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Long noncoding RNA activated by TGF-β in human cancers: A meta-analysis
Clinica Chimica Acta 468 (2017) 10–16
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Long noncoding RNA activated by TGF-β in human cancers: A meta-analysis Yang-Hua Fan 1, Chen-xing Ji 1, Bing Xu, Heng-yi Fan, Zu-jue Cheng ⁎, Xin-Gen Zhu ⁎ Department of Neurosurgery, The Second Affiliated Hospital, Nanchang University, Nanchang, China
a r t i c l e
i n f o
Article history: Received 4 December 2016 Received in revised form 30 January 2017 Accepted 1 February 2017 Available online 3 February 2017 Keywords: LncRNA-ATB Neoplasm Metastasis Prognosis Meta-analysis
a b s t r a c t Background: Because long non-coding RNA ATB (activated by TGF-β) is dysregulated in many cancers, we performed a meta-analysis to determine its prognostic potential in malignant tumors. Methods: We searched electronic databases, including PubMed, Medline, OVID, Cochrane Library and Web of Science from inception until November 15, 2016 and identified eight studies with 818 cancer patients for the metaanalysis. We analyzed the hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the relationship between lncRNA-ATB expression and overall survival (OS), recurrence -free survival (RFS), disease-free survival (DFS). We also use RevMan5.3 software to calculate odds ratio (ORs) to assess the association between lncRNAATB expression and pathological parameters including lymph node metastasis (LNM), distant metastasis (DM) and tumor stage. Results: Our analysis showed that increased lncRNA-ATB expression was associated with OS (HR = 2.82, 95% CI:1.98–4.00, P b 0.00001), DFS (HR = 2.75, 95% CI:1.73–4.38, P b 0.0001), RFS(HR = 3.96, 95% CI:2.30–6.81, P b 0.00001), LNM (OR = 4.07, 95% CI 1.74–9.53, P = 0.001), DM (OR = 3.21, 95% CI 1.06–9.72, P = 0.04) and high tumor stage (OR = 2.81, 95% 1.78–4.43, P b 0.0001) in patients with other types of cancers that excluded pancreatic cancer. Conclusions: Meta-analysis demonstrated that increased lncRNA-ATB expression can be a useful prognostic biomarker in human cancer. © 2017 Elsevier B.V. All rights reserved.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Literature search to identify relevant studies for meta-analysis . . . 2.2. Selection criteria for including studies in meta-analysis . . . . . . 2.3. Data extraction from relevant studies for meta-analysis . . . . . . 2.4. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Literature search analysis results . . . . . . . . . . . . . . . . 3.2. Association between lncRNA-ATB expression and OS . . . . . . . 3.3. Association between lncRNA-ATB expression and DFS, RFS . . . . . 3.4. Association between lncRNA-ATB expression level and metastasis . 3.5. Association between lncRNA-ATB expression levels and tumor stage 3.6. Begg's funnel plot analysis . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: ATB, activated by TGF-β; HR, hazard ratio; CI, confidence interval; OR, odds ratio; CRC, colorectal cancer; NSCLC, non-small cell lung cancer; PRC, pancreatic cancer; GC, gastric cancer; RCC, renal cell carcinoma; PSC, prostate carcinoma; HCC, hepatocellular carcinoma; LNM, lymph node metastasis; DM, distant metastasis; HTS, high tumor stage; OS, overall survival; DFS, disease-free survival; RFS, recurrence -free survival; NOS, Newcastle-Ottawa Scale. ⁎ Corresponding authors at: Department of Neurosurgery, The Second Affiliated Hospital, Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi, People's Republic of China. E-mail addresses: [email protected] (Z. Cheng), [email protected] (X.-G. Zhu). 1 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.cca.2017.02.001 0009-8981/© 2017 Elsevier B.V. All rights reserved.
