Copyright ©The Author(s) 2016.
World J Gastroenterol. Sep 7, 2016; 22(33): 7389-7401
Published online Sep 7, 2016. doi: 10.3748/wjg.v22.i33.7389
Table 1 Summary of experiments relevant to microRNA detection of colorectal cancer
miRNASample size
FindingsSpecimen typeRef.
Cases (n)Controls (n)
miR-21 miR-106a miR-17 miR-143 miR-622 miR-654-3p9 non-advanced adenomas and AA 10 CRC10 controls (normal colonoscopy)miR-21, miR-106a: Colorectal neoplasia (adenoma, CRC) patients had higher stool expression of these two miRNA compared to normal colonoscopy subjects (P < 0.05). Adenoma patients had higher stool miR-21 and miR-106a expression compared to CRC patients miR-17, miR-143, miR-622, miR-654-3p: No differences between groupsStoolLink et al[23]
miR-21 miR-92a miR-31 miR-18a miR-106a50 AA 200 CRC80 controls (do not have a current or previous malignancy or inflammatory condition)miR-21, miR-92a: miR-21 and miR-92a levels in CRC patients and AA patients were significantly higher compared to controls (all P < 0.05). miR-21 yielded an AUC of 0.709 in differentiating AA from controls. miR-92a yielded an AUC of 0.701 in differentiating AA from controls. Both miRNA together yielded an AUC of 0.722 in differentiating AA from controls miR-18a, miR-31, and miR-106a: No significant differences between groupsSerumLiu et al[24]
miR-21 miR-3143 AA 60 postoperative patients 186 CRC53 controls (negative colonoscopic examination, no prior diagnosis of any other malignancy)miR-21: Serum levels were increased in adenomatous polyp patients compared with controls (P < 0.001). Serum miR-21 levels yielded an AUC of 0.803 (95%CI: 0.669-0.869) in differentiating AA from controls. The sensitivity, specificity, positive predictive value and negative predictive values were 76.8 % and 81.1%, 76.7%, and 81.1%, respectively, at a cut-off value of 0.0013SerumToiyama et al[25]
miR-92a miR-2144 patients with minor polyp (defined as hyperplastic polyp or adenoma less than 1 cm in diameter) 13 AA 88 CRC101 controls (asymptomatic individuals)miR-92a: Stool miR-92a was significantly increased in polyp patients compared with controls (P < 0.0001). Sensitivity of 56.1% for polyp, specificity of 73.3%. Higher sensitivity for AA than minor polyps (P < 0.05). The removal of AA led to a decrease in stool miR-92a level (P < 0.05). miR-21: No difference between polyps and controlsStoolWu et al[26]
miR-29a, miR -106b, miR -133a, miR -342-3p, miR -532-3p miR-18a, miR -20a, miR -21, miR -92a, miR -143, miR -145, miR -181bMarker validation phase 50 AAMarker validation phase 50 controls (free of colorectal neoplasms)No statistically significant differences between AA patients and controls for any of the investigated miRNAPlasmaLuo et al[27]
miR-10a, miR-29a, miR-31, miR-92a, miR-100, miR-125b, miR-184, miR-187, miR-196a, miR-200b, miR-203, miR-17-3p73 non-advanced adenoma 43 AA 8 CRC48 controls (polyp-free)No statistically significant associations with non-advanced adenoma or AA for any of the investigated miRNAPlasmaAdams et al[28]
miR-34a miR-150 miR-923Discovery set 8 polyp 16 adenoma 8 CRC (stage I/II) 8 CRC (stage III/IV)Discovery set 8 controlsmiR-34a: Validation cohort: Significantly higher in adenoma group compared to controls (FC 2.09, P = 0.028). Significantly higher in adenoma group compared to the polyp group (FC 2.71, P = 0.002). miR-923: Validation cohort: No significantly different levelsPlasmaAherne et al[29]
Validation set 20 polyp 20 adenoma 23 CRC (stage I/II) 14 CRC (stage III/IV)Validation set 20 controls
miR-18a miR-15b miR-19a miR-19b miR-29a miR-335Set 1 20 AA 21 CRC Set 2 40 AA 42 CRCSet 1 20 controls Set 2 53 controlsmiR-18a: Set 1 and Set 2: Significantly overexpressed in AA patients compared to controls in both sets. Set 1: Good discriminative capacity in AA patients (AUROC, 0.84; 95%CI: 0.72-0.96; sensitivity [S], 80%; specificity [Sp], 80%). Set 2: Lower discriminative capacity in AA patients (AUROC, 0.64; 95%CI: 0.52- 0.75; S, 72%; Sp, 57%)PlasmaGiráldez et al[30]
