Circular RNAs (circRNAs) have emerged as novel molecules of interest in gene regulation as other noncoding RNAs. Though they have been explored in some species and tissues, the expression and functions of circRNAs in human reproductive systems remain unknown. Here we revealed the expression profiles of circRNAs in human testis tissue using high-throughput sequencing. The conformation of these testis-derived circRNAs in seminal plasma was also investigated, aiming to provide a non-invasive liquid biopsy surrogate for testicular biopsy. We predicted >15,000 circRNAs in human testis, with most of them (10,792; 67%) new. In all the 5,928 circRNA forming genes, 1,017 are first reported by us to generate circRNAs. Interestingly, these genes are mostly related to spermatogenesis, sperm motility, fertilization, etc. The sequence feature, chromosome location, alternative splicing and other characteristics of the circRNAs in human testis were also explored. Moreover, we found that these testis-derived circRNAs could be stably detected in seminal plasma. Most of them were probably bound with proteins in seminal plasma and were very stable at room temperature. Our work has laid the foundations to decipher regulation mechanisms of circRNAs in spermatogenesis and to develop circRNAs as novel noninvasive biomarkers for male infertile diseases.

Leucine-rich-repeat-containing G protein-coupled receptors (LGRs) have been widely found to be implicated with development and progression in multiple cancer types. However, the clinical significance and biological functions of LGR6 in ovarian cancer remains unclear. In this study, LGR6 expression was mainly examined by immunohistochemistry. Functional assays in vitro and animal experiments in vivo were carried out to explore the effect of LGR6 on cancer stem cell (CSC) characteristics and chemotherapeutic responses in ovarian cancer cells. Luciferase assays and GSEA were used to discern the underlying mechanisms contributing to the roles of LGR6 in ovarian cancer. Here, we reported that LGR6 was upregulated in ovarian cancer, which positively correlated with poor chemotherapeutic response and progression survival in ovarian cancer patients. Loss-of-function assays showed that downregulating LGR6 abrogated the CSC-like phenotype and chemoresistance in vitro. More importantly, silencing LGR6 improved the chemoresistance of ovarian cancer cells to cisplatin in vivo. Mechanistic investigation further revealed that silencing LGR6 inhibited stemness and chemoresistance by repressing Wnt/b-catenin signaling. Collectively, our results uncover a novel mechanism contributing to LGR6-induced chemotherapeutic resistance in ovarian cancer, providing the evidence for LGR6 as a potential therapeutic target in ovarian cancer.

Asthenoszoopermia, characterized by reduced sperm motility, is one of the primary forms of male infertility. Whereas most cases were diagnosed into unexplained asthenozoospermia (UA) because the etiology cannot be identified. In animal models, epigenetic dysregulation in epididymis can impair sperm maturation and result in asthenozoospermia. However, researches of epididymal epigenetic regulation on humans are impeded by the difficulty in obtaining epididymal tissues. We previously identified cell-free seminal microRNAs predominately derived from epididymis in human ejaculate. In the present study, these microRNAs were used to screen and validate the microRNA dysregulation in men with UA, which were divided into screening set and validation set. The expression of five miRNAs (miR-891b, miR-892b, miR-892a, miR-888 and miR-890) was found and confirmed to be dysregulated in men with UA. Interestingly, these five miRNAs belong to a primate-specific miRNA cluster located on the X chromosome with epididymis specific expression. Moreover, obvious coherent dysregulation of these miRNAs were observed in 13% men with UA. Regression analysis demonstrated that levels of these miRNAs were significantly correlated with progressive sperm motility. Functions and pathways of predicted target genes of this cluster suggested its role in sperm maturation. Dysregulation of this miRNA cluster might be an epigenetic basis for some patients with UA. We also showed a noninvasive and feasible approach to get epigenetic information of human epididymis.

CFTR variants are common in CUAVD, and the 5T allele may be associated with increased CUAVD risk. CUAVD patients bear a higher RA risk than CBAVD patients, but this is not associated with CFTR variants.