Prognostic roles of microRNA 143 and microRNA 145 in colorectal cancer: A meta-analysis

Abstract

Background:

A systematic analysis was conducted to clarify the relationship between miR-143/145 and the prognosis of colorectal cancer.

Materials and methods:

We searched four databases: PubMed, EMBASE, Web of Science, and the Cochrane Library. We extracted and estimated the hazard ratios for survival outcomes, which compared low and high expression levels of miR-143/145 in colorectal cancer patients in the available studies. Each individual hazard ratio was used to calculate the pooled hazard ratio.

Results:

A total of 17 articles including 5128 patients were ultimately included. The results showed that there was no significant difference between low expression and high expression of miR-143 in the overall survival of colon cancer patients. However, low expression of miR-143 was significantly associated with high event-free survival (hazard ratio (HR) 0.6; 95% confidence interval (CI) 0.40, 0.88). Low expression of miR-145 was associated with poor prognosis of patients (HR 1.92; 95% CI 1.45, 2.54); those with low expression of miR-145 were at 1.92-fold higher risk for short-term overall survival than those with high expression of miR-145. MiR-145 was an unfavorable factor for the prognosis of colorectal cancer. There were no significant differences between low expression of miR-145 and high expression of miR-143 in event-free survival.

Conclusion:

miR-143 and miR-145 have promising prognostic value for colorectal cancer. Low expression of miR-143 can predict high event-free survival, and low expression of miR-145 can predict poor overall survival.

Keywords

miR-143 miR-145 colorectal cancer prognosis meta-analysis

Introduction

Colorectal cancer (CRC), also known as bowel cancer and colon cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Modern medical research has achieved great success in CRC treatment, but the prognosis and overall survival (OS) of CRC patients is still poor. For rectal examination, cancerous lesions located within 12 cm from the anal verge are defined as rectal cancer.¹ The OS is worse for symptomatic cancers because they are usually quite advanced. The survival of CRC patients diagnosed early is about five times that of those with advanced cancer. The 5-year survival rate is 100% in patients without invasion of the muscularis mucosa (tumor-node-metastasis (TNM) staging Tis, N0, M0); approximately 90% in patients with invasive T1 (submucosa) or T2 (inner muscle) cancer; approximately 70% in patients with high tumor infiltration depth but no lymph node metastasis (T3-4, N0, M0); approximately 40% in patients who are positive for a regional lymph node metastasis (any T, N1-3, M0); and approximately only 5% in patients with distant metastasis (any T, any N, M1).² Thus, finding biomarkers related to early diagnosis and prognosis of patients with CRC is a focus of current research,³ and emphasizes the significance of developing rapid and reliable prognostic biomarkers to improve the survival rate of CRC patients.

MicroRNAs (miRNAs) are a family of approximately 22 nucleotide-long RNAs that play an important role by target-ing key post-transcriptional gene expression regulators.^4,5 Some miRNAs function as oncogenes that regulate cell proliferation and other cancer-related biological behaviors.^3,6 Evidence from clinical studies has suggested that many miRNAs are deregulated in a variety of cancers, and the expression levels of some miRNAs were correlated with cancer stage. It has been suggested that miRNAs could play potential roles as diagnostic and prognostic biomarkers of cancers.^7,8

Many studies have shown that specific miRNA expression patterns correlate with the characteristics of certain cancers.⁹ Both the miR-143 and miR-145 genes are located close to each other on chromosome 5q32. It was demonstrated that miR-143 and miR-145 are tumor-related miRNAs in CRC. Michael et al.¹⁰ published the first study of miRNA in colon cancer, identifying miR-143 and miR-145 as novel dysregulated miRNAs. miR-143 and miR-145 have important physiological functions in tumor cell proliferation, apoptosis, invasion, metastasis, angiogenesis, and cell division.¹¹ The differential expression of miR-143/miR-145 may be a molecular marker for the clinical diagnosis and prognosis of tumors. To evaluate the relationship between the expression level of miR-143/miR-145 and the survival prognosis of patients with CRC, and to reduce the differences and biases between the reported studies, we performed a meta-analysis to evaluate the relationship between miR-143/miR-145 expression and the survival of postoperative CRC patients.

Material and methods

This meta-analysis was performed according to the guidelines of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement issued in 2009 (Checklist S1).

