Some researchers suggest that the number of lung cancer cases and deaths is on the rise globally (Bade and Dela Cruz, 2020). According to the morphology of tumor cells, lung cancer can mainly be divided into small cell lung cancer (SCLC) and NSCLC. Most lung cancer cases are NSCLC (85%), so NSCLC is currently the most familiar type of lung cancer (Siegel et al., 2013). Liu et al. found that the level of circ-SHPRH was decreased in NSCLC tissues and cells, and circ-SHPRH expression was negatively correlated with the progression of NSCLC (Liu et al., 2018). Through further experimental analysis, they found that patients with higher circ-SHPRH levels had longer overall survival than patients with lower circ-SHPRH levels. Moreover, multivariate Cox regression analysis found that circ-SHPRH was an independent prognostic biomarker in NSCLC patients (p = 0.031). A study of the effect of circ-SHPRH on the function of NSCLC cells showed that upregulated circ-SHPRH expression suppressed the proliferation and metastasis of NSCLC. In a further study of the mechanism of circ-SHPRH in NSCLC, circ-SHPRH was found to inhibit the proliferation, migration, and invasion of NSCLC by directly sponging miR-331-3p and miR-338-5p. These results suggest that the circ-SHPRH/miR-331-3p/miR-338-5p signaling pathway is a potential therapeutic target, but the downstream target genes of this pathway remain unexplored.

Liver cancer ranks third among the cancers that kill men and is sixth among the top ten most common cancers in the world (Sung et al., 2021). Liver cancer can be divided into two main categories: HCC (accounting for 75%–85%) and intrahepatic cholangiocarcinoma (accounting for 10%–15%). Some HCC patients develop symptoms late, making an early diagnosis difficult to obtain, and these patients have higher rates of metastasis and recurrence, resulting in a poor 5-year survival rate (Wang M. et al., 2018). Hence, finding new biomarkers is essential to improve the prognosis and treatment of HCC. With in-depth research on circRNA, new ideas have been provided for the early diagnosis and treatment of tumors. Circ-SHPRH has been found to have antitumor effects in HCC(Qin et al., 2016; Zhang X. et al., 2018; Su et al., 2019). Qin et al. found that circ-SHPRH is downregulated in HCC compared with normal liver (Qin et al., 2016). Circ-SHPRH expression reduction is associated with adverse HCC prognosis. Furthermore, the lower the circ-SHPRH expression in the tumor, the larger the tumor volume, which suggests that circ-SHPRH is related to tumor growth. In addition, ROC analysis showed that the area under the ROC curve for circ-SHPRH was 0.63, and its specificity and sensitivity were 0.81 and 0.69; thus, circ-SHPRH may be a potential biomarker for HCC diagnosis. In terms of function, Su et al. detected that overexpression of circ-SHPRH suppressed the proliferation and migration of HCC. Mechanistically, circ-SHPRH regulates the function of HCC cells by sponging miR-4688, miR-612, and miR-127-5p (Su et al., 2019). Similarly, Zhang et al. discovered that overexpression of circ-SHPRH suppressed the proliferation, migration, and invasion of HCC cells. Moreover, Cox multivariate analysis also suggested that circ-SHPRH is a new independent prognostic factor in HCC patients, but it was not associated with clinical characteristics, such as age, TNM stage and lymphatic metastasis (Zhang X. et al., 2018). In addition, overexpression of circ-SHPRH caused increased expression of caspase-3 and caspase-9 in hepatoma cells, further enhancing apoptosis (Sun et al., 2022). The results indicate that circ-SHPRH regulates the progression of HCC and is a potential treatment target for HCC.

Cholangiocarcinoma (CCA) is a malignant tumor that occurs in the bile duct system, and its incidence is on the rise worldwide. Currently, it accounts for approximately 15% of all primary hepatobiliary malignancies, second only to hepatocellular carcinoma (Bergquist and von Seth, 2015). CCA is highly invasive and the therapeutic effects of chemotherapy and radiotherapy are poor, so the prognosis of CCA is also poor. Its overall incidence has gradually increased in the past few decades (Saha et al., 2016). Through qRT–PCR experiments, Xu et al. confirmed that circ-SHPRH expression was abnormally decreased in CCA tumor tissues (Xu et al., 2018). Fisher’s exact test results show that the level of circ-SHPRH is closely related to the volume and degree of differentiation of the tumor. Functionally, circ-SHPRH can suppress the proliferation, invasion, and migration of CCA cells and induce apoptosis of CCA cells. The above findings suggest that circ-SHPRH has potential value as a clinical diagnostic and prognostic predictor of CCA.

