review article long noncoding rna h19 in digestive...

Review ArticleLong Noncoding RNA H19 in Digestive System Cancers:A Meta-Analysis of Its Association with Pathological Features

Yang Lin,1 Lijian Xu,1 Wei Wei,1 Xiaohui Zhang,1 and Rongchao Ying2

1Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China2Department of Gastroenterological Surgery, Hangzhou First People’s Hospital, School of Clinical Medicine,Nanjing Medical University, Hangzhou 310006, China

Correspondence should be addressed to Lijian Xu; [email protected] and Wei Wei; [email protected]

Received 23 June 2016; Accepted 17 August 2016

Academic Editor: Xin-yuan Guan

Copyright © 2016 Yang Lin et al.This is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Long noncoding RNA (lncRNA) H19 has been reported to be upregulated in malignant digestive tumors, but its clinical relevanceis not yet established. The meta-analysis was to investigate the association between H19 expression and pathological features ofdigestive system cancers. The databases of PubMed, EMBase, Web of Science, CNKI, and WanFang were searched for the relatedstudies. A total of 478 patients from 6 studies were finally included. The meta-analysis showed that the patient group of high H19expression had a higher risk of poorly differentiated grade, deep tumor invasion (T2 stage or more), lymph node metastasis, andadvanced TNM stage than the group of low H19 expression, although there was no difference between them in terms of distantmetastasis.Therefore, the high expression of lncRNAH19might predict poor oncological outcomes of patients with digestive systemcancers.

1. Introduction

The digestive system consists of the gastrointestinal tract(the esophagus, stomach, intestine, and colorectum) plus theaccessory organs of digestion (the pancreas, liver, and gall-bladder). The high morbidity and mortality rate of digestivesystem cancers remain a critical health problem worldwide[1]. Early-stage digestive system cancers have a significantlyhigher survival rate than advanced cancers, in which tumorinvasion and metastasis are common pathological features ofpoor prognosis. Molecular analyses of cancer cells in variousstages of progression have revealed that genetic alterationsaccumulate during tumor progression and correlate with theclinical aggressiveness of cancer. In recent years, a numberof studies have found that long noncoding RNAs (lncRNAs),which refer to a class of RNA transcripts of greater than 200nucleotides without protein-coding function [2], are closelyrelated to tumor progression [3]. Their possible mechanismof action involves regulation of tumor suppressor genes andoncogenes on multiple levels [4], including transcriptionand posttranscription modification. lncRNA H19, imprintedmaternally expressed transcript H19, is localized in 11p15.5

and encodes a noncoding RNA of 2.3 kb [5]. Previous studieshave shown that lncRNA H19 is upregulated and related tothe cell proliferation and migration in a variety of cancers,including breast cancer [6], bladder cancer [7], pancreaticcancer [8], gallbladder cancer [9], and glioma [10]. To validateits clinical relevance as a biomarker or therapeutic target, it isnecessary to investigate whether lncRNA H19 expression isassociated with pathological features. The current study wasto conduct a systematic review and quantitativemeta-analysisof this association in digestive system cancers.

2. Methods

2.1. Literature Search Strategies. The databases of PubMed,EMBase,Web of Science, CNKI, andWanFang were searchedfrom their establishment to June 15, 2016, for the relatedstudies in Chinese or English, which reported the associationbetween lncRNA H19 expression and pathological featuresin digestive system cancers. The literature search strategyinvolved a combination of keywords (“long non-codingRNA or lncRNA”, “H19”, “cancer or carcinoma or tumor

Hindawi Publishing CorporationBioMed Research InternationalVolume 2016, Article ID 4863609, 8 pageshttp://dx.doi.org/10.1155/2016/4863609

2 BioMed Research International

Table 1: Characteristics of the included studies.

Authors Year Country Cancer type Total number H19 expression Cut-off (high/low) Detection method Quality scoreHigh Low

Zhang et al. [11] 2014 China GC 80 40 40 Mean RT-qPCR 7Huang et al. [12] 2015 China EC 133 66 67 Median RT-qPCR 8Chen et al. [13] 2016 China GC 128 64 64 Median RT-qPCR 8Wang et al. [14] 2016 China GBC 24 13 11 Median RT-qPCR 6You et al. [15] 2014 China GC 30 15 15 Median RT-qPCR 6Han et al. [16] 2016 China CRC 83 48 35 Fold change RT-qPCR 7GC: gastric cancer; EC: esophageal cancer; GBC: gallbladder cancer; CRC: colorectal cancer; RT-qPCR: real-time quantitative PCR.

or neoplasm”, and “pathology”). Besides, the references ofobtained literature were also traced to identify additionalrelevant studies.

