Circular RNA CDR1as/ciRS-7-- A Novel Biomarker in Solid Tumors

doi:10.21203/rs.3.rs-3196859/v1

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Research Article

Circular RNA CDR1as/ciRS-7-- A Novel Biomarker in Solid Tumors

https://doi.org/10.21203/rs.3.rs-3196859/v1

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Background

Circular RNA CDR1as/ciRS-7 has been reported to function as an oncogenic regulator in various cancers. However, the prognostic value of CDR1as/ciRS-7 expression in solid tumors remains unclear. Herein, we conducted an updated meta-analysis to investigate the association between CDR1as/ciRS-7 expression and clinical outcomes in solid tumors.

Methods

A systematic search was performed through the PubMed, EMBASE, Web of Science, Ovid, Cochrane library, CNKI and WanFang databases for eligible studies on clinical values of CDR1as/ciRS-7 in solid tumors. The pooled hazard ratios (HRs) or odd ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the correlation between CDR1as/ciRS-7 and clinical outcomes.

Results

A total of 2342 patients from 16 studies between 2017 and 2023 were included. The results suggested that elevated CDR1as/ciRS-7 expression predicted a poor OS for 12 types of solid tumors (HR = 1.90, 95% CI: 1.40–2.59, P < 0.001) with no heterogeneity (I² = 80.9%, P < 0.001). Stratified analysis indicated that there was a negative relationship between CDR1as/ciRS-7 expression and OS in digestive system cancers (HR = 2.28, 95% CI: 1.81–2.88, P < 0.001), and respiratory cancers (HR = 2.40, 95% CI: 1.75–3.30, P < 0.001). Furthermore, we also revealed that CDR1as/ciRS-7 was positively related to tumor size (OR = 2.11, 95%CI: 1.64–2.71, P < 0.001), TNM stage (OR = 2.05, 95%CI: 1.65–2.54, P < 0.001), lymph node metastasis (LNM) (OR = 1.74, 95%CI: 1.38–2.21, P < 0.001), and distant metastasis (OR = 2.79, 95%CI: 1.71–4.55, P < 0.001). Although the probable evidence of publication bias was found in the studies with OS, tumor size, TNM stage, and LNM, the trim and fill analysis confirmed the reliability of these results was not affected.

Conclusion

Elevated CDR1as/ciRS-7 expression was associated with larger tumor size, advanced TNM stage, worse LNM, distant metastasis, and shorter OS, suggesting that CDR1as/ciRS-7 may act as an independent prognostic biomarker in solid tumors.

circular RNA

ciRS-7

cancer

prognosis

meta-analysis

solid tumors

Cancer is a human complex genetic disease and it is one of the crucial public health problems worldwide[1]. With the raising of cancer incidence and mortality, cancer has become the leading cause of death since 2010 in China[2]. Despite great advances in the diagnosis and treatment of cancers, the clinical prognosis of cancer patients is still poor. However, one of the main reasons is the lack of effective biomarkers to diagnose cancer at the early stage and predict the clinical prognosis of cancer patients. Therefore, the development of early detection and novel therapeutic methods based on the elucidation of the molecular pathogenesis of human cancers are urgently needed.

Long noncoding RNAs (lncRNAs) are one of the most important parts of the human transcribed genome without protein-coding capacity, play diverse roles in a great number of cellular processes, and have been involved in numerous pathological conditions[3, 4]. Circular RNAs (circRNAs) are one new kind of lncRNAs, which have no 5’ or 3’ ends but are covalently linked to form a closed circular structure[5]. Increasing evidence suggested that circRNAs could regulate gene expression at the transcriptional or posttranscriptional level through binding to miRNAs or other molecules. circRNAs are tissue and cell-type specific. And circRNAs play crucial roles in multiple human diseases, such as diabetes, arteriosclerosis, cardiac hypertrophy, and cancer[6–12].

