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. 2015 Feb 12;8:421–425. doi: 10.2147/OTT.S78647

Single-nucleotide polymorphisms of microRNA processing machinery genes and risk of colorectal cancer

Yufei Zhao 1, Yanming Du 1, Shengnan Zhao 1, Zhanjun Guo 1,
PMCID: PMC4334349  PMID: 25709475

Abstract

Objective

MicroRNA (miRNA)-related single-nucleotide polymorphisms (miR-SNPs) in miRNA processing machinery genes can affect cancer risk, treatment efficacy, and patient prognosis. We genotyped 6 miR-SNPs of miRNA processing machinery genes including XPO5 (rs11077), RAN (rs14035), Dicer (rs3742330), TNRC6B (rs9623117), GEMIN3 (rs197412), and GEMIN4 (rs2740348) in a case-control study to evaluate their impact on colorectal cancer (CRC) risk.

Materials and methods

miR-SNPs were genotyped using the polymerase chain reaction– ligase detection reaction. The χ2 test was used to analyze dichotomous values, such as the presence or absence of any individual SNP in CRC patients and healthy controls.

Results

Two of these SNPs were identified for their association with cancer risk in the Dicer and GEMIN3 genes. The AA allele of rs3742330 located in the Dicer gene exhibited a significantly increased risk of CRC (odds ratio, 2.11; 95% confidence interval: 1.33–3.34; P=0.001); the TT allele of rs197412 located in GEMIN3 also exhibited a significantly increased risk of CRC (odds ratio, 1.68; 95% confidence interval: 1.07–2.65; P=0.024).

Conclusion

Our results suggest that the specific genetic variants in miRNA machinery genes may affect CRC susceptibility.

Keywords: miR-SNP, CRC, GEMIN3, Dicer

Introduction

Colorectal cancer (CRC) is the third most common cancer in males and the second in females, which make it the third most common cause of cancer-related mortality in both sexes worldwide.1 It accounts for an estimated 1.2 million new cancer cases and over 630,000 cancer deaths per year.2 The CRC incidence displayed a trend of rapid rise in a study involving Asian countries including the People’s Republic of China, Japan, South Korea, and Singapore.3 Dietary patterns, obesity, smoking, heavy alcohol consumption, physical inactivity, genetic and epigenetic have been identified as risk factors for CRC,46 but the underlying mechanism of this cancer remains unknown.710

MicroRNAs (miRNAs) are RNA molecules that are ~22 nucleotides long and which play important roles in various biological processes, such as embryonic development, cell differentiation, proliferation, apoptosis, cancer development, and insulin secretion.11,12 A growing body of studies suggests that miRNAs play important roles in cancer development through regulating the expressions of proto-oncogenes or tumor suppressor genes.11,13,14 During miRNA processing, long primary transcripts of miRNAs (pri-miRNAs) are processed in the nucleus by the RNase III Drosha and are transported to the cytoplasm by the nuclear transport factor exportin-5 (XPO5) and RAN. In the cytoplasm, RNase III Dicer and transactivation-responsive RNA-binding protein (TRBP) mediate pre-miRNA processing to release a 21-bp miRNA, the RNA-induced silencing complex (RISC) including GEMIN3 and GEMIN4 will select one strand as the mature miRNA and guide mature miRNAs to their target mRNA sites.11,1519 miRNA-related single-nucleotide polymorphisms (miR-SNPs), defined as single-nucleotide polymorphisms (SNPs) in miRNA genes, miRNA binding site and miRNA processing machinery, are able to modulate miRNA and target gene expressions so as to influence cancer risk, treatment efficacy, and patient prognosis.1922

It is reported that genetic variants in both miRNA processing pathway genes and miRNA genes might affect susceptibility to cancers such as bladder cancer, esophageal cancer, and renal cell carcinoma, but few studies focus on miR-SNPs of miRNA processing machinery genes and CRC risk.2325 In the present study, we genotyped six miR-SNPs of miRNA processing machinery genes including XPO5 (rs11077), RAN (rs14035), Dicer (rs3742330), TNRC6B (rs9623117), GEMIN3 (rs197412), and GEMIN4 (rs2740348), which have shown susceptibility to carcinogenesis in a previous report, in a case-control study to evaluate the impact of these miR-SNPs on CRC risk.19

