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ORIGINAL ARTICLE
Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk Qi Liu a,1, Guocan Yang a,1, Xiao-Ling Song b, Zongxin Wang a, Ge Shi a,∗ a
Department of Clinical Laboratory Center, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang 312000, China b Department of Integrative Medicine, Zhongshan Hospital, and Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, Shanghai 200032, China
Summary Genetic polymorphism of miR-34b/c gene is a candidate factor for attributing predisposition to carcinoma. However, results of mounting studies, concerning association of miR-34b/c gene rs4938723 with risk of cancer, present contradictory results. Therefore, a metaanalysis was performed to systematically assessment the possible association between them. The overall results of meta-analysis indicate a significant association was only observed between rs4938723 and cancer risk in genotype model (Ph = 0.203, OR = 1.09, 95% CI = 1.01—1.70 for CT vs. TT). After stratifying by ethnicity and cancer type, genotype CT of rs4938723 was significantly association with an increased cancer risk in Asian population (Ph = 0.187, OR = 1.10, 95%CI = 1.01—1.20), allele C and genotype CT were significantly positive associated with hepatocellular cancer (Ph = 0.113, OR = 1.11, 95%CI = 1.01—1.23 for C vs. T; Ph = 0.121, OR = 1.19, 95%CI = 1.03—1.37 for CT vs. TT), but rs4938723 was negative associated with risk of colorectal cancer (Ph = 0.342, OR = 0.66, 95%CI = 0.47—0.92 for CC vs. TT; Ph = 0.519, OR = 0.67, 95%CI = 0.49—0.93 for CC vs. CT/TT; Ph = 0.443, OR = 0.71, 95%CI = 0.51—0.99 for CC/TT vs. CT). These findings suggested that rs4938723 was a susceptible locus only for hepatocellular cancer and colorectal cancer. © 2014 Elsevier Masson SAS. All rights reserved.
∗ 1
Correspondence author. Tel.: +86 0575 88228566. E-mail address: [email protected] (G. Shi). Qi Liu and Guocan Yang contributed equally to this study and should be considered as co-first authors.
http://dx.doi.org/10.1016/j.clinre.2014.10.007 2210-7401/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Liu Q, et al. Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.10.007
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Introduction
Materials and method
MicroRNA (miRNA) is an abundant class of endogenously expressed 17-25 nucleotide and single-stranded non-coding RNA that post-transcriptionally regulate targeted gene expression primary by binding to targeted 3 -untranslational region (3 -UTR) of targeted m-RNA, resulting in gene silencing and translational repression [1—3]. It plays an important role in a series of physiological and pathophysiological processes in human, such as cell proliferation and differentiation [4], tissue and organ development as well as carcinogenesis and progression [5—7]. Using high throughput array, lots of cancer related miRNAs were identified and demonstrated that these were implicated in the regulation of processes that are important for carcinogenesis and progression as well as metastasis [6—8]. MicroRNA-34(miR-34), an evolutionarily conserved miRNA family including miR-34a, b and c forms, was turned out to be a target of p53 gene that encoded a transcriptional factor which is involved in growth suppression and apoptosis pathways. MiR-34a was encoded by its own gene; miR-34b and miR-34c shared a common primary transcript (pri-miR-34b/c). Aberrant expression of miR-34a and miR34b/c was observed to induce a cell-cycle arrest in the G1 phase [9,10]. Moreover, miR-34b/c could inhibit cell proliferation and colony formation in soft agar [11]. Furthermore, higher expression of miR-34a and miR-34b/c in human fibroblasts could cause cellular senescence [9]. In addition, low expression of miR-34a and miR-34b/c was detected in many kinds of cancer with mutation of p53 tumor suppressor gene [12]. To our interesting, Ectopic miR-34b/c could affect expression of hundreds putative target genes that are involved in cell-cycle control and DNA damage response, such as CDK4/6, Cyclin E2 and Bcl-2 [9,10]. These findings indicated that miR-34b/c gene can be considered as a tumor suppressor gene. Whereas, miR-34b/c gene also can be regulated by genetic or epigenetic mechanism in cancer. High methylation of miR-34b/c was examined in lung cancer, colorectal cancer and pancreatic cancer that correlated with metastasis [13,14]. Single nucleotide polymorphism in the promoter of miR-34b/c gene displayed a significant difference in promoter transcriptional efficiency, which led to ectopic expression of miR-34b/c [15]. Rs4938723 is located within the CpG island of miR34b/c gene promoter [16]. Different genotypes of rs4938723 were associated with aberrant expression of miR-34b/c [15]. Thus, this locus may affect miRNA processing and ultimately result in modification of miRNA expression and aberrant expression of targeted gene that are involved in carcinogenesis. Therefore, it is considered as candidate susceptible locus for cancer. Recently, several studies reported the association between rs4938723 and risk of cancer, but these displayed contradictory conclusions. Gao et al. reported that CT/CC genotype of rs4938723 was associated with a decreased risk for colorectal cancer [17]. But some studies showed a positive association between the locus and susceptibility to cancer [15,16,18]. In order to explore a more precise conclusion between them, a systematical meta-analysis was conducted using accumulating evidences to estimate the association between rs4938723 and risk of cancer.