In recent years, the incidence of pancreatic ductal adenocarcinoma (PDAC) has been increasing, and its 5-year survival rate is only approximately 9%, making it a deadly malignant tumor (Siegel et al., 2020). Due to the lack of effective screening methods, many patients have been diagnosed with advanced cancer, so the prognosis of these patients is extremely poor (Stathis and Moore, 2010; Koch et al., 2020). Jiang et al. confirmed that circ-SHPRH expression was abnormally decreased in PDAC cells through qRT–PCR experiments (Jiang et al., 2018). In terms of clinicopathological features, Fisher’s exact test analysis showed that the level of circ-SHPRH was lower in poorly differentiated tumors (p = 0.018). Kaplan–Meier survival curve analysis found that patients with higher circ-SHPRH expression had better 5-year overall survival than patients with lower circ-SHPRH expression (p = 0.002). The level of circ-SHPRH was positively associated with the 5-year overall survival rate of patients. In addition, Cox regression analysis suggested that the level of circ-SHPRH was an independent prognostic factor for PDAC (p = 0.039). In further exploration of the role of circ-SHPRH in cell function, upregulation of circ-SHPRH was discovered to suppress the proliferation and colony formation of PDAC cells. Furthermore, circ-SHPRH promoted the apoptosis of PDAC cells by activating caspase-9 and caspase-3. Caspase-9 and caspase-3 can promote apoptosis and play important roles in cell apoptosis (Brentnall et al., 2013). In summary, circ-SHPRH inhibits PDAC growth and promotes apoptosis, so it may become a new PDAC therapeutic target in the future.

Gastric cancer (GC) is one of the most common malignant cancers in the world, and the incidence and mortality of gastric cancer rank fifth and fourth, respectively (Machlowska et al., 2020). Gastric cancer has a higher degree of malignancy and a poor prognosis, and many patients are diagnosed with advanced gastric cancer (Sung et al., 2021). A study by Li et al. discovered that the level of circ-SHPRH in gastric cancer tissues was significantly reduced compared with that in normal tissues (Li et al., 2017). By comparing the level of circ-SHPRH in serum samples of GC patients before and after surgery, the expression of circ-SHPRH in the serum of GC patients after surgery was found to be significantly increased. ROC curve analysis indicated that circ-SHPRH has high accuracy, specificity, and sensitivity, and can be a biomarker for GC. In addition, researchers discovered that the level of circ-SHPRH was correlated with the pathological differentiation of GC. This result suggests that circ-SHPRH has the potential to be used as a novel biomarker for GC. A study by Sun et al. also proved that circ-SHPRH is downregulated in GC (Sun et al., 2020). In addition, they found that upregulation of circ-SHPRH suppressed the proliferation, migration, and invasion of GC cells. It can also promote the apoptosis of GC cells. At present, studies have found that miR-20a expression is higher in GC and can promote the growth of GC cells (Jafarzadeh-Samani et al., 2017). Mechanistically, researchers found that circ-SHPRH further inhibited the downstream ERK and Wnt/β-catenin pathways, mainly by inhibiting miR-20a. Overexpression of miR-20a significantly reversed these effects. These data suggest that circ-SHPRH inhibits the ERK and Wnt/β-catenin pathways by downregulating the expression of miR-20a, thereby achieving a tumor suppressor effect (Huang et al., 2017; Yang et al., 2017).

Approximately 900,000 people worldwide die from colorectal cancer every year, often at an advanced stage after diagnosis (Sung et al., 2021). The prognosis of CRC patients remains poor due to postoperative recurrence and metastasis. Therefore, finding new biomarkers is essential to improve the prognosis and treatment of CRC. Ji et al. confirmed that the level of circ-SHPRH in colorectal cancer tissues was significantly lower than that in the corresponding normal tissues. In addition, by comparing the levels of circ-SHPRH in the serum of CRC patients before and after surgery, they discovered that the level of circ-SHPRH was noticeably increased after surgery. In addition, they discovered that the higher the level of circ-SHPRH, the better the pathological differentiation of colon cancer. This result indicated that the level of circ-SHPRH was correlated with pathological differentiation (p = 0.037). The results of the ROC curve analysis showed that circ-SHPRH has potential diagnostic value in CRC (Ji et al., 2018). These results indicate that circ-SHPRH can be used as a new biomarker for specific and sensitive CRC detection.

