Background
Methods
Ethics statement
Patients and material
RNA preparation
Global miRNA expression profiling
Quantitative reverse transcription-polymerase chain reaction (RT-qPCR)
Ingenuity pathway analysis (IPA)
Statistical analysis
Results
Patient characteristics
Parameter | HGSC
a
, n = 35 | CCC
a
, n = 19 | |
---|---|---|---|
Age; mean ± SD (range) | 64.0 ± 11.3 (45–87) | 63.9 ± 15.3 (28–83) | |
Preoperative CA125 (kU/L); mean ± SD | 3023 ± 4129 | 1438 ± 2198 | |
FIGO stage | I | 0 | 10 |
II | 0 | 3 | |
III | 25 | 5 | |
IV | 10 | 1 | |
Residual disease | 0 cm | 3 | 13 |
<2 cm | 9 | 4 | |
>2 cm | 23 | 2 | |
Start of chemotherapy (days after surgery); mean ± SD | 27.7 ± 11.6 | 25.7 ± 13.8 | |
CA125 response
b
| Yes | 31 | 15 |
No | 1 | 0 | |
Optimal CA125 normalization
b
| Yes | 20 | 13 |
No | 14 | 3 | |
Median time (months) until progression (95% CI) | 10 (7–13) | NA
c
| |
Median time (months) until death (95% CI) | 26 (18–34) | 105 (35–175) | |
Status at last follow-up
d
| NED | 1 | 11 |
AWD | 1 | 1 | |
DOD | 33 | 6 | |
DOUC | 0 | 1 |
Global miRNA expression analyses
Evaluation of associations between global miRNA expression and survival
RT-qPCR validation of selected miRNAs
HGSC vs. OSE
a
| CCC vs. OSE
a
| CCC vs. HGSC
a
| ||||
---|---|---|---|---|---|---|
miRNAs | p-values | FC values | p-value | FC value | p-value | FC value |
miR-134
| 8.3 × 10-8
| -16.7
b
| 1.0 × 10-4
| 5.8 | ||
miR-141-3p
| 1.1 × 10-11
| 46.1 | 2.4 × 10-10
| 34.9 | ||
miR-182-5p
| 6.0 × 10-9
| 30.2 | 1.4 × 10-8
| 32.7 | ||
miR-200a-3p
| 7.3 × 10-10
| 33.6 | 1.3 × 10-9
| 38.8 | ||
miR-200a-5p
| 3.0 × 10-13
| 33.5 | 6.9 × 10-12
| 26.5 | ||
miR-200b-3p
| 1.1 × 10-9
| 29.1 | 2.9 × 10-8
| 21.1 | ||
miR-200c-3p
| 1.2 × 10-12
| 16.5 | 1.2 × 10-11
| 15.0 | ||
miR-202-3p
| 8.0 × 10-6
| -36.9 | 2.3 × 10-4
| 16.3 | ||
miR-205-5p
| 4.9 × 10-5
| 105.1 | 3.1 × 10-3
| -23.1 | ||
miR-383
| 8.2 × 10-12
| -33.7 | 1.5 × 10-11
| -38.7 | ||
miR-424-5p
| 2.6 × 10-9
| -26.0 | 4.0 × 10-6
| -10.1 | ||
miR-508-5p
| 4.4 × 10-3
| 11.6 | 3.1 × 10-6
| 75.0 | ||
miR-509-3p
| 4.3 × 10-3
| -10.3 | 2.6 × 10-6
| 83.4 | ||
miR-509-5p
| 5.6 × 10-4