Search and screen eligible study In the present study, we retrieved relevant studies in databases of Pubmed, Wanfang and Web of science dating up to July of 2014 using search terms of ‘‘rs4938723 and cancer’’, ‘‘miR-34b/c polymorphism and cancer’’ as well as ‘‘miR-34b/c and cancer’’. Trying to gain substantial studies, we performed manual retrieval by browsing references. Relevant studies were firstly obtained through identification of title and abstract of searched study. Then, eligible study was identified by browsing relevant full-text article. The inclusion criteria of eligible study were followed as below: • case-control study concerning rs4938723 and cancer risk in English or Chinese; • cases were solid cancer patients and controls were cancer-free healthy individuals; • sufficient genotype frequency data were provided to calculate Odds ratio (OR) and 95% confidence interval (95%CI); • genotype distribution of control group was should consistent with Hardy-Weinberg equilibrium (HWE); 5) The quality assessment of study should be higher than 20 scores. Whereas, review, meta-analysis, letter, comment, communication, and single group designed study, duplicative data published study or low quality score assessed study were excluded from our study.
Data extraction and quality assessment The following baseline characteristics data, the first author name, published year, country, race, cases and controls, genotyping method, genotype data, were independently extracted from each eligible article. We also conducted the quality assessment for each eligible study according to the STROME quality score systems [19]. The quality system includes 30 items, each item means one score, and quality score less than 20 is considered as low level of quality. These actions were conducted by two investigators (XL Song and Z Wang). Any disagreement was solved by the third person (Liu Q) to reach a final decision.
Statistics Odds ratio and 95% confidence interval was used as common measurement for assessing the strength of the association of rs4938273 with cancer risk. Z test was used to assess the overall effect and P-value < 0.05 was set up to consider statistical significance. Q test and estimated I2 was selected to estimate the heterogeneity between including studies, P-value < 0.1 was observed to be a significant heterogeneity [20,21]. According to the result of the heterogeneity test, the random model was chosen to assess OR and 95%CI when Ph < 0.1, on the contrary the fixed model was selected when Ph > 0.1. Meanwhile, sensitivity analysis was conducted to estimate the stability of finally result by changing estimated
Please cite this article in press as: Liu Q, et al. Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.10.007
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model or omitting an eligible study a time. The publication bias was evaluated by Begg’s funnel plot and Egger’s test [22,23]. The asymmetrical funnel plot and P-values of Begg’s test and Bgger’s test were less than 0.05 were considered as the existence the significant publication bias.
Result In our study, we searched substantial relevant study by retrieving the Pubmed and Wanfang databases and manual search. The detail search and screen flow chart was listed in Fig. 1. As shown from Fig. 1, a total of 93 studies were successfully searched (88 from the databases and 5 from manual search). Twenty-seven unrelated articles, 42 duplicated retrieval articles, 14 reviews, meta-analysis, letters and comments were excluded from the present study according to inclusion and exclusion criteria. Finally, 10 original articles containing 11 studies were included to evaluate the final overall effect [15—18,24—29]. Nine of them were related to Asian population, three, two and two studies were concerned hepatocellular cancer, colorectal cancer and ESCC, respectively. The detail baseline characteristics of including studies were described in Table 1. The combined overall effect was evaluated in 11 suitable studies containing 6364 cases and 6451 controls. The detail results of the heterogeneity test and overall effect of total and subgroups as well as Begg’s and Egger’s test were listed in Table 2 and Fig. 2. Showing
Figure 2
Figure 1 Flow diagram of retrieval and identification for eligible studies.
The meta-analysis results of rs4938723 and cancer in comparison of genotype CT vs. TT.
Please cite this article in press as: Liu Q, et al. Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.10.007
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The baseline characteristics of eligible study including in present study. Country
Ethnicity
Cancer
Cases
Controls
Resource of control
Detection
HWE
Genotype and allele distribution Cases
Gao 2013 OH 2014 Li 2013 Son 2013 Xu 2013 Han 2013 Bensen 2013 Bensen 2013 Zhang 2014 Yin 2013 You 2011
Chinese Korea Chinese Korea Chinese Chinese USA USA Chinese Chinese Chinese
Asian Asian Asian Asian Asian Asian Caucasian African Asian Asian Asian
CRC CRC NPC HC HC HC BC BC RCC ESCC ESCC
373 545 217 157 501 1021 1203 742 710 629 266
488 428 360 201 548 1012 1088 658 760 686 222
Hospital Hospital Hospital Hospital Hospital Hospital population population hospital Hospital Hospital
PCR-RFLP PCR-RFLP PCR-RFLP PCR-RFLP PCR-RFLP Taqman Illumina Illumina Taqman LDR Massarray
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Quality score
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Author and year
Controls CC
T
TT
CT
175 272 82 69 204 451 496 362 302 277 120
144 28 494 233 40 777 104 31 268 75 13 213 236 62 644 444 118 1346 563 144 1555 317 63 1041 324 84 928 278 45 832 103 28 343
C 200 313 166 101 360 680 851 443 492 368 159
TT 216 216 168 110 266 456 430 343 352 310 88
CT
CC
T
210 62 642 171 41 603 155 37 491 74 17 294 229 54 761 424 119 1336 503 155 1363 257 58 943 344 64 1048 290 73 910 86 15 262
C 334 253 229 108 337 662 813 373 472 436 116
25 23 22 21 24 23 25 25 21 24 23
CRC: colorectal cancer; NPC: nasopharyngeal carcinoma; HC: hepatocellular cancer; BC: breast cancer; ESCC: esophageal cell carcinoma; RCC: renal cell cancer; LDR: ligation detection reaction.