Materials and methods

Tissue specimens and DNA extraction

Blood samples were collected at the Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China from 163 CRC patients who underwent tumor resection in the Department of Surgery. Blood samples were also collected from 142 age- and sex-matched health controls. The personal information about smoking, obesity, and alcohol consumption were reviewed in patients and controls. Total DNA was extracted using the Wizard Genomic DNA extraction kit (Promega Corporation, Fitchburg, WI, USA) and stored at −20°C. The program was approved by the Human Tissue Research Committee of the Fourth Hospital of Hebei Medical University. Written informed consent was obtained from all the patients for the collection of samples and subsequent analysis.

Genotyping of miR-SNPs

The miR-SNPs of the miRNA processing genes including XPO5 (rs11077), RAN (rs14035), Dicer (rs3742330), TNRC6B (rs9623117), GEMIN3 (rs197412), and GEMIN4 (rs2740348) were genotyped with polymerase chain reaction-ligase detection reaction assay that amplify the DNA fragment flanking miR-SNPs basing on the sequence in the NCBI SNP database (http://www.ncbi.nlm.nih.gov/snp/). All the primers and probes are listed in Table 1. The ligation was performed using the different probes matched to the miR-SNPs, and the ligated products were separated using the ABI PRISM Genetic Analyzer 3730XL (Thermo Fisher Scientific, Waltham, MA, USA). Polymorphisms were confirmed based on the length difference of ligated products.

Table 1.

Primers and probes used for genotyping of miR-SNPs

Gene rs NCBI Primer sequence Probe sequence
XPO5 rs11077 (A/C) F GAATCTGGTCACCTGATGGGA
R GTGCCTGAGTGGACCTTGAG
S1 GTACCTCCAAGGACCAGGGCTGGGA
S2 TTTGTACCTCCAAGGACCAGGGCTGGGC
S3 AGTCTTTAGTGCTAACATCCCCTTT
RAN rs14035 (C/T) F GCACTTGCTCAAAATCTGTGA
R TAACAGCAAGAATTCCCAACC
S1 TTTTAGTAATCATGTTTTAATGTAGAACC
S2 TTTTTTTAGTAATCATGTTTTAATGTAGAACT
S3 TCAAACAGGATGGAACATCAGTGGATTT
Dicer1 rs3742330 (A/G) F AAAGGTATCAAGGTCTCAGTTTG
R CTGCAGAGGATCACTGGAATC
S1 TTTTTTTTTTCAATCTTGTGTAAAGGGATTAGA
S2 TTTTTTTTTTTTTCAATCTTGTGTAAAGGGATTAGG
S3 CACCCTAACAGAGCAAGATCCAATATTTTTT
TNRC6B rs9623117 (C/T) F TTTCTGTCTCCTCCTATCCAT
R CATTAGTTTAGCCAACAAGGT
S1 TCTCCCTGTTACTCTTAAGTAGTGC
S2 TTTTCTCCCTGTTACTCTTAAGTAGTGT
S3 CTCCTTTCCCCATCCACCCCATCTC
GEMIN3 rs197412 (T/C) F TAGAGAAACCTGTGGAAATCA
R GAAGAGGTTCTTGAGCTGTAA
S1 TTTTATGGTTTTGTGAGAAATAAAGTTAC
S2 TTTTTTTATGGTTTTGTGAGAAATAAAGTTAT
S3 TGAACAGAGAGTCCCTGTGTTGGCATTT
GEMIN4 rs2740348 (G/C) F TTGCCTCTGAGAAGAAGTGG
R GACTCAGGGATGGCTCTGTC
S1 TTTTTTTTGGGAGTAACAGGGCCCTCTTCCGAC
S2 TTTTTTTTTTTGGGAGTAACAGGGCCCTCTTCCGAG
S3 AGCCAGACTTGGTGTTGAGGCTGCTTTTTTT

Abbreviation: miR-SNPs, microRNA-related single-nucleotide polymorphisms.