2.2. Inclusion and Exclusion Criteria. The collected studieswere considered eligible if they met the following criteria:(1) the expression of lncRNA H19 was detected in digestivesystem cancers; (2) the study provided at least one of follow-ing pathological features: histological grade, tumor invasiondepth, lymph node metastasis, and distant metastasis; (3) itshould be a case-control or cohort study; (4) the method ofdetecting lncRNA H19 was restricted to reverse transcrip-tion polymerase chain reaction (RT-PCR) with or withoutsequencing of PCR products. Exclusion criteria were asfollows: (1) reviews, case reports,meta-analysis, and duplicatepublications (only the most recent or high quality studieswere included); (2) the studies with inaccurate description ofpathological features or with description not for all patients;(3) the studies focusing on the molecular structure andfunction of lncRNA H19.

2.3. Literature Screening and Data Extraction. Two inves-tigators (Yang Lin and Wei Wei) independently collectedthe data, according to the inclusion and exclusion criteria,with disagreement resolved by consensus or by discussionwith a third investigator (Xiaohui Zhang) before analysisoccurred. Data extraction of literature was as follows: firstauthor, publication date, country of origin, cancer type, totalnumber of patients, number of patients in high and low H19expression groups, the detection method, and the cut-offestimates for H19 levels.

2.4. Quality Assessment. The quality of included studies wasevaluated by using Newcastle-Ottawa Scale standard [17],which included selection (4 points), comparability (2 points),and outcome (3 points) with a score range of 0–9. Two inves-tigators (Yang Lin and Wei Wei) independently evaluatedeach article with disagreement resolved by consensus or bydiscussion with a third investigator (Xiaohui Zhang). Alleligible studies were scored in Table 1, with a higher scoreindicative of better methodological quality.

2.5. Statistical Analysis. Odds ratios (ORs) with 95% confi-dence intervals (CIs) were estimated to evaluate the associ-ation between lncRNA H19 expression and the pathological

features in digestive system cancers. Statistical analysis wasperformed using Stata statistical software version 12.0 (StataCorporation, College Station, Texas, USA). Chi-square-based𝑄 and 𝐼2 tests were used to determine the heterogeneityamong the included studies. If the𝑃 valuewas greater than 0.1and the 𝐼2-value was less than 50%, the heterogeneity amongstudies did not reach statistical significance, and the fixed-effectsmodel was subsequently implemented. Conversely, therandom-effects model was applied for the analysis. Subgroupanalysis and sensitivity analysis were used to determine thesources of heterogeneity. The publication bias was assessedusing Begg’s funnel plot, and a 𝑃 value less than 0.05 wasconsidered as the presence of publication bias.

3. Results

3.1. Data Selection and Characteristics. Six studies involvinga total of 478 patients met the inclusion criteria. All studiescame from China, in which three studies concentrated ongastric cancer, and the others involved esophageal cancer, col-orectal cancer, and gallbladder cancer. RT-PCR was appliedin detection of lncRNA H19, according to which the patientswere categorized into the groups of high and low H19expression.The cut-off estimates for H19 expression were themean,median, or fold change (high expression group: greaterthan a 3-fold increase; low expression group: no more thana 3-fold increase). The flow chart of the study search andselection was showed in Figure 1. The characteristics of theincluded studies were summarized in Table 1.

3.2. Association between lncRNA H19 Expression andPathological Features

3.2.1. Histological Grade. A total of five studies reported theassociation between lncRNAH19 expression and histologicalgrade. The heterogeneity among studies was not statisticallysignificant (𝑃 = 0.855, 𝐼2 = 0.0%), so the fixed-effects modelwas applied to calculate the pooled OR and its 95% CI, whichwas significantly different [OR = 2.33, 95% CI (1.49, 3.64),and 𝑃 < 0.001] (Figure 2). It revealed that the group ofhighH19 expression had a higher risk of poorly differentiatedgrade than those of low H19 expression.

3.2.2. Tumor Invasion Depth (T). A total of four studies re-ported the association between lncRNA H19 expression and

BioMed Research International 3

Articles after duplicates

Studies remaining afterreading title and abstract

Eligibility of full-text articles

Studies included in this

Not dividing patients intothe high and low H19expression groups (n = 14)

Insufficient related dataReview articlesMeta-analysis

Excluded studies (n = 24):

meta-analysis (n = 6)

assessed (n = 20)

(n = 44)

removed (n = 165)

Publications identifiedthrough described databasesearch (n = 195)

Figure 1: Flow chart of the study search and selection.