Y.-H. Fan et al. / Clinica Chimica Acta 468 (2017) 10–16
6. Conclusions . Disclosures . . . . Acknowledgments References . . . .
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1. Introduction In 2012, 8.2 and 14.1 million people died from and were diagnosed with cancer worldwide, respectively [1]. The American National Center for Health Statistics estimated that nearly 600,000 Americans will die from cancer in 2016 [2]. The five year survival rate of most cancers is extremely low and since survival depends on early diagnosis of cancer, there is a constant need to identify and develop better diagnostic and prognostic markers. Long noncoding RNA (lncRNA) are transcribed RNA molecules are N200 nucleotides in length that lack an open reading frame [3]. They are involved in epigenetic regulation, transcriptional and posttranscriptional regulation, ie, key cellular processes that determine tumorigenesis [4]. Dysregulation of lncRNAs has been reported in many types of cancers [5–8]. Because they have been implicated in different stages of cancer progression including proliferation, invasion and metastasis, they appear to be promising prognostic markers [9–11]. LncRNA-ATB (activated by TGF-β) was first reported as highly expressed in hepatocellular carcinoma and showed extensive regulatory functions. This lncRNA, located on chromosome 14, induces epithelial-mesenchymal transition (EMT) and promotes hepatocellular carcinoma cell invasion through the TGF-b/miR-200 s/ZEB signaling pathway [12–13]. Because lncRNA-ATB expression is involved in cancer growth and metastasis, it is a promising prognostic biomarker candidate for human cancer [14]. Unfortunately, most studies regarding lncRNA-ATB are limited by discrete outcomes and small patient sample. Therefore, we performed this meta-analysis to determine the prognostic value of lncRNA-ATB by combined analysis of data from multiple studies. 2. Methods 2.1. Literature search to identify relevant studies for meta-analysis A systematic search of multiple electronic databases, Medline, Pubmed, OVID, and Web of Science, was performed independently by two authors, Yanghua Fan and Hua Fang in accordance with the standard guidelines of meta-analysis. Literature was searched from inception until November 15, 2016 for articles that reported lncRNA-ATB as a probable prognostic marker for survival of cancer patients [15–16]. Searches were performed by both the text word and MeSH strategy and included terms like ‘lncRNA-ATB’, ‘long noncoding RNA activated by TGF-β’, ‘ATB or activated by TGF-β’, ‘lncRNA’, ‘noncoding RNA’, ‘long intergenic noncoding RNA’, ‘carcinoma’, ‘neoplasm’, ‘tumor’, ‘cancer’, ‘prognostic’, ‘prognosis’, ‘outcome’, ‘survival’ or ‘recurrence’. The strategy was adjusted in different databases to maximize search findings. Manual searches were also performed using the reference lists of the relevant articles to retrieve eligible studies for inclusion. 2.2. Selection criteria for including studies in meta-analysis The two researchers, Yanghua Fan and Chen-xing Ji, independently evaluated all data to select relevant studies for meta-analysis. The criteria used to include studies in the meta-analysis were: 1) the relationship between lncRNA-ATB expression and survival was measured in multiple human tumors; 2) the expression level of lncRNA-ATB was measured either in human tumor tissue and the patients were grouped according to lncRNA-ATB expression; and 3) all tumors were confirmed
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by pathologic or histologic exam with pathologic parameters such as LNM and tumor stage described. The criteria to exclude studies were: 1) articles that were reviews, letters, editorials, case reports and expert opinions; 2) non-English language and non-human studies; 3) studies lacking data listed in the criteria for included studies; and 4) basic characterization studies of lncRNA-ATB. 2.3. Data extraction from relevant studies for meta-analysis The two reviewers, Yanghua Fan and Zu-jue Cheng, independently extracted and examined the data from the selected original articles. Disagreements in assessment were resolved through consensus with a third reviewer, Xingen Zhu. The following details were collected from each of the study: surname of the first author, publication year, country, tumor type, sample size, the number of patients with lymph node metastasis and high tumor stage, HR and 95% CI of elevated lncRNA-ATB for survival(OS, DFS, RFS), the Newcastle-Ottawa Scale (NOS) score and the detection method of lncRNA-ATB. The study quality was assessed in accordance with the NewcastleOttawa Scale (NOS). A total of nine items, each of which was assigned a score of 1, were measured in each study. The total scores for different studies ranged from 0 to 9. If the score was ≥7, the study was considered to be of high quality. 2.4. Statistical analysis The statistical analysis was performed by RevMan version 5.3 software. The heterogeneity among different studies was measured by the Q and I2 tests. A probability value of I2 ≥ 50% and P b 0.1 indicated the existence of significant heterogeneity [17]. A random effects model or fixed effects model was selected based on the results of heterogeneity analysis. The random-effects model was used if there was significant heterogeneity among the studies or else, the fixed effects model was used. The potential publication bias was assessed by the Begg's funnel plot through Stata 12.0 software. Pooled HRs and ORs were obtained from the published data. We used the HRs and 95% CIs reported in a publication when it was available and when they were not reported, the HR values were estimated from the survival information obtained from Kaplan-Meier curve. OS, DFS, RFS were calculated using the log HR and standard error (SE) values [18]. Odds ratios (ORs) and their 95% CIs were used to assess the association between lncRNA-ATB expression and the tumor parameters, including LNM, DM and tumor stage. 3. Results 3.1. Literature search analysis results The detailed screening process of lncRNA-ATB studies is shown in Fig. 1. A total of 34 records were retrieved from the databases in initial search and 19 duplicate reports were excluded. After detailed screening of the title and abstract, seven irrelevant and non-comparative articles [13,26–31] were excluded. After reviewing the full text of the remaining 9 studies, the article [14] by Ma et al. was excluded because of insufficient data to estimate HR for further analysis. Based on the inclusion and exclusion criteria, a total of eight studies and 818 patients were included in the meta-analysis [12,19–25].
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Fig. 1. Flowchart showing the steps of literature search and selection criteria for the meta-analysis.
The diagnosis of LNM and tumor stage depended on the pathology. The NOS scores of all the studies were ≥7.
The characteristics of the eight studies are summarized (Table 1). The total number of subjects analyzed in the eight studies ranged from 57 to 183, with a mean sample size of 102.25. Six of the eight studies were conducted in China whereas two studies were from Japan and were published between 2014 and 2016. Among the eight studies, two focused on colorectal cancer [19,25], and one each on non-small cell lung cancer [20], pancreatic cancer [21], gastric cancer [22], renal cell carcinoma [23], prostate carcinoma [24] and hepatocellular carcinoma [12]. LncRNA-ATB expression was measured in the tumor specimen.