Measurement of Dicer levels in CRC tissue

Dicer immunochemistry was performed with CRC tissue. The tissue sections were incubated with an anti-Dicer antibody (Abcam, Cambridge, UK) at a dilution of 1:100 overnight at 4°C followed by incubation with a biotinylated secondary anti-rabbit IgG antibody for 1 hour at room temperature. The sections were subsequently incubated with HRP-conjugated streptavidin and developed using 3,3-diaminobenzidine.

The immunostaining results for all receptors were semi-quantified by two investigators using the HSCORE as described previously.26 Briefly, the score was calculated by the percentage of positively stained CRC tissue with five intensity categories (0, 1+, 2+, 3+, and 4+). The HSCORE represents the sum of each of the percentages multiplied by the weighted intensity of staining as follows:

HSCORE=(i+1)π, (1)

where i =1, 2, 3, and 4 and π varies from 0% to 100% for the percentage of positive stained area. A score >100% was defined as high expression and ≤100% as low expression

Statistical analysis

The χ2 test was used to analyze dichotomous values, such as the presence or absence of any individual SNP in CRC patients and healthy controls. Statistical analyses were performed using SPSS 18.0 software (SPSS Inc., Chicago, IL, USA). For all the statistical tests, P<0.05 was considered to indicate a statistically significant difference.

Results

A total of 163 CRC patients were enrolled in this study. The control group consisted of 142 people without any history of hereditary or malignant disease by physical and imaging examinations. No distribution difference existed between patients and controls referring to age and sex. All patients and controls were the same nationality (Han Chinese) and recruited from Shijiazhuang and surrounding areas in North China. The clinical characteristics of the CRC patients and healthy controls are listed in Table 2.

Table 2.

Association of clinical characteristics with cancer risk in CRC patients

CRC (n=163) Control (n=142) P-value
Age (years)
 ≤60 79 66
 >60 84 76 0.729
Sex
 Male 93 93
 Female 70 49 0.132
Smoking
 Yes 32 36
 No 131 106 0.231
Obesity
 Yes 12 18
 No 151 124 0.120
Alcohol consumption
 Yes 27 30
 No 136 112 0.308
Tumor stage, TNM
 I 9
 II 82
 III 53
 IV 19

Abbreviation: CRC, colorectal cancer.

We genotyped the six miR-SNPs of miRNA processing machinery genes including XPO5 (rs11077), RAN (rs14035), Dicer (rs3742330), TNRC6B (rs9623117), GEMIN3 (rs197412), and GEMIN4 (rs2740348) in 163 CRC patients and 142 healthy controls and evaluated the impact of these miR-SNPs on CRC risk. The genotype distributions and allele frequencies of the SNPs are shown in Table 3. Two SNPs of these miR-SNPs were identified for their association with CRC risk by χ2 test. For the rs3742330 located in Dicer genes, the frequencies of genotype AA and AG + GG were 56.4% and 43.6% in patients but 38.0% and 62.0% in the controls. The AA genotype carrier of rs3742330 was associated with a 2.11-fold increased risk when compared with AG + GG genotype carrier (odds ratio, 2.11; 95% confidence interval: 1.33–3.34; P=0.001). As for the rs197412 located in GEMIN3, the frequencies of genotype TT and CT + CC were 55.2% and 44.8% in the patients and 42.3% and 57.7% in controls. The TT genotype carrier showed a significantly increased risk for CRC compared with CT + CC carrier (odds ratio, 1.68; 95% confidence interval: 1.07–2.65; P=0.024).

Table 3.

Associations of the six SNPs with colorectal cancer risk

Gene SNP Genotype Number (%) of patients with each genotype
Odds ratio 95% CI P-value
Case Control
XPO5 rs11077 AA 143 (12.3) 123 (86.6) 1.10 0.56–2.16 0.772
AC + CC 20 (87.7) 19 (13.4)
RAN rs14035 CC 113 (69.3) 107 (75.4) 0.74 0.45–1.23 0.242
CT + TT 50 (30.7) 35 (24.6)
Dicer rs3742330 AA 92 (56.4) 54 (38.0) 2.11 1.33–3.34 0.001
AG + GG 71 (43.6) 88 (62.0)
TNRC6B rs9623117 TT 149 (91.4) 128 (90.1) 1.16 0.54–2.53 0.702
CT + CC 14 (8.6) 14 (9.9)
GEMIN3 rs197412 TT 90 (55.2) 60 (42.3) 1.69 1.07–2.65 0.024
CT + CC 73 (44.8) 82 (57.7)
GEMIN4 rs2740348 GG 128 (78.5) 114 (80.3) 0.89 0.51–1.57 0.706
GC + CC 35 (21.5) 28 (19.7)