miR-29a, miR-92a,Large-scale validation 37 AA 100 CRCLarge-scale validation 59 controls (negative results of health examination including blood test, chest X-ray, abdominal ultrasound examination, fecal occult-blood testing, rectal touch, CT scan and colonoscopy. None of these controls had previously been diagnosed with any types of malignancy previously)miR-29a and miR-92a: Significantly higher in AA compared to controls (P < 0.0001 for miR-29a, P < 0.0001 for miR-92a). Both miRNAs together yielded an AUC of 0.773 (95%CI: 0.669-0.877), sensitivity 73.0% and specificity 79.7%, in discriminating AA. miR-29a: Yielded an AUC of 0.769 (95%CI: 0.669-0.869) for differentiating AA from controls. The sensitivity was 62.2% and specificity 84.7%, at a cut-off value of 1.210 for miR-29a. The odds ratio for cases with miR-29a > 1.210 being associated with AA was 12.20 (95%CI: 4.350-34.237). miR-92a: Yielded an AUC of 0.749 (95%CI: 0.642-0.856) for differentiating AA from controls. Sensitivity 64.9% and specificity 81.4%, at a cut-off value of 1.682 for miR-92a. The odds ratio for cases with miR-92a > 1.682 being associated with AA was 4.56 (95%CI: 1.893-10.988)PlasmaHuang et al[31]
A panel of 8 miRNAs miR-532-3p + miR-331 + miR-195 + miR-17 + miR-142-3p + miR-15b + miR-532 + miR-652Initial Screening 9 adenoma 20 CRC (stage III/IV) Validation 16 adenoma 15 CRC (stage I/II) 15 CRC (stage III) 15 CRC (stage IV)Initial Screening 12 controls (without CR neoplasia) Validation 26 controls (without CR neoplasia)Initial Screening 15 out of 380 screened miRNAs most dys-regulated in plasma of adenoma patients compared to controls (P < 0.05, FDR: 5%). Validation A panel of 8 plasma miRNAs yielded an AUC of 0.868 (95%CI: 0.76-0.98), sensitivity 88% and specificity 64% in differentiating adenoma from controlsPlasmaKanaan et al[32]
miR-601 miR-760Large scale validation 43 AA 90 CRCLarge scale validation 58 controlsmiR-601: AUC of 0.638, sensitivity of 72.1% and specificity of 51.7% in differentiating AA from controls miR-760: AUC of 0.682, sensitivity of 69.8% and specificity of 62.1% in differentiating AA from controls miR-601 + miR-760: Significantly decreased in colorectal neoplasia (AA and CRC) compared to controls. Both miRNAs together yielded AUC of 0.683, sensitivity 72.1% and specificity 62.1% in differentiating AA from controlsPlasmaWang et al[33]
miR-135b miR-31110 adenomas < 1 cm in size 59 AA 42 IBD 104 CRC109 controls (normal colonoscopy)miR-135b: Significantly increased in adenoma subjects (median, 28.4; IQR, 0.2-79.7; P < 0.0001) compared to controls (median, 0; IQR, 0-30.8). No significant difference in IBD subjects compared to controls. AUC of 0.71 for detection of adenoma. Sensitivity of 73% for AA, 61% for adenoma < 1 cm in diameter, 65% for any adenoma and specificity of 68%, at a cut-off of 14 copies/ng of stool RNA. Sensitivity of 44% for adenoma < 1 cm, 46% for AA, and specificity of 80%, at a cut-off of 38 copies/ng of stool RNA. Removal of AA or CRC resulted in a significant reduction of stool miR-135b. miR-31: No significant differences between groupsStoolWu et al[34]
miR-18a miR-221151 adenoma 48 AA 198 CRC198 controls (normal colonoscopy)miR-18a, miR-221: No significant up-regulation in adenoma or AAStoolYau et al[35]
A panel of 4 miRNAs miR-19a-3p + miR-223-3p + miR-92a-3p + miR-422aValidation of the diagnostic performance of the miRNA panel: 73 adenoma 117 CRCValidation of the diagnostic performance of the miRNA panel: 102 controls (healthy individuals seeking a routine health check- up)Validation of the miRNA panel The miRNA panel yielded an AUC of 0.765 (95%CI: 0.669-0.845) in differentiating adenoma from controlsSerumZheng et al[36]
Table 2 Summary of dietary regulation of microRNAs, potentially relevant to colorectal cancer
MicroRNAStudy populationDiet or nutrientAnalysis methodFindingsSpecimen typeRef.
