Long noncoding RNA CCAT2 can predict metastasis and poor prognosis: A meta-analysis

Accepted Manuscript Long noncoding RNA CCAT2 can predict metastasis and poor prognosis: A meta-analysis

Yang-Hua Fan, Hua Fang, Chen-xing Ji, Huan Xie, Bing Xiao, Xin-Gen Zhu PII: DOI: Reference:

S0009-8981(17)30028-1 doi: 10.1016/j.cca.2017.01.016 CCA 14633

To appear in:

Clinica Chimica Acta

Received date: Revised date: Accepted date:

15 December 2016 10 January 2017 12 January 2017

Please cite this article as: Yang-Hua Fan, Hua Fang, Chen-xing Ji, Huan Xie, Bing Xiao, Xin-Gen Zhu , Long noncoding RNA CCAT2 can predict metastasis and poor prognosis: A meta-analysis. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Cca(2017), doi: 10.1016/j.cca.2017.01.016

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ACCEPTED MANUSCRIPT Long noncoding RNA CCAT2 can predict metastasis and poor prognosis: A meta-analysis Yang-Hua Fan1, Hua Fang1, Chen-xing Ji, Huan Xie, Bing Xiao*，Xin-Gen Zhu* Department of Neurosurgery, The Second Affiliated Hospital, Nanchang University,

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Nanchang, China

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Abbreviations: CCAT2, Colon cancer-associated transcript 2; HR, hazard ratio; CI, confidence interval; OR, odds ratio; OS, overall survival; LNM, lymph node

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metastasis; DM, distant metastasis; PFS, progression-free survival; NOS,

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Newcastle-Ottawa Scale; BC, breast cancer; CSCC, cervical squamous cell cancer; SCLC, small cell lung cancer; OC, ovarian cancer; GC, gastric cancer; ESCC,

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esophageal squamous cell carcinoma;

*Corresponding author at: Department of Neurosurgery, The Second Affiliated

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Hospital, Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi, People’s Republic of China

E-mails: [email protected] (X. Zhu) and [email protected](B. Xiao)

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These authors contributed equally to this work.

ACCEPTED MANUSCRIPT ABSTRACT Background: It has been reported that Colon cancer-associated transcript 2 (CCAT2) is dysregulated in various cancers. We performed this meta-analysis to clarify its promising functions as a prognosis marker in malignant tumors.

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Methods: Electronic databases, including PubMed, Medline, OVID, Cochrane Library, and

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Web of Science, were searched from inception to October 20, 2016. The hazard ratio (HR) and 95% confidence interval (CI) were calculated to explore the relationship

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between CCAT2 expression and survival, which were extracted from the eligible studies. The odds ratio (OR) was calculated to assess the association between CCAT2

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expression and pathological parameters using RevMan5.3 software. Results:

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Six original studies were included in this meta-analysis including 725 cancer patients. The pooled HR suggested that high CCAT2 expression was significantly

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correlated with overall survival (OS) (HR= 2.30, 95% CI: 1.62–3.25, p＜0.00001) in

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cancer patients. Subgroup analysis revealed a significant association between CCAT2 and OS in urogenital system (HR=1.70, 95%CI: 1.27–2.26，p＜0.003) and non-urogenital system cancer patients (HR=3.18, 95% CI: 2.09–4.83, p＜0.0001). A

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significant association was observed between high CCAT2 expression and poor progression-free survival (PFS) in cancer patients (pooled HR= 2.76, 95% CI:

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1.74–4.37). CCAT2 expression was significantly related to lymph node metastasis (LNM) (OR=4.33, 95% CI 2.03–9.22), distant metastasis (DM) (OR=11.66, 95% CI: 5.36–25.37) and tumor stage (OR=2.58, 95% CI 1.86–3.57). Conclusions: This meta-analysis demonstrated that high CCAT2 expression significantly predicts poor OS, poor PFS, LNM, DM and tumor stage, suggesting that high CCAT2 expression may serve as a novel biomarker for poor prognosis and metastasis in cancers. Keywords: CCAT2, Neoplasms, prognosis, metastasis, Meta-analysis

ACCEPTED MANUSCRIPT 1. Introduction A total of 8.2 million people die from malignant tumors and 14.1 million people are diagnosed with cancer worldwide each year [1]. According to the American National Center for Health Statistics, approximately 600 thousand Americans will die of cancer in 2016 [2]. The five-year survival rate of most cancers is low, and many

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studies have focused on the identification of new biomarkers for diagnosis or prognosis in cancer. Therefore, the development of new prognostic markers is needed

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to help modify clinical application in cancers.