CiRS-7 is a highly conserved circRNA. It is also named CDR1as. It contains more than 70 repetitive miR-7 binding sites that function as miR-7 sponges. The biological function of miR-7 is abolished by the overexpression of CDR1as/ciRS-7, which results in decreased miR-7 activity and elevated expression of miR-7 targeting genes[13, 14]. Recent studies have shown that CDR1as/ciRS-7 plays critical roles in cancer, including cancer cell proliferation, angiogenesis, invasion, and metastasis. Studies demonstrate that CDR1as/ciRS-7 is abnormally expressed in different types of solid tumors, including cholangiocarcinoma (CCA)[15], colorectal cancer (CRC)[16, 17], non-small cell lung cancer (NSCLC)[18–20], larynx-geal squamous cell carcinoma (LSCC)[21], esophageal squamous cell carcinoma (ESCC)[22, 23], breast cancer(BrC)[24], gastric cancer (GC)[25], melanoma[26], nasopharyngeal carcinoma (NPC)[27], ovarian cancer (OC)[28], clear cell renal cell carcinoma (ccRCC)[29], and cervical cancer (CC)[30].

As a cancer-related circRNA, increasing evidence supports that CDR1as/ciRS-7 may serve as a negative prognostic biomarker in various cancers, and high CDR1as/ciRS-7 expression correlated with larger tumor size, advanced TNM stage, worse lymph node metastasis and distant metastasis[31–34]. However, most studies reported on the prognostic role of CDR1as/ciRS-7 expression are limited by sample size and discrete clinical outcomes. In this study, we conducted a systematic review and quantitative meta-analysis to investigate the clinicopathological and prognostic value of CDR1as/ciRS-7 as a potential biomarker in human solid tumors.

2.1. Search strategy and study selection

We searched through the PubMed, EMBASE, Web of Science, Ovid, Cochrane library, CNKI and WanFang databases for potentially eligible studies on clinical values of CDR1as/ciRS-7 expression in human solid tumors from inception up to April 18, 2023. The search terms were included: “circular RNA”, “CDR1as” or “ciRS-7”, “cancer” or “tumor” or “carcinoma” or “neoplasm”. The reference lists of the retrieved studies were searched manually, and the literature search was performed by two independent researchers (Yun Zhang and Shikai Zhu).

The studies were considered eligible if they met the following criteria: any type of human cancer was studied; the studies investigated the prognostic value of CDR1as/ciRS-7 expression in cancers; the levels of CDR1as/ciRS-7 expression in cancerous tissues were detected; patients were grouped according to the levels of CDR1as/ciRS-7 expression; the studies included an association between CDR1as/ciRS-7 and clinicopathologic parameters; the studies provided sufficient data to estimate the HRs with corresponding 95% CI for OS; and the studies were published in English. The exclusion criteria were as follows: letters, editorials, expert opinions, case reports and reviews; the studies only investigated the molecular structure and functions of CDR1as/ciRS-7; the studies did not include the usable data for further analysis; and duplicate publications.

2.2. Data extraction and quality assessment

Two researchers (Yun Zhang and Zhiqiang Kang) independently evaluated and extracted the eligible research data from each study, and the third researcher (Shikai Zhu) achieved a consensus for disagreements. The following elements were extracted from the Included studies: first author, publication date, country, tumor type, TNM stage, sample size, cut-off value, follow-up period, detection method, adjuvant therapy before the surgery, survival analysis methodology, HRs with corresponding 95% CIs for OS, disease-free survival (DFS) and progression‑free survival (PFS), and other clinicopathologic parameters including age, gender, tumor size, tumor differentiation, TNM stage, lymph node metastasis and distant metastasis. HRs with corresponding 95% CIs were preferentially extracted from univariate or multivariate analyses. If the data was not available, the we calculated the HRs from Kaplan-Meier survival curves using Engauge Digitizer V4.1 software.