Bladder cancer (BC) is a relatively common malignant tumor of the urinary system, with more than 500,000 new cases worldwide every year (Lenis et al., 2020; Richters et al., 2020). Zuo et al. found that the level of circ-SHPRH in BC tissues and cell lines was significantly decreased and low expression of circ-SHPRH was associated with high grade, advanced pathological T stage and lymph node metastasis of BC. It has been reported that silencing of circ-SHPRH significantly enhances the proliferation, migration, and invasion of BC cells. Overexpression of circ-SHPRH inhibits tumor growth in vivo. Elevated circ-SHPRH upregulated the expression of a downstream gene (BARX2) by adsorbing miR-942 and effectively suppressed the proliferation, invasion, and migration of BC cells (Zuo et al., 2022). In conclusion, targeting circ-SHPRH to explore new therapeutic methods for BC has good application prospects.

Osteosarcoma is a malignant tumor originating from mesenchymal tissue that mainly occurs in adolescents and has the characteristics of high malignancy and pulmonary metastasis (Bozorgi and Sabouri, 2021). Sun et al. found that upregulation of circ-SHPRH can inhibit the proliferation of OS cells and induce apoptosis. By qRT–PCR, they found that circ-SHPRH was dramatically reduced in OS compared with normal tissues (Sun and Zhu, 2020). Mechanistically, they found that there is a potential regulatory relationship between circ-SHPRH and miR-338-5p, miR-942, and miR-647. Further study confirmed that circ-SHPRH can combine with miR-338-5p, miR-647, and miR-942 to act as a molecular sponge, thereby inhibiting OS proliferation and inducing OS apoptosis (Liu et al., 2017; Long et al., 2018; Zhang et al., 2019). The STAT signaling pathway plays a significant role in cancer cell proliferation and differentiation and participates in tumor cell recognition and tumor-driven immune escape (Quesnelle et al., 2007; Roberts et al., 2007). Among the STATs, STAT3, and STAT5 play a major role in cancer by mediating the processes of tumor generation and development and regulating downstream gene expression (Linher-Melville and Singh, 2017). circ-SHPRH can further inhibit the STAT pathway by combining with three miRNAs (miR-338-5p, miR-647, and miR-942).

Glioma is a malignant tumor of the central nervous system. Because of its strong invasion and high recurrence rate, a surgical cure is difficult to achieve (Van Meir et al., 2010; Gittleman et al., 2018). Wang et al. discovered that circ-SHPRH was generally downregulated in glioma specimens (Wang Y. et al., 2018). They found that downregulated circ-SHPRH was related to larger tumor size and advanced grade. The study also found that the upregulation of circ-SHPRH can suppress the growth and cloning ability of glioma cells and promote the apoptosis of glioma cells. Bcl-2 and Bax regulate the release of cytochrome c and therefore play a central regulatory role in cell growth and apoptosis (Knudson et al., 1995; Evan and Littlewood, 1998). Researchers found that circ-SHPRH regulates apoptosis induced by the Bcl-2/caspase-3 pathway. In another study, Chen et al. examined 14 candidate circRNAs for analysis and finally screened three circRNAs (circFOXO3, circ0029426, and circ-SHPRH) whose expression in the serum of patients was much higher than that of healthy volunteers (Chen et al., 2020). The results showed that circ-SHPRH is a tumor suppressor in glioma and a possible biomarker for this type of cancer. In another study, Zhang et al. found that the circ-SHPRH encodes a new protein called SHPRH-146aa (Zhang M. et al., 2018). Compared with normal tissues, the expression levels of circ-SHPRH and SHPRH-146aa were both downregulated in gliomas. Overexpression of SHPRH-146aa can reduce the malignant behavior and tumorigenicity of glioma in vitro and in vivo. Mechanistically, SHPRH-146aa can protect SHPRH from degradation by the ubiquitin–proteasome and promote the ubiquitination of proliferating cell nuclear antigen (PCNA). These results suggest that SHPRH-146aa, encoded by circ-SHPRH, is a cancer suppressor in glioma.

