Exploring the oncogenic potential of circSOD2 in clear cell renal cell carcinoma: a novel positive feedback loop.

BACKGROUND: Existing studies have found that circular RNAs (circRNAs) act as sponges for micro RNAs (miRNAs) to control downstream genes. However, the specific functionalities and mechanisms of circRNAs in human clear cell renal cell carcinoma (ccRCC) have yet to be thoroughly investigated. METHODS: Patient cohorts from online databases were used to screen candidate circRNAs, while another cohort from our hospital was obtained for validation. CircSOD2 was identified as a potential oncogenic target, and its relevant characteristics were investigated during ccRCC progression through various assays. A positive feedback loop containing downstream miRNA and its target gene were identified using bioinformatics and validated by luciferase reporter assays, RNA pull-down, and high-throughput sequencing. RESULTS: CircSOD2 expression was elevated in tumor samples and significantly correlated with overall survival (OS) and the tumor stage of ccRCC patients, which appeared in the enhanced proliferation, invasion, and migration of tumor cells. Through competitive binding to circSOD2, miR-532-3p can promote the expression of PAX5 and the progression of ccRCC, and such regulation can be salvaged by miR-532-3p inhibitor. CONCLUSION: A novel positive feedback loop, PAX5/circSOD2/miR-532-3p/PAX5 was identified in the study, indicating that the loop may play an important role in the diagnosis and prognostic prediction in ccRCC patients.

Non-invasive prediction of preeclampsia using the maternal plasma cell-free DNA profile and clinical risk factors.

Background: Preeclampsia (PE) is a pregnancy complication defined by new onset hypertension and proteinuria or other maternal organ damage after 20 weeks of gestation. Although non-invasive prenatal testing (NIPT) has been widely used to detect fetal chromosomal abnormalities during pregnancy, its performance in combination with maternal risk factors to screen for PE has not been extensively validated. Our aim was to develop and validate classifiers that predict early- or late-onset PE using the maternal plasma cell-free DNA (cfDNA) profile and clinical risk factors. Methods: We retrospectively collected and analyzed NIPT data of 2,727 pregnant women aged 24-45 years from four hospitals in China, which had previously been used to screen for fetal aneuploidy at 12 + 0 ~ 22 + 6 weeks of gestation. According to the diagnostic criteria for PE and the time of diagnosis (34 weeks of gestation), a total of 143 early-, 580 late-onset PE samples and 2,004 healthy controls were included. The wilcoxon rank sum test was used to identify the cfDNA profile for PE prediction. The Fisher's exact test and Mann-Whitney U-test were used to compare categorical and continuous variables of clinical risk factors between PE samples and healthy controls, respectively. Machine learning methods were performed to develop and validate PE classifiers based on the cfDNA profile and clinical risk factors. Results: By using NIPT data to analyze cfDNA coverages in promoter regions, we found the cfDNA profile, which was differential cfDNA coverages in gene promoter regions between PE and healthy controls, could be used to predict early- and late-onset PE. Maternal age, body mass index, parity, past medical histories and method of conception were significantly differential between PE and healthy pregnant women. With a false positive rate of 10%, the classifiers based on the combination of the cfDNA profile and clinical risk factors predicted early- and late-onset PE in four datasets with an average accuracy of 89 and 80% and an average sensitivity of 63 and 48%, respectively. Conclusion: Incorporating cfDNA profiles in classifiers might reduce performance variations in PE models based only on clinical risk factors, potentially expanding the application of NIPT in PE screening in the future.

A panel of seven immune-related genes can serve as a good predictive biomarker for cervical squamous cell carcinoma.

Objective: Cervical cancer is one of the most common gynecological malignancies. The interaction between tumor microenvironment and immune infiltration is closely related to the progression of cervical squamous cell carcinoma (CSCC) and patients' prognosis. Herein, a panel of immune-related genes was established for more accurate prognostic prediction. Methods: The transcriptome information of tumor and normal samples were obtained from TCGA-CSCC and GTEx. Differentially expressed genes (DEGs) were defined from it. Immune-related genes (IRGs) were retrieved from the ImmPort database. After removing the transcriptome data which not mentioned in GSE44001, IR-DEGs were preliminarily identified. Then, TCGA-CSCC samples were divided into training and testing set (3:1) randomly. Univariate Cox analysis, LASSO regression analysis and multivariate Cox analysis were used in turn to construct the signature to predict the overall survival (OS) and disease-free survival (DFS). External validation was performed in GSE44001, and initial clinical validation was performed by qRT-PCR. Function enrichment analysis, immune infiltration analysis and establishment of nomogram were conducted as well. Results: A prognostic prediction signature consisting of seven IR-DEGs was established. High expression of NRP1, IGF2R, SERPINA3, TNF and low expression of ICOS, DES, HCK suggested that CSCC patients had shorter OS (POS<0.001) and DFS (PDFS<0.001). AUC values of 1-, 3-, five- year OS were 0.800, 0.831 and 0.809. Analyses in other validation sets showed good consistency with the results in training set. The signature can serve as an independent prognostic factor for OS (HR = 1.166, p < 0.001). AUC values of 1-, 3-, five- year OS based on the nomogram were 0.769, 0.820 and 0.807. Functional enrichment analysis suggested that these IR-DEGs were associated with receptor interaction and immune cell activity. Immune infiltration analysis indicated that patients in high-risk group had lower immune infiltration, weaker immune function, and were more likely to benefit from immune checkpoint inhibitor therapy. Through qRT-PCR on clinical samples, expression of NRP1, IGF2R, SERPINA3 and TNF were significantly upregulated in tumor tissue, while ICOS and DES were significantly downregulated. Conclusion: To conclude, the immune-related signature can provide strong support for exploration of immune infiltration, prediction of prognosis and response to immunotherapy through stratify CSCC patients into subgroups.