Prostate cancer (PCa) is a high morbidity malignancy in males, and biochemical recurrence (BCR) may appear after the surgery. Our study is designed to build up a risk score model using circular RNA sequencing data for PCa. The dataset is from the GEO database, using a cohort of 144 patients in Canada. We removed the low abundance circRNAs (FPKM < 1) and obtained 546 circRNAs for the next step. BCR-related circRNAs were selected by Logistic regression using the “survival” and “survminer” R package. Least absolute shrinkage and selector operation (LASSO) regression with 10-fold cross-validation and penalty was used to construct a risk score model by “glmnet” R software package. In total, eight circRNAs (including circ_30029, circ_117300, circ_176436, circ_112897, circ_112897, circ_178252, circ_115617, circ_14736, and circ_17720) were involved in our risk score model. Further, we employed differentially expressed mRNAs between high and low risk score groups. The following Gene Ontology (GO) analysis were visualized by Omicshare Online tools. As per the GO analysis results, tumor immune microenvironment related pathways are significantly enriched. “CIBERSORT” and “ESTIMATE” R package were used to detect tumor-infiltrating immune cells and compare the level of microenvironment scores between high and low risk score groups. What’s more, we verified two of eight circRNA’s (circ_14736 and circ_17720) circular characteristics and tested their biological function with qPCR and CCK8 in vitro. circ_14736 and circ_17720 were detected in exosomes of PCa patients’ plasma. This is the first bioinformatics study to establish a prognosis model for prostate cancer using circRNA. These circRNAs were associated with CD8+ T cell activities and may serve as a circRNA-based liquid biopsy panel for disease prognosis.
Background The gut microbiota is reportedly involved in the progression and chemoresistance of various human malignancies. However, the underlying mechanisms behind how it exerts some effect on prostate cancer, as an extra-intestinal tumor, in a contact-independent way remain elusive and deserve exploration. Antibiotic exposure, one of the various factors affecting the gut microbiota community and capable of causing gut dysbiosis, is associated with multiple disorders. This study aims to preliminarily clarify the link between gut dysbiosis and prostate cancer. Results First, we discovered that perturbing the gut microbiota by consuming broad-spectrum antibiotics in water promoted the growth of subcutaneous and orthotopic tumors in mice. Fecal microbiota transplantation could transmit the effect of antibiotic exposure on tumor growth. Then, 16S rRNA sequencing for mouse feces indicated that the relative abundance of Proteobacteria was significantly higher after antibiotic exposure. Meanwhile, intratumoral lipopolysaccharide (LPS) profoundly increased under the elevation of gut permeability. Both in vivo and in vitro experiments revealed that the NF-κB-IL6-STAT3 axis activated by intratumoral LPS facilitated prostate cancer proliferation and docetaxel chemoresistance. Finally, 16S rRNA sequencing of patients’ fecal samples revealed that Proteobacteria was enriched in patients with metastatic prostate cancer and was positively correlated with plasma IL6 level, regional lymph node metastasis status, and distant metastasis status. The receiver operating characteristic (ROC) curves showed that the relative abundance of Proteobacteria had better performance than the prostate-specific antigen (PSA) level in predicting the probability of distant metastasis in prostate cancer (area under the ROC curve, 0.860; p < 0.001). Conclusion Collectively, this research demonstrated that gut dysbiosis, characterized by the enrichment of Proteobacteria due to antibiotic exposure, resulted in the elevation of gut permeability and intratumoral LPS, promoting the development of prostate cancer via the NF-κB-IL6-STAT3 axis in mice. Considering findings from human patients, Proteobacteria might act as an intestinal biomarker for progressive prostate cancer.
The circRNAs, a new subclass of non-coding RNAs that are catalyzed by RNA-binding proteins (RBPs), have been reported to be associated with the progression of multiple types of cancer. We previously discovered that heterogeneous nuclear ribonucleoprotein L (HnRNP-L), a multi-functional RBP, is associated with pro-proliferation and anti-apoptosis activities in prostate tumor cells. In this study, we aim to establish the biological relevance of circCSPP1 (a newly discovered signature circRNA in prostate cancer [PCa]) and HnRNP-L to prostate cancer progression. First, we demonstrated that circCSPP1 expression was higher in prostate cancer tissues than in benign tissues and higher in prostate cancer cells than in benign cells. Then, the in vitro gain- and loss-of-function experiments showed that the circCSPP1 expression in prostate cancer cells was regulated by HnRNP-L, and the increased circCSPP1 significantly induced autophagy, which led to an enhanced potential in proliferation, migration, and invasion of prostate cancer cells. These results were consistent with the in vivo experiment where increased or decreased circCSPP1 was associated with higher or slower growth rate in grafted tumors. Finally, we demonstrated the potential competing endogenous RNA network, involving circCSPP1, miR-520h, and early growth response factor 1 ( EGR1 ), in prostate cancer cells, which may play an important role in prostate cancer progression. Our study indicated that the increase in circCSPP1 in prostate cancer, which may be catalyzed by HnRNP-L, can induce cellular autophagy through the circCSPP1-miR-520h- EGR1 axis, leading to the progression of prostate tumor. This newly discovered circRNA biomarker may be used for clinical prognosis of prostate cancer as well as for development of novel therapy plans.
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