| 11.4 | 1.8 × 10-6
| 34.0 | ||
miR-509-3-5p
| 3.9 × 10-3
| -10.2 | 1.9 × 10-6
| 84.6 | ||
miR-510
| 9.3 × 10-3
| -5.2 | 7.9 × 10-3
| 6.1 | 3.0 × 10-6
| 31.7 |
miR-513a-5p
| 4.8 × 10-3
| 7.4 | 4.1 × 10-6
| 33.5 | ||
miR-514b-5p
| 9.7 × 10-3
| -6.5 | 3.8 × 10-3
| 9.8 | 1.3 × 10-6
| 63.6 |
HGSC vs. OSE
a
| CCC vs. OSE
a
| CCC vs. HGSC
a
| ||||
---|---|---|---|---|---|---|
miRNAs | p-values | FC values | p-values | FC values | p-values | FC values |
miR-134
| 8.7 × 10-11
| -5.7
b
| 3.1 × 10-6
| 4.3 | ||
miR-141-3p
| 1.7 × 10-18
| 40.3 | 7.2 × 10-11
| 45.3 | ||
miR-182-5p
| 9.5 × 10-15
| 42.4 | 1.2 × 10-8
| 66.2 | ||
miR-200a-3p
| 3.6 × 10-5
| 33.0 | 9.3 × 10-10
| 57.8 | ||
miR-200a-5p
| 3.1 × 10-15
| 33.8 | 4.3 × 10-11
| 53.0 | ||
miR-200b-3p
| 5.3 × 10-18
| 38.8 | 3.7 × 10-11
| 51.0 | ||
miR-200c-3p
| 6.0 × 10-21
| 48.2 | 3.2 × 10-12
| 53.4 | ||
miR-202-3p
| 1.3 × 10-14
| -14.7 | 1.6 × 10-7
| 10.1 | ||
miR-205-5p
| 9.0 × 10-9
| 74.3 | 4.4 × 10-3
| -8.4 | ||
miR-383
| 2.2 × 10-14
| -36.6 | 9.8 × 10-10
| -15.1 | 2.2 × 10-3
| 2.4 |
miR-424-5p
| 3.1 × 10-13
| -10.7 | 3.5 × 10-4
| -4.2 | 1.6 × 10-3
| 2.5 |
miR-508-5p
| 3.5 × 10-3
| 10.1 | 1.0 × 10-8
| 27.5 | ||
miR-509-3p
| 2.0 × 10-7
| 46.3 | ||||
miR-509-5p
| 5.0 × 10-3
| -4.1 | 2.4 × 10-3
| 13.3 | 1.3 × 10-8
| 54.7 |
miR-509-3-5p
| 1.1 × 10-4
| -11.0 | 2.2 × 10-8
| 95.3 | ||
miR-510
| 2.5 × 10-3
| 9.0 | 8.7 × 10-10
| 32.9 | ||
miR-513a-5p
| 6.6 × 10-4
| 6.2 | 9.1 × 10-7
| 8.3 | ||
miR-514b-5p
| 9.7 × 10-5
| 12.1 | 2.3 × 10-9
| 25.8 |
miRNAs | mRNA targets | Cancer association | OC association |
---|---|---|---|
miR-134↓
| x | ||
miR-141-3p↑
| TGFB2↓, ZEB2↓, JAG1, BAP1, CLOCK, ELMO2, ERBB2IP, KLHL20, MAP2K4, PLCG1, PTPRD, WDR37 | x | x (EC) |
miR-182-5p↑
| FOXO3, ADCY6, CASP2↑, CLDN17, NCAM1↓, NFASC↓, RARG, BCL2L14↑, CARD11↑, CASP10↑, CASP12, CDH1↑, CDH4, CDK6, CLDN15↓, COL11A2, COL4A4↓, FNDC3A↓, FOXO1↓, GADD45G↓, GJA3, IGF1R↓, INHBC, ITGA4, LRP6, MALAT1↓, MITF↓, MTSS1, NLGN2, PGF, PIK3CA↑, RPS6KB1, SOS1, VWF↑
| x | x (EC) |
miR-200a-3p↑
| CTNNB1, VIM↓, ZEB1↓, ZEB2↓, BAP1, CDK6, CDKN1B↓, CTBP2, CYP1B1↑, ELMO2, ERBB2IP, KLHL20, PLCG1, PTPRD↓, TUBB↑, WDR37, ZFPM2↓