We assessed the quality of included studies based on the Newcastle-Ottawa scale (NOS) criteria. The NOS criteria use a “star” rating system ranging from 0 to 9 stars for the judgment of methodological quality, which was based on selection (0–4 stars), comparability (0–2 stars), and outcome (0–3 stars). Studies with more than 5 points were considered to be high quality. The quality of each study was independently evaluated by two aforementioned researchers. Inconsistent evaluations or data in the included studies were resolved by discussion with the third investigator (Shikai Zhu).

2.3. Statistical analyses

STATA 14.0 statistical software (Stata Corporation, College Station, TX, USA) was used to analyze all the data. The pooled HRs with 95% CIs were used to estimate the prognostic value of CDR1as/ciRS-7 on OS, DFS and PFS in patients with solid tumors. Pooled ORs with 95% CIs were used to evaluate the relationship between CDR1as/ciRS-7 and clinicopathological characteristics of patients such as age, gender, tumor size, tumor differentiation, TNM stage, lymph node metastasis and distant metastasis. X²-based Cochran Q test and Higgins I² statistic were utilized to analyze the heterogeneity among studies. If P-value < 0.05 in combination with I²-value > 50%, it was able to be considered significant heterogeneity. Random-effects models were used in cases which with significant heterogeneity. Subgroup analysis and sensitivity analysis were applied to dissect the heterogeneity. In addition, Begg's funnel plot and Egger's linear regression test were used to determine publication bias. Trim and fill analysis were performed if there was the possible evidence of publication bias. P-value < 0.05 was considered statistically significant.

3.1. Study Selection and Characteristics

A total of 333 potentially relevant studies were identified in this meta-analysis. To achieve relevant studies, we evaluated the titles, abstracts, and author information of all collected articles, and 198 duplicate studies were excluded. After screening the titles and abstract carefully, 103 irrelevant studies, such as letters, editorials, expert opinions, case reports, reviews, and other types of uninvolved publications for the analysis and full-text review, were excluded. Through evaluating the eligibility of full-text articles, 16 articles without sufficient data or without dividing into high and low-expression groups were excluded. Finally, 16 eligible studies were included in this meta-analysis (Fig. 1).

A total of 2342 patients from 16 studies (2 studies included 2 cohorts, respectively) from 2017 to 2022 were included (Table 1). Those studies were derived from China (n = 13), Japan (n = 1), Netherlands (n = 1), and Spain (n = 1). Among those studies, the sample size ranged from 30 to 352 patients, and more than 100 patients were enrolled in 9 studies. Twelve types of solid tumors, including CRC (n = 3), CCA (n = 1), GC (n = 2), NSCLC (n = 3), LSCC (n = 1), ESCC (n = 1), BrC (n = 1), Melanoma (n = 1), NPC (n = 1), OC (n = 1), ccRCC(n = 1) and CC (n = 1), were analyzed. The levels of CIRS-7 expression were measured by quantitative real-time polymerase chain reaction qRT-PCR (n = 16) in all of the studies. None of the patients received adjuvant therapy before the surgery in 16 studies. Multivariate analysis was included in 6 studies. Clinical outcomes were analyzed, including 15 studies for OS, 1 for DFS, and 1 for PFS. HRs with the corresponding 95% CIs for OS were extracted from the original data in 8 studies, and calculated from Kaplan-Meier Curves in other 8 studies (Table 1). Clinicopathologic parameters were also analyzed in 15 studies including age, gender, tumor size, tumor differentiation, TNM stages, lymph node metastasis (LNM) and distant metastasis (Table 2). Additionally, the studies with more than 6 according to the NOS score criteria were included to make sure the quality of the analysis (Table 1).

