The public databases PubMed, EMBASE, Web of Science, Wiley Online Library, and Medline were searched with the terms “CDR1NAT” or “ciRS-7” or “CDR1as” and “Cancer” or “Tumor” or “Neoplasia” and “prognos*” or “surviv*” or “outcome” or “predict.” The last search was on December 1, 2020.

All eligible study data were evaluated and extracted by two researchers; the relationship between CDR1as, tumor tissue, and patient survival was analyzed only when expression levels were reported. The inclusion criteria were as follows: (a) expression levels of CDR1as in cancer tissues; (b) correlation between the expression levels of CDR1as and survival outcomes (OS, progression-free survival [PFS], metastasis-free survival [MFS], or disease-free survival [DFS]); (c) hazard ratio (HR) and 95% confidence interval (CI) for survival time were reported or could be calculated from the reported data. Exclusion criteria were as follows: (a) Animal studies, case reports, meta-analysis articles, and reviews; (b) Papers lacking raw data or from which we could not calculate the HR, 95% CI, and p values.

We extracted the following data: first author’s name, publication year, study region, sample size, cancer type, tumor size, tumor node metastasis (TNM) stage, the method of CDR1as testing, outcome, HR with 95% CI, and HR statistics from each eligible study.

STATA 12.0 (StataCorp, College Station, TX, USA) was used in this study. HR, OR, and corresponding 95% CIs were used as indicators to evaluate each clinical parameter and patient prognosis or survival. p < 0.05 was considered statistically significant.

Cerebellar degeneration-related protein 1 antisense RNA (CDR1as), also known as asciRS-7, is a circRNA that is transcribed in the antisense orientation with respect to the CDR1 gene (30, 31). CDR1as is predominantly found in the human brain, it is 1485bp in length and located on the X chromosome (chrX: 139865339–139866824) (32). It functions as a miR-7 sponge/inhibitor in the embryonic zebra fish (33), and it is also expressed in a variety of tissues and organs in the human body. Its expression imbalance is associated with a variety of diseases, such as Alzheimer’s disease, diabetes, myocardial infarction, and cancer (34–36). CDR1as has diverse biological functions and it is mainly involved in the proliferation, migration, and invasion of tumor cells. It regulates the biological function of tumors in two main ways (1): binding to the miRNA as a competing endogenous RNA through the base complementary pairing principle (2); regulating gene expression at the transcriptional and post-transcriptional level (2, 13, 15, 37). Numerous studies have shown that CDR1as is dysregulated in many human malignancies, such as CRC, non-small cell lung cancer (NSCLC), HCC, and gastric cancer (GC); they may serve as new diagnostic biomarkers and cancer treatment targets (38, 39). We systematically reviewed the literature to provide information on CDR1as expression patterns and roles in various tumors.

Recently, four research groups have analyzed the expression of CDR1as in HCC and its relationship with prognosis (40–43) (Table 1). Although the expression of CDR1as in HCC tissues remains controversial, upregulation of CDR1as is an independent risk factor for hepatic microvascular invasion (MVI) and promotes the proliferation and invasion of HCC cells by inhibiting the expression of mir-7 and its downstream target genes CCNE1, PIK3CD, KLF4, and p70S6K (Figure 1A). Jiang et al. evaluated the relationship between CDR1as expression levels and clinicopathological features of cholangiocarcinoma (CCA) and assessed the association of CDR1as expression with OS. The results showed that upregulation of CDR1as was closely associated with advanced TNM stage, lymph node invasion, and postoperative recurrence, and the OS of patients with CCA with high CDR1as expression was worse than that of patients with CCA with low CDR1as expression (48). CDR1as binds to Mir-641 and accelerates the degradation of Mir-641, which may lead to upregulation of relative mRNA levels of AKT3 and mTOR and thus promote tumor progression (49). These data indicate that CDR1as plays an important regulatory role in the progression of HCC and may provide insights for the treatment of HCC and CCA.

