text:
Pathol. Oncol. Res., 17 March 2022
https://doi.org/10.3389/pore.2022.1610037
Circular RNAs as Diagnostic and Prognostic Indicators of Colorectal Cancer: A Pooled Analysis of Individual Studies
Cong Long1, Qiu-bo Xu1, Li Ding1, Li-juan Huang1 and Yong Ji2*
1Department of Clinical Laboratory, Jingjiang People's Hospital, Taizhou, China
2Department of General Surgery, Jingjiang People's Hospital, Taizhou, China
Background: Circular RNAs (circRNAs) have proven as a special subset of endogenous RNAs that are implicated in the tumorigenesis of various cancers. This study sought to evaluate the role of circRNAs in the diagnosis and prognosis of colorectal cancer (CRC).
Methods: The online databases were searched for collecting relevant studies on circRNAs as diagnostic and prognostic biomarkers of CRC. Two researchers independently screened literature, extracted data, and evaluated the bias and risks of included studies. The diagnostic and prognostic indicators were merged and analyzed using STATA 12.0 software, and sources of heterogeneity were traced by the sensitivity analysis and the meta-regression test.
Results: A total of 29 articles representing 2639 CRC patients were included. The pooled sensitivity, specificity, and area under the curve (AUC) of circRNAs in differentiating CRC from non-tumor control were 0.75 (95% CI: 0.69–0.80) and 0.74 (95% CI: 0.69–0.78) and 0.81, respectively. The survival analysis showed that up-regulations of up-regulated circRNAs were significantly related to dismal survival in CRC patients (HR = 2.38, p < 0.001). A stratified analysis showed that the comprehensive diagnostic value of up-regualted circRNAs in CRC was higher than that of down-regualted circRNAs (AUC: 0.83 vs. 0.77; Z test, p < 0.05). The efficacy of tissue-derived circRNAs in the diagnosis of CRC was equal to that of plasma/serum-derived ones (AUC: 0.81 vs. 0.82; Z test, p > 0.05).
Conclusion: Abnormally expressed circRNAs as auxiliary biomarkers present underlying value in the diagnosis and prognosis prediction of CRC.
CRC as one of the most common malignant tumors of the digestive tract accounts for 10.2% of total cancer cases—18.1 million new cases worldwide in 2018—according to Global Cancer Statistics 2018 released by WHO, ranking the third (1). As with the 2015 China Cancer report, CRC ranks the fourth and third in morbidity and mortality in the nation, respectively (2). Due to the concealment of early symptoms of the disease, most of the patients initially visit a doctor until the middle and late stage (3). Along with the limited therapeutic effect and multiple relapses, the prognosis of the patients is very poor (4). Therefore, establishing an early diagnostic system for CRC, which means better prognosis and timely adoptions of new and effective therapies, is the preoccupation for reducing the mortality and ameliorating the prognosis. Though endoscopic biopsy combined with histopathology is the gold standard for its diagnosis, such an invasive examination cannot be easily accepted by some patients (5,6). The diagnostic efficacy of traditional biomarkers including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and CA72-4 are limited (4). A published meta-analysis has shown that the total sensitivity of CA19-9 in the diagnosis of CRC is only from 0.68 to 0.71 (a threshold of 5 μg/L to 10 μg/L), far from the requirements of clinical diagnosis and treatments (7). In this respect, searching for new markers is an important means of early diagnosis of CRC.
CircRNAs are a class of non-coding RNA featuring covalent bindings that form a closed loop with the 3′ and 5′ ends (8,9). CircRNAs, widely expressed in mammalian cells, are tissue-cell specific, structurally stable and sequence-conserved (10). Some types of circRNAs are proven to play roles in the transcription and expression of genes via multiple ways, which play an important role in cell cycle, cell aging and other physiological processes (10,11). Accumulating studies have shown that circRNAs are critical in the occurrence and development of malignant tumors (12,13). At present, many studies have reported that circRNAs have underlying clinical values in the early diagnosis and prognosis evaluation of CRC (14–42). In view of the fact that there are noticeable problems of single-item single-center trials, such as small sample size and large result bias, this study intends to systematically evaluate the potential application value of circRNAs in clinical diagnosis and prognosis evaluation of CRC through a PRISMA-compliant pair-wise meta-analysis.
Data Search Strategy
Retrieval data were extracted from papers published in English on PubMed, EMBASE, Web of Science and CNKI databases due November 1st, 2021. The key words encompassed "colorectal cancer", "colorectal carcinoma", "carcinoma of colon", "colorectal neoplasms", "circular RNA", "circRNA", "hsa circ", "diagnoses", "diagnosis", "sensitivity", "specificity", "area under the curve", "AUC", "ROC curve", "prognoses", "prognosis", "survival", "overall survival", "progression free survival", "hazard ratio", "OS", "PFS" and "HR". Besides, references attached to the paper were also searched manually to prevent omission of any eligible literature.
Inclusion and Exclusion Criteria
Inclusion criteria were listed as follows: 1) case-control studies; 2) studies on the evaluation of diagnostic value and/or prognosis of circRNA in CRC; 3) data of true positive number (TP), false positive number (FP), false negative number (FN) and true negative number (TN) that could be obtained directly or indirectly to construct a 2 × 2 four-grid table for the diagnostic meta-analysis; 4) the prognostic observation indice was total survival time (overall survival, OS), or progression free survival (PFS), for outputting the hazard ratio (HR) and 95% confidence interval (CI) directly or indirectly. Exclusion criteria were defined as follows: 1) a study size of less than 20 cases; 2) data used for statistical analysis were insufficient or unavailable even after contacting original authors; 3) non-English language articles or low quality research.
All relevant literature was screened by two trained authors. The basic information was extracted independently: name of the first author, date of publication, study population, sample size, the control type, circRNA signatures, detection methods, reference genes, cut-off value settings, follow-up time, as well as values of sensitivity, specificity, AUC, HR, and 95% CI(s) and so forth.
The Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool was adopted to evaluate the quality of references prior to the diagnostic meta-analysis (43). The evaluation system comprised two parts: bias evaluation and applicability. Specifically, the bias evaluation consisted of case selection, index tests, reference standards, and flow and timing, and the applicability evaluation of case selection, trials to be evaluated and gold standard. Each item could be classified as low risk, high risk and unknown, with the corresponding scores of 1, 0, and 0, respectively. The total score of ≥4 (with a full score of 7) indicated that the quality of literature research was high. The case-control study was evaluated according to 8 items of the Newcastle-Ottawa Scale (NOS scale) (44), categorized into study selection, comparability, and outcome. The total rated score of ≥5 (with a full score of 9) suggested that the quality of literature research was high.
Statistical analysis was carried out using MetaDiSc 1.4 and STATA 12.0 software, and the combined-effect indices involved sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), AUC, HR and 95% CIs. The difference in the merged area under the curve (AUC) between groups was compared by Z test. Spearman correlation coefficients were calculated to evaluate the threshold effect using MetaDiSc 1.4, while Cochran' Q and I2 tests to assess the non-threshold effect using STATA 12.0. The level of significance was set at p < 0.01 or I2 > 50%. When there was no heterogeneity between studies, the statistics could be merged by the fixed-effect model; and when heterogeneity appeared, the statistics would be combined using the random-effect model. The sources of heterogeneity were deeply traced by a sensitivity analysis and a meta-regression test. Publication bias was judged by Deek's quantitative funnel plot, as well as Begg's and Egger's tests, and the significant level was set at p < 0.1. The trim-and-fill method was adopted to assess the possible effect of publication bias (45).
Study Selection and Data Characteristics
Of the initially screened 536 references from the aforesaid online databases according to the retrieval strategy, 29 articles (19 for diagnosis and 14 for prognosis) (14–42) that met the inclusion and exclusion criteria were eventually enrolled for our meta-analysis. The literature retrieval process was depicted in Figure 1.
FIGURE 1. The flow chart of literature inclusion and exclusion process according to the PRISMA statement.
The basic characteristics of the 29 articles (14–42) were summarized in Tables 1, 2. A total of 2639 CRC patients and 1471 matched controls were enrolled. The CRC cases were confirmed by pathological examinations and the included control group encompassed healthy subjects and paracancerous controls. All tissue and plasma samples were obtained preoperatively without any other treatment. The included individuals in our study included Asians and Caucasians, and 34 circRNAs were involved in the meta-analysis, of which 25 acting as oncogenes were up-regulated and 9 as tumor-suppressor genes were down-regulated in CRC. The expression levels of circRNAs in CRC were determined by RT-qPCR or RNA sequencing, and GAPDH, 18srRNA, or β-actin mRNAs were used as internal reference genes. Of the 15 included studies on the prognosis of CRC, 9 provided available HRs and 95% CIs, 6 offered relevant data that could indirectly calculate the indices by formulas or prognosis curves. The median follow-up time varied from 1 to 39 months.
TABLE 1. Basic characteristics of the included studies for assessing diagnostic performances of circRNAs in CRC.
TABLE 2. Basic characteristics of the included studies for the appraisal of prognostic effects of circRNAs on CRC.
Heterogeneity Test
The Spearman correlation coefficient analysis showed a p value of 0.356 (Spearman correlation coefficient: −0.267) in diagnostic meta-analysis, suggesting that there was no heterogeneity resulted from the threshold effect. A p value of <0.001 and I2 of 97.46% for the overall combined diagnostic effect were presented in Cochran' Q and I2 tests, indicating that substantial heterogeneity existed in the non-threshold effect. No heterogeneity was observed in the combined prognostic meta-analysis (oncogenic circRNAs: I2 = 0.0%, p = 1.000; adjusted effect of the tumor-suppressor circRNAs: I2 = 0.0%, p = 0.994).
Bias Risk Assessments for the Included Studies
For the diagnostic meta-analysis, the QUADAS-2 scale was used to assess the risk of bias. As a result, the rated scores of all 19 articles were higher than 4 (Table 3), suggesting that the overall quality of the included studies was high. Consistently, the NOS scale showed high scores of over 6 in the observational studies (Table 4), indicating the high quality of the included case-control studies.
TABLE 3. The study quality and the bias risk in studies on the diagnostic efficacy of circRNAs were assessed by the QUADAS II checklist.
TABLE 4. The study quality and the bias risk in case-control studies were rated by the NOS scale.
Diagnostic Efficiency
The forest plots showed that the pooled sensitivity, specificity, PLR, NLR, DOR and AUC of circRNAs in the diagnosis of CRC were 0.75 (95% CI: 0.69–0.80), 0.74 (95% CI: 0.69–0.78), 2.87 (95% CI: 2.46–3.34), 0.34 (95% CI: 0.28–0.42), 8.37 (95% CI: 6.32–11.09) and 0.81, as shown in Figure 2. Subgroup analysis showed that the AUC of up-regulated circRNAs in the diagnosis of CRC was higher than that of down-regulated circRNAs (AUC: 0.83 versus 0.77; Z test, p < 0.05), and the former had higher diagnostic specificity and DOR (Table 5). Analysis based on different control sources showed that the efficacy of circRNA expression profile was higher in distinguishing CRC from healthy differentiation than its ability to distinguish CRC from PNC (Table 5). Analysis based on different sample type and reference gene showed that the efficacy of circRNA abnormal expression profile based on issue was equivalent to that of ACU based on plasma/serum; GAPDH based testing and non-GAPDH based testing could also obtain similar results (Table 5).
FIGURE 2. Forest plots of pooled (A) sensitivity, (B) specificity, (C) DOR, and (D) AUC for the diagnostic effect of circRNAs in CRC.
TABLE 5. Subgroup study of the diagnostic efficacy of circRNAs in CRC.
Prognostic Analysis
The subgroup classification was conducted according to the gene functions of circRNAs. The prognosis analysis showed that high expression levels ofup-regulated circRNAs were associated with the poor OS in GC patients (HR = 2.38, 95% CI: 1.66–3.41, p = 0.000), whereas the total survival time in GC patients with high expressed down-regulated circRNAs was significantly prolonged (an outlier eliminated adjusted HR = 0.33, 95% CI: 0.15–0.72, p = 0.006) (Figure 3).
FIGURE 3. Forest plots of the prognostic effect of (A) up-regulated, (B) un-adjusted down-regulated circRNAs and (C) adjusted down-regulated circRNAs on survival in CRC patients.
Sensitivity Analysis and the Meta-Regression Test