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Please cite this article in press as: Liu Q, et al. Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.10.007
Table 1
Table 2
The results of meta-analysis between miR-34b/c r4938723 and cancer.
C vs. T
Genotype model
CT vs.TT
Dominant
CC/CT vs.TT
Recessive
CC vs.CT/TT
Over-dominant
CC/TT vs.CT
2
Z test
Publication bias
OR and 95%CI
I (%)
PZ
PB
PE
Fixed model
Random model
0.003 0.005 0.124 0.154 0.113 0.124 0.459 0.203 0.187 0.197 0.222 0.121 0.197 0.393 0.003 0.003 0.302 0.342 0.285 0.302 0.091 0.035 0.04 0.135 0.157 0.090 0.135 0.837 0.015 0.011 0.483 0.519 0.493 0.483 0.045 0.055 0.042 0.421 0.443 0.430 0.421 0.153
62.0 63.7 57.6 50.9 54.2 57.6 0.0 25.2 29.0 39.8 32.9 52.6 39.8 0.0 62.2 65.5 6.0 0.0 20.4 6.0 64.9 48.5 50.6 55.2 50.0 58.6 55.2 0.00 54.7 59.8 0.0 0 0.0 0.0 75.1 44.4 50.0 0.0 0.0 0.0 0.0 50.9
0.357 0.288 0.545 0.058 0.036 0.545 0.515 0.030 0.029 0.547 0.741 0.016 0.547 0.847 0.838 0.646 0.206 0.015 0.221 0.206 0.275 0.134 0.126 0.900 0.288 0.065 0.900 0.870 0.772 0.142 0.956 0.016 0.579 0.142 0.874 0.896 0.685 0.324 0.040 0.315 0.324 0.354
0.533
0.330
0.298
0.276
0.876
0.504
0.640
0.287
1.00
0.617
1.00
0.534
1.03 1.05 0.97 0.87 1.11 0.97 0.95 1.09 1.10 1.04 0.97 1.19 1.04 1.02 0.99 1.05 0.87 0.66 1.15 0.87 0.83 0.94 0.92 0.99 1.11 0.85 0.99 1.02 0.96 1.01 0.86 0.67 1.06 0.86 0.82 1.00 1.04 0.90 0.71 1.12 0.90 0.85
1.04 (0.95—1.14) 1.06 (0.95—1.18) 0.98 (0.84—1.15) 0.87 (0.71—1.07) 1.15 (0.97—1.36) 0.98 (0.84—1.15) 0.95 (0.82—1.10) 1.09 (1.00—1.19) 1.11 (0.99—1.23) 1.05 (0.88—1.26) 0.96 (0.76—1.23) 1.25 (0.99—1.57) 1.05 (0.88—1.26) 1.02 (0.84—1.25) 1.02 (0.83—1.26) 1.06 (0.82—1.38) 0.87 (0.70—1.09) 0.66 (0.47—0.93) 1.17 (0.9—1.54) 0.87 (0.70—1.09) 0.92 (0.47—1.78) 0.93 (0.84—1.02) 0.91 (0.80—1.03) 0.98 (0.80—1.20) 1.11 (0.85—1.45) 0.80 (0.63—1.01) 0.98 (0.80—1.20) 1.02 (0.84—1.23) 0.97 (0.81—1.17) 0.86 (0.700—1.05) 1.01 (0.80—1.27) 0.67 (0.49—0.93) 1.06 (0.86—1.31) 0.86 (0.70—1.05) 0.94 (0.44—2.01) 1.01 (0.86—1.20) 1.05 (0.85—1.29) 0.90 (0.73—1.11) 0.71 (0.51—0.99) 1.12 (0.90—1.39) 0.90 (0.73—1.11) 0.91 (0.53—1.57)
(0.98—1.08) (0.99—1.21) (0.88—1.07) (0.75—1.01) (1.01—1.23) (0.88—1.70) (0.83—1.10) (1.01—1.70) (1.01—1.20) (0.91—1.20) (0.80—1.18) (1.03—1.37) (0.91—1.20) (0.84—1.25) (0.88—1.12) (0.91—1.22) (0.70—1.08) (0.47—0.92) (0.92—1.44) (0.70—1.08) (0.59—1.17) (0.87—1.01) (0.84—099) (0.87—1.13) (0.92—1.33) (0.74—0.97) (0.87—1.13) (0.84—1.23) (0.86—1.07) (0.88—1.15) (0.70—1.05) (0.49—0.93) (0.86—1.31) (0.70—1.05) (0.59—1.14) (0.89—1.12) (0.90—1.20) (0.73—1.11) (0.51—0.99) (0.90—1.39) (0.73—1.11) (0.61—1.20)
PH : P-value of heterogeneity test; PZ : P-value of Z test; PB : P-value of Begg’s test; PE : P-value of Egger’s test; OR: odds ratio; 95%CI: 95% confidence interval.