3.2. Association between lncRNA-ATB expression and OS We performed cumulative meta-analysis to determine the role of lncRNA-ATB in overall survival (OS) of all 563 cancer patients from the five studies [12,20–22,25]. The random effects model was adopted because of the significant heterogeneity between studies (I2 = 89%,
Table 1 The basic information and data of all included studies in the meta-analysis. Study
Year
Region
Tumor type
Sample size
lncRNA-ATB expression High
Survival Analysis
Method
HR(95% CI)
NOS
Method
DFS OS OS OS – RFS OS RFS OS DFS
Multivariate Multivariate Multivariate Multivariate – Multivariate Multivariate
2.04(1.047–3.86) 2.22(1.14–4.35) 0.597(0.416–0.857) 3.50(1.73–7.44) – 5.74(2.313–14.249) 2.70(1.373–5.310) 3.23(1.64–6.33) 3.16(2.03–8.87) 3.74(2.51–9.38)
8 7 8 8 7 7 7
qRT-PCR qRT-PCR qRT-PCR qRT-PCR qRT-PCR qRT-PCR qRT-PCR
7
qRT-PCR
Low
Total
LNM
HTS
Total
LNM
HTS
Iguchi [19] Ke [20] Qu [21] Saito [22] Xiong [23] Xu [24] Yuan [12]
2015 2016 2015 2015 2016 2016 2014
Japan China China Japan China China China
CRC NSCLC PRC GC RCC PSC HCC
124 84 150 183 74 57 86
62 46 75 105 38 25 43
28 34 32 73 12 7 –
28 28 33 – 20 14 –
62 38 75 78 36 32 43
16 7 49 46 3 1 –
16 15 49 – 10 6 –
Yue [25]
2015
China
CRC
60
37
–
–
23
–
–
Multivariate
Note: The dashes represent no data. Abbreviations: CRC, colorectal cancer; NSCLC, non-small cell lung cancer; PRC, pancreatic cancer; GC, gastric cancer; RCC, renal cell carcinoma; PSC, prostate carcinoma; HCC, hepatocellular carcinoma; LNM, lymph node metastasis; HTS, high tumor stage; OS, overall survival; DFS, disease-free survival; RFS, recurrence -free survival.
Y.-H. Fan et al. / Clinica Chimica Acta 468 (2017) 10–16
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Fig. 2. Forest plot showing association between OS and elevated lncRNA-ATB expression in the different types of cancer.
PQ b 0.00001). Reflecting the presence of heterogeneity, we performed a sensitivity analysis. After excluding the Qu study [21], the observed heterogeneity disappeared (I2 = 0%, PQ = 0.82). The subgroup analysis showed that high levels of lncRNA-ATB were significantly correlated with a poorer OS for patients with other types of cancer that excluded PRC (HR = 2.82, 95% CI: 1.98–4.00, P b 0.00001; Fig. 2). Therefore, our data demonstrated that lncRNA-ATB was an independent OS factor
among cancer patients and its high expression was associated with shorter OS. 3.3. Association between lncRNA-ATB expression and DFS, RFS We performed cumulative meta-analysis to determine the role of lncRNA-ATB in disease-free survival (DFS) of 184 cancer patients [19,
Fig. 3. Forest plot showing association between DFS, RFS and elevated lncRNA-ATB expression in the different types of cancer.
Fig. 4. Forest plot showing association between lncRNA-ATB expression levels and lymph node metastasis.
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Fig. 5. Forest plot showing association between lncRNA-ATB expression levels and distant metastasis.
25] and recurrence-free survival (RFS) of 143 cancer patients [12,24] from the eligible studies (Fig. 3). Statistical analyses revealed that lncRNA-ATB was associated with DFS (pooled HR = 2.75, 95% CI: 1.73–4.38, P b 0.0001), RFS (pooled HR = 3.96, 95% CI: 2.30–6.81, P b 0.00001) of cancer patients. Our analyses did not find any significant heterogeneity among the studies. Therefore, our data demonstrated that lncRNA-ATB was an independent DFS, RFS factor among cancer patients and its high expression was associated with shorter DFS, RFS.
3.4. Association between lncRNA-ATB expression level and metastasis We performed cumulative meta-analysis to determine the role of lncRNA-ATB in LNM of 672 cancer patients [19–24] and DM of 491 cancer patients [20–23] from the eligible studies. The random effects model was used for significant heterogeneity. Meta-regression analysis and subgroup analysis were performed to explore the sources of heterogeneity. The subgroup analysis showed that increased lncRNA-ATB was significantly correlated with LNM (OR = 4.07, 95% CI 1.74–9.53, P = 0.001; Fig. 4) and DM (OR = 3.21, 95% CI 1.06–9.72, P = 0.04; Fig. 5) for patients with other types of cancer that excluded PRC. Our analysis demonstrated significant differences in the LNM and DM incidence
between the two groups, patients with higher expression of lncRNAATB were more prone to developing LNM and DM.