Sources of heterogeneity were traced by a sensitivity analysis, and no outliers were identified in the diagnostic meta-analyses and the prognostic effect for the plasma/serum-based circRNA testing (Figures 4A–C). However, it was found that data of one independent study of the prognostic effect was identified as an outlier (18) (Figure 4D). After the removal of the outlier, the p value of Cochran' Q test varied from 0.000 to 0.961, and I2 decreased to 0.0% from 29.0%. All this suggested that the inclusion of outliers for statistical consolidation could be considered as one of the important reasons for the heterogeneity of the analysis results. Thus, the adjusted HR of the down-regulated circRNAs was calculated after an elimination of the outlier (Figure 3C).
FIGURE 4. The influence analysis of the homogeneity among the included studies. (A) the overall diagnostic efficacy of the studies. (B) the diagnostic efficacy of plasma/serum-based circRNA testing. (C) up-regulated and (D) down-regulated circRNAs in predicting the OS in CRC patients.
On the other hand, a meta-regression test was performed to analyze factors comprising the quality of the study, the type of study, the type of specimen, the number of cases and the number of control groups. The results showed that these factors were not the source of heterogeneity among the studies with nonsignificant differences (data not shown).
Assessment of the publication bias is shown in Figure 5. We observed publication bias in the combined prognostic effect forup-regulated circRNAs (Egger's test, p = 0.021) (Figure 5C). The missing studies were adjusted through the trim-and-fill method (Figure 5D). Nevertheless, the pooled analysis incorporating the hypothetical studies (moment-based estimate of between studies variance = 0.000, p = 1.000) altered slightly from the unadjusted ones (moment-based estimate of between studies variance = 0.000, p = 1.000), suggesting that the bias did not have a significant impact on the combined effect ofup-regulated circRNAs in CRC.
FIGURE 5. Appraising the publication bias among the included studies. (A) the overall diagnostic effect assessed by the Deek's funnel plot. Begg's test for the effects of (B) down-regulated and (C) up-regulated circRNAs in predicting the OS in CRC patients. (D) funnel plot of the trim-and-fill method shows no significant impacts on the combined effect of up-regulated circRNAs in CRC.
CRC is a common malignant tumor of the digestive tract, with nearly 0.6 million newly diagnosed cases across the world every year (1,2). Early detection, diagnosis and treatment of the disease can maximize the survival of the patients (3,5,7). CircRNAs as a class of coding/non-coding competitive endogenous RNA, are characterized by a closed covalent continuous ring structure without the 5′-3′ structure and a poly (A) tail (8,9). A large number of circRNAs existing in mammals affect their functional expressions by binding to miRNAs and other target molecules at the transcriptional or post-transcriptional level (10,11). Although mechanisms behind their biofunctions have not been completed expounded, increasing evidences have shown that circRNAs are associated with multiple diseases, especially malignant tumors (12,13). In recent years, it has been found that expression profiles of circRNAs in CRC cancerous tissues are significantly different from those in the corresponding paracancerous tissues, suggesting that the abnormally expressed circRNAs can be critical in the onset and development of this malady. And they are expected to become new biomarkers in the early diagnosis and treatment of CRC (14–31). Herein, we conducted a pair-wire meta-analysis, and assessed the diagnostic and prognostic significance of abnormally expressed circRNAs in CRC.
In our study, expression levels of circRNAs present clinical values in its diagnosis, with the sensitivity and specificity of 0.75 and 0.74 respectively and the corresponding AUC of 0.81. DOR, the rate of true positive to false positive, is another important indice to evaluate the effectiveness of circRNA-based diagnostic tests (46). A DOR of less than 1 indicates the very low efficiency in the diagnosis of CRC (46). However, a prominent outcome of 8.37 was presented in our study, suggesting the high efficiency of circRNA-based diagnosis. In addition, the pooled PLR of 2.86 means the probability of positive circRNA expressions in CRC patients is approximately 5 times higher than that in controls. The pooled NLR of 0.34 indicates that only 34% of the negative results of circRNA tests are false negative. These findings fully prove that circRNA detection can be applied in the early diagnosis of CRC. As proven by two previous studies, the sensitivity, specificity and AUC of combined circRNA expression profiles in the diagnosis of all malignant tumors are 0.72, 0.74, and 0.79 (47), and 0.79, 0.73, and 0.83 in the diagnosis of gastrointestinal cancers (48). These findings are consistent with our results.
The expression characteristics and sample types of circRNAs have been analyzed by subgroup analyses. We find that up-regulated circRNAs are more effective in diagnosing CRC than down-regulated circRNAs, acting as oncogenes. The analysis based on the sample type indicates that the high kurtosis in the newly diagnosed CRC patients is more beneficial to the detection. The AUC in tissue-derived circRNAs is higher than that in plasma-derived ones, suggesting that the tissue-based circRNA tests may be more accurate than the plasma-related tests; however, this also may attribute to a higher expression peak of circRNAs in cancerous tissues. In spite of this, the number of samples in the subgroup analysis is lower than that of the whole, and the conclusion needs to be confirmed by large sample size trials with later-stage patients.
As circRNAs have been proven to be associated with the prognosis of malignant tumors, systematical evaluations for the prognostic efficacy of circRNA expressions in lung cancer and hepatocellular carcinoma have been conducted (49,50). The results show that the higher the levels of up-regulated circRNAs are, the worse the prognosis of the cancer patients will be. Evidences show that expressions of down-regulated circRNAs in hepatocellular carcinoma are associated with a dismal survival time. These patients with high expressed circRNAs are more likely to extend the OS time. It can be seen that biological functions of different expression states of circRNAs in malignant tumors are distinct. Therefore, we evaluated circRNA as a potential prognostic biomarker of CRC. According to the principle of different biofunctions of circRNAs corresponding to their types, we have divided the circRNA expression profile into two groups: oncogenes and tumor-suppressor ones. The survival analysis showed that the total survival time of the patients with high-expressed up-regulated circRNAs was significantly shorter than that of patients with low-expression levels. And the CRC patients with low expressions of up-regulated circRNAs and high expressions of tumor-suppressor circRNAs significantly presented favorable prognosis, suggesting that circRNA profiling can be used as indicators for evaluating and monitoring the prognosis of CRC.