Search strategy

We searched PubMed, Web of Science, and EMBASE from 1 January 1966 to 30 May 2018 to identify relevant studies. The search used the following keywords: “colon or colorectal or colonic or rectum or rectal” and “cancer or carcinoma or tumor” and “prognosis or prognostic or survival or survive” and “miR-145 or miRNA-145 or miR-145 or has-miR-145” or miR-143 or miRNA-143 or miR-143 or has-miR-143.”

Inclusion criteria

Publications that (a) studied patients with CRC; (b) measured expression of miR-143/145 in human samples; and (c) measured at least one survival curve of OS, disease-free survival, recurrence-free survival, progression-free survival, and metastasis-free survival, with or without hazard ratios (HRs) or 95% confidence intervals (CIs).

Exclusion criteria

The exclusion criteria were (a) review articles or letters; (b) non-English articles; (c) investigation of a set of miRNAs but not miR-143/145 alone; (d) publications that did not include dichotomous miR-143/145 expression levels; and (e) publications lacking key information such as HR, 95% CI, and P value.

Data extraction

Eligible articles were reviewed by two investigators independently. Any controversial research opinion was resolved by discussion and consensus. The multivariate Cox regression analysis reported in the article was included in our analysis. If these data were not available, we extracted Kaplan–Meier survival curves for univariate Cox risk regression analysis or log-rank P-values and survival outcomes. The above main information was extracted by two independent investigators. Additional data extracted from the studies included first author, year of publication, study design, sample, study size, sex, tumor grade, tumor localization, detection method, survival analysis, and the type of miRNA (miR-145 or miR-143). All data of miRNA expression was dichotomized into low and high expression using a cutoff value for the expression level with the smallest P-value to test whether the specific miRNA expression was associated with survival outcomes based on the Kaplan–Meier method and log-rank test. Estimated HRs and their 95% CIs for each miRNA between low expression and high expression were reported for both OS and event-free survival (EFS).

Quality assessment

In this study, the quality of the selected studies was evaluated by the Newcastle–Ottawa Scale. Low-quality studies had scores under 6, while high quality studies had scores of 6 and above.¹² The studies included in this study were all 6 and above (in Supplementary Table 1, Newcastle–Ottawa quality assessment scale).

Statistical analysis

Stata12.0 software was used to perform a statistical analysis on the extracted data. The HR of the survival analysis was used, and the 95% CI was used to represent the effect level.

The method used to obtain HR was: (a) the HR and 95% CI included in the literature was directly entered into the statistical software; (b) the survival data extracted from the literature, such as survival rate and Log-rank analysis, or P values obtained from Cox analysis were calculated; and (c) if Kaplan–Meier survival curves were given, the survival data were read from the survival curve using Engauge Digitizer 4.1 software; then the obtained survival data were used to calculate HR and its 95% CI as described by Tierney et al.¹³

Heterogeneity analysis was performed using χ2 test. α=0.1 was the significance test level. When P<0.1, the hetero-geneity test was statistically significant. Meanwhile, I² was used to quantify the heterogeneity. If the heterogeneity test result was P>0.1 and I²<50%, the heterogeneity among the included studies was not considered statistically significant, and a fixed effects model (FEM) was used for the meta-analysis. If P ⩽ 0.1 and I²> 50%, the heterogeneity among the studies included was considered statistically significant. A random effects model (REM) was used for data analysis, and the effects of each study were combined. A sensitivity analysis was conducted to determine the cause of heterogeneity. The publication bias was quantitatively analyzed using Egger’s linear regression method and the Begg’s rank correlation test. When P<0.1, it indicated that there was publication bias.

Results

Characteristics of the eligible studies

According to the previous literature search strategy, after excluding duplicated articles, a total of 101 articles were retrieved. Based on the established criteria for inclusion and exclusion, a total of 17 articles^14-30 were selected. The literature screening process is shown in Figure 1. The characteristics of available studies are listed in Table 1. Studies are listed more than once if they provided survival data for different cohorts.

Figure 1.

Flow chart of this study.

Table 1.

Summary table of the meta-analysis.