3.5. Association between lncRNA-ATB expression levels and tumor stage A total of 489 patients from five eligible studies [19–21,23–24] were analyzed for the relationship between the lncRNA-ATB expression levels and the tumor stage in this meta-analysis. Our data demonstrated that increased lncRNA-ATB expression was associated with higher tumor grade with a pooled OR of 2.81(95% CI: 1.78– 4.43, P b 0.00001; Fig. 6) for patients with other types of cancer that excluded PRC. Therefore, our results demonstrated that higher expression of lncRNA-ATB significantly increased risk of higher tumor stage.
3.6. Begg's funnel plot analysis We did not find any obvious asymmetry for either survival(DFS,RFS) (Fig. 7) or metastasis (LNM) (Fig. 8) when we used Begg's funnel plot to analyze publication bias. Therefore, our findings were due to a
Fig. 6. Forest plot showing meta-analysis of the role of lncRNA-ATB on tumor stage in the different types of cancer.
Y.-H. Fan et al. / Clinica Chimica Acta 468 (2017) 10–16
Fig. 7. Funnel plot analysis to determine publication bias for the independent role of lncRNA-ATB on DFS and RFS in the different types of cancers.
relationship between lncRNA-ATB expression and the pathological parameters analyzed and not due to publication bias. 4. Discussion Cancer is a major threat to human health worldwide and the incidence of cancer has increased gradually over the years [2]. Most cancers eventually metastasize as lymph node metastasis (LNM). The occurrence of metastasis indicates poor prognosis and hence is an important indicator for survival [32–33]. Moreover, LNM is important for the diagnosis of TNM (tumor–node–metastasis) staging for cancer patients, as well as important indicators for predicting prognosis. Since the precise mechanism on metastasis remains unknown in most cancers, molecular biomarkers play a critical role in the diagnosis, prognosis and treatment of cancer [34–35]. Therefore finding new molecular markers that accurately predict tumor metastasis are of paramount importance. Genome-wide analysis of the mammalian genome has shown that N80% of its transcription is associated with lncRNAs [36]. LncRNA play a central role in the regulation of differentiation, cell development and proliferation [37]. Due to the specific expression of lncRNA in the development of tumor and their presence in body fluids and tumor tissues, they are promising biomarkers to diagnose and monitor tumors [38]. Therefore, identification of tumor related lncRNAs that are vital in tumorigenesis are promising biomarkers for cancer prognosis. In recent years, lncRNA-ATB has been found to be dysregulated in colorectal cancer, gastric cancer, renal cell carcinoma, prostate carcinoma and hepatocellular carcinoma [12–14,19–25]. Zhu and others found that the lncRNA-ATB governs the autocrine secretion of TGF-β2 in
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keloid fibroblasts by downregulating the expression level of ZNF217 via miR-200c [31]. Shi et al. found that lncRNA-ATB could promote breast cancer invasion-metastasis cascade via miR-200c/ZEB1/ZNF217, and the high level of lncRNA-ATB was closely related to trastuzumab resistance of breast cancer patients [30]. LncRNA-ATB is also a molecular target for regulating epithelial-mesenchymal transition (EMT) change, which contributes to cancer progression [22]. LncRNAATB stimulated EMT associated with ZEB1 and ZNF217 expression levels through ERK and PI3K/AKT signaling pathways in prostate carcinoma [24]. These studies revealed that lncRNA-ATB has potential prognostic value in cancer patients. Because the role of lncRNA-ATB as a molecular biomarker in human cancer was unclear, our study explored the prognostic value of lncRNAATB in cancer patients using meta-analysis. A random effects model or fixed effects model was used to analyze the data based on the results of heterogeneity analysis. Our data showed that higher lncRNA-ATB expression was indicative of advanced cancer and highlighted poor prognosis. Because of significant heterogeneity existed, subgroup analysis and sensitivity analysis were conducted according to different cancer types. After excluding the Qu study [21], the observed heterogeneity disappeared, by combining HRs from Cox multivariate analyses, there was a significant difference in OS between high and low lncRNA-ATB expression level groups, and statistical analyses revealed that lncRNA-ATB was associated with LNM, DM, advanced tumor stage of cancers except pancreatic cancer. In addition, we showed that higher lncRNA-ATB expression was associated with DFS (pooled HR = 2.75, 95% CI: 1.73–4.38, P b 0.0001) and RFS (pooled HR = 3.96, 95% CI: 2.30–6.81, P b 0.00001) without obvious heterogeneity in different types of cancer. 5. Limitations There are few limitations that must be taken into account with respect to this meta-analysis. First, most studies were from China. Only two studies were from Japan. As such, our data may lack global extrapolation. Second, included type and number of cancers were small. Third, criterion for high expression varied for different studies. Therefore, well-designed and high-quality studies are clearly needed to confirm these preliminary findings. 6. Conclusions In conclusion, increased lncRNA-ATB expression in most cancers was associated with poor OS, LNM and tumor stage. As such, it represents a promising prognostic marker. Disclosures None. Acknowledgments This article was supported by the National Natural Science Foundation of China (grants No. 81660420); the Youth Science Foundation project of Jiangxi Province (No. 20161BAB215253); the Science and Youth Technology Research Project of Jiangxi Province Education Department (No. GJJ14191). References
Fig. 8. Funnel plot analysis to determine publication bias for the independent role of lncRNA-ATB on LNM in the different types of cancers.