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PH
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Overall Asian Other CRC HC BC ESCC Overall Asian Other CRC HC BC ESCC Overall Asian Other CRC HC BC ESCC Overall Asian Other CRC HC BC ESCC Overall Asian Other CRC HC BC ESCC Overall Asian Other CRC HC BC ESCC
Heterogeneity test
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Allele model
Subgroup
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Please cite this article in press as: Liu Q, et al. Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.10.007
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Figure 3
The sensitivity analysis result of rs4938723 and cancer in comparison of genotype CT vs. TT.
from the Table 2, genotype CT was significantly associated with susceptibility to cancer risk in overall population (PH = 0.203, OR = 1.09, 95%CI = 1.01—1.70). No significant association between rs4938723 and cancer risk was observed in allele, dominant, recessive and over-dominant model. After stratification in accordance with race and cancer type, genotype CT of rs4938723 was examined to be associated with increased cancer risk in Asian population (Ph = 0.187, OR = 1.10, 95%CI = 1.01—1.20), rs4938723 was significantly positive associated with an increased risk for hepatocellular cancer in comparison of allele C vs. T(Ph = 0.113, OR = 1.11, 95%CI = 1.01—1.23) and genotype CT vs. TT (Ph = 0.121, OR = 1.19, 95%CI = 1.03—1.37). Whereas, rs4938723 was found to be negative associated with colorectal cancer in the comparison model of CC vs.TT (Ph = 0.342, OR = 0.66, 95%CI = 0.47-0.92), CC vs. CT/TT (Ph = 0.519, OR = 0.67, 95%CI = 0.49—0.93) and CC/TT vs. CT (Ph = 0.443, OR = 0.71, 95%CI = 0.51—0.99), respectively. The sensitivity analysis was performed to assess the stability of meta-analysis and the influence of each suitable study on the pooled ORs and 95%CI. As shown from Table 2 and Fig. 3, the corresponding pooled ORs and 95%CI were not materially changed in all comparisons, indicating that the results of meta-analysis were stable. Begg’s funnel plot and Egger’s test were selected to evaluate the possible publication bias in our study. As shown from Table 2 and Fig. 4, the symmetrical funnel plot and P-values of Begg’s and Bgger’s test suggested that no publication bias was observed in all comparisons.
significantly associated with a decreased risk of colorectal cancer. These findings suggested that rs4938723 of miR34b/c might be a susceptible locus for cancer, particular in Asian population; allele C and genotype CT of rs4938723 might increase susceptibility to hepatocellular cancer and rs4938723 might be a protective locus for colorectal cancer. Rs4938723, a locus of allele T convert to allele C, was located not only within the CpG island, but also in the promoter of miR-34b/c gene [16]; moreover, convention of allele T to allele C may create a transcription binding site for GATA transcription factor [16]. These evidences indicated that genotype CC or CT of this locus may lead to aberrant expression of miR-34b/c both by affecting promoter transcription efficiency and aberrant methylation of CpG island. In addition, miR-34b and miR-34c showed tumor suppression function and down-regulated expression of miR-34b/c was observed in cancer tissue compared to adjacent tissue, including hepatocellular cancer [13,30]. Furthermore, aberrant expression of miR-34b/c may affect the translation regulation of many target genes, which are involved in carcinogenesis and procession [31—34]. Therefore,
Discussion In our study, we performed a meta-analysis to explore a more precise conclusion between rs4938723 and risk of cancer. The results showed that genotype CT of rs4938723 was significantly associated with increased risk of cancer, especially in Asian population; allele C and genotype CT of rs4938723 were found to be significantly associated an elevated risk of hepatocellular cancer. On the contrary, rs4938723 was
Figure 4 The Begg’s funnel plot of rs4938723 and cancer in comparison of genotype CT vs.TT.
Please cite this article in press as: Liu Q, et al. Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.10.007
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Rs4938723 and cancer genotype CT of rs4938723 may increase susceptibility to cancer, especially hepatocellular cancer. Due to miR-34b/c gene may interact with environmental factor, frequencies of miR-34b/c CpG methylation were varied in different kinds of cancer leading to the different genetic effect of the rs4938723 polymorphism on the risk of HCC and CRC. The methylation frequency of the gene in CRC is high up to 99%, but 79.1% in hepatocellular cancer [14]. It may be the reason that rs4938723 is associated with decreased risk for colorectal cancer. To our best knowledge, the meta-analysis is the first time to systematically evaluate the association between rs4938723 and cancer risk. The conclusion of this study is more precise than a single study, for it includes the largest sample size till now. Whereas, there are several limitations should be addressed as following. Retrieval of suitable study was only performed in the databases of Pubmed and Wangfang, which might miss some other relevant studies leading to selection bias; sample sizes of cases and controls were less than 1000 in the majority of included studies, and the sample size was not large enough to achieve a stable conclusion, especially in subgroups. Due to insufficient data of including studies, we cannot perform the meta-analysis based on adjustment with age, diet, smoking and other environmental factors. In conclusion, the present meta-analysis indicated that rs4938723 was a genetic susceptible locus for cancer, especially in Asian population. Allele C and genotype CT might be a risk factor for hepatocellular cancer, but the locus was considered as a protective factor for colorectal cancer. With the limitations of the present study, large sample size and well-designed are warrant to validate our results.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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[31] Maroof H, Salajegheh A, Lam AK:. Role of microRNA-34 family in cancer with particular reference to cancer angiogenesis. Exp Mol Pathol 2014;97(2):298—304. [32] Wang AM, Huang TT, Hsu KW, Huang KH, Fang WL, Yang MH, et al. Yin Yang 1 is a target of microRNA-34 family and contributes to gastric carcinogenesis. Oncotarget 2014;5(13):5002—10. [33] Yu G, Li H, Wang J, Gumireddy K, Li A, Yao W, et al. MiRNA34a suppresses cell proliferation and metastasis by targeting CD44 in human renal carcinoma cells. J Urol 2014;192(4): 1229—37. [34] Hermeking H. The miR-34 family in cancer and apoptosis. Cell Death Differ 2010;17(2):193—9.