Author	Year	Study design	Sample	Number of patients (M/F)	Tum or grade I/II(III/IV)	Tumor localization(colon/rectum)	Detection method	Survival analysis	Hazard ratios	miR
Schee et al.¹⁴	2012	P, C	Tissue	193 (112/81)	132 (61)	129/64	qRT-PCR	MFS	Estimated	miR-145
Yang et al.¹⁵	2017	P	Tissue	205 (104/101)	89 (116)	NR	qRT-PCR	OS, PFS	Reported in text	miR-145, miR-143
Slattery et al.¹⁶	2015	R, C	Tissue	1141 (615/526)	640 (501)	745/396	miRNA microarray	OS	Reported in text	miR-145
Jacob et al.¹⁸	2017	P, C (study cohort)	Tissue	111 (60/51)	66 (45)	NR	qRT-PCR	DFS	Reported in text	miR-143
Jacob et al.¹⁸	2017	P, C (validation cohort)	Tissue	209 (111/98)	122 (87)	NR	qRT-PCR	DFS	Reported in text	miR-143
Ak et al.¹⁹	2014	P	Tissue	40 (17/23)	20 (20)	18/22	qRT-PCR	OS	Estimated	miR-143
Li et al.²⁰	2015	P	Serum	175 (113/62)	101 (74)	74/101	qRT-PCR	DFS	Reported in text	miR-145
Slattery et al.²¹	2017	R	Tissue	1893 (1027/866)	1048 (814) *	1150/743	miRNA microarray	OS	Reported in text	miR-145, miR-143
Drebber et al.²²	2011	P	Tissue	40( 24/16)	26 (14)	NR	qRT-PCR	OS	Estimated	miR-145, miR-143
Zhou et al.²³	2016	Unclear	Tissue	60 (33/27)	45 (15)	NR	qRT-PCR	OS, DFS	Reported in text	miR-145
Schou et al.²⁴	2014	P	Serum	138 (84/54)	116 (22)	NR	miRNA microarray	OS	Reported in text	miR-143
Pichler et al.²⁵	2012	R	Tissue	77 (52/25)	57 (20)	49/28	qRT-PCR	OS, PFS	Reported in text	miR-143
Zhang et al.²⁶	2013	R (Training set)	Tissue	138 (79/59)	(138)	NR	miRNA microarray	DFS	Reported in text	miR-143
Zhang et al.²⁶	2013	R (Internal testing set)	Tissue	137 (86/51)	(137)	NR	miRNA microarray	DFS	Reported in text	miR-143
Zhang et al.²⁶	2013	R (Independent validation set)	Tissue	460 (266/194)	(460)	NR	miRNA microarray	DFS	Reported in text	miR-143
Simmer et al.²⁷	2015	P	Tissue	55	NR	NR	qRT-PCR	PFS	Estimated	miR-143
Kulda et al.²⁸	2010	P	Tissue	46 (31/15)	31(15)	NR	qRT-PCR	DFS	Estimated	miR-143
Guo et al.²⁹	2013	P	Tissue	79 (39/40)	28(51)	NR	qRT-PCR	OS	Estimated	miR-143
Pecqueux et al.³⁰	2016	p	Tissue	47 (31/16)	NR	NR	RT-PCR	OS	Estimated	miR-145

C: consecutive patients; DFS: disease-free survival; MFS: metastasis-free survival; NR: not reported; OS: overall survival; P: prospective; PFS: progression-free survival; R: retrospective; qRT-PCR: quantitative reverse transcription polymerase chain reaction; RFS: recurrence-free survival.

Tumor grade was most often described using the tumor-node-metastasis stage, but occasionally other systems were utilized. For this table, the studies were grouped as good/moderate (I/II) or poor (III/IV) degrees of differentiation.

Incomplete data.

The association between miR-143 expression and OS in CRC

Of seven studies,^{15,19,21,22,24,25,29} the relationship between miR-143 expression and OS in CRC tissue of 2472 patients was analyzed. The results (Figure 2(a)) showed that I² = 78.3%, P = 0.000, suggesting that each study had high heterogeneity when using the REM to analyze the combined effect of the index. The pooled HR was 0.98; 95% CI was 0.59, 1.63; and the difference was not statistically significant (P=0.943). The 95% CI included 1, suggesting that the low expression of miR-143 was not significantly associated with poor OS outcomes in CRC. Sensitivity analysis results showed that the studies of Schou et al.²⁴ and Pichler et al.²⁵ (Figure 2(b)) highly influenced the overall HR.

Figure 2.