GC

You et al. (2014)

Chen et al. (2016)

GBC

Wang et al. (2016)

Han et al. (2016)

Zhang et al. (2014)

CRC

81/165

60/119

5/11

16/35

8/15

27/64

5/11

16/35

25/40

2.33 (1.49, 3.64)

2.00 (1.17, 3.41)

2.70 (0.51, 14.37)

3.56 (1.40, 9.05)

1.75 (0.40, 7.66)

1.88 (0.93, 3.79)

2.70 (0.51, 14.37)

3.56 (1.40, 9.05)

2.40 (0.88, 6.56)

124/180

79/119

9/13

36/48

10/15

37/64

9/13

36/48

32/40

10.0696 1 14.4

Study IDcontrolEvents,Events,

100.00

75.18

6.57

18.25

10.52

44.93

6.57

18.25

19.72

% weightOR (95% CI)treatment

Subtotal (I2 = .%, P = .)


Subtotal (I2 = 0.0%, P = 0.910)

Overall (I2 = 0.0%, P = 0.855)

Figure 2: Forest plot for the association between lncRNA H19 expression and histological grade in digestive system cancers.

tumor invasion depth. The heterogeneity among studies wasnot statistically significant (𝑃 = 0.172, 𝐼2 = 40.0%), so thefixed-effects model was applied to calculate the pooled ORand its 95% CI, which was significantly different [OR = 4.51,95% CI (2.65, 7.76), and 𝑃 < 0.001] (Figure 3). It suggestedthat the group of high H19 expression had a higher risk ofdeep tumor invasion (T2 stage or more) than those of lowH19 expression.

3.2.3. Lymph NodeMetastasis. A total of five studies reportedthe association between lncRNA H19 expression and lymphnode metastasis. There was moderate heterogeneity amongstudies (𝑃 = 0.011, 𝐼2 = 69.3%), so the random-effectsmodel was applied to calculate the pooled OR and its95% CI, which reached significant difference [OR = 2.92,95% CI (1.20, 7.13), and 𝑃 = 0.018] (Figure 4(a)). Mean-while, a subgroup analysis was performed by cancer types.


Zhang et al. (2014)

EC

Chen et al. (2016)

You et al. (2014)

GC

Huang et al. (2015)

106/185

80/119

32/40

26/66

40/64

8/15

26/66

100.00

29.32

2.87

70.68

22.60

3.86

70.68

4.51 (2.65, 7.67)

9.14 (3.73, 22.37)

21.18 (1.18, 380.90)

2.58 (1.28, 5.20)

7.08 (2.49, 20.11)

12.25 (1.27, 118.36)

2.58 (1.28, 5.20)

155/186

113/119

40/40

42/67

59/64

14/15

42/67

10.00263 1 381

Study IDcontrolEvents,Events, % weightOR (95% CI)

treatment


Subtotal (I2 = 0.0%, P = 0.734)

Overall (I2 = 40.0%, P = 0.172)

Figure 3: Forest plot for the association between lncRNA H19 expression and tumor invasion depth in digestive system cancers.

One study by Han et al. [16] was omitted to measure itseffect on the pooled OR. The heterogeneity among the fourremaining studies was not statistically significant (𝑃 =0.181, 𝐼2 = 38.5%), so the fixed-effects model was appliedto calculate the pooled OR and its 95% CI, which wassignificantly different [OR=3.99, 95%CI (2.01, 5.61), and𝑃 <0.001] (Figure 4(b)). It demonstrated that the group of highH19 expression had a higher risk of lymph node metastasisthan those of low H19 expression.

3.2.4. Distant Metastasis. There were only two studies thatreported the association between lncRNAH19 expression anddistant metastasis. The heterogeneity among studies was notstatistically significant (𝑃 = 0.311, 𝐼2 = 2.6%), so the fixed-effects model was applied to calculate the pooled OR and its95%CI,which did not reach significant difference [OR=0.64,95% CI (0.28, 1.44), and 𝑃 = 0.276] (Figure 5). It suggestedthat H19 expression levels were not correlated with distantmetastasis.