In non-small cell lung cancer tissues, the expression of CDR1as is upregulated compared with para-carcinoma tissues. The dysregulation of CDR1as is significantly related to the clinical features and prognosis of NSCLC (44). Su et al. (45) confirmed that upregulation of CDR1as could inhibit the expression of miR-7 and that it correlates with advanced histopathological grade, larger tumor size, and more severe lymph node metastasis. Furthermore, researchers have confirmed that overexpression of CDR1as and downregulation of mir-7 increases the proliferation, metastasis, and invasion ability of NSCLC cells by the CDR1as/miR-7/NF-kB (p65) axis (Figure 1B). Zhang et al. demonstrated that patients with high expression of CDR1as had a high TNM stage, more frequent lymph node metastasis, shorter OS time, and that CDR1as was an independent prognostic factor for patients with NSCLC. Mechanistically, CDR1as functioned as a miR-7 sponge to upregulate the key target genes of miR-7, including EGFR, CCNE1, and PIK3CD (46) (Figures 1A, B). Li et al. indicated that knockdown of circCDR1as inhibited the progression of NSCLC by decreasing cell viability, migration, and invasion, and increasing apoptosis by upregulating miR-219a-5p and downregulating SOX5 (47). These studies indicate that CDR1as may play an important role in the development of NSCLC and may contribute to the diagnosis and prognosis of NSCLC.

Tang et al. found that the expression of CDR1as was upregulated in CRC tissues compared to the adjacent normal mucosa. High expression of CDR1as was positively correlated with tumor size, T stage, lymph node metastasis, and poor OS. Dysregulation of CDR1as inhibited CRC cell proliferation and suppressed EGFR and IGF-1R expression by blocking miR-7expression (50) (Figures 1B, C). Weng et al. analyzed the clinical significance of CDR1as in CRC patients and found that CDR1as was significantly upregulated in CRC tissues compared with matched normal mucosae. Furthermore, they revealed by multivariate survival analysis that CDR1as could be an independent risk factor for OS. Upregulation of CDR1as led to blocking of miR-7 and resulted in a more aggressive oncogenic phenotype, and subsequent activation of EGFR and RAF1 oncogenes in HCT116 and HT29 cells (51) (Figure 1C). These findings suggest that CDR1as could be a prognostic biomarker in CRC patients and may serve as a therapeutic target in CRC patients.

A study performed by Sang et al. suggested that CDR1as is upregulated in ESCC and that it is associated with poor clinicopathological parameters in ESCC patients. High expression of ciRS-7 increased the proliferation, migration, and invasion abilities of ESCC cells. Mechanistic studies revealed that CDR1as acts as a sponge for miR-876-5p in ESCC cells. Furthermore, CDR1as reverses miR-876-5p-mediated repression of the tumor antigen MAGE-A family in ESCC cells (52) (Figure 1D). Li et al. (53) evaluated the expression of CDR1as in 123 ESCC patients and found that CDR1as expression was significantly upregulated in ESCC tissues compared with normal tissues. High expression of CDR1as was positively correlated with poor survival and advanced TNM stage, and inhibited the tumor inhibition of miR-7, including cell proliferation, migration, and invasion. Research on the mechanisms revealed that CDR1as functioned as a sponge for miR-7 and reactivated its downstream HOXB13-mediated NF-κB pathway (Figure 1D). Huang et al. demonstrated that the expression of ciRS-7 was significantly increased in ESCC tissues and cells compared with their corresponding controls, and that ciRS-7 triggers the migration and invasion of ESCC via miR-7/KLF4 and NF-κB signals (54). These studies indicate that CDR1as may play an important role in the development of ESCC and might contribute to the diagnosis and prognosis of ESCC.

CDR1as was identified as a circRNA in the brain and it is highly expressed in normal brain tissues (65). Barbagallo et al. observed that the expression of CDR1as is significantly decreased in glioblastoma multiforme biopsies and compared to normal brain parenchyma (average change= −3.51-fold), in glioblastoma multiforme cell lines and other cancer cell lines, except HCT116. Furthermore, the researchers identified CDR1as as a downstream miR-671-5p target in glioblastoma multiforme and that it is the only circRNA known to be targeted and degraded by miR-671-5p (55, 65). Lou et al. revealed that CDR1as expression decreased with the increase in glioma grade and that it was a reliable independent predictor of overall glioma survival. In terms of mechanism, CDR1as functions as a tumor suppressor by binding directly to p53 at its DBD region to restrict MDM2 interaction (56).