Long noncoding RNAs (lncRNAs) are defined as transcribed RNA molecules

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that lack an open reading frame of significant length, and the length of lncRNA is greater than 200 nucleotides [3]. lncRNA has many important functions in disease,

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including epigenetic regulation and transcriptional and posttranscriptional regulation [4]. Recently, increasing studies have reported dysregulation of lncRNAs in various

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types of cancers [5-8]. Some lncRNAs play a vital role in cancer progression, such as proliferation, invasion and metastasis [9-10], and lncRNAs have been implicated as

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promising markers for the prognosis and treatment of cancer [11].

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In 2013, Ling et al. first detected colon cancer-associated transcript 2 (CCAT2), which was highly expressed in colon cancer tissues compared with normal adjacent tissues [12], and these authors showed that CCAT2 could promote colon cancer

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growth and metastasis. Colon cancer cases, demonstrating high CCAT2 expression, were all microsatellite stable, confirming that CCAT2 expression is associated with

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microsatellite-stable colon cancer. Recently, an increasing number of studies have shown that CCAT2 might play important roles in cancer progression [13], as CCAT2 expression is associated with the overall survival (OS), progression-free survival (PFS)，lymph node metastasis (LNM) and distant metastasis (DM) of human cancers. However, most studies reported so far are limited in discrete outcome and sample size. Therefore, we analyzed all previously published data based on the robust evidence of the expression and impact of CCAT2 in tumorigenesis to determine the prognostic value of CCAT2 in cancer patients.

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2. Methods 2.1 Literature collection According to the standard guidelines of meta-analyses [14, 15], a systematic search was independently performed by two authors in the electronic databases of

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Medline, PubMed, OVID, and Web of Science for relevant articles concerning CCAT2 as a prognostic biomarker for the survival of cancer patients. The most recent

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search was updated on October 20, 2016. We performed a literature search using both text word and MeSH strategies with the terms ‘‘CCAT2’’, “colon cancer-associated

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transcript 2”, ‘‘long intergenic noncoding RNA or lncRNA or noncoding RNA’’, ‘‘cancer or tumor or carcinoma or neoplasm’’, ‘‘prognostic or prognosis’’, and

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‘‘outcome or survival or recurrence’’. The strategy was correspondingly adjusted in the different databases. In the retrieval process, we performed a manual search using

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the reference lists of relevant articles to include eligible studies.

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2.2 Study selection

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Two researchers (Yanghua Fan and Chenxing Ji) evaluated all of the included studies and independently extracted the data. The following inclusion criteria were considered: 1) the relationship between CCAT2 expression and survival was

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measured in multiple human tumors; 2) the expression levels of CCAT2 in human tumor tissues were measured, and the patients were grouped according to the

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expression levels of CCAT2; 3) all tumors were confirmed through pathological or histological examinations, and the clinicopathological parameters were described; and 4) studies described sufficient information on survival, such as the hazard ratio (HR) and 95% confidence interval (CI). The following studies were excluded: 1) reviews, letters, editorials, case reports and expert opinions; 2) non-English language and non-human studies; 3) studies without available data; and 4) laboratory studies with the molecular structure and functions of CCAT2 only.

ACCEPTED MANUSCRIPT 2.3 Data extraction Two reviewers (Yanghua Fan and Bing Xiao) independently extracted and examined the data from the original articles. Disagreements in the literature assessment were resolved through consensus with a third reviewer (Xingen Zhu). The following data were collected: surname of the first author, publication year, country,

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tumor type, sample size, number of patients with LNM and DM, HR and 95% CI of elevated CCAT2 for OS, Newcastle-Ottawa Scale (NOS) score, and CCAT2 detection

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method.