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Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Long noncoding RNA activated by TGF-β in human cancers: A meta-analysis Yang-Hua Fan 1, Chen-xing Ji 1, Bing Xu, Heng-yi Fan, Zu-jue Cheng ⁎, Xin-Gen Zhu ⁎ Department of Neurosurgery, The Second Affiliated Hospital, Nanchang University, Nanchang, China
a r t i c l e
i n f o
Article history: Received 4 December 2016 Received in revised form 30 January 2017 Accepted 1 February 2017 Available online 3 February 2017 Keywords: LncRNA-ATB Neoplasm Metastasis Prognosis Meta-analysis
a b s t r a c t Background: Because long non-coding RNA ATB (activated by TGF-β) is dysregulated in many cancers, we performed a meta-analysis to determine its prognostic potential in malignant tumors. Methods: We searched electronic databases, including PubMed, Medline, OVID, Cochrane Library and Web of Science from inception until November 15, 2016 and identified eight studies with 818 cancer patients for the metaanalysis. We analyzed the hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the relationship between lncRNA-ATB expression and overall survival (OS), recurrence -free survival (RFS), disease-free survival (DFS). We also use RevMan5.3 software to calculate odds ratio (ORs) to assess the association between lncRNAATB expression and pathological parameters including lymph node metastasis (LNM), distant metastasis (DM) and tumor stage. Results: Our analysis showed that increased lncRNA-ATB expression was associated with OS (HR = 2.82, 95% CI:1.98–4.00, P b 0.00001), DFS (HR = 2.75, 95% CI:1.73–4.38, P b 0.0001), RFS(HR = 3.96, 95% CI:2.30–6.81, P b 0.00001), LNM (OR = 4.07, 95% CI 1.74–9.53, P = 0.001), DM (OR = 3.21, 95% CI 1.06–9.72, P = 0.04) and high tumor stage (OR = 2.81, 95% 1.78–4.43, P b 0.0001) in patients with other types of cancers that excluded pancreatic cancer. Conclusions: Meta-analysis demonstrated that increased lncRNA-ATB expression can be a useful prognostic biomarker in human cancer. © 2017 Elsevier B.V. All rights reserved.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Literature search to identify relevant studies for meta-analysis . . . 2.2. Selection criteria for including studies in meta-analysis . . . . . . 2.3. Data extraction from relevant studies for meta-analysis . . . . . . 2.4. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Literature search analysis results . . . . . . . . . . . . . . . . 3.2. Association between lncRNA-ATB expression and OS . . . . . . . 3.3. Association between lncRNA-ATB expression and DFS, RFS . . . . . 3.4. Association between lncRNA-ATB expression level and metastasis . 3.5. Association between lncRNA-ATB expression levels and tumor stage 3.6. Begg's funnel plot analysis . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: ATB, activated by TGF-β; HR, hazard ratio; CI, confidence interval; OR, odds ratio; CRC, colorectal cancer; NSCLC, non-small cell lung cancer; PRC, pancreatic cancer; GC, gastric cancer; RCC, renal cell carcinoma; PSC, prostate carcinoma; HCC, hepatocellular carcinoma; LNM, lymph node metastasis; DM, distant metastasis; HTS, high tumor stage; OS, overall survival; DFS, disease-free survival; RFS, recurrence -free survival; NOS, Newcastle-Ottawa Scale. ⁎ Corresponding authors at: Department of Neurosurgery, The Second Affiliated Hospital, Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi, People's Republic of China. E-mail addresses: [email protected] (Z. Cheng), [email protected] (X.-G. Zhu). 1 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.cca.2017.02.001 0009-8981/© 2017 Elsevier B.V. All rights reserved.