The association (a) and sensitivity analysis (b) of miR-143 expression and OS, and the association (c) and sensitivity analysis (d) of miR-143 expression and EFS in patients with colorectal cancer. EFS: event-free survival; OS: overall survival.

The association between miR-143 expression and EFS in CRC

Of nine studies,^15,18,25-28 the relationship between miR-143 expression and EFS in CRC tissue of 1438 patients was analyzed. The results (Figure 2(c)) showed that I² = 72.2%, P = 0.000, suggesting that each study has high heterogeneity when using the REM to analyze the combined effect of the index. The pooled HR was 0.60; 95% CI was (0.40, 0.88); and the difference was statistically significant (P=0.009). The 95% CI did not include 1; HR<1. The EFS of the low expression level of miR-143 in patients with CRC was statistically significant compared to the high miR-143 expression, suggesting that the low expression of miR-143 is significantly associated with high EFS outcome in CRC. In sensitivity analysis results, the studies of Jacob et al.¹⁸ and Pichler et al.²⁵ (Figure 2(d)) influenced the overall HR.

The association between miR-145 expression and OS in CRC

Of six studies,^{15,16,21-23,30} the relationship between miR-145 expression and OS in CRC tissue of 1604 patients was analyzed. The results (Figure 3(a)) showed that I² = 25.9%, P = 0.240, suggesting that each study had no obvious heterogeneity when using the FEM to analyze the combined effect of the index. The pooled HR was 1.92; 95% CI was 1.45, 2.54; and the difference was statistically significant (P=0.000). The 95% CI did not include 1, and the combined HR>1, suggesting that low expression of miR-145 is significantly associated with poor prognosis of CRC patients, and the risk of death in patients with low expression of miR-145 is 1.92 times that of patients with a high expression of miR-145. Sensitivity analysis results showed that the study of Slattery et al.²¹ (Figure 3(b)) influenced the overall HR.

Figure 3.

The association (a) and sensitivity analysis (b) of miR-145 expression and OS, and the association (c) and sensitivity analysis (d) of miR-145 expression and EFS in patients with colorectal cancer. EFS: event-free survival; OS: overall survival.

The association between miR-145 expression and EFS in CRC

Of four studies,^14,15,20,23 the relationship between miR-145 expression and EFS in CRC tissue in 633 patients was analyzed. The results (Figure 3(c)) showed that I² = 74.0%, P = 0.009, suggesting that each study has high heterogeneity when using the REM to analyze the combined effect of the index. The combined HR was 1.33; 95% CI was 0.67, 2.64; and the difference between low and high expression of miR-145 was not statistically significant (P=0.408). The 95% CI included 1, suggesting that the EFS of patients between low and high expression of miR-145 was not statistically significant. Sensitivity analysis results showed that the studies of Yang et al.¹⁵ and Zhou et al.²³ (Figure 3(d)) influenced the overall HR.

Publication bias

The publication bias of the studies included in this study was evaluated by funnel plots and Egger’s tests. As shown in Figure 4, the funnel plot shows symmetry. Both the Begg’s test and the Egger’s test were used in this meta-analysis, which were more than 0.1, suggesting no publication bias existed among the included studies (in Supplementary Table 2: The P value of Begg’s test and Egger’s test). The test results showed that there was no publication bias in this study.

Figure 4.

Funnel plots of studies included in the meta-analysis: (a) miR-143 OS; (b) histological miR-143 EFS; (c) miR-145 OS; (d) miR-143 EFS. EFS: event-free survival; OS: overall survival.

Discussion

CRC is a common malignancy of the digestive system, and its morbidity and mortality have increased in recent years. Overall, the prognosis of patients with CRC is poor; however, there is evidence that reducing CRC mortality can be achieved through its early detection and treatment.³¹ Thus, early detection and treatment is a promising treatment strategy.

miRNAs are endogenous 22-nt RNAs that can play impor-tant regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression. Although they have gone relatively unnoticed until recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence many protein-coding genes.³² The understanding of miRNA and its association with tumorigenesis has gradually deepened, making it possible for miRNA to become a marker for tumor diagnosis and a new therapeutic target.³³ Abnormally expressed miRNAs and specific miRNAs in tumors have been found to play crucial roles in cell growth, progression, invasion, and tumor progression.³⁴ Compared to protein and mRNA, miRNAs are more stable and more slowly degraded, making them stable markers in serum and even in formalin-fixed and paraffin-embedded tissues.³⁵ Therefore, miRNAs have attracted great attention as novel biomarkers for the diagnosis and prognosis of cancer.