miR-16 miR-21 miR-34a miR-92a miR-106a miR-146 miR-222Italian-based 8 vegans 8 vegetarians 8 omnivoresMeat, processed meat, fish, cheeseFood frequency and lifestyle questionnairemiR-92a was significantly decreased by meat and dairy products, and associated with low body mass index. Weaker associations found between miR-21 levels and vegetable intakePlasma and stoolTarallo et al[38]
Let-7d miR-15b miR-107 miR-191 miR-324-5Sprague-Dawley rats, treated with saline or the carcinogen, azoxymethaneCorn oil vs fish oil in the dietEffects of diets on the expression of 368 miRNAs in the colonic mucosaThe five identified miRNAs were the most strongly affected by diet X carcinogen actions. The fish fed animals showed the smallest number of differentially expressed miRNAs - interpreted as due to a reduction in inflammationColonic mucosaDavidson et al[39]
miR-1903 miR-467c miR-368 miR-927cFemale athymic nude mice, injected with HT-29 colon cancer cellsCorn oil vs ground walnuts in the dietEffects of the diets on the expression of four microRNAs in the colon tumoursThe first three of these microRNAs were down-regulated and the latter up-regulated in expression. These data were related to significant increases in α-linolenic, eicosapentaenoic, docosahexaenoic and total omega-3 acids, and a decrease in arachidonic acid in the walnut fed miceColorectal tumour tissueTsoukas et al[40]
miR-155Young subjects (22 + 2 yr), smokers and non-smokersHigh dose vitamin C daily for 8 wkExpression level of miR-155 in HDL3miR-155 reduced in HDL fraction by 49% in non-smokers and 75% in smokers after 8 wk supplementation. This effect was related to a reduction in reactive oxygen speciesSerum lipoprotein levelsKim et al[43]
miR-98 miR-92a miR-30e miR-140-5p miR-1387 different prostate cell models including malignant and non-malignant30 min treatment with 1a,25(OH)2D3MiRNA microarray analyses111 miRNAs showed changed expression levels, but only 5 were seen affected in more than one cell line and only 3 were changed in the same directionTotal mRNA and miRNA from each cell line.Singh et al[44]
miR-22 miR-29ab miR-134 miR-1207-5p miR-371-5p miR-17 miR-20aLNCaP human prostate cancer cells48 h treatment with 100 nmol/L 1,25(OH)2D3 compared with non-treated control, cellsAgilent human microRNA v3 microarrays to measure microRNA expressionFour hundred and twenty genes were up-regulated and 413 genes down-regulated in the 1,25(OH)2D3-treated cells. The most strongly affected are those identified in column 1 (the last two of these miRNAs is downregulated)Integrative network-based analysis using a publicly available data setKutmon et al[45]
miR-155RAW264.7 macrophage cells stimulated with lipopolysaccharide (LPS)24 h in the presence of EtOH or 20 nmol/L 1,25(OH)2D3miRNA profiling by microarraysSeveral miRNAs were induced by LPS and suppressed by 1,25(OH)2D3, of which miR-155 was on the top of the list, suppressing about 50% of the LPS inductionTotal mRNA and miRNA from each cell lineLi et al[46]