Y.-H. Fan et al. / Clinica Chimica Acta 468 (2017) 10–16
6. Conclusions . Disclosures . . . . Acknowledgments References . . . .
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1. Introduction In 2012, 8.2 and 14.1 million people died from and were diagnosed with cancer worldwide, respectively [1]. The American National Center for Health Statistics estimated that nearly 600,000 Americans will die from cancer in 2016 [2]. The five year survival rate of most cancers is extremely low and since survival depends on early diagnosis of cancer, there is a constant need to identify and develop better diagnostic and prognostic markers. Long noncoding RNA (lncRNA) are transcribed RNA molecules are N200 nucleotides in length that lack an open reading frame [3]. They are involved in epigenetic regulation, transcriptional and posttranscriptional regulation, ie, key cellular processes that determine tumorigenesis [4]. Dysregulation of lncRNAs has been reported in many types of cancers [5–8]. Because they have been implicated in different stages of cancer progression including proliferation, invasion and metastasis, they appear to be promising prognostic markers [9–11]. LncRNA-ATB (activated by TGF-β) was first reported as highly expressed in hepatocellular carcinoma and showed extensive regulatory functions. This lncRNA, located on chromosome 14, induces epithelial-mesenchymal transition (EMT) and promotes hepatocellular carcinoma cell invasion through the TGF-b/miR-200 s/ZEB signaling pathway [12–13]. Because lncRNA-ATB expression is involved in cancer growth and metastasis, it is a promising prognostic biomarker candidate for human cancer [14]. Unfortunately, most studies regarding lncRNA-ATB are limited by discrete outcomes and small patient sample. Therefore, we performed this meta-analysis to determine the prognostic value of lncRNA-ATB by combined analysis of data from multiple studies. 2. Methods 2.1. Literature search to identify relevant studies for meta-analysis A systematic search of multiple electronic databases, Medline, Pubmed, OVID, and Web of Science, was performed independently by two authors, Yanghua Fan and Hua Fang in accordance with the standard guidelines of meta-analysis. Literature was searched from inception until November 15, 2016 for articles that reported lncRNA-ATB as a probable prognostic marker for survival of cancer patients [15–16]. Searches were performed by both the text word and MeSH strategy and included terms like ‘lncRNA-ATB’, ‘long noncoding RNA activated by TGF-β’, ‘ATB or activated by TGF-β’, ‘lncRNA’, ‘noncoding RNA’, ‘long intergenic noncoding RNA’, ‘carcinoma’, ‘neoplasm’, ‘tumor’, ‘cancer’, ‘prognostic’, ‘prognosis’, ‘outcome’, ‘survival’ or ‘recurrence’. The strategy was adjusted in different databases to maximize search findings. Manual searches were also performed using the reference lists of the relevant articles to retrieve eligible studies for inclusion. 2.2. Selection criteria for including studies in meta-analysis The two researchers, Yanghua Fan and Chen-xing Ji, independently evaluated all data to select relevant studies for meta-analysis. The criteria used to include studies in the meta-analysis were: 1) the relationship between lncRNA-ATB expression and survival was measured in multiple human tumors; 2) the expression level of lncRNA-ATB was measured either in human tumor tissue and the patients were grouped according to lncRNA-ATB expression; and 3) all tumors were confirmed
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by pathologic or histologic exam with pathologic parameters such as LNM and tumor stage described. The criteria to exclude studies were: 1) articles that were reviews, letters, editorials, case reports and expert opinions; 2) non-English language and non-human studies; 3) studies lacking data listed in the criteria for included studies; and 4) basic characterization studies of lncRNA-ATB. 2.3. Data extraction from relevant studies for meta-analysis The two reviewers, Yanghua Fan and Zu-jue Cheng, independently extracted and examined the data from the selected original articles. Disagreements in assessment were resolved through consensus with a third reviewer, Xingen Zhu. The following details were collected from each of the study: surname of the first author, publication year, country, tumor type, sample size, the number of patients with lymph node metastasis and high tumor stage, HR and 95% CI of elevated lncRNA-ATB for survival(OS, DFS, RFS), the Newcastle-Ottawa Scale (NOS) score and the detection method of lncRNA-ATB. The study quality was assessed in accordance with the NewcastleOttawa Scale (NOS). A total of nine items, each of which was assigned a score of 1, were measured in each study. The total scores for different studies ranged from 0 to 9. If the score was ≥7, the study was considered to be of high quality. 2.4. Statistical analysis The statistical analysis was performed by RevMan version 5.3 software. The heterogeneity among different studies was measured by the Q and I2 tests. A probability value of I2 ≥ 50% and P b 0.1 indicated the existence of significant heterogeneity [17]. A random effects model or fixed effects model was selected based on the results of heterogeneity analysis. The random-effects model was used if there was significant heterogeneity among the studies or else, the fixed effects model was used. The potential publication bias was assessed by the Begg's funnel plot through Stata 12.0 software. Pooled HRs and ORs were obtained from the published data. We used the HRs and 95% CIs reported in a publication when it was available and when they were not reported, the HR values were estimated from the survival information obtained from Kaplan-Meier curve. OS, DFS, RFS were calculated using the log HR and standard error (SE) values [18]. Odds ratios (ORs) and their 95% CIs were used to assess the association between lncRNA-ATB expression and the tumor parameters, including LNM, DM and tumor stage. 3. Results 3.1. Literature search analysis results The detailed screening process of lncRNA-ATB studies is shown in Fig. 1. A total of 34 records were retrieved from the databases in initial search and 19 duplicate reports were excluded. After detailed screening of the title and abstract, seven irrelevant and non-comparative articles [13,26–31] were excluded. After reviewing the full text of the remaining 9 studies, the article [14] by Ma et al. was excluded because of insufficient data to estimate HR for further analysis. Based on the inclusion and exclusion criteria, a total of eight studies and 818 patients were included in the meta-analysis [12,19–25].
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Fig. 1. Flowchart showing the steps of literature search and selection criteria for the meta-analysis.
The diagnosis of LNM and tumor stage depended on the pathology. The NOS scores of all the studies were ≥7.
The characteristics of the eight studies are summarized (Table 1). The total number of subjects analyzed in the eight studies ranged from 57 to 183, with a mean sample size of 102.25. Six of the eight studies were conducted in China whereas two studies were from Japan and were published between 2014 and 2016. Among the eight studies, two focused on colorectal cancer [19,25], and one each on non-small cell lung cancer [20], pancreatic cancer [21], gastric cancer [22], renal cell carcinoma [23], prostate carcinoma [24] and hepatocellular carcinoma [12]. LncRNA-ATB expression was measured in the tumor specimen.