Table 1

The main characteristics of the included studies in the meta-analysis.
First author	Year	Region	Tumor Type	TNM Stage	Sample Size	Cut-off Value	Follow-up (months)	Detection Method	Adjuvant therapy	Survival Analysis	HR statistic	Outcome Measure	NOS
Jiang XM	2017	China	CCA	I-IV	54	Median	50(total)	qRT-PCR	None	U/M	reported	OS	9
Weng WH¹	2017	China	CRC	II-IV	153	Median	44.4(median)	qRT-PCR	None	U/M	reported	OS	6
Weng WH²	2017	Japan	CRC	II-IV	165	Median	61.2(median)	qRT-PCR	None	U/M	reported	OS	9
Tang WT	2017	China	CRC	I-IV	182	Median	60(total)	qRT-PCR	None	U	reported	OS	9
Pan HY¹	2018	China	GC	II-IV	102	Median	60(total)	qRT-PCR	None	U	calculated	OS	6
Pan HY²	2018	China	GC	II-IV	154	Median	60(total)	qRT-PCR	None	U	calculated	OS	6
Su CY	2017	China	NSCLC	I-IV	128	Mean	60(total)	qRT-PCR	None	U/M	reported	OS	9
Zhang JZ	2018	China	LSCC	NA	30	NA	60(total)	qRT-PCR	NA	U	calculated	OS	6
Li RC	2018	China	ESCC	I-III	123	Median	100(total)	qRT-PCR	None	U	calculated	OS/DFS	7
Uhr K	2018	Netherlands	BrC	NA	345	Median	91(median)	qRT-PCR	None	U	reported	OS	9
Yan B	2018	China	NSCLC	NA	132	Median	46(median)	qRT-PCR	None	U/M	reported	OS	9
Zhang XF	2018	China	NSCLC	I-IV	60	Median	100(total)	qRT-PCR	None	U/M	reported	OS	9
Sang MX	2018	China	ESCC	NA	86	Median	NA	qRT-PCR	None	NA	NA	NA	6
Hanniford D	2020	Spain	Melanoma	NA	105	Quarter	175(total)	qRT-PCR	NA	U	calculated	OS/MFS	6
Zhong Q	2019	China	NPC	I-IV	44	Mean	100(total)	qRT-PCR	NA	U	calculated	OS	8
Zhang FH	2020	China	OC	I-IV	40	NA	80(total)	qRT-PCR	NA	U	calculated	OS	6
Zhao YH	2020	China	ccRCC	I-IV	87	Median	100(total)	qRT-PCR	NA	U	calculated	PFS	9
Zhou Y	2020	China	CC	I-II	352	Median	60(total)	qRT-PCR	None	U/M	calculated	OS	9

Table 2

Correlation between CDR1as/ciRS-7 expression and clinicopathological characteristics of cancers
Clinical parameters	No. of studies	No. of patients	OR (95% CI)	P-value	Heterogeneity
					I²	P-value
Age (elder vs. younger)	12	1516	1.00(0.81–1.23)	0.990	0.0	0.78
Gender (male vs. female)	11	1156	0.83(0.65–1.06)	0.135	3.0	0.41
Tumor size (larger vs. smaller)	10	1372	2.11(1.64–2.71)	< 0.001	0.0	0.54
TNM stage (III + IV vs. I + II)	12	1518	2.05(1.65–2.54)	< 0.001	21.4	0.23
Lymph node metastasis (present vs. absent)	9	1205	1.74(1.38–2.21)	< 0.001	62.4	0.01
Distant metastasis (present vs. absent)	7	780	2.79(1.71–4.55)	< 0.001	0.0	0.44
Tumor differentiation (poor vs. well)	10	1380	1.95(1.46–2.61)	< 0.001	51.1	0.03

