.61) | 1.19 (0.04) | 2.60 (1.92e-20) | 1.21 (0.02) | 1.11 (0.23) | -1.10 (0.30) |
SRC
| 1.23 (0.16) | 1.20 (0.0008) |
-1.37
(0.02)
| -1.37 (0.10) |
-1.57
(0.03)
| 1.79 (0.03) |
b.
| ||||||
Multivariate analysis of EPHA2 genetic signature without hsa-miR-423-5p
| ||||||
Relative Risk
|
95% CI
|
P
value
| ||||
TCGA-COAD (OS)
| ||||||
ADAMTS14 | 1.07 | 0.97 to 1.19 | 0.17 | |||
CREB1 | 0.97 | 0.87 to 1.09 | 0.65 | |||
GSE33113 (MR3)
| ||||||
ADAMTS14 | 1.03 | 0.99 to 1.06 |
0.05
| |||
CREB1 | 1.01 | 0.99 to 1.03 | 0.44 | |||
GSE14333 (DFS)
| ||||||
ADAMTS14 | 0.76 | 0.65 to 0.90 |
0.001
| |||
CREB1 | 0.99 | 0.54 to 1.84 | 0.99 | |||
GSE17536 (OS)
| ||||||
ADAMTS14 | 0.79 | 0.26 to 2.45 | 0.69 | |||
CREB1 | 1.43 | 0.59 to 3.48 | 0.44 | |||
GSE29623 (OS)
| ||||||
ADAMTS14 | 0.36 | 0.04 to 3.06 | 0.36 | |||
CREB1 | 0.82 | 0.13 to 5.1 | 0.83 | |||
Multivariate analysis of EPHB2 genetic signature without hsa-miR-31-5p
| ||||||
Relative Risk
|
95% CI
|
P
value
| ||||
TCGA-COAD (OS)
| ||||||
CRK | 0.97 | 0.94 to 1.01 | 0.15 | |||
CXCL12 | 1.03 | 0.99 to 1.07 | 0.17 | |||
ARPC5 | 0.99 | 0.96 to 1.02 | 0.53 | |||
SRC | 1.00 | 0.97 to 1.02 | 0.79 | |||
GSE33113 (MR3)
| ||||||
CRK | 1.01 | 1.00 to 1.01 |
0.01
| |||
CXCL12 | 1.00 | 1.00 to 1.00 |
0.02
| |||
ARPC5 | 1.00 | 1.00 to 1.01 |
0.05
| |||
SRC | 1.00 | 0.95 to 1.05 | 0.95 | |||
GSE14333 (DFS)
| ||||||
CRK | 0.80 | 0.54 to 1.20 | 0.29 | |||
CXCL12 | 0.74 | 0.60 to 0.92 |
0.01
| |||
ARPC5 | 0.81 | 0.50 to 1.30 | 0.38 | |||
SRC | 1.08 | 0.79 to 1.48 | 0.63 | |||
GSE17536 (OS)
| ||||||
CRK | 1.14 | 0.49 to 2.66 | 0.75 | |||
CXCL12 | 0.98 | 0.69 to 1.39 | 0.90 | |||
ARPC5 | 1.27 | 0.37 to 4.35 | 0.70 | |||
SRC | 0.10 | 0.02 to 0.54 |
0.01
| |||
GSE29623 (OS)
| ||||||
CRK | 0.83 | 0.15 to 4.52 | 0.83 | |||
CXCL12 | 1.02 | 0.45 to 2.32 | 0.96 | |||
ARPC5 | 0.25 | 0.03 to 2.03 | 0.19 | |||
SRC | 0.09 | 0.002 to 4.13 | 0.22 | |||
Multivariate analysis of EPHA2 genetic signature with hsa-miR-423-5p
| ||||||
Relative Risk
|
95% CI
|
P
value
| ||||
TCGA-COAD (OS)
| ||||||
ADAMTS14 | 1.07 | 0.97 to 1.18 | 0.18 | |||
CREB1 | 0.98 | 0.87 to 1.1009 | 0.67 | |||
hsa-miR-423-5p | 1.00 | 0.99 to 1.00 | 0.69 | |||
GSE 29623 (OS)
| ||||||
ADAMTS14 | 0.35 | 0.04 to 3.02 | 0.34 | |||
CREB1 | 0.82 | 0.13 to 5.12 | 0.83 | |||
hsa-miR-423-5p | 1.04 | 0.71 to 1.52 | 0.85 | |||
Multivariate analysis of EPHB2 genetic signature with hsa-miR-31-5p
| ||||||
Relative Risk
|
95% CI
|
P
value
| ||||
TCGA-COAD (OS)
| ||||||
CRK | 0.97 | 0.93 to 1.01 | 0.11 | |||
CXCL12 | 1.03 | 0.99 to 1.07 | 0.10 | |||
ARPC5 | 0.99 | 0.97 to 1.02 | 0.65 | |||
SRC | 1.00 | 0.98 to 1.03 | 0.90 | |||
hsa-miR-31-5p | 1.00 | 1.00 to 1.01 |
0.001
| |||
GSE29623 (OS)
| ||||||
CRK | 0.69 | 0.12 to 3.81 | 0.67 | |||
CXCL12 | 1.31 | 0.53 to 3.21 | 0.56 | |||
ARPC5 | 0.28 | 0.04 to 2.23 | 0.23 | |||
SRC | 0.12 | 0.003 to 4.88 | 0.26 | |||
hsa-miR-31-5p | 1.17 | 0.95 to 1.46 | 0.14 |