Human miR-143 and miR-145, like other miRNAs, do not encode proteins and do not contain an open reading frame. Both miR-143 and miR-145 are located near each other on chromosome 5 of humans. miR-143 and miR-145 have precursors of stem-loop structure and can be processed to form miR-143-3p (21 nt, miRbase accession number: MIMAT0000435) or miR-143-5p (22 nt, miR-base Accession Nos: MIMAT0004599), depending on the site of cleavage, and miR-145-3p (22 nt, miR-base accession number: MIMAT0004601) or miR-145-5p (23 nt, miR-base accession number: MIMAT0000437), respectively. The function of miRNAs mainly depends on their complete/incomplete complementarity with the 3′-untranslational region of the target gene, so identifying the target genes of a miRNA is key to gaining insight into its function. At present, there have been several identified miR-143 and miR-145 target genes, including KRAS and others. miR-143 can exert negative regulation through binding with the KRAS 3′UTR. Overexpression of miR-143 in CRC Lovo cells can reduce KRAS protein expression and inhibit cell proliferation, while low expression of miR-143 can enhance expression of KRAS and promote cell proliferation.^36,37 miR-143 also inhibits the growth of CRC cells 228 and SW480 through another target gene, DNA methyltransferase 3A (DNMT3A). Animal experiments confirmed that overexpression of miR-143 can reduce the tumor growth, the NF-кB activity, the cell proliferation index, and the Bcl-2 and extracellular signal-regulated protein kinases 5 (ERK5) expression levels, and can increase the Caspase3 activity, the PARP cleavage ability, and the number of apoptotic cells.³⁸ Many studies from different laboratories, such as those by Michael et al.¹⁰ and Kulda et al.,²⁸ have resulted in contradictory conclusions. This was likely due to different experimental methods used by the researchers, the small sample size, and the failure to exclude genetic differences between different ethnic groups.¹⁰

In this study, by expanding the sample size, we found no significant difference between low and high expression of miR-143 in terms of the effect on OS. However, low expression of miR-145 was significantly associated with the OS of patients, suggesting a role of low miR-145 expression in predicting poor prognosis, but there was no statistical significance of miR-145 for EFS. This may be due to factors such as the studies’ unclear descriptions of sample location, tumor size and stage, and small sample size. It is expected that future studies can clarify these factors to better understand the role of miR-143 and miR-145 in the prognosis of colon cancer.

This meta-analysis still has some limitations. First, although the REM was used in some studies, the heterogeneity of the studies was not completely eliminated, which may lead to bias in the results to some extent. Second, due to the lack of direct HR and 95% CI data, we only used the Engauge software to extract data indirectly, which may lead to minor errors in HR and 95% CI. Third, the lack of rich miR-143/145 expression data in the global population made it difficult to set standard cutoff values for measuring expression levels, and there was no consensus on the classification between studies. In addition, other parameters that may partially lead to heterogeneity, such as pathological grade and body mass index, were not explored. Despite these limitations, this comprehensive meta-analysis suggests that miR-143/145 is associated with poor survival in CRC patients, which should have valuable implications. Further large-scale, well-designed and multicenter prospective studies need be performed to confirm these findings before using miR-145 as a biomarker to predict survival outcomes for CRC. Additionally, the prognostic value of the combination of miR-143 and miR-145 should be studied.

Conclusion

miR-143 and miR-145 have promising prognostic value in the treatment of CRC. Low expression of miR-143 predicts high EFS, and low expression of miR-145 predicts poor OS.

Supplemental Material

Supplement_materials – Supplemental material for Prognostic roles of microRNA 143 and microRNA 145 in colorectal cancer: A meta-analysis

Supplemental material, Supplement_materials for Prognostic roles of microRNA 143 and microRNA 145 in colorectal cancer: A meta-analysis by Chenyao Li, Guoqiang Yan, Libin Yin, Tao Liu, Chao Li and Lei Wang in The International Journal of Biological Markers

Footnotes

Author contributions

All authors were involved in the research conception and design, the analysis of data, and the drafting of the article. LC and WL accept full responsibility for the work. All authors were involved in publication decisions.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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