3.2. Prognostic value of CDR1as/ciRS-7 expression in solid tumor

2342 patients from a total of 18 studies were applied to assess the prognostic of CDR1as/ciRS-7 on OS in human solid tumors. The results suggested that elevated CDR1as/ciRS-7 expression predicted a poor OS for 12 types of solid tumors (HR = 1.90, 95% CI: 1.40–2.59, P < 0.001) with significant heterogeneity (I² = 80.9%, P < 0.001) (Fig. 2). Furthermore, subgroup analysis was also conducted to investigate the association between HRs and cancer type/ethnicity/sample size/NOS. Stratified analysis indicated that there was a negative relationship between CDR1as/ciRS-7 and OS in the studies with digestive system cancers (HR = 2.28, 95% CI: 1.81–2.88, P < 0.001), gynecologic cancers (HR = 0.52, 95% CI: 0.33–0.81, P = 0.004), and respiratory cancers (HR = 2.40, 95% CI: 1.75–3.30, P < 0.001) (Fig. 3A). And we found that upregulation of CDR1as/ciRS-7 expression significantly correlated with short OS in patients from Asian (HR = 1.97, 95% CI: 1.45–2.67, P < 0.001), while this correlation does not exist in Caucasian patients (HR = 1.69, 95% CI: 0.51–5.61, P = 0.389) (Fig. 3B). Higher CDR1as/ciRS-7 expression predicted shorter OS in the studies with sample size > 100 (HR = 1.80, 95% CI: 1.27–2.54, P = 0.001) as well as those with sample size < 100 (HR = 2.55, 95% CI: 1.72–3.79, P < 0.001) (Fig. 3C). In addition, the effect of CDR1as/ciRS-7 overexpression on predicting poor OS was found in the studies with NOS < 7 (HR = 2.42, 95% CI: 1.82–3.21, P < 0.001) as well as those with NOS > 7 (HR = 1.65, 95% CI: 1.11–2.45, P = 0.013) (Fig. 3D).

The association between CDR1as/ciRS-7 expression and clinicopathological characteristics are examined in 12 studies with 2065 cancer patients (Table 2). 10 studies with 1372 cancer patients were included to analyze the correlation between CDR1as/ciRS-7 and tumor size, and the pooled data showed an obvious association between CDR1as/ciRS-7 and tumor size (OR = 2.11, 95%CI: 1.64–2.71, P < 0.001) (Fig. 4A). The analysis results of 12 studies with 1518 cancer patients showed that there was a significant correlation between CDR1as/ciRS-7 and TNM stage (OR = 2.05, 95%CI: 1.65–2.54, P < 0.001) (Fig. 4B). As indicated in Fig. 4C, 1205 cancer patients from 9 studies were included to assess the association between CDR1as/ciRS-7 and LNM, and the results demonstrated that the patients with high CDR1as/ciRS-7 expression were more susceptibility to develop LNM (OR = 1.74, 95%CI: 1.38–2.21, P < 0.001). In addition, 7 studies with 780 cancer patients were included to analyze the association between CDR1as/ciRS-7 and distant metastasis. The results showed an obviously association between CDR1as/ciRS-7 expression and distant metastasis (OR = 2.79, 95%CI: 1.71–4.55, P < 0.001) (Fig. 4D). We also analyzed the relationship between CDR1as/ciRS-7 and tumor differentiation using the data of 1380 cancer patients from 10 studies. The results showed CDR1as/ciRS-7 expression is also correlated with tumor differentiation (OR = 2.00, 95%CI: 1.49–2.68, P < 0.001) (Fig. 4E). However, there was no significantly correlation between CDR1as/ciRS-7 and other clinicopathological features, such as age (Z = 0.01, P = 0.990) and gender (Z = 1.50, P = 0.135).

3.3. Publication bias and sensitivity analysis

To evaluate the publication bias, the Begg's funnel plots and Egger's linear regression tests were applied in this meta-analysis. According to the analysis of publication bias in our study, visual inspection of the Begg’s funnel plot revealed obvious asymmetry (Fig. 5A), and Egger’s test suggested this study may get significant publication bias (t = 2.84, P = 0.012). Thus, to assess the impact of potential publication bias, the trim and fill analysis was performed with the fixed-effects model. Two which conservatively imputes hypothetical negative unpublished studies to mirror the positive studies that cause funnel plot asymmetry. The imputed studies produce a symmetrical funnel plot (Fig. 5B). The pooled analysis incorporation the hypothetical studies continued to show a statistically significant association between CDR1as/ciRS-7 expression on OS in solid tumors (corrected HR = 1.78, 95% CI: 1.34–2.41, P < 0.001).