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ORIGINAL ARTICLE
Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk Qi Liu a,1, Guocan Yang a,1, Xiao-Ling Song b, Zongxin Wang a, Ge Shi a,∗ a
Department of Clinical Laboratory Center, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang 312000, China b Department of Integrative Medicine, Zhongshan Hospital, and Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, Shanghai 200032, China
Summary Genetic polymorphism of miR-34b/c gene is a candidate factor for attributing predisposition to carcinoma. However, results of mounting studies, concerning association of miR-34b/c gene rs4938723 with risk of cancer, present contradictory results. Therefore, a metaanalysis was performed to systematically assessment the possible association between them. The overall results of meta-analysis indicate a significant association was only observed between rs4938723 and cancer risk in genotype model (Ph = 0.203, OR = 1.09, 95% CI = 1.01—1.70 for CT vs. TT). After stratifying by ethnicity and cancer type, genotype CT of rs4938723 was significantly association with an increased cancer risk in Asian population (Ph = 0.187, OR = 1.10, 95%CI = 1.01—1.20), allele C and genotype CT were significantly positive associated with hepatocellular cancer (Ph = 0.113, OR = 1.11, 95%CI = 1.01—1.23 for C vs. T; Ph = 0.121, OR = 1.19, 95%CI = 1.03—1.37 for CT vs. TT), but rs4938723 was negative associated with risk of colorectal cancer (Ph = 0.342, OR = 0.66, 95%CI = 0.47—0.92 for CC vs. TT; Ph = 0.519, OR = 0.67, 95%CI = 0.49—0.93 for CC vs. CT/TT; Ph = 0.443, OR = 0.71, 95%CI = 0.51—0.99 for CC/TT vs. CT). These findings suggested that rs4938723 was a susceptible locus only for hepatocellular cancer and colorectal cancer. © 2014 Elsevier Masson SAS. All rights reserved.
∗ 1
Correspondence author. Tel.: +86 0575 88228566. E-mail address: [email protected] (G. Shi). Qi Liu and Guocan Yang contributed equally to this study and should be considered as co-first authors.
http://dx.doi.org/10.1016/j.clinre.2014.10.007 2210-7401/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Liu Q, et al. Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.10.007
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Introduction
Materials and method
MicroRNA (miRNA) is an abundant class of endogenously expressed 17-25 nucleotide and single-stranded non-coding RNA that post-transcriptionally regulate targeted gene expression primary by binding to targeted 3 -untranslational region (3 -UTR) of targeted m-RNA, resulting in gene silencing and translational repression [1—3]. It plays an important role in a series of physiological and pathophysiological processes in human, such as cell proliferation and differentiation [4], tissue and organ development as well as carcinogenesis and progression [5—7]. Using high throughput array, lots of cancer related miRNAs were identified and demonstrated that these were implicated in the regulation of processes that are important for carcinogenesis and progression as well as metastasis [6—8]. MicroRNA-34(miR-34), an evolutionarily conserved miRNA family including miR-34a, b and c forms, was turned out to be a target of p53 gene that encoded a transcriptional factor which is involved in growth suppression and apoptosis pathways. MiR-34a was encoded by its own gene; miR-34b and miR-34c shared a common primary transcript (pri-miR-34b/c). Aberrant expression of miR-34a and miR34b/c was observed to induce a cell-cycle arrest in the G1 phase [9,10]. Moreover, miR-34b/c could inhibit cell proliferation and colony formation in soft agar [11]. Furthermore, higher expression of miR-34a and miR-34b/c in human fibroblasts could cause cellular senescence [9]. In addition, low expression of miR-34a and miR-34b/c was detected in many kinds of cancer with mutation of p53 tumor suppressor gene [12]. To our interesting, Ectopic miR-34b/c could affect expression of hundreds putative target genes that are involved in cell-cycle control and DNA damage response, such as CDK4/6, Cyclin E2 and Bcl-2 [9,10]. These findings indicated that miR-34b/c gene can be considered as a tumor suppressor gene. Whereas, miR-34b/c gene also can be regulated by genetic or epigenetic mechanism in cancer. High methylation of miR-34b/c was examined in lung cancer, colorectal cancer and pancreatic cancer that correlated with metastasis [13,14]. Single nucleotide polymorphism in the promoter of miR-34b/c gene displayed a significant difference in promoter transcriptional efficiency, which led to ectopic expression of miR-34b/c [15]. Rs4938723 is located within the CpG island of miR34b/c gene promoter [16]. Different genotypes of rs4938723 were associated with aberrant expression of miR-34b/c [15]. Thus, this locus may affect miRNA processing and ultimately result in modification of miRNA expression and aberrant expression of targeted gene that are involved in carcinogenesis. Therefore, it is considered as candidate susceptible locus for cancer. Recently, several studies reported the association between rs4938723 and risk of cancer, but these displayed contradictory conclusions. Gao et al. reported that CT/CC genotype of rs4938723 was associated with a decreased risk for colorectal cancer [17]. But some studies showed a positive association between the locus and susceptibility to cancer [15,16,18]. In order to explore a more precise conclusion between them, a systematical meta-analysis was conducted using accumulating evidences to estimate the association between rs4938723 and risk of cancer.