The study quality was assessed in accordance with the NOS. Nine items were

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extracted, and each item scored 1. The total scores ranged from 0 to 9. If the scores

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were ≥7, then the study was considered high quality.

2.4 Statistical methods

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Statistical analyses were performed using RevMan version 5.3 software. The heterogeneity among different studies was measured using Q and I2 tests. A

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probability value of I2 ≥ 50% and P < 0.1 indicated the existence of significant

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heterogeneity [16]. A random effects model or fixed effects model was used depending on the results of the heterogeneity analysis. If there was significant heterogeneity among the studies, then the random-effects model was adopted. The

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potential publication bias was assessed using Begg’s funnel plot. Pooled HRs and Odds ratios (ORs) were extracted from the published data. Because the HRs could be

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directly obtained from the publication, we used crude HR values. Although the HR and 95% CI values were not directly reported in these studies, the survival information was extracted from Kaplan-Meier curves and used to estimate the HR. The log HR and standard error (SE) were used to summarize the outcome of OS and PFS [17]. The OR and 95% CI values were combined to assess the association between CCAT2 expression and clinicopathological parameters, including LNM, DM and tumor stage.

3. Result

ACCEPTED MANUSCRIPT 3.1 Studies characteristics A total of 136 articles were identified through the literature search. The titles and abstracts were reviewed, and 127 irrelevant studies and duplicates were excluded. In addition, three studies were excluded, and the detailed screening process is shown in Figure 1.

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According to the inclusion and exclusion criteria, six studies and 725 patients were included in the meta-analysis [18-23]. Additionally, the characteristics of the 6

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studies included in the present meta-analysis are summarized in Table 1. The subject number of 6 studies ranged from 77 to 229, with a mean sample size of 120.8. The

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studies were all conducted in China. The publication times of the six studies ranged from 2015 to 2016. Among the six studies, one study [18] focused on breast cancer

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(BC), one study [19] focused on cervical squamous cell cancer (CSCC), one study [20] focused on small cell lung cancer (SCLC), one study [21] focused on ovarian cancer

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(OC), one study [22] focused on gastric cancer (GC), and one study [23] focused on Esophageal Squamous Cell Carcinoma (ESCC). CCAT2 expression was measured in

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cancerous specimens and serum. All diagnoses of LNM, DM and tumor stage were

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based on pathology. The NOS scores for all included studies were ≥7.

ACCEPTED MANUSCRIPT Figure.1 Flowchart presenting the steps of the literature search and selection 3.2 Association between the CCAT2 expression level and OS We performed a cumulative meta-analysis to assess the function of CCAT2 for OS in patients with cancer. Additionally, all of the included studies with 725 patients reported the relationship between OS and CCAT2. The random effects model was

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used for significant heterogeneity (I2=48%, P=0.09). A significant association was observed between CCAT2 and OS in cancer patients (pooled HR= 2.30, 95% CI:

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1.62–3.25, p＜0.00001; Figure.2). Meta-regression analysis and subgroup analysis were performed to explore the sources of heterogeneity. In subgroup analysis, a

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significant association between CCAT2 and OS in urogenital system (HR=1.70, 95%CI: 1.27–2.26，p＜0.003) and non-urogenital system cancer patients (HR=3.18,

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95% CI: 2.09–4.83, p＜0.0001) was observed. Although the HR value was different in the two groups, the expression levels of CCAT2 could be used to predict the OS in

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both urogenital system and non-urogenital system cancer patients. This result demonstrated that cancer patients with high lncRNA- CCAT2

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expression might be correlated with a shorter OS. Thus, lncRNA-CCAT2 is an

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independent factor of OS among patients with cancer in China.

Figure 2 Forest plot showing the subgroup analyses of the pooled HRs of OS with elevated CCAT2 expression in different cancer types.

3.3 Association between the CCAT2 expression level and PFS

ACCEPTED MANUSCRIPT A total of 208 patients in two studies were included to detect the relationship between CCAT2 expression levels and PFS in this meta-analysis. We observed a significant association between PFS and CCAT2 expression (HR =2.76, 95% CI: 1.74–4.37, p＜0.0001；Figure. 3). In addition, we did not observe any significant heterogeneity among the studies (I2=0%, PQ=0.56). This result demonstrated that high

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CCAT2 expression was significantly associated with shorter PFS. The analysis results

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showed that lncRNA-CCAT2 is an important factor of PFS in cancer patients.