The main sources of heterogeneity in a meta-analysis consist of the threshold effect and the non-threshold effect. Results of the Spearman correlation coefficient analysis indicate that the heterogeneity in the overall merger statistics and subgroup analyses mainly result from the threshold effect, which may attribute to different boundary values or cut-off values. In this study, the relative quantitative cut-off values and internal reference genes for circRNAs are different, which can be one of the main causes of heterogeneity. Besides, our study has discussed the possible factors leading to heterogeneity by the sensitivity analysis and the meta-regression analysis. We identified an outlier study in the sensitivity analysis and its impact on the prognostic effect was verified. However, the meta-regression test has ruled out factors including the quality of the study, the type of study, the type of specimen, the number of cases and the number of control groups as the possible sources of heterogeneity among the studies.
As the biofunctions of circRNAs in CRC have been clarified above, some limitations still exist in our study. Firstly, the types of circRNA molecules and samples enrolled are not uniform, featuring a large heterogeneity among the studies. Secondly, the included subjects are predominantly Chinese population, which means certain population bias exists in the merged data. Thirdly, there are merely a handful of studies using plasma- or serum-derived circRNAs, and the relevant findings need to be verified by further researches.
To sum up, circRNAs can be used as promising auxiliary biomarkers for the diagnosis and prognosis prediction of CRC. Our findings still need to be confirmed based on more high-quality trials.
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.
CL was in charge of designing, writing and supervising whole process; Q-BX was in charge of collecting date; LD was in charge of analyzing date; L-JH was in charge of decorating words; YJ is the corresponding author, in charge of all process as well.
1. Siegel, RL, Miller, KD, Fuchs, HE, and Jemal, A. Cancer Statistics, 2021. CA A Cancer J Clin (2021) 71(1):7–33. PMID: 33433946. doi:10.3322/caac.21654
2. Chen, W, Zheng, R, Baade, PD, Zhang, S, Zeng, H, Bray, F, et al. Cancer Statistics in China, 2015. CA: a Cancer J clinicians (2016) 66(2):115–32. PMID: 26808342. doi:10.3322/caac.21338
3. Simon, K. Colorectal Cancer Development and Advances in Screening. Clin Interv Aging (2016) 11:967–76. PMID: 27486317. doi:10.2147/CIA.S109285
4. Díaz-Tasende, J. Colorectal Cancer Screening and Survival. Rev Esp Enferm Dig (2018) 110(11):681–3. PMID: 30284905. doi:10.17235/reed.2018.5870/2018
5. Maida, M, Macaluso, FS, Ianiro, G, Mangiola, F, Sinagra, E, Hold, G, et al. Screening of Colorectal Cancer: Present and Future. Expert Rev Anticancer Ther (2017) 17(12):1131–46. PMID: 29022408. doi:10.1080/14737140.2017.1392243
6. Dumoulin, FL, and Hildenbrand, R. Endoscopic Resection Techniques for Colorectal Neoplasia: Current Developments. Wjg (2019) 25(3):300–7. PMID: 30686899. doi:10.3748/wjg.v25.i3.300
7. Nicholson, BD, Shinkins, B, Pathiraja, I, Roberts, NW, James, TJ, Mallett, S, et al. Blood CEA Levels for Detecting Recurrent Colorectal Cancer. Cochrane Database Syst Rev (2015) 2015(12):CD011134. PMID: 26661580. doi:10.1002/14651858.CD011134.pub2
8. Fischer, JW, and Leung, AKL. CircRNAs: a Regulator of Cellular Stress. Crit Rev Biochem Mol Biol (2017) 52(2):220–33. PMID: 28095716. doi:10.1080/10409238.2016.1276882
9. Patop, IL, Wüst, S, and Kadener, S. Past, Present, and Future of Circ RNA S. EMBO J (2019) 38(16):e100836. PMID: 31343080. doi:10.15252/embj.2018100836
10. Wilusz, JE. A 360° View of Circular RNAs: From Biogenesis to Functions. Wiley Interdiscip Rev RNA (2018) 9(4):e1478. PMID: 29655315. doi:10.1002/wrna.1478
11. Salzman, J. Circular RNA Expression: Its Potential Regulation and Function. Trends Genet (2016) 32(5):309–16. [PMID: 27050930]. doi:10.1016/j.tig.2016.03.002
12. Kristensen, LS, Hansen, TB, Venø, MT, and Kjems, J. Circular RNAs in Cancer: Opportunities and Challenges in the Field. Oncogene (2018) 37(5):555–65. PMID: 28991235. doi:10.1038/onc.2017.361
13. Meng, S, Zhou, H, Feng, Z, Xu, Z, Tang, Y, Li, P, et al. CircRNA: Functions and Properties of a Novel Potential Biomarker for Cancer. Mol Cancer (2017) 16(1):94. PMID: 28535767. doi:10.1186/s12943-017-0663-2
14. Fang, G, Ye, B-L, Hu, B-R, Ruan, X-J, and Shi, Y-X. CircRNA_100290 Promotes Colorectal Cancer Progression through miR-516b-Induced Downregulation of FZD4 Expression and Wnt/β-Catenin Signaling. Biochem Biophysical Res Commun (2018) 504(1):184–9. PMID: 30173892. doi:10.1016/j.bbrc.2018.08.152
15. Ge, Z, Li, LF, Wang, CY, Wang, Y, and Ma, WL. CircMTO1 Inhibits Cell Proliferation and Invasion by Regulating Wnt/β-Catenin Signaling Pathway in Colorectal Cancer. Eur Rev Med Pharmacol Sci (2018) 22(23):8203–9. PMID: 30556859. doi:10.26355/eurrev_201812_16513
16. Hsiao, K-Y, Lin, Y-C, Gupta, SK, Chang, N, Yen, L, Sun, HS, et al. Noncoding Effects of Circular RNA CCDC66 Promote Colon Cancer Growth and Metastasis. Cancer Res (2017) 77(9):2339–50. PMID: 28249903. doi:10.1158/0008-5472.CAN-16-1883
17. Ji, W, Qiu, C, Wang, M, Mao, N, Wu, S, and Dai, Y. Hsa_circ_0001649: A Circular RNA and Potential Novel Biomarker for Colorectal Cancer. Biochem Biophysical Res Commun (2018) 497(1):122–6. PMID: 29421663. doi:10.1016/j.bbrc.2018.02.036
18. Li, J, Ni, S, Zhou, C, and Ye, M. The Expression Profile and Clinical Application Potential of Hsa_circ_0000711 in Colorectal Cancer. Cmar (2018) Vol. 10:2777–84. PMID: 30147374. doi:10.2147/cmar.s172388
19. Li, R, Wu, B, Xia, J, Ye, L, and Yang, X. Circular RNA hsa_circRNA_102958 Promotes Tumorigenesis of Colorectal Cancer via miR-585/CDC25B axis. Cmar (2019) Vol. 11:6887–93. PMID: 31413634. doi:10.2147/cmar.s212180
20. Li, X-N, Wang, Z-J, Ye, C-X, Zhao, B-C, Huang, X-X, and Yang, L. Circular RNA circVAPA Is Up-Regulated and Exerts Oncogenic Properties by Sponging miR-101 in Colorectal Cancer. Biomed Pharmacother (2019) 112:108611. PMID: 30797148. doi:10.1016/j.biopha.2019.108611
21. Ruan, H, Deng, X, Dong, L, Yang, D, Xu, Y, Peng, H, et al. Circular RNA Circ_0002138 Is Down-Regulated and Suppresses Cell Proliferation in Colorectal Cancer. Biomed Pharmacother (2019) 111:1022–8. PMID: 30841415. doi:10.1016/j.biopha.2018.12.150
22. Wang, F, Wang, J, Cao, X, Xu, L, and Chen, L. Hsa_circ_0014717 Is Downregulated in Colorectal Cancer and Inhibits Tumor Growth by Promoting P16 Expression. Biomed Pharmacother (2018) 98:775–82. PMID: 29571246. doi:10.1016/j.biopha.2018.01.015
23. Wang, J, Li, X, Lu, L, He, L, Hu, H, and Xu, Z. Circular RNA Hsa_circ_0000567 Can Be Used as a Promising Diagnostic Biomarker for Human Colorectal Cancer. J Clin Lab Anal (2018) 32(5):e22379. PMID: 29333615. doi:10.1002/jcla.22379