3.2. Association between lncRNA-ATB expression and OS We performed cumulative meta-analysis to determine the role of lncRNA-ATB in overall survival (OS) of all 563 cancer patients from the five studies [12,20–22,25]. The random effects model was adopted because of the significant heterogeneity between studies (I2 = 89%,
Table 1 The basic information and data of all included studies in the meta-analysis. Study
Year
Region
Tumor type
Sample size
lncRNA-ATB expression High
Survival Analysis
Method
HR(95% CI)
NOS
Method
DFS OS OS OS – RFS OS RFS OS DFS
Multivariate Multivariate Multivariate Multivariate – Multivariate Multivariate
2.04(1.047–3.86) 2.22(1.14–4.35) 0.597(0.416–0.857) 3.50(1.73–7.44) – 5.74(2.313–14.249) 2.70(1.373–5.310) 3.23(1.64–6.33) 3.16(2.03–8.87) 3.74(2.51–9.38)
8 7 8 8 7 7 7
qRT-PCR qRT-PCR qRT-PCR qRT-PCR qRT-PCR qRT-PCR qRT-PCR
7
qRT-PCR
Low
Total
LNM
HTS
Total
LNM
HTS
Iguchi [19] Ke [20] Qu [21] Saito [22] Xiong [23] Xu [24] Yuan [12]
2015 2016 2015 2015 2016 2016 2014
Japan China China Japan China China China
CRC NSCLC PRC GC RCC PSC HCC
124 84 150 183 74 57 86
62 46 75 105 38 25 43
28 34 32 73 12 7 –
28 28 33 – 20 14 –
62 38 75 78 36 32 43
16 7 49 46 3 1 –
16 15 49 – 10 6 –
Yue [25]
2015
China
CRC
60
37
–
–
23
–
–
Multivariate
Note: The dashes represent no data. Abbreviations: CRC, colorectal cancer; NSCLC, non-small cell lung cancer; PRC, pancreatic cancer; GC, gastric cancer; RCC, renal cell carcinoma; PSC, prostate carcinoma; HCC, hepatocellular carcinoma; LNM, lymph node metastasis; HTS, high tumor stage; OS, overall survival; DFS, disease-free survival; RFS, recurrence -free survival.
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Fig. 2. Forest plot showing association between OS and elevated lncRNA-ATB expression in the different types of cancer.
PQ b 0.00001). Reflecting the presence of heterogeneity, we performed a sensitivity analysis. After excluding the Qu study [21], the observed heterogeneity disappeared (I2 = 0%, PQ = 0.82). The subgroup analysis showed that high levels of lncRNA-ATB were significantly correlated with a poorer OS for patients with other types of cancer that excluded PRC (HR = 2.82, 95% CI: 1.98–4.00, P b 0.00001; Fig. 2). Therefore, our data demonstrated that lncRNA-ATB was an independent OS factor
among cancer patients and its high expression was associated with shorter OS. 3.3. Association between lncRNA-ATB expression and DFS, RFS We performed cumulative meta-analysis to determine the role of lncRNA-ATB in disease-free survival (DFS) of 184 cancer patients [19,
Fig. 3. Forest plot showing association between DFS, RFS and elevated lncRNA-ATB expression in the different types of cancer.
Fig. 4. Forest plot showing association between lncRNA-ATB expression levels and lymph node metastasis.
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Fig. 5. Forest plot showing association between lncRNA-ATB expression levels and distant metastasis.
25] and recurrence-free survival (RFS) of 143 cancer patients [12,24] from the eligible studies (Fig. 3). Statistical analyses revealed that lncRNA-ATB was associated with DFS (pooled HR = 2.75, 95% CI: 1.73–4.38, P b 0.0001), RFS (pooled HR = 3.96, 95% CI: 2.30–6.81, P b 0.00001) of cancer patients. Our analyses did not find any significant heterogeneity among the studies. Therefore, our data demonstrated that lncRNA-ATB was an independent DFS, RFS factor among cancer patients and its high expression was associated with shorter DFS, RFS.
3.4. Association between lncRNA-ATB expression level and metastasis We performed cumulative meta-analysis to determine the role of lncRNA-ATB in LNM of 672 cancer patients [19–24] and DM of 491 cancer patients [20–23] from the eligible studies. The random effects model was used for significant heterogeneity. Meta-regression analysis and subgroup analysis were performed to explore the sources of heterogeneity. The subgroup analysis showed that increased lncRNA-ATB was significantly correlated with LNM (OR = 4.07, 95% CI 1.74–9.53, P = 0.001; Fig. 4) and DM (OR = 3.21, 95% CI 1.06–9.72, P = 0.04; Fig. 5) for patients with other types of cancer that excluded PRC. Our analysis demonstrated significant differences in the LNM and DM incidence
between the two groups, patients with higher expression of lncRNAATB were more prone to developing LNM and DM.