3.2.5. TNM Stage. There were five studies that reported theassociation between lncRNA H19 expression and TNM stage(III/IV versus I/II). The heterogeneity among studies was notstatistically significant (𝑃 = 0.618, 𝐼2 = 0.0%), so the fixed-effects model was applied to calculate the pooled OR andits 95% CI, which reached significant difference [OR = 4.48,95% CI (2.83, 7.11), and 𝑃 < 0.001] (Figure 6). It suggestedthat high H19 expression was linked with advanced TNMstage.

3.3. Assessment of Sensitivity Analysis. Sensitivity analysiswas performed to assess the effect of individual study on

the pooled ORs for the association between H19 expressionand lymph node metastasis (Figure 7). The main source ofheterogeneity was the work by Han et al. [16]. When theirstudy was excluded, the analytical result was not significantlyaltered. Similarly, sensitivity analysis was applied in inves-tigation of other pathological features. As each study wasomitted sequentially, the analytical results had not yet beensignificantly altered.

3.4. Assessment of Publication Bias. Begg’s funnel plot wasperformed to assess publication bias in the study. There wasno significant publication bias in analysis of histological grade(𝑃 = 0.772), lymph node metastasis (𝑃 = 0.226), and TNMstage (𝑃 = 0.331). Due to the small number of studies,publication bias was not analyzed in tumor invasion depthand distant metastasis.

4. Discussion

lncRNAs have been reported to play significant roles incarcinogenesis and progression of malignant tumors [15, 16,18, 19]. Comparative analysis of lncRNA expression profilesbetween cancerous tissues of different stages has revealedthat some lncRNAs are differentially expressed in associ-ation with the metastatic potential of cancer cells. Theyhave been also identified as having functions of inducingor suppressing metastasis in experimental models, amongwhichH19 is closely related to progression of digestive systemcancers. High expression of H19 promoted the proliferationand invasion of esophageal cancer cell lines, whereas theopposing effects were observed by H19 knockdown [12]. Incolorectal cancer, H19 acted as miRNA sponges to restore


Note: weights are fromrandom-effects analysis

Zhang et al. (2014)Chen et al. (2016)

Wang et al. (2016)

You et al. (2014)

Han et al. (2016)CRC

GC

GBC

69/165

18/4024/64

20/35

2/11

2/11

47/1195/15

20/35

2.92 (1.20, 7.13)

4.89 (1.81, 13.21)2.01 (0.99, 4.07)

0.75 (0.31, 1.80)

10.13 (1.47, 69.93)

10.13 (1.47, 69.93)

3.49 (1.58, 7.69)8.00 (1.52, 42.04)

0.75 (0.31, 1.80)

112/180

32/4035/64

24/48

9/13

9/13

79/11912/15

24/48

10.0143 1 69.9


100.00

22.4426.04

23.92

12.63

12.63

63.4514.97

23.92




Overall (I2 = 69.3%, P = 0.011)

Subtotal (I2 = 42.8%, P = 0.174)

(a)

Zhang et al. (2014)

Wang et al. (2016)

You et al. (2014)

GBC

Chen et al. (2016)

GC

49/130

18/40

2/11

5/15

2/11

47/119

24/64

100.00

22.30

4.13

6.20

4.13

95.87

67.37

3.36 (2.01, 5.61)

4.89 (1.81, 13.21)

10.13 (1.47, 69.93)

8.00 (1.52, 42.04)

10.13 (1.47, 69.93)

3.07 (1.80, 5.24)

2.01 (0.99, 4.07)

88/132

32/40

9/13

12/15

9/13

79/119

35/64

10.0143 1 69.9

Study IDcontrolEvents,Events, % weightOR (95% CI)

treatment


Overall (I2 = 38.5%, P = 0.181)

Subtotal (I2 = 42.8%, P = 0.174)

(b)

Figure 4: Forest plot for the association between lncRNA H19 expression and lymph node metastasis in digestive system cancers with (a)and without (b) including the work by Han et al.

activation of multiple oncogenes, which promoted epithelial-to-mesenchymal transition (EMT) and were inherently sup-pressed by miR-138 and miR-200a [20]. Furthermore, ele-vated expression ofH19 activatedmiR-194-5p targetingAKT2gene expression by downregulating miR-194-5p and stimu-lated proliferation of gallbladder cancer cells by promoting

cells into S-phase [9]. H19 and its mature product miR-675enhanced the proliferation and invasion of gastric cancerAGS cells by activation of Akt/mTOR pathway, in whichtumor suppressor RUNX1 served as a pivotal mediator [21].The recent studies have indicated that overexpression of H19also promoted EMT progression in EC, GC, GBC, and CRC


GC

Chen et al. (2016)

CRCHan et al. (2016)

21/99

1/64

20/35

1/64

20/35

0.64 (0.28, 1.44)

2.03 (0.18, 22.99)

0.54 (0.22, 1.29)

2.03 (0.18, 22.99)

0.54 (0.22, 1.29)

22/112

2/64

20/48

2/64

20/48

10.0435 1 23


100.00

6.70

93.30

6.70

93.30




Overall (I2 = 2.6%, P = 0.311)

Figure 5: Forest plot for the association between lncRNA H19 expression and distant metastasis in digestive system cancers.