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Figure 3 Forest plot showing the association between PFS and CCAT2 expression in cancer.

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3.4 Association between the CCAT2 expression level and LNM Five-hundred-forty-nine cancer patients from four eligible studies were collected

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and analyzed. The random effects model was used for significant heterogeneity

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(I2=74%, p =0.01). The OR, expressed as the high CCAT2 expression group versus the low CCAT2 expression group, was 4.33 (95% CI: 2.03–9.22, p =0.0001; Figure 4). Reflecting the presence of heterogeneity, we performed a sensitivity analysis. After

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excluding the Wang study [22], the observed heterogeneity disappeared and the results did not change.

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The results also revealed a significant difference in the LNM incidence between the two groups. Additionally, the results demonstrated that high CCAT2 expression significantly predicted a higher tendency to develop LNM in patients with cancer.

Figure 4 Forest plot showing the association between the CCAT2 expression levels

ACCEPTED MANUSCRIPT with LNM. 3.5 Association between CCAT2 expression and DM The correlations between CCAT2 expression and DM are presented in Figure 5. Three studies with 306 patients reported the association between the CCAT2 expression levels and number of cancer patients with DM. In these studies, there was

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no significant heterogeneity and the fixed-effects model was used (I2=35%, PQ=0.21). The analysis showed a pooled OR =11.66 (95% CI: 5.36–25.37, p＜0.00001; high

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versus low CCAT2 expression；Figure 4).

The patients with DM were significantly increased in the high CCAT2

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expression group, suggesting that patients with a high CCAT2 expression level in

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tumor tissues may indicate an increased probability of DM.

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Figure 5 Forest plots for the association between CCAT2 expression and DM. 3.6 Association between CCAT2 expression and tumor stage Six-hundred-fifty-eight patients in five studies were included to detect the

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relationship between the CCAT2 expression levels and tumor stage in this meta-analysis. A significant association was observed between high CCAT2

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expression and high tumor stage in cancer patients (pooled OR= 2.58, 95% CI: 1.86–3.57, p＜0.00001; Figure 6) with no obvious heterogeneity (I2=38%, PQ=0.17). The results also showed that the tumor stage was significantly increased in the high CCAT2 expression group compared with that in the low CCAT2 expression group, and the results demonstrated that high CCAT2 expression significantly increased the risk of a high tumor stage.

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Figure 6 Forest plot showing the meta-analysis of the independent role of CCAT2 in tumor stage in different cancer types.

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3.7 Publication bias

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Next, publication bias was evaluated using Begg’s funnel plot. Begg’s funnel plot (Figure 7) showed no evidence of obvious asymmetry for OS. Similarly, there

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was no evidence of a significant publication bias in terms of the tumor stage (Figure

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8).

Figure 7 Funnel plot of the publication bias for the analysis of the independent role of CCAT2 in OS in the different cancer types.

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Figure 8 Funnel plot of the publication bias for the analysis of the independent role of

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CCAT2 in tumor stage in the different cancer types.

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4. Discussion

Cancer remains a serious threat to human health, and the incidence of cancer has gradually increased in recent years [2]. Most cancers could eventually progress to

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metastasis, including LNM and DM. The occurrence of metastasis is an important indicator for survival, indicating that these cancers have a poor prognosis [24, 25].

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Moreover, LNM and DM show important significance in the diagnosis of TNM (tumor–node–metastasis) staging for cancer patients and represent important indicators for predicting prognosis. Hitherto, the precise mechanism underlying metastasis remains uncertain in cancer patients. Currently, as a cancer research hotspot, molecular biomarkers play a critical role in the prediction and treatment of cancer [26, 27]. Therefore, it is still necessary and significant to identify new molecular markers to predict tumor metastasis and prognosis. Recently, genome-wide studies have shown that the mammalian genome is abundantly transcribed and that more than 80% of this transcription is associated with

ACCEPTED MANUSCRIPT lncRNAs [28, 29, 30]. Mounting evidence has shown that lncRNAs play a central role in the regulation of differentiation, cell development and proliferation [31]. Reflecting the specific expression of lncRNAs in the occurrence and development of tumors, lncRNAs can be used as promising biomarkers to diagnose and monitor tumors and can easily be collected from body fluids and tumor tissues [32]. Thus, the

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identification of tumor-related lncRNAs is important to understand their function in tumorigenesis, and lncRNAs may represent promising biomarkers for the prognosis of

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cancer.