Zhang et al. collected 30 laryngeal squamous cell carcinoma (LSCC) tissues and corresponding relative normal tissues to determine the expression of CDR1as and their clinical significance. The results indicated that patients with high TNM stages, poorly differentiated tumors, lymph node metastases, and poor prognosis had high CDR1as levels. Overexpression of CDR1as enhanced cell vitality and promoted the proliferation, migration, and invasion of two LSCC cell lines. Mechanistically, CDR1as functioned as miR-7 sponges and upregulated the key targets of miR-7, CCNE1, and PIK3CD (57). Zhong et al. examined 44 nasopharyngeal carcinoma (NPC) tissues and 20 non-tumor tissues, and the results confirmed that CDR1as was highly expressed in NPC tissues and cell lines, which might be related to the promotion of NPC cells development. Moreover, CDR1as could upregulate E2F3 expression by binding to miR-7-5p, and promote the growth and glucose metabolism of NPC cells (58). These results indicate that CDR1as is an oncogene in NPC and LSCC.

Zhang et al. predicted the regulatory role of CDR1as in melanoma through bioinformatics analysis and showed that CDR1as may act as a competing endogenous RNA for the vital genes, which are associated with the invasion and migration of melanoma (59). Recent research has revealed that epigenetic silencing of LINC00632 can lead to the depletion of CDR1as and promote invasion in vitro, and metastasis in vivo through a miR-7-independent, IGF2BP3-mediated mechanism (60). These results indicate that CDR1as plays an important regulatory role in the biological process of melanoma.

Li et al. found that the expression of CDR1as in bladder cancer was significantly lower than that in adjacent tissues. CDR1as overexpression inhibits the proliferation, invasion, and migration of bladder cancer cells and directly binds to miR-135a and inhibits its activity in bladder cancer (61) (Figure 1E). Yuan et al. reported that Cdr1as induced apoptosis and enhanced the chemosensitivity of bladder cancer cells both in vitro and in vivo. We verified that CDR1as exerts a cisplatin-chemosensitization effect on bladder cancer cells through the CDR1as/miR-1270/APAF1 axis (62).

A study by Pan et al. investigated the clinical significance of CDR1as in 102 primary gastric cancer tissues and matched para-carcinoma tissues, and subsequently confirmed the clinical relevance in an independent validation cohort. The results indicated that CDR1as expression was higher in gastric cancer tissues than in para-carcinoma tissues, and increased with the tumor stage. The overexpression of CDR1as blocks tumor inhibition induced by miR-7 in MGC-803 and HGC-27 cells by antagonizing the miR-7-mediated PTEN/PI3K/AKT pathway (Figure 1E), leading to a more aggressive oncogenic phenotype (63).

Uhr et al. revealed the relationship between miR-7 and its binding compound CDR1as and the prognosis and prediction of first-line tamoxifen treatment for breast cancer (66). Xu et al. showed that CDR1as was upregulated in osteosarcoma tissues and its expression was positively correlated with tumor size and distant metastasis. Knockdown of CDR1as leads to de-repression of miR-7 levels and inhibition of its target genes, including EGFR, CCNE1, PI3KCD, and RAF1, impaired cell vitality and increased apoptosis and G1/S arrest in parallel with reduced cell migration ability (64). In addition, CDR1as has been reported to play an important role in the development of ovarian cancer and pancreatic cancer (67, 68).

An increasing number of studies have shown that upregulation of CDR1as is associated with prognosis in various types of cancer (69, 70). We performed a comprehensive literature search from a public database (PubMed, Medline, and Web of Science) to identify all eligible studies describing the use of CDR1as as a prognostic factor for different types of cancer. A total of eight studies were included in this study (45, 46, 48, 50, 51, 53, 57, 63). The results showed that high expression of CDR1as was significantly associated with poor OS (HR = 2.50, 95% CI: 2.06−3.04; p < 0.001) (Figure 2). Furthermore, the results revealed the prognostic significance of CDR1as in digestive system neoplasms (HR = 1.69, 95% CI = 2.14−2.71; p < 0.001), CRC (HR = 1.34, 95% CI = 1.96−2.85; p < 0.001), and NSCLC (HR = 2.40, 95% CI = 3.42−4.83; p = 0.008) (Figure 3). High expression levels of CDR1as were also associated with TNM stage (OR = 2.13, 95% CI = 1.63–2.78; p = 0.001), distant metastases (OR = 3.50, 95% CI = 1.90–6.64; p = 0.008), and lymph node metastases (OR = 1.68, 95% CI = 1.24−2.26; p = 0.001), but not with the differentiation status and lymph node invasion (Figure 4). These results suggest that the expression of CDR1as may be an effective biomarker for the diagnosis, treatment, and prognosis of tumors.