Search and screen eligible study In the present study, we retrieved relevant studies in databases of Pubmed, Wanfang and Web of science dating up to July of 2014 using search terms of ‘‘rs4938723 and cancer’’, ‘‘miR-34b/c polymorphism and cancer’’ as well as ‘‘miR-34b/c and cancer’’. Trying to gain substantial studies, we performed manual retrieval by browsing references. Relevant studies were firstly obtained through identification of title and abstract of searched study. Then, eligible study was identified by browsing relevant full-text article. The inclusion criteria of eligible study were followed as below: • case-control study concerning rs4938723 and cancer risk in English or Chinese; • cases were solid cancer patients and controls were cancer-free healthy individuals; • sufficient genotype frequency data were provided to calculate Odds ratio (OR) and 95% confidence interval (95%CI); • genotype distribution of control group was should consistent with Hardy-Weinberg equilibrium (HWE); 5) The quality assessment of study should be higher than 20 scores. Whereas, review, meta-analysis, letter, comment, communication, and single group designed study, duplicative data published study or low quality score assessed study were excluded from our study.
Data extraction and quality assessment The following baseline characteristics data, the first author name, published year, country, race, cases and controls, genotyping method, genotype data, were independently extracted from each eligible article. We also conducted the quality assessment for each eligible study according to the STROME quality score systems [19]. The quality system includes 30 items, each item means one score, and quality score less than 20 is considered as low level of quality. These actions were conducted by two investigators (XL Song and Z Wang). Any disagreement was solved by the third person (Liu Q) to reach a final decision.
Statistics Odds ratio and 95% confidence interval was used as common measurement for assessing the strength of the association of rs4938273 with cancer risk. Z test was used to assess the overall effect and P-value < 0.05 was set up to consider statistical significance. Q test and estimated I2 was selected to estimate the heterogeneity between including studies, P-value < 0.1 was observed to be a significant heterogeneity [20,21]. According to the result of the heterogeneity test, the random model was chosen to assess OR and 95%CI when Ph < 0.1, on the contrary the fixed model was selected when Ph > 0.1. Meanwhile, sensitivity analysis was conducted to estimate the stability of finally result by changing estimated
Please cite this article in press as: Liu Q, et al. Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.10.007
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model or omitting an eligible study a time. The publication bias was evaluated by Begg’s funnel plot and Egger’s test [22,23]. The asymmetrical funnel plot and P-values of Begg’s test and Bgger’s test were less than 0.05 were considered as the existence the significant publication bias.
Result In our study, we searched substantial relevant study by retrieving the Pubmed and Wanfang databases and manual search. The detail search and screen flow chart was listed in Fig. 1. As shown from Fig. 1, a total of 93 studies were successfully searched (88 from the databases and 5 from manual search). Twenty-seven unrelated articles, 42 duplicated retrieval articles, 14 reviews, meta-analysis, letters and comments were excluded from the present study according to inclusion and exclusion criteria. Finally, 10 original articles containing 11 studies were included to evaluate the final overall effect [15—18,24—29]. Nine of them were related to Asian population, three, two and two studies were concerned hepatocellular cancer, colorectal cancer and ESCC, respectively. The detail baseline characteristics of including studies were described in Table 1. The combined overall effect was evaluated in 11 suitable studies containing 6364 cases and 6451 controls. The detail results of the heterogeneity test and overall effect of total and subgroups as well as Begg’s and Egger’s test were listed in Table 2 and Fig. 2. Showing
Figure 2
Figure 1 Flow diagram of retrieval and identification for eligible studies.
The meta-analysis results of rs4938723 and cancer in comparison of genotype CT vs. TT.
Please cite this article in press as: Liu Q, et al. Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.10.007
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The baseline characteristics of eligible study including in present study. Country
Ethnicity
Cancer
Cases
Controls
Resource of control
Detection
HWE
Genotype and allele distribution Cases
Gao 2013 OH 2014 Li 2013 Son 2013 Xu 2013 Han 2013 Bensen 2013 Bensen 2013 Zhang 2014 Yin 2013 You 2011
Chinese Korea Chinese Korea Chinese Chinese USA USA Chinese Chinese Chinese
Asian Asian Asian Asian Asian Asian Caucasian African Asian Asian Asian
CRC CRC NPC HC HC HC BC BC RCC ESCC ESCC
373 545 217 157 501 1021 1203 742 710 629 266
488 428 360 201 548 1012 1088 658 760 686 222
Hospital Hospital Hospital Hospital Hospital Hospital population population hospital Hospital Hospital
PCR-RFLP PCR-RFLP PCR-RFLP PCR-RFLP PCR-RFLP Taqman Illumina Illumina Taqman LDR Massarray
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Quality score
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Author and year
Controls CC
T
TT
CT
175 272 82 69 204 451 496 362 302 277 120
144 28 494 233 40 777 104 31 268 75 13 213 236 62 644 444 118 1346 563 144 1555 317 63 1041 324 84 928 278 45 832 103 28 343
C 200 313 166 101 360 680 851 443 492 368 159
TT 216 216 168 110 266 456 430 343 352 310 88
CT
CC
T
210 62 642 171 41 603 155 37 491 74 17 294 229 54 761 424 119 1336 503 155 1363 257 58 943 344 64 1048 290 73 910 86 15 262
C 334 253 229 108 337 662 813 373 472 436 116
25 23 22 21 24 23 25 25 21 24 23
CRC: colorectal cancer; NPC: nasopharyngeal carcinoma; HC: hepatocellular cancer; BC: breast cancer; ESCC: esophageal cell carcinoma; RCC: renal cell cancer; LDR: ligation detection reaction.