3.5. Association between lncRNA-ATB expression levels and tumor stage A total of 489 patients from five eligible studies [19–21,23–24] were analyzed for the relationship between the lncRNA-ATB expression levels and the tumor stage in this meta-analysis. Our data demonstrated that increased lncRNA-ATB expression was associated with higher tumor grade with a pooled OR of 2.81(95% CI: 1.78– 4.43, P b 0.00001; Fig. 6) for patients with other types of cancer that excluded PRC. Therefore, our results demonstrated that higher expression of lncRNA-ATB significantly increased risk of higher tumor stage.
3.6. Begg's funnel plot analysis We did not find any obvious asymmetry for either survival(DFS,RFS) (Fig. 7) or metastasis (LNM) (Fig. 8) when we used Begg's funnel plot to analyze publication bias. Therefore, our findings were due to a
Fig. 6. Forest plot showing meta-analysis of the role of lncRNA-ATB on tumor stage in the different types of cancer.
Y.-H. Fan et al. / Clinica Chimica Acta 468 (2017) 10–16
Fig. 7. Funnel plot analysis to determine publication bias for the independent role of lncRNA-ATB on DFS and RFS in the different types of cancers.
relationship between lncRNA-ATB expression and the pathological parameters analyzed and not due to publication bias. 4. Discussion Cancer is a major threat to human health worldwide and the incidence of cancer has increased gradually over the years [2]. Most cancers eventually metastasize as lymph node metastasis (LNM). The occurrence of metastasis indicates poor prognosis and hence is an important indicator for survival [32–33]. Moreover, LNM is important for the diagnosis of TNM (tumor–node–metastasis) staging for cancer patients, as well as important indicators for predicting prognosis. Since the precise mechanism on metastasis remains unknown in most cancers, molecular biomarkers play a critical role in the diagnosis, prognosis and treatment of cancer [34–35]. Therefore finding new molecular markers that accurately predict tumor metastasis are of paramount importance. Genome-wide analysis of the mammalian genome has shown that N80% of its transcription is associated with lncRNAs [36]. LncRNA play a central role in the regulation of differentiation, cell development and proliferation [37]. Due to the specific expression of lncRNA in the development of tumor and their presence in body fluids and tumor tissues, they are promising biomarkers to diagnose and monitor tumors [38]. Therefore, identification of tumor related lncRNAs that are vital in tumorigenesis are promising biomarkers for cancer prognosis. In recent years, lncRNA-ATB has been found to be dysregulated in colorectal cancer, gastric cancer, renal cell carcinoma, prostate carcinoma and hepatocellular carcinoma [12–14,19–25]. Zhu and others found that the lncRNA-ATB governs the autocrine secretion of TGF-β2 in
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keloid fibroblasts by downregulating the expression level of ZNF217 via miR-200c [31]. Shi et al. found that lncRNA-ATB could promote breast cancer invasion-metastasis cascade via miR-200c/ZEB1/ZNF217, and the high level of lncRNA-ATB was closely related to trastuzumab resistance of breast cancer patients [30]. LncRNA-ATB is also a molecular target for regulating epithelial-mesenchymal transition (EMT) change, which contributes to cancer progression [22]. LncRNAATB stimulated EMT associated with ZEB1 and ZNF217 expression levels through ERK and PI3K/AKT signaling pathways in prostate carcinoma [24]. These studies revealed that lncRNA-ATB has potential prognostic value in cancer patients. Because the role of lncRNA-ATB as a molecular biomarker in human cancer was unclear, our study explored the prognostic value of lncRNAATB in cancer patients using meta-analysis. A random effects model or fixed effects model was used to analyze the data based on the results of heterogeneity analysis. Our data showed that higher lncRNA-ATB expression was indicative of advanced cancer and highlighted poor prognosis. Because of significant heterogeneity existed, subgroup analysis and sensitivity analysis were conducted according to different cancer types. After excluding the Qu study [21], the observed heterogeneity disappeared, by combining HRs from Cox multivariate analyses, there was a significant difference in OS between high and low lncRNA-ATB expression level groups, and statistical analyses revealed that lncRNA-ATB was associated with LNM, DM, advanced tumor stage of cancers except pancreatic cancer. In addition, we showed that higher lncRNA-ATB expression was associated with DFS (pooled HR = 2.75, 95% CI: 1.73–4.38, P b 0.0001) and RFS (pooled HR = 3.96, 95% CI: 2.30–6.81, P b 0.00001) without obvious heterogeneity in different types of cancer. 5. Limitations There are few limitations that must be taken into account with respect to this meta-analysis. First, most studies were from China. Only two studies were from Japan. As such, our data may lack global extrapolation. Second, included type and number of cancers were small. Third, criterion for high expression varied for different studies. Therefore, well-designed and high-quality studies are clearly needed to confirm these preliminary findings. 6. Conclusions In conclusion, increased lncRNA-ATB expression in most cancers was associated with poor OS, LNM and tumor stage. As such, it represents a promising prognostic marker. Disclosures None. Acknowledgments This article was supported by the National Natural Science Foundation of China (grants No. 81660420); the Youth Science Foundation project of Jiangxi Province (No. 20161BAB215253); the Science and Youth Technology Research Project of Jiangxi Province Education Department (No. GJJ14191). References
Fig. 8. Funnel plot analysis to determine publication bias for the independent role of lncRNA-ATB on LNM in the different types of cancers.
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