CCAT2 is highly expressed in colorectal cancer, particularly in cases of

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metastatic cancer, promoting colon cancer growth, metastasis, and chromosomal instability [12]. In recent years, increasing evidence has revealed the contribution of

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CCAT2 in playing oncogenic roles in tumorigenesis, and CCAT2 is dysregulated in many tumors, including breast cancer [18,33], cervical squamous cell cancer [19],

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small cell lung cancer [20,34], ovarian cancer [21], gastric cancer [22], Esophageal Squamous Cell Carcinoma [23], hepatocellular carcinoma [35], etc. Additionally,

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Ling reported that CCAT2 could enhance the ability of invasion and metastasis in

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colon cancer via miRNA-17-5p and miRNA-20a [12], and CCAT2 expression was associated with microsatellite-stable CRC [36]. CCAT2 has also been implicated in the mechanism of metastasis and drug resistance in breast cancer [33]. Moreover, Guo

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et al. showed that the knockdown of lncRNA-CCAT2 could inhibit glioma cell proliferation and migration through inhibition of Wnt/β-catenin signal pathway

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activity [37].

However, the underlying mechanisms concerning the role of CCAT2 in human cancer remain largely unclear, and CCAT2 may act as a common molecular biomarker.

Therefore,

in

the

present

meta-analysis,

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explored

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clinicopathological significance and prognostic value of CCAT2 in cancer patients. Seven-hundred-twenty-five patients with cancer from 6 eligible studies were collected and analyzed in the present study. A random-effects model or fixed-effects model was used depending on the results of heterogeneity analysis. The results showed that high CCAT2 expression might indicate a worse prognosis in cancer

ACCEPTED MANUSCRIPT patients. By combining HRs from the Cox multivariate analyses, we observed that CCAT2 was an independent prognostic factor of OS for cancer patients (pooled HR=2.30, 95%CI: 1.62–3.25). In the subgroup analysis, a significant association between CCAT2 and OS in urogenital system (HR=1.70, 95%CI: 1.27–2.26，p＜ 0.003) and non-urogenital system cancer patients (HR=3.18, 95% CI: 2.09–4.83, p＜

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0.0001) was observed. Additionally, a significant association between PFS and CCAT2 expression (HR =2.76, 95% CI: 1.74–4.37, p＜0.0001) was also observed.

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Furthermore, high CCAT2 expression in tumor issues was significantly correlated with LNM. Reflecting the presence of heterogeneity, we performed a

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sensitivity analysis, and the observed heterogeneity disappeared after excluding the Wang et al. study [22], but the results did not change. Moreover, we observed that

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high CCAT2 expression was significantly correlated with DM. In the present meta-analysis, 5 studies reported the correlation between the CCAT2 expression level

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and tumor stage, and high CCAT2 expression was significantly associated with a high tumor stage without obvious heterogeneity in the different cancer types.

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5. Limitations

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Several limitations must be considered when interpreting the conclusions of the present meta-analysis. First, all of the included studies were from China; thus, the results may only represent Chinese cancer patients. Additionally, the included type

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and number of cancers were small; thus, additional studies are needed to verify the obtained results. Third, the criteria for high expression were different in these studies.

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Therefore, further well-designed and high-quality studies are needed to confirm the function of CCAT2 in various cancers. 6. Conclusions

High levels of CCAT2 expression in multiple cancers are significantly correlated with poor OS, PFS, LNM, DM and tumor stage. Therefore, CCAT2 expression may serve as a promising biomarker for predicting prognosis and metastasis in cancer patients. Disclosures None Acknowledgments

ACCEPTED MANUSCRIPT This article is financially supported by grants from the National Natural Science Foundation of China (grant No. 81660420), the construction plan of the superior science and technology innovation team of Jiangxi Province (grant No. 20152BCB24009), and the foreign science and technology cooperation plan of Jiangxi Province (grant No. 20151BDH80009).