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Table 1
Table 2
The results of meta-analysis between miR-34b/c r4938723 and cancer.
C vs. T
Genotype model
CT vs.TT
Dominant
CC/CT vs.TT
Recessive
CC vs.CT/TT
Over-dominant
CC/TT vs.CT
2
Z test
Publication bias
OR and 95%CI
I (%)
PZ
PB
PE
Fixed model
Random model
0.003 0.005 0.124 0.154 0.113 0.124 0.459 0.203 0.187 0.197 0.222 0.121 0.197 0.393 0.003 0.003 0.302 0.342 0.285 0.302 0.091 0.035 0.04 0.135 0.157 0.090 0.135 0.837 0.015 0.011 0.483 0.519 0.493 0.483 0.045 0.055 0.042 0.421 0.443 0.430 0.421 0.153
62.0 63.7 57.6 50.9 54.2 57.6 0.0 25.2 29.0 39.8 32.9 52.6 39.8 0.0 62.2 65.5 6.0 0.0 20.4 6.0 64.9 48.5 50.6 55.2 50.0 58.6 55.2 0.00 54.7 59.8 0.0 0 0.0 0.0 75.1 44.4 50.0 0.0 0.0 0.0 0.0 50.9
0.357 0.288 0.545 0.058 0.036 0.545 0.515 0.030 0.029 0.547 0.741 0.016 0.547 0.847 0.838 0.646 0.206 0.015 0.221 0.206 0.275 0.134 0.126 0.900 0.288 0.065 0.900 0.870 0.772 0.142 0.956 0.016 0.579 0.142 0.874 0.896 0.685 0.324 0.040 0.315 0.324 0.354
0.533
0.330
0.298
0.276
0.876
0.504
0.640
0.287
1.00
0.617
1.00
0.534
1.03 1.05 0.97 0.87 1.11 0.97 0.95 1.09 1.10 1.04 0.97 1.19 1.04 1.02 0.99 1.05 0.87 0.66 1.15 0.87 0.83 0.94 0.92 0.99 1.11 0.85 0.99 1.02 0.96 1.01 0.86 0.67 1.06 0.86 0.82 1.00 1.04 0.90 0.71 1.12 0.90 0.85
1.04 (0.95—1.14) 1.06 (0.95—1.18) 0.98 (0.84—1.15) 0.87 (0.71—1.07) 1.15 (0.97—1.36) 0.98 (0.84—1.15) 0.95 (0.82—1.10) 1.09 (1.00—1.19) 1.11 (0.99—1.23) 1.05 (0.88—1.26) 0.96 (0.76—1.23) 1.25 (0.99—1.57) 1.05 (0.88—1.26) 1.02 (0.84—1.25) 1.02 (0.83—1.26) 1.06 (0.82—1.38) 0.87 (0.70—1.09) 0.66 (0.47—0.93) 1.17 (0.9—1.54) 0.87 (0.70—1.09) 0.92 (0.47—1.78) 0.93 (0.84—1.02) 0.91 (0.80—1.03) 0.98 (0.80—1.20) 1.11 (0.85—1.45) 0.80 (0.63—1.01) 0.98 (0.80—1.20) 1.02 (0.84—1.23) 0.97 (0.81—1.17) 0.86 (0.700—1.05) 1.01 (0.80—1.27) 0.67 (0.49—0.93) 1.06 (0.86—1.31) 0.86 (0.70—1.05) 0.94 (0.44—2.01) 1.01 (0.86—1.20) 1.05 (0.85—1.29) 0.90 (0.73—1.11) 0.71 (0.51—0.99) 1.12 (0.90—1.39) 0.90 (0.73—1.11) 0.91 (0.53—1.57)
(0.98—1.08) (0.99—1.21) (0.88—1.07) (0.75—1.01) (1.01—1.23) (0.88—1.70) (0.83—1.10) (1.01—1.70) (1.01—1.20) (0.91—1.20) (0.80—1.18) (1.03—1.37) (0.91—1.20) (0.84—1.25) (0.88—1.12) (0.91—1.22) (0.70—1.08) (0.47—0.92) (0.92—1.44) (0.70—1.08) (0.59—1.17) (0.87—1.01) (0.84—099) (0.87—1.13) (0.92—1.33) (0.74—0.97) (0.87—1.13) (0.84—1.23) (0.86—1.07) (0.88—1.15) (0.70—1.05) (0.49—0.93) (0.86—1.31) (0.70—1.05) (0.59—1.14) (0.89—1.12) (0.90—1.20) (0.73—1.11) (0.51—0.99) (0.90—1.39) (0.73—1.11) (0.61—1.20)
PH : P-value of heterogeneity test; PZ : P-value of Z test; PB : P-value of Begg’s test; PE : P-value of Egger’s test; OR: odds ratio; 95%CI: 95% confidence interval.