Abbreviations: CI, confidence interval; SNP, single-nucleotide polymorphism.

One hundred and sixty-four CRC patients including 89 rs3742330 AA carriers and 75 rs3742330 AG + GG carriers with cancer tissue available were used for Dicer protein measurement by immunostaining. The AA type (35 high Dicer expression and 54 low Dicer expression) displayed a great trend toward association with low Dicer expression at borderline statistical level (P=0.073) compared with that of AG + GG (40 high Dicer expression and 35 low Dicer expression).

Discussion

The identification of predictive markers from miR-SNPs for cancer risk is a new field in cancer research. We evaluated the potential associations of six miR-SNPs in miRNA processing machinery genes including XPO5 (rs11077), RAN (rs14035), Dicer (rs3742330), TNRC6B (rs9623117), GEMIN3 (rs197412), and GEMIN4 (rs2740348) with the risk of CRC. Two miR-SNPs in Dicer (rs3742330) and GEMIN3 (rs197412) were found to be associated with CRC risk.

Dicer is an endonuclease in the RNase III family that specially cleaves double-stranded RNAs to produce miRNA and small interfering RNA so as to repress gene expression.27,28 The miR-SNP of rs3742330 of Dicer has been identified for its association with the cancer outcome of T-cell lymphoma as well as the risk of oral premalignant lesions and renal cell carcinoma.25,29,30 The mechanism by which this SNP modifies the CRC risk remains unclear. rs3742330 located in the 3′-untranslated region of Dicer might potentially influence the gene stability and expression. Our immunostaining data show that this SNP seems to associate with different Dicer expression levels. Moreover, the altered Dicer expression may further affect miRNA expression profiles, thereby mediates the CRC carcinogenesis, deregulation of Dicer are strongly associated with the adverse development of CRC.31

GEMIN proteins in miRNA ribonucleoprotein particles is involved in the processing of miRNA precursors through their interaction with the key components of the RNA-induced silencing complex.25,32,33 rs197412 located in exon 11 of GEMIN3 gene could induce Ile to Thr substitution at 636 amino acid position through the T to C transition. This SNP showed a trend toward susceptibility to the risk of renal cell carcinoma.25 This amino acid substitution might change mRNA stability or protein function, thereby influencing miRNA expression profiles to modify the CRC carcinogenesis. In addition, GEMIN3 can form a complex with p53 and EBNA3C through the C-terminal domain (amino acid 546-825) to block p53-mediated apoptosis.34 The amino acid substitution of this miR-SNP, which is located in the C-terminal of GEMIN3, might alter binding affinity to p53, thereby modifying the apoptosis process of CRC cells.

The relationships of the frequency distribution of these two SNPs and metastasis status were compared; no association exists by our analysis (data not shown). These six miR-SNPs were analyzed for their association with postoperative survival in 55 patients with 5-year follow-up data available. rs14035 and rs3742330 showed association with survival at borderline statistical level (Fan et al, unpublished data, 2014), these findings should be validated in a larger sample size.

To our knowledge, this is the first study investigating the associations between SNPs of miRNA processing machinery genes and CRC susceptibility. miR-SNPs emerged as new promising markers for disease prediction in cancer. Although miR-SNP studies for miRNA processing machinery genes are at an early stage, our results are encouraging because they indicate that miR-SNPs may have an effect on cancer susceptibility. However, further laboratory-based functional studies in other populations are warranted to validate these results.

Acknowledgments

This work was supported by the Key Basic Research Program of Hebei (14967713D).

Footnotes

Disclosure

The authors report no conflicts of interest in this work.

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