Retinoblastoma (RB) is a rare pediatric cancer, but it is the most common intraocular malignancy in adolescents. There are approximately 9000 newly diagnosed patients worldwide each year. In less developed regions, the mortality rate of retinoblastoma is approximately 70% (Dimaras et al., 2012). Through qRT–PCR detection, Xing et al. discovered that circ-SHPRH was reduced in RB tissue samples compared to normal tissue (Xing et al., 2018). After upregulation of circ-SHPRH, the proliferative capacity of RB cells was significantly reduced, and the proportion of apoptotic cells was significantly increased. Further exploration of the tumor suppressor mechanism showed that circ-SHPRH inhibited RB proliferation and promoted RB apoptosis by regulating the AKT/mTOR signaling pathway. The results of animal experiments showed that the growth of xenografts in the circ-SHPRH overexpression group was obviously slower than that in the blank group. Furthermore, Fisher’s exact test showed that circ-SHPRH was significantly related to cancer volume (p = 0.017) and advanced intraocular international retinoblastoma classify (IIRC) stage (p = 0.01). Kaplan–Meier survival analysis showed that the 5-year survival rate of patients with downregulated circ-SHPRH was poor (p = 0.005). Furthermore, Cox regression analysis showed that circ-SHPRH may be an independent prognostic indicator for RB (p = 0.023). In conclusion, enhancing the role of circ-SHPRH in RB may become a new therapeutic strategy.

Oral squamous cell carcinoma (OSCC) is one of the most common tumors of the head and neck, ranking eighth among the most common tumors in the world (Bouaoud et al., 2022). OSCC is the most common oral cancer with a poor prognosis and a high mortality rate. Tobacco, alcohol, and genetic alterations are the main factors. In addition, patients with secondary tumors have a lower survival rate because of the higher rate of secondary tumor formation compared with other tumors (Chamoli et al., 2021). Hung et al. found that the expression of circ-SHPRH was downregulated in OSCC tissues and plasma samples (Hung et al., 2022). The expression of circ-SHPRH in advanced OSCC patients was significantly lower than that in healthy controls. In addition, the expression of circ-SHPRH in the plasma of patients with recurrent OSCC was significantly lower than that of patients without recurrent OSCC. Patients with reduced plasma circ-SHPRH levels had a higher risk of early tumor recurrence and poor prognosis. These results suggested that circ-SHPRH, as a biomarker in plasma, has a high value in predicting recurrent OSCC. There is also great potential for risk classification and improved treatment strategies in OSCC patients.

A flow chart of screening eligible articles for the meta-analysis is shown in Figure 4. The 11 included studies were published between 2016 and 2022. Three eligible published studies about circ-SHPRH were enrolled based on their tumor diagnosis aspect (Qin et al., 2016; Li et al., 2017; Ji et al., 2018), 7 eligible published studies were related to overall survival (OS) (Zhang M. et al., 2018; Wang Y. et al., 2018; Zhang X. et al., 2018; Jiang et al., 2018; Liu et al., 2018; Xing et al., 2018; Xu et al., 2018; Zuo et al., 2022), and 3 eligible published studies were related to tumor grade (Jiang et al., 2018; Liu et al., 2018; Xu et al., 2018). Expression of circ-SHPRH was measured using quantitative real-time polymerase chain reaction (RT-qPCR).

A total of 3 publications involving 229 cases were included in the diagnostic meta-analysis. The main characteristics of all included studies are shown in Table 1. The quality assessment results of the diagnostic studies are shown in Figure 5. The meta-analysis of the sensitivity and specificity of circ-SHPRH showed that the combined study had a sensitivity and specificity of 0.78 (0.72–0.83) and 0.73 (0.67–0.79), respectively, and a PLR and an NLR of 3.02 (1.95–4.66) and 0.30 (0.23–0.39), respectively, which are more important values than the first two indicators (Figures 6A–D). Due to the high heterogeneity of the specificity and PLR, we switched to a random effects model for analysis. The DOR value was 10.15 (6.63–13.52) (Figure 6E). The corresponding area under the SROC curve (AUC) was calculated to be 0.8357 (Q* = 0.7679), revealing moderate diagnostic accuracy (Figure 6G). Egger’s publication bias plot was conducted to evaluate publication bias. The shape of the funnel plots showed symmetry for all included studies and the p-value of Egger’s test was 0.296 (Figure 6F).

Meta-analysis of 7 eligible studies, involving 434 patients, showed better OS in malignancies with high circ-SHPRH expression (HR = 0.53, 95% CI 0.38–0.74, I-squared = 0.0%, p-value <0.05) (Figure 7A) (Table 2). To further understand the association between circ-SHPRH expression and TNM stage, a meta-analysis of 3 eligible studies, involving 187 patients, was performed. The results showed that patients with higher circ-SHPRH expression had lower TNM stage (HR = 0.33, 95% CI 0.18–0.62, I-squared = 0.0%, p-value = 0.001) (Figure 7B). The potential publication bias was estimated by using Begg’s funnel plot. As shown in Figure 7C, the Begg’s funnel plot showed symmetry, the p-value = 0.649.