miR-22SW480-ADH and HCT116 colon cancer cells10-7 mol/L 1,25(OH)2D3 for 24, 48 or 96 hmiRNA profiling by microarraysAlthough there were 12 microRNAs that showed differential expression with and without vitamin D, miR-22 showed the most consistent differencesTotal miRNA from each cell lineAlvarez-Díaz et al[48]
Let-7f Let-7a miR-151-5p miR-22 miR-221 miR-28-5p miR-552-3p miR-766 miR-99bMales, generally in good health, with no diabetes or other concomitant diseasesHigh dose vitamin D3 (20000-40000 IU per week)Quantitative real-time PCRIn 10 pilot subjects, 136 miRNAs were changed in expression in one or more plasma samples drawn at baseline and after 12 mo of vitamin D supplementation. The twelve miRNAs that showed the greatest change in expression in the pilots were further measured in RNA from baseline and 12 mo plasma samples in 40 subjects given vitamin D and 37 subjects given placeboPlasmaJorde et al[47]
miR-122a miR-125bFischer 344 rats0, 12 or 24 mg/kgQuantitative real-time PCRVitamin E sufficiency resulted in increased concentrations of miRNA-122a and miRNA-125bLiver tissueGaedicke et al[49]
miR-625 miR-492 miR-373 miR-22, miR-532-5p miR-106b miR-30b miR-185 miR-203 miR1308 miR-28-5p miR-10bCaCO2 human colon cancer cellsSelenium-deficient or sufficient mediumMicroarray validated with quantitative real-time PCRSelenium deficiency resulted in altered expression of 12 genesTotal miRNA from combined cells of each treatmentMaciel-Dominguez et al[50]
miR-21U251 human glioblastoma cells10, 50 or 100 umol/L Resveratrol for 72 hQuantitative real-time PCRResveratrol inhibited miR-21 expression which in turn suppressed NF-κB activity. However, over-expression of miR-21 could reverse the effect of resveratrol on NF-κB activity and apoptosisCell extractsLi et al[54]
miR-21Estrogen-dependent MCF-7 and estrogen receptor-negative p53 mutant MDA-MB-468 human breast cancer cells0, 30 or 60 umol/LQuantitative real-time PCRCells were studied either in tissue culture or as a xenograft in BALB/C female athymic mice miR-21 was up-regulated in DIM-treated MCF-7 cells, but not in the ER negative, p53 mutant MDA-MB-468 cellsCell extractsJin[55]
miR-30b miR-1224-3p miR-197 miR-523-3HepG2 human hepatocarcinoma cells3-3’-Diindoyl-methane for 24-96 h 50 mg/L of epigallocatechin gallate (EGCG), 100 mg/L of grape seed extract (GSPE) or 100 mg/L of cocoa proanthocyanidin extract (CPE)Microarray analysis validated by quantitative real-time PCRMiR-30b was downregulated by all three treatments, while treatment with GSPE or CPE upregulated miR-1224-3p, miR-197 and miR-532-3pCell extractsArola-Arnal et al[57]
miR-210 (plus 13 other miRNAs upregulated and 7 down-regulated)Tobacco carcinogen-induced lung cancer in A/J micePurified mouse chow containing 0.4% EGCGMicroarray analysis validated by quantitative real-time PCRMiR-210 had been previously found upregulated by EGCG in in vitro experiments, but this ranked behind the 13 most strongly upregulated miRNAs (miR-2137, miR-449a, miR-144, miR-486, miR-3107, miR-193, miR-5130, miR-2861, miR-511-3p, miR-763, miR-3473, miR-211, miR-210) or seven most down regulated in this in vivo studyTumour tissue, all tumours from a single mouse combined to a single sampleZhou et al[58]