24. Wang, X, Zhang, Y, Huang, L, Zhang, J, Pan, F, Li, B, et al. Decreased Expression of Hsa_circ_001988 in Colorectal Cancer and its Clinical Significances. Int J Clin Exp Pathol (2015) 8(12):16020–5. PMID: 26884878.
25. Weng, W, Wei, Q, Toden, S, Yoshida, K, Nagasaka, T, Fujiwara, T, et al. Circular RNA ciRS-7-A Promising Prognostic Biomarker and a Potential Therapeutic Target in Colorectal Cancer. Clin Cancer Res (2017) 23(14):3918–28. PMID: 28174233. doi:10.1158/1078-0432.CCR-16-2541
26. Yuan, Y, Liu, W, Zhang, Y, Zhang, Y, and Sun, S. CircRNA Circ_0026344 as a Prognostic Biomarker Suppresses Colorectal Cancer Progression via microRNA-21 and microRNA-31. Biochem Biophysical Res Commun (2018) 503(2):870–5. PMID: 29928882. doi:10.1016/j.bbrc.2018.06.089
27. Zeng, K, Chen, X, Xu, M, Liu, X, Hu, X, Xu, T, et al. CircHIPK3 Promotes Colorectal Cancer Growth and Metastasis by Sponging miR-7. Cell Death Dis (2018) 9(4):417. PMID: 29549306. doi:10.1038/s41419-018-0454-8
28. Zhang, P, Zuo, Z, Shang, W, Wu, A, Bi, R, Wu, J, et al. Identification of Differentially Expressed Circular RNAs in Human Colorectal Cancer. Tumour Biol (2017) 39(3):101042831769454–1010428317694546. PMID: 28349836. doi:10.1177/1010428317694546
29. Zhang, W, Yang, S, Liu, Y, Wang, Y, Lin, T, Li, Y, et al. Hsa_circ_0007534 as a Blood-Based Marker for the Diagnosis of Colorectal Cancer and its Prognostic Value. Int J Clin Exp Pathol (2018) 11(3):1399–406. PMID: 31938236.
30. Zheng, X, Chen, L, Zhou, Y, Wang, Q, Zheng, Z, Xu, B, et al. A Novel Protein Encoded by a Circular RNA circPPP1R12A Promotes Tumor Pathogenesis and Metastasis of colon Cancer via Hippo-YAP Signaling. Mol Cancer (2019) 18(1):47. PMID: 30925892. doi:10.1186/s12943-019-1010-6
31. Zhuo, F, Lin, H, Chen, Z, Huang, Z, and Hu, J. The Expression Profile and Clinical Significance of circRNA0003906 in Colorectal Cancer. Ott (2017) Vol. 10:5187–93. PMID: 29123417. doi:10.2147/ott.s147378
32. Liu, F, Xiao, X-L, Liu, Y-J, Xu, R-H, Zhou, W-J, Xu, H-C, et al. CircRNA_0084927 Promotes Colorectal Cancer Progression by Regulating miRNA-20b-3p/glutathione S-Transferase Mu 5 axis. Wjg (2021) 27(36):6064–78. PMID: 34629820 PMCID: PMC8476332. doi:10.3748/wjg.v27.i36.6064
33. Wang, J, Wang, T, Hu, S, Li, J, Ni, C, and Ye, M. Hsa_circ_0043278 Inhibits Tumorigenesis and Is Downregulated in Colorectal Cancer. Cmar (2021) Vol. 13:965–75. PMID: 33568942 PMCID: PMC7868253. doi:10.2147/cmar.s289775
34. Li, J, Song, Y, Wang, J, and Huang, J. Plasma Circular RNA Panel Acts as a Novel Diagnostic Biomarker for Colorectal Cancer Detection. Am J Transl Res (2020) 12(11):7395–403. PMID: 33312376 PMCID: PMC7724351.
35. Alkhizzi, B, Khan, M, Al-Ghafari, A, and Choudhry, H. Upregulation of Circular and Linear METTL3 and USP3 in Colorectal Cancer. Oncol Lett (2021) 22(3):675. PMID: 34345300 PMCID: PMC8323003. doi:10.3892/ol.2021.12936
36. Mai, S, Zhang, Z, and Mi, W. Upregulation of circ_PVT1 and Circ_001569 Indicate Unfavorable Prognosis in Colorectal Cancer. Ann Clin Lab Sci (2021) 51(1):55–60. PMID: 33653781.
37. Xu, Y, Wang, C, Lu, X, Qi, R, Wang, X, and Zhao, J. CircRNA_002178 as a ceRNA Promotes the Development of Colorectal Cancer by Regulating miR-542-3p/CREB1. Am J Transl Res (2021) 13(9):10038–55. PMID: 34650680 PMCID: PMC8507087.
38. Wang, J, Zhang, Y, Song, H, Yin, H, Jiang, T, Xu, Y, et al. The Circular RNA circSPARC Enhances the Migration and Proliferation of Colorectal Cancer by Regulating the JAK/STAT Pathway. Mol Cancer (2021) 20(1):81. PMID: 34074294 PMCID: PMC8167978. doi:10.1186/s12943-021-01375-x
39. Song, Y, Cao, P, and Li, J. Plasma Circular RNA Hsa_circ_0001821 Acts as a Novel Diagnostic Biomarker for Malignant Tumors. J Clin Lab Anal (2021) 35(11):e24009. PMID: 34523755. doi:10.1002/jcla.24009
40. Karousi, P, Artemaki, PI, Sotiropoulou, CD, Christodoulou, S, Scorilas, A, and Kontos, CK. Identification of Two Novel Circular RNAs Deriving from BCL2L12 and Investigation of Their Potential Value as a Molecular Signature in Colorectal Cancer. Ijms (2020) 21(22):8867. PMID: 33238574 PMCID: PMC7709015. doi:10.3390/ijms21228867
41. Wang, G, and Yang, H. CircRNA DUSP16 Knockdown Suppresses Colorectal Cancer Progression by Regulating the miR-432-5p/E2F6 Axis. Cmar (2021) Vol. 13:6599–609. PMID: 34456589 PMCID: PMC8387644. doi:10.2147/cmar.s323437
42. Gao, L, Tang, X, He, Q, Sun, G, Wang, C, and Qu, H. Exosome-transmitted circCOG2 Promotes Colorectal Cancer Progression via miR-1305/tgf-Β2/smad3 Pathway. Cell Death Discov. (2021) 7(1):281. PMID: 34635639 PMCID: PMC8505430. doi:10.1038/s41420-021-00680-0
43. Whiting, PF, Rutjes, AWS, Westwood, ME, Mallett, S, Deeks, JJ, Reitsma, JB, et al. QUADAS-2 Group. QUADAS-2: a Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies. Ann Intern Med (2011) 155(8):529–36. PMID: 22007046. doi:10.7326/0003-4819-155-8-201110180-00009
44. Stang, A. Critical Evaluation of the Newcastle-Ottawa Scale for the Assessment of the Quality of Nonrandomized Studies in Meta-Analyses. Eur J Epidemiol (2010) 25(9):603–5. PMID: 20652370. doi:10.1007/s10654-010-9491-z
45. Lin, N, Lin, Y, Fu, X, Wu, C, Xu, J, Cui, Z, et al. MicroRNAs as a Novel Class of Diagnostic Biomarkers in Detection of Oral Carcinoma: a Meta-Analysis Study. Clin Lab (2016) 62(3):451–61. PMID: 27156336. doi:10.7754/clin.lab.2015.150802
46. Glas, AS, Lijmer, JG, Prins, MH, Bonsel, GJ, and Bossuyt, PMM. The Diagnostic Odds Ratio: a Single Indicator of Test Performance. J Clin Epidemiol (2003) 56(11):1129–35. PMID: 14615004. doi:10.1016/s0895-4356(03)00177-x
47. Wang, M, Yang, Y, Xu, J, Bai, W, Ren, X, and Wu, H. CircRNAs as Biomarkers of Cancer: a Meta-Analysis. BMC Cancer (2018) 18(1):303. PMID: 29554887. doi:10.1186/s12885-018-4213-0
48. Lin, Y, Luo, X, Cui, Z, and Chen, Y. Diagnostic Potential for Circular RNAs in Gastric Carcinoma: a Meta-Analysis. Clin Lab (2019) 65(3). PMID: 30868864. doi:10.7754/Clin.Lab.2018.180810
49. Hao, Q, Han, Y, Xia, W, Wang, Q, and Qian, H. Systematic Review and Meta-Analysis of the Utility of Circular RNAs as Biomarkers of Hepatocellular Carcinoma. Can J Gastroenterol Hepatol (2019) 2019:1–13. PMID: 31187026. doi:10.1155/2019/1684039
50. Huang, X, Zhang, W, and Shao, Z. Prognostic and Diagnostic Significance of circRNAs Expression in Lung Cancer. J Cel Physiol (2019) 234(10):18459–65. PMID: 30895620. doi:10.1002/jcp.28481
Keywords: colorectal cancer, circular RNA, diagnosis, prognosis, pooled analysis
Citation: Long C, Xu Q-b, Ding L, Huang L-j and Ji Y (2022) Circular RNAs as Diagnostic and Prognostic Indicators of Colorectal Cancer: A Pooled Analysis of Individual Studies. Pathol. Oncol. Res. 28:1610037. doi: 10.3389/pore.2022.1610037
Received: 23 August 2021; Accepted: 08 February 2022;
Published: 17 March 2022.
Andrea Ladányi, National Institute of Oncology (NIO), Hungary
Copyright © 2022 Long, Xu, Ding, Huang and Ji. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yong Ji, jjrmyongji@163.com
Comment deleted on