Sensitivity analyses demonstrated that the studies by Uhr K et al[24] and Zhou Y et al(30) were the top one with heterogeneity in the OS group, and their removal changed the results into more significant ones with no heterogeneity (HR = 2.30, 95% CI: 1.95–2.71; I² = 0%, P = 0.823) (Fig. 5C). And as indicated in Fig. 5D, the pooled HR for the independent prognostic value of CDR1as/ciRS-7 in cancers was not significantly affected by the exclusion of any of the studies.

In addition, we also evaluated the association between CDR1as/ciRS-7 and tumor size, TNM stages, LNM, distant metastases and tumor differentiation. Visual inspection of the Begg’s funnel plots revealed symmetry in the studies investigating CDR1as/ciRS-7 on tumor size (t = 0.39, P = 0.707), TNM stages (t = 1.28, P = 0.228), LNM (t = 0.25, P = 0.81,), distant metastases (t = 0.72, P = 0.502) and tumor differentiation (t = 0.31, P = 0.764), which suggested that there was no evidence of publication bias among the studies investigating CDR1as/ciRS-7 on tumor size, TNM stages, LNM, distant metastases and tumor differentiation.

CircRNAs are endogenous non-coding RNAs with functions similar to lncRNAs. They have been indicated to play functions in the occurrence and development of cancer. Recent studies have shown that abnormal circRNAs expression in various types of solid tumors. CircRNAs might have diagnostic value. Targeting CircRNAs may sensitize the drug treatment, and it is a promising therapeutic target for cancer patients.

CDR1as/ciRS-7, as a newly discovered oncogene, is an important CircRNA in human malignancies. Recent studies have found that CDR1as/ciRS-7 has multiple biological functions and is involved in cell proliferation, chemotherapy-resistance, invasion and metastasis, leading to the initialization and development of tumors. Comprehensive analysis indicates that in many solid tumors, abnormal expression of CDR1as/ciRS-7 is associated with clinical characteristics such as tumor size, tumor differentiation, TNM stage, lymph node metastasis, and distant metastasis[35–39]. However, due to heterogeneity, the perplexity and inconsistence conclusion exists in different studies. In this study, we found that elevated CDR1as/ciRS-7 expression predicted shorter OS for 13 different solid tumors and was an independent predictor of patient prognosis. CDR1as/ciRS-7 was positively correlated with differentiation, TNM stage, lymph node metastasis and distant metastasis. Taken together, our results provide compelling evidence supporting CDR1as/ciRS-7 as a negative, adverse prognostic biomarker for the human solid tumors we analyzed. Of note, the expression of CDR1as/ciRS-7 was inversely associated with poor prognosis in gynecologic cancer.

The underlying molecular mechanisms involved in CDR1as/ciRS-7 are complex and diverse in different cancers (Fig. 6). NSCLC cell growth can be promoted by the overexpression of CDR1as/ciRS-7 which sponges miR-7 to upregulate target genes, such as EGFR, CCNE1, and PIK3CD[20]. It was reported that CDR1as/ciRS-7 increased the proliferation, invasion, migration, and apoptosis of NSCLC cells through the miR-7/RELA axis[18]. The levels of p70S6K mRNA and protein expression can be increased by the downregulation of miR-7, which may be correlated with microvascular invasion (MVI), younger age, and higher AFP level in HCC[40]. CDR1as/ciRS-7 also promotes the proliferation and migration of HCC cells by sponging miR-1270 to upregulate AFP expression[41]. CDR1as/ciRS-7 enhances MMP expression to increase cellular invasion and migration in BC cells by acting as a ceRNA of miR-1299[42]. One study shows that the level of CDR1as/ciRS-7 expression is increased in ESCC, and it is correlated with poor survival. Moreover, CDR1as/ciRS-7 sponges miR-7 to reactivate HOXB13-NF-κB/p56 signaling[43]. CDR1as/ciRS-7 accelerates the invasion and migration of cells through miR-7-KLF4-NF-κB pathways in ESCC[44]. CDR1as/ciRS-7 acts as a sponge of miR-876-5p to increase MAGE-A family expression in ESCC cells, which promotes the progression of ESCC [23]. Further research is reported that CDR1as/ciRS-7 sponge miR-1299 to inhibit ESCC cell autophagy by targeting the EGFR-AKT-mTOR pathway[45]. CDR1as/ciRS-7 up-regulates the expression of E2F3 by binding miR-7-5p, which may promote the occurrence and development of NPC[27]. The overexpression of CDR1as/ciRS-7 promotes an aggressive behavior of GC cells by suppressing miR-7-involved PTEN/PI3K/AKT signaling[25]. CDR1as/ciRS-7 upregulates CCNE1 and PIK3CD expression by sponging miR-7, and it may promote LSCC progression[21]. Another study shows that CDR1as/ciRS-7 promotes the oncogenic behavior of CCC cells through combining with miR-641 to activate the AKT3/mTOR signaling pathway[46].