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[34] M. Qiu, Y. Xu, X. Yang, J. Wang, J. Hu, L. Xu, R. Yin, CCAT2 is a lung adenocarcinoma-specific long non-coding RNA and promotes invasion of non-small cell lung cancer, Tumour Biol 35 (2014) 5375-5380.

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[35] N. Zhou, Z. Si, T. Li, G. Chen, Z. Zhang, H. Qi, Long non-coding RNA CCAT2 functions as an oncogene in hepatocellular carcinoma, regulating cellular proliferation,

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migration and apoptosis, Oncol Lett 12 (2016) 132-138. [36] Y. Kasagi, E. Oki, K. Ando, S. Ito, T. Iguchi, M. Sugiyama, Y. Nakashima, K. Ohgaki, H. Saeki, K. Mimori, Y. Maehara, The Expression of CCAT2, a Novel Long Noncoding RNA Transcript, and rs6983267 Single-Nucleotide Polymorphism Genotypes in Colorectal Cancers, Oncology-basel (2016). DOI: 10.1159/000452143 [37] H. Guo, G. Hu, Q. Yang, P. Zhang, W. Kuang, X. Zhu, L. Wu, Knockdown of long non-coding RNA CCAT2 suppressed proliferation and migration of cells, Oncotarget (2016). DOI: 10.18632/oncotarget.13242

glioma

ACCEPTED MANUSCRIPT

CCAT2 expression Tumor Study

Year

High

Region type

Cai

[18]

Chen

[19]

Sample

Analysis

HR(95% CI)

(OS)

High / Low

Low

size Total

LNM

DM

Total

LNM

DM

NOS

Method

2015

China

BC

67

25

-

-

42

-

-

Multivariate

5.92(1.92-18.27)

7

qRT-PCR

2015

China

CSCC

123

62

34

-

61

11

-

Multivariate

2.813(1.504-6.172)

7

qRT-PCR

[20]

2015

China

SCLC

112

56

45

14

56

22

0

Multivariate

2.034(1.216-3.402)

8

qRT-PCR

[21]

OC

99

55

-

36

54

-

6

Multivariate

2.938(1.526-5.873)

7

qRT-PCR

Cheng

China

Wang

2015

China

GC

85

44

28

11

41

8

3

Multivariate

2.315(1.097-5.283)

8

qRT-PCR

Zhang[23]

2015

China

ESCC

229

115

65

-

114

48

-

Multivariate

1.432(1.005–2.041)

7

qRT-PCR

PT

2016

[22]

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Table 1 The basic information and data of all included studies in the meta-analysis Note: The dashes represent no data.

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Abbreviations: BC, breast cancer; CSCC, cervical squamous cell cancer; SCLC , small cell lung cancer; OC, ovarian cancer; GC, gastric cancer; ESCC, esophageal squamous cell carcinoma; LNM, lymph node metastasis; DM, distant metastasis; OS, overall survival; HR,

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D

MA

NU

hazard ratio; NOS, Newcastle-Ottawa Scale.

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Huang

ACCEPTED MANUSCRIPT Highlights 1. It has been reported that Colon cancer-associated transcript 2 (CCAT2) was dysregulated in different cancers. We performed this meta-analysis to

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clarify its promising functios as a prognosis marker in malignant tumor.

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2. Our result demonstrated that cancer patients with high expression of

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lncRNA- CCAT2 might be correlated with shorter overall survival.

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3. Our data demonstrated that LncRNA- CCAT2 was an independent factor among cancer patients and its high expression was associated with

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shorter progression-free survival.

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4. Our results demonstrated that higher expression of LNCRNA-CCAT2 significantly increased the risk of high tumor stage , lymph node

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metastasis and distant metastasis.

5. This meta-analysis data demonstrate that higher lncRNA- CCAT2 expression can be a useful prognostic biomarker in human cancers.