text:
Marvel Madness
Here's the real reason Natalie Portman isn't in the next "Thor" (and probably won't be back ever again)
Rachel Paige
Relationships are hard work. Long-distance relationships are even harder. So, yeah, in the back of our minds we never expected Thor and Jane Foster to make it work in the long run. In the back of our mind we kinda just assumed that, eventually, the trip between Asgard and Earth would become too much for the couple, and that time is now.
Thor and Jane have officially broken up.
While Natalie Portman played the spunky astrophysicist, Jane Foster, for the first two Thor movies, she's missing from the upcoming third, Ragnarok. Jane Foster was also missing from both The Avengers, and Avengers: Age of Ultron. (For Avengers, she was moved to a "secure location" and for Ultron, she was off studying somewhere, or doing something, it was all left very vague OKAY? Keep better track of your girlfriend, Thor.)
Last we saw her, she and Thor were very much in a relationship, and trying to make it work — as well as a God of Thunder and a world-renowned astrophysicist can, that is.
Well, sounds like they didn't last too long. According to Chris Hemsworth himself, Thor is a single man right now. (Quick, get in line, because Thor is officially back on the market!!)
"He's off exploring the universe, still trying to police it and control the mayhem," Hemsworth explained to Entertainment Weekly. "But he's certainly enjoying being a drifter, being a solo cowboy out there."
Natalie hinted at this breakup last summer, when she told The Wall Street Journal,
"As far as I know, I'm done. I don't know if maybe one day they'll ask for an 'Avengers 7' or whatever I have no idea. But as far as I know, I'm done."
We're certainly sad to see Natalie and Jane go, so let's take a sec to think of happier memories together.
Thor: Ragnarok will open without Jane Foster on November 3rd.
By Rachel Paige
The best rom-coms on Netflix right now, Spring 2019 edition
5 reasons why watching the Halloweentown movies will bring you happiness on All Hallows' Eve
A new Spice Girls movie is coming and all five members are on board, so get your sky-high platforms ready
Ariana Grande just joined Ryan Murphy's The Prom, and now it might have the most famous people in one movie ever
Chris Hemsworth revealed an Avengers: Endgame behind-the-scenes clip, and we don't know whether to laugh or cry
Frozen 2's first-ever trailer is here, and fans are spotting this Harry Potter connection
Harry Potter's Rupert Grint and Tom Felton said they'd return to the Wizarding World, but in this new way
If you can only watch one Netflix trailer this week, make sure it's Knock Down The House
We can finally hear Beyoncé sing in The Lion King, and sorry, Elton John, but this is our new everything
Someone put the Avengers theme song over the Frozen 2 trailer, and it's weirdly perfect
Sophie Turner is Boy George's top pick to play the singer in his biopic, and just send us tickets now
Anne Hathaway is officially starring in a Sesame Street movie, and our inner child is stoked
The OG Disney Ariel and other stars are defending Halle Bailey from casting backlash
Ariana Grande makes a cameo in Men in Black: International, and maybe this is what "NASA" was about all along
Here's how to watch the new Lifetime movie about Prince Harry and Meghan Markle
Legally Blonde is leaving Netflix, and Twitter is as distraught as we are
Anne Hathaway and Rebel Wilson think sexism contributed to The Hustle's R-rating
A Harry Potter-themed homecoming performance went viral, because the world needed to see Voldemort dance to "Chun Li"
The Little Mermaid live-action remake has cast its Ariel, and we're so ready to go under the sea
Disney's live-action Mulan trailer shows major differences from the animated version