| x | x (EC, ROC) |
miR-200a-5p↑
| x | ||
miR-200b-3p↑
| VIM↓, ZEB1↓, ZEB2↓, BAP1, ELMO2, ERBB2IP, ERRFI1, KLHL20, PLCG1, PTPRD↓, RERE, WASF3, WDR37, ZFPM2↓
| x | x (ROC) |
miR-200c-3p↑
| CDH1↑, PTPN13↓, ZEB1↓, ZEB2↓, FHOD1, PPM1F, JAG1, MARCKS, VIM↓, CDKN1B↓, ERRFI1↓, PLCG1 | x | x (EC) |
miR-202-3p↓
| |||
miR-205-5p↑
| ERBB3↑, F Actin, INPPL1↑, MED1, VEGFA↑, ZEB1↓, ZEB2↓, PRKCE | x | x (EC) |
miR-383↓
| |||
miR-424-5p↓
| FGFR1, MAP2K1, NFIA↓, PLAG1 | x | |
miR-508-5p
| |||
miR-509-3p↓
| NTRK3 | ||
miR-509-5p↓
| |||
miR-509-3-5p↓
| |||
miR-510↓
| HTR3E, SPDEF↑
| x | |
miR-513a-5p
| CD274 | x | |
miR-514b-5p↓
|
Associations between validated miRNA expression and clinical parameters
Ingenuity pathway analysis (IPA)
miRNAs and mRNA targets | FC values |
---|---|
miR-1341,5
| -16.7 |
KLHL141, PAX8
1,3,5
| 9.6 – 29.3 |
miR-141-3p
1,2,6/ miR-200a-3p
1,2,6
| 46.1 |
FOXP2
1,2,5, HLF1, PCDH95, PEG3
1,6, SCN7A1, SDC21,2,3,4,5,6
| -9.6 – -24.7 |
miR-182-5p
1,2
| 30.2 |
ANGPTL11,2,5, CACNB21,5, FOXP2
1,2,5, KCNMB21,5, PID11, SDC21,2,3,4,5,6, TMEM150C | -9.6 – -14.6 |
miR-183-5p
1,2,6
| 11.7 |
ABCA8
1, HLF1
| -11.6 – -17.8 |
miR-187-3p1
| 12.8 |
TSPAN51,2
| -11.3 |
miR-200b-3p
1,2,6/ miR-200c-3p
1,2,6
| 29.1 |
CACNB21,5,CDH111,2,5,6, COL4A31,2,5,6, GPM6A1, HLF1, HS3ST3A11, LEPR1,2,4,5,6, MCC1,2, NEGR11,2,6, SDC21,2,3,4,5,6
| -9.6 – -21.6 |
miR-202-3p | -36.9 |
RRM2
1,2,4,6
| 16.9 |
miR-203-3p
1,2,6
| 13.6 |
ANGPTL11,2,5, EDNRA1,2,6, FOXP2
1,2,5,GNG42,6, IGFBP51,2,3,4,5,6, NEGR11,2,6, SMAD91
| -9.7 – -15.0 |
miR-205-5p
1,6
| 105.1 |
BAMBI1,2,5,6, NR3C21,2,5,6, PEG3
1,6
| -10.1 – -24.7 |
miR-376c-3p1
| -11.7 |
EHF1,2,3,6, LRP8
1,5,6
| 11.9 – 12.6 |
miR-379-5p | -10.3 |
KLHL141
| 29.3 |
miR-381-3p1
| -12.6 |
EGFL61, NOTCH3
1,2,3,5,6, RRM2
1,2,4,6
| 9.7 – 16.9 |
miR-383 | -33.7 |
MAL2 | 32.8 |
miR-424-5p
1,2,3,4,5,6
| -26.0 |
AHNAK21, CCNE1
1,2,3,4,6, ESRP1
1,6, HMGA1
1,2,3,4,6, LAMP31,2, PSAT1
1, UCP2
2,5, VAMP81,2
| 9.9 – 24.0 |
miR-485-5p1
| -13.6 |
KRT71,3,4, LRP8
1,5,6, ST141
| 10.5 – 16.2 |
miR-887 | -9.6 |
TMEM139 | 11.7 |
miR-4324 | -12.5 |
ERBB3
1,2,3,5,6, GALNT6 | 17.9 – 23.7 |