Schisandrin B Inhibits Cell Viability and Migration, and Induces Cell Apoptosis by circ_0009112/miR-708-5p Axis Through PI3K/AKT Pathway in Osteosarcoma

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.

Accumulating evidences indicate that long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) play important roles in tumorigenesis. However, the mechanisms remain largely unknown. To explore lncRNAs and circRNAs expression profiling and their biological functions in bladder cancer, we surveyed the lncRNA/circRNA and mRNA expression profiles of bladder cancer and para-cancer tissues using microarray for four patients. Thousands of significantly changed lncRNAs and mRNAs as well as hundreds of circRNAs were identified. Five dysregulated lncRNAs and four mRNAs were confirmed by quantitative real-time PCR in 30 pairs of samples. GO and KEGG pathway enrichment analyses were executed to determine the principal functions of the significantly deregulated genes. Further more, we constructed correlated expression networks including coding-noncoding co-expression (CNC), competing endogenous RNAs (ceRNA), cis regulation, lncRNAs-transcription factor (TF)-mRNA with bioinformatics methods. Co-expression analysis showed lncRNA APLP2 expression is correlated with apoptosis-related genes, including PTEN and TP53INP1. CeRNA network inferred that lncRNA H19 and circRNA MYLK could bind competitively with miRNA-29a-3p increasing target gene DNMT3B, VEGFA and ITGB1 expressions. Moreover, the nearby genes pattern displayed that overexpressing ADAM2 and C8orf4 are cis-regulated by lncRNA RP11-359E19.2, involving in progression of bladder cancer. In addition, lncRNAs-TF-mRNA diagram indicated that lncRNA BC041488 could trans-regulate CDK1 mRNA expression through SRF transcription factor. Taken together, these results suggested lncRNAs and circRNAs could implicate in the pathogenesis and development of bladder cancer. Our findings provide a novel perspective on lncRNAs and circRNAs and lay the foundation for future research of potential roles of lncRNAs and circRNAs in bladder carcinoma.

Osteosarcoma is the most common nonhematologic malignancy of bone in children and adults. The peak incidence occurs in the second decade of life, with a smaller peak after age 50. Osteosarcoma typically arises around the growth plate of long bones. Most osteosarcoma tumors are of high grade and tend to develop pulmonary metastases. Despite clinical improvements, patients with metastatic or recurrent diseases have a poor prognosis. Here, we reviewed the current understanding of human osteosarcoma, with an emphasis on potential