redpajama_set_name: RedPajamaCommonCrawl


text:
Le Red Bull Brasil est un club de football brésilien basé à São Paulo et sponsorisé par le groupe Red Bull, ayant fusionné avec le CA Bragantino pour créer le Red Bull Bragantino le .

Le Red Bull Brasil reste néanmoins actif après cette date, en tant qu'équipe réserve du RB Bragantino dans les ligues régionales.

Historique

Palmarès
 Campeonato Paulista Série A3 (D3) :
 Champion : 2010

 Campeonato Paulista Série B (D4) :
 Champion : 2009

Notes et références

Voir aussi
 Red Bull
 Red Bull GmbH
 Red Bull Salzbourg
 Red Bull New York
 RB Leipzig

Club de football fondé en 2007
Club de football à São Paulo

redpajama_set_name: RedPajamaWikipedia


text:
Home Labor News From Our Region Dollar General manager fired after sharing post about unionizing
Labor News From Our Region
Dollar General manager fired after sharing post about unionizing
Glasgow, MO – A former Dollar General manager is speaking out after she said she was fired for sharing a post about employees unionizing.
Workers at a Dollar General store in Auxvasse, MO, voted to join United Food and Commercial Workers Local 655, in December, becoming the first Dollar General store in the country where employees have successfully voted to unionize.
Margeorie Nation shared a post by a page called Dollar General Mayhem, which linked to an article by KOMU 8 News about the unionization vote by employees at the Auxvasse location.
The copy that accompanied the page's post included the language: "Finally, it's a start! I hope this becomes a trend in the rest of the company. S**** your anti-union mission statement, Dollar General."
Nation posted in the comments section that she was sharing the post for the purpose of asking what people thought about the page's stance.
"I never said that this is Dollar General's beliefs. None of that," she said. "And then… I was fired over it. Well, I don't know if it was that, but that's the only thing that I posted."
'VIOLATED SOCIAL MEDIA POLICY'
Nation told KOMU she was told she was being fired because she "violated social media policy."
"I said, 'How did I violate it? What did I post?' Their response was they couldn't tell me. Okay, well can you show me? I asked 'Can you show me?' and the HR guy started to reach back I guess for like his phone or tablet or whatever and then he was like 'Oh, well that's unavailable to us right now,'" she said.
In an email statement, Dollar General said:
"While we do not discuss personnel matters publicly out of respect for the privacy of individuals, it is unfortunate that Ms. Nation has decided to suggest that her departure was unfair or she was mistreated in any way. That is simply not true."
MOST PEOPLE WOULD WANT BETTER RIGHTS AND PAY
Nation said she did not have an opinion on the employee vote to unionize the Auxvasse store, but added her thoughts that most people would want better pay and better rights as employees.
Nation also said the Glasgow store never considering unionizing, but her coworkers wanted to know what the possible unionization in Auxvasse meant for them. She is now seeking a new job and legal representation.
"My heart and soul was in that store," she said. "I showed up to work, I stayed late, I worked my butt off for that store. I missed time with my kids – things that I can't get back because of my job. But I also took pride in what I did and I was happy."
Auxvasse
manager fired
Margeorie Nation
unionize
Previous articleAnother racist vulgarity, this time with consequences
Next articleTrump nominates partner at anti-union law firm to Labor Board seat