Han et al. (2016)

GBC

Zhang et al. (2014)

CRC

Chen et al. (2016)

GC

Wang et al. (2016)

You et al. (2014)

Study ID

4.48 (2.83, 7.11)

2.74 (1.11, 6.72)

7.15 (2.65, 19.33)

6.00 (1.02, 35.37)

4.05 (1.87, 8.74)

2.74 (1.11, 6.72)

5.29 (2.99, 9.35)

6.00 (1.02, 35.37)

8.00 (1.52, 42.04)

117/180

31/48

9/13

34/64

31/48

77/119

9/13

12/15

49/165

14/35

14/35

control

13/40

3/11

14/64

32/119

3/11

5/15

Events,Events,

100.00

33.30

% weight

16.98

5.81

38.10

33.30

60.89

5.81

5.81

OR (95% CI)treatment

31/40

10.0238 1 42

Subtotal (I2 = 0.0%, P = 0.589)



Overall (I2 = 0.0%, P = 0.618)

Figure 6: Forest plot for the association between lncRNA H19 expression and TNM stage in digestive system cancers.

[12–14, 20] in vitro, which suggested that lncRNA H19 mightplay an important role in invasiveness and metastasis, as abiomarker for prognosis of digestive system cancers.

The current meta-analysis was to investigate the asso-ciation between lncRNA H19 expression and pathologicalfeatures in digestive system cancers. A total of 478 patientsfrom 6 studies were finally enrolled. The fixed-effects model

was applied for histological grade, tumor invasion depth,distant metastasis, and TNM stage. Since there was moderateheterogeneity among the studies in terms of lymph nodemetastasis (𝑃 = 0.011, 𝐼2 = 69.3%), the random-effectsmodel was used to pool data. As a result, the group of highH19 expression had a higher risk of poorly differentiatedgrade, deep tumor invasion, lymph node metastasis, and


Zhang et al. (2014)

Chen et al. (2016)

Wang et al. (2016)

You et al. (2014)

Han et al. (2016)

Lower CI limit Estimate Upper CI limit

Meta-analysis estimates, given that named study is omitted

1.48

2.27

3.49

5.61

1.16

Figure 7: Sensitivity analysis of the included studies for the association between lncRNA H19 expression and lymph node metastasis.

advanced TNM stage than those of low H19 expression,although there was no significant difference in terms ofdistant metastasis (𝑃 = 0.276).

Then the subgroup analysis and sensitivity analysis wereperformed to investigate whether the heterogeneity of datatook effect on interpretation of the analytic results. Conse-quently, the work by Han et al. [16] was the main source ofheterogeneity among the studies of lymph node metastasis,and it was therefore omitted to assess its effect on the pooledOR. The heterogeneity among the rest of the studies was notstatistically significant (𝑃 = 0.181, 𝐼2 = 38.5%), and theresult was not significantly altered. Besides, the assessmentof publication bias did not reach statistical significance (𝑃 =0.226).

However, there were some limitations in the study: (1)all of the studies came from China and did not includethe patients of other countries; (2) the number of patientsenrolled in some studies was relatively small, and not allcancer types of digestive system were under investigation; (3)there was no consensus on the cut-off estimates for differ-entiating high or low H19 expression; (4) no cohort studiesmet the inclusion criteria and were included. High qualityand large sample-size studies are guaranteed to confirm theinvestigation outcomes.

In summary, the high expression of lncRNA H19 waslinked with poorly differentiated grade, deep tumor invasion,and lymph node metastasis, suggesting it as a biomarker ofpoor prognosis for patients with digestive system cancers.

Competing Interests

The authors have no competing interests to declare.

Acknowledgments

The work is sponsored by Health Scientific Research Projectof Jiangsu Province (no. H201409) and Project of MedicineandHealth Science andTechnology of Zhejiang Province (no.2014KYB192).

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