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PH
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Overall Asian Other CRC HC BC ESCC Overall Asian Other CRC HC BC ESCC Overall Asian Other CRC HC BC ESCC Overall Asian Other CRC HC BC ESCC Overall Asian Other CRC HC BC ESCC Overall Asian Other CRC HC BC ESCC
Heterogeneity test
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Subgroup
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Figure 3
The sensitivity analysis result of rs4938723 and cancer in comparison of genotype CT vs. TT.
from the Table 2, genotype CT was significantly associated with susceptibility to cancer risk in overall population (PH = 0.203, OR = 1.09, 95%CI = 1.01—1.70). No significant association between rs4938723 and cancer risk was observed in allele, dominant, recessive and over-dominant model. After stratification in accordance with race and cancer type, genotype CT of rs4938723 was examined to be associated with increased cancer risk in Asian population (Ph = 0.187, OR = 1.10, 95%CI = 1.01—1.20), rs4938723 was significantly positive associated with an increased risk for hepatocellular cancer in comparison of allele C vs. T(Ph = 0.113, OR = 1.11, 95%CI = 1.01—1.23) and genotype CT vs. TT (Ph = 0.121, OR = 1.19, 95%CI = 1.03—1.37). Whereas, rs4938723 was found to be negative associated with colorectal cancer in the comparison model of CC vs.TT (Ph = 0.342, OR = 0.66, 95%CI = 0.47-0.92), CC vs. CT/TT (Ph = 0.519, OR = 0.67, 95%CI = 0.49—0.93) and CC/TT vs. CT (Ph = 0.443, OR = 0.71, 95%CI = 0.51—0.99), respectively. The sensitivity analysis was performed to assess the stability of meta-analysis and the influence of each suitable study on the pooled ORs and 95%CI. As shown from Table 2 and Fig. 3, the corresponding pooled ORs and 95%CI were not materially changed in all comparisons, indicating that the results of meta-analysis were stable. Begg’s funnel plot and Egger’s test were selected to evaluate the possible publication bias in our study. As shown from Table 2 and Fig. 4, the symmetrical funnel plot and P-values of Begg’s and Bgger’s test suggested that no publication bias was observed in all comparisons.
significantly associated with a decreased risk of colorectal cancer. These findings suggested that rs4938723 of miR34b/c might be a susceptible locus for cancer, particular in Asian population; allele C and genotype CT of rs4938723 might increase susceptibility to hepatocellular cancer and rs4938723 might be a protective locus for colorectal cancer. Rs4938723, a locus of allele T convert to allele C, was located not only within the CpG island, but also in the promoter of miR-34b/c gene [16]; moreover, convention of allele T to allele C may create a transcription binding site for GATA transcription factor [16]. These evidences indicated that genotype CC or CT of this locus may lead to aberrant expression of miR-34b/c both by affecting promoter transcription efficiency and aberrant methylation of CpG island. In addition, miR-34b and miR-34c showed tumor suppression function and down-regulated expression of miR-34b/c was observed in cancer tissue compared to adjacent tissue, including hepatocellular cancer [13,30]. Furthermore, aberrant expression of miR-34b/c may affect the translation regulation of many target genes, which are involved in carcinogenesis and procession [31—34]. Therefore,
Discussion In our study, we performed a meta-analysis to explore a more precise conclusion between rs4938723 and risk of cancer. The results showed that genotype CT of rs4938723 was significantly associated with increased risk of cancer, especially in Asian population; allele C and genotype CT of rs4938723 were found to be significantly associated an elevated risk of hepatocellular cancer. On the contrary, rs4938723 was
Figure 4 The Begg’s funnel plot of rs4938723 and cancer in comparison of genotype CT vs.TT.
Please cite this article in press as: Liu Q, et al. Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.10.007
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Rs4938723 and cancer genotype CT of rs4938723 may increase susceptibility to cancer, especially hepatocellular cancer. Due to miR-34b/c gene may interact with environmental factor, frequencies of miR-34b/c CpG methylation were varied in different kinds of cancer leading to the different genetic effect of the rs4938723 polymorphism on the risk of HCC and CRC. The methylation frequency of the gene in CRC is high up to 99%, but 79.1% in hepatocellular cancer [14]. It may be the reason that rs4938723 is associated with decreased risk for colorectal cancer. To our best knowledge, the meta-analysis is the first time to systematically evaluate the association between rs4938723 and cancer risk. The conclusion of this study is more precise than a single study, for it includes the largest sample size till now. Whereas, there are several limitations should be addressed as following. Retrieval of suitable study was only performed in the databases of Pubmed and Wangfang, which might miss some other relevant studies leading to selection bias; sample sizes of cases and controls were less than 1000 in the majority of included studies, and the sample size was not large enough to achieve a stable conclusion, especially in subgroups. Due to insufficient data of including studies, we cannot perform the meta-analysis based on adjustment with age, diet, smoking and other environmental factors. In conclusion, the present meta-analysis indicated that rs4938723 was a genetic susceptible locus for cancer, especially in Asian population. Allele C and genotype CT might be a risk factor for hepatocellular cancer, but the locus was considered as a protective factor for colorectal cancer. With the limitations of the present study, large sample size and well-designed are warrant to validate our results.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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Please cite this article in press as: Liu Q, et al. Association between rs4938723 functional polymorphism in the promoter region of miR-34b/c gene and cancer risk. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.10.007