text:
Josef Kott (* 7. prosince 1957) a Michael Kutílek (23. února 1951 – 15. března 2017) je dvojice českých sériových vrahů, kteří v roce 1990 během 26 hodin zavraždili čtyři lidi a jednoho zranili. Michael Kutílek vraždil ještě před společnou sérií. Oba byli později odsouzeni na doživotí. Tato dvojice mužů je považována za první sériové vrahy v polistopadové historii České republiky. Zajímavé je, že tři z těchto vražd byly spáchány právě v den, kdy byl v zemi zrušen trest smrti (2. května 1990).

Životy mužů před vraždami
Josef Kott se narodil v Rakovníku. Působil jako voják z povolání, později na federálním ministerstvu vnitra. Zde začaly jeho potíže. Vrátil se k armádě, získal hodnost poručíka, začal však také krást, proto brzy svou hodnost ztratil.

Michael Kutílek se narodil v Praze. Už v předškolním věku hrál na klavír a chodil na tenis. Byl inteligentní, zároveň však okrádal spolužáky. Znalci později označili Kutílka za polymorfního psychopata.

Kott s Kutílkem se poznali roku 1988 v minkovické věznici. Kott slíbil Kutílkovi, že mu po propuštění ukáže, jak se dají vydělávat peníze za pomoci vraždy. Oba muži opustili vězení v roce 1990 na základě amnestie prezidenta Havla – Kutílek byl propuštěn hned 6. ledna, Kott 1. března. Oba se do vězení vrátili v květnu již jako vrazi.

Vraždy
V noci na 2. května 1990 přijeli limuzínou Tatra 613 do Nýřan. V přestrojení za policisty navštívili strážného podniku Stavební stroje Nýřany Františka Korbela. Tvrdili, že musí provést rutinní kontrolu jeho zbraně. Když jim zbraň vydal a oni se ji pokusili na základě vymyšlené nesrovnalosti v dokumentech zabavit, obvinil je z toho, že nejsou skuteční policisté. Kott ho proto zastřelil jednou ranou do hlavy. Náhodný svědek popsal dva muže: jednoho v civilu a druhého v uniformě Veřejné bezpečnosti.

Kott a Kutílek odjeli po vraždě do Zbiroha, kde naložili dvě stopařky Ditu Dubskou (16) a Sylvii Landovou (16). Odvezli je na odlehlé místo (49.9054161N, 13.8148936E) nedaleko obce Líšná, kde jim svázali ruce za zády a jednu po druhé zavraždili. Kutílek se přiznal, že obě byly zavražděny prostřednictvím "satanského" rituálu. Mělo padnout více než 57 ran nožem.

Dne 3. května odjeli Kott a Kutílek do Prahy, kde zastřelili a okradli taxikáře. Poté u motorestu Tři sudy u Kařezu střelili do hlavy britského řidiče kamionu. Muž díky obrovskému štěstí přežil a útočníky identifikoval. Kott a Kutílek tak byli brzy zadrženi.

Soud
Kott svou vinu nikdy nepřiznal. Kutílek tvrdil, že v době jejich dopadení bylo nejvyšším možným trestem 25 let, navíc si jej měli s Kottem soudní znalci splést. Se žádostí neuspěl a oba muži byli roku 1995 odsouzeni na doživotí.

V roce 2006 řekl Kutílek, že jen on je vrahem a že Kott nemá s vraždami nic společného. Soud jeho návrh zamítl s tím, že nebyly shledány nové důkazy potřebné k obnovení procesu.

Roku 2008 se Kutílek přiznal k páté vraždě, kterou měl provést brzy po svém propuštění na jaře 1990, ještě bez Kotta. Obětí byl devatenáctiletý mladík, kterému měl Kutílek způsobit smrtelné bodné poranění srdce. Tato vražda se však Kutílkovi do výkonu trestu nezapočítala. Dne 29. března 2022 se Kott obnovy procesu nedočká. Jeho žádost zamítl Krajský soud v Plzni. Kott se snažil znevěrohodnit výpověď Kutílka, který se na rozdíl od něj k činům doznal a který v roce 2017 zemřel ve výkonu trestu.

Reference

Čeští sérioví vrazi
Dvojice
Satanisté
Kott
Kutílek
Kott
Kutílek
Kott
Kutílek


Each pack contains 12 nappies with 4 vibrant designs! Did someone say pink and pastels? We thought so! Our 4 additional prints are for those who prefer pinker side of life. There's flutterbyes, unicorns, moo cows, fairies, flowers and fluffy RAINBOWS!


OK2SAY Ambassadors are motivated and enthusiastic individuals. They make a positive impact within their school. Take the pledge and learn how you can use OK2SAY to bring kindness, inclusion, and awareness activities and ideas into your school.
Help develop and lead the OK2SAY Ambassador programs in Michigan to inspire other young people to tackle issues that impact their safety and well-being.
Provide input to the OK2SAY Student Safety Program.
Apply below to join our team and work towards a better Michigan.
If you feel strongly about OK2SAY or our Michigan Cyber Safety Initiative (CSI), or any other Consumer Education Program provided by the Department of Attorney General, we'd love to hear from you. We are especially interested in hearing from people willing to give presentations in their communities and schools. Learn more about how to join our team.
Interested individuals should send a letter of interest that highlights your public speaking experience and a resume to the following address. We may be in touch with you.
Help us recognize and share your best practices. Send us an email and tell us or show us with an audio or visual attachment what you are doing to celebrate and reinforce the OK2SAY message.
Promote the Michigan Student Safety Initiative by adding the OK2SAY logo to your website or other promotional materials. Use the image provided to the left and set the image to link to the OK2SAY homepage: ok2say.com.