Some limitations exist in this meta-analysis. At first, the data across these clinical studies is discrete. And the definitions of the cutoff values of CDR1as/ciRS-7 expression level in different studies are not the same. Third, we only analyzed the reported HR or survival curves of these studies, which may lead to the potential for selection bias. Moreover, this study is limited due to the following reasons: some of the HRs and CIs were calculated by the Kaplan-Meier curves, sample size is different, and the survival rate were chosen at a specified time. Hence, a calculation bias might exist. In addition, the data collection may be incomplete as we the language of the involved studies was limited to English. Furthermore, in this meta-analysis, most of the included studies reported positive results, and the summarized data rather than individual patient data were used. Therefore, it is possible that our results might overestimate the effects of abnormal CDR1as/ciRS-7 expression on survival and clinical characteristics in different types of cancers. These limitations might be considered in the further clinical studies. Future study may analyze the potential prognostic value of CDR1as/ciRS-7 expression in other types of cancer which were not included in this study. The relationship between CDR1as/ciRS-7 and cancers may be determined by a larger sample size in future studies.

In summary, this meta-analysis suggested that the expression of CDR1as/ciRS-7 was correlated with the prognosis of cancer patients. Our results showed that the abnormal expression of CDR1as/ciRS-7 was significantly correlated with the differentiation of tumors, TNM stage, lymph node metastasis, distant metastasis, and other clinicopathological factors. Therefore, CDR1as/ciRS-7 can be used as a new biomarker for the prognosis of patients with cancers.

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Availability of data and materials: All data generated or analysed during this study are included in this published article.

Competing interests: The authors declare that they have no competing interests.

Funding: This work was supported by grants from National Natural Science Foundation of China (81970825), Natural Science Foundation of Sichuan Province (2019YJ0592), and Natural Science Foundation of Chengdu (2019-YF05-00746-SN).

Author Contributions: Shikai Zhu, Yu Zhou, and Haizhen Wang conceived this project. Yun Zhang contributed to the statistical analysis and data interpretation. Yun Zhang and Feng Pu wrote the first manuscript. Zhiqiang Kang, Tang Zhao, Qiu Zhang, Zihan Xu, and Haizhen Wang contributed to the writing and review and editing. Shikai Zhu contributed to the funding acquisition. Shikai Zhu, Yu Zhou and Hongji Yang are responsible for supervision. All authors read and approved the final manuscript submitted for publication.

Acknowledgments: We thank the authors of 16 selected studies for using their data

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No competing interests reported.

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Circular RNA CDR1as/ciRS-7-- A Novel Biomarker in Solid Tumors

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Abstract

Background

Methods

Results

Conclusion

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1. Introduction

2. Methods

2.1. Search strategy and study selection

2.2. Data extraction and quality assessment

2.3. Statistical analyses

3. Results

3.1. Study Selection and Characteristics

3.2. Prognostic value of CDR1as/ciRS-7 expression in solid tumor

3.3. Publication bias and sensitivity analysis

4. Discussion

5. Conclusions

Declarations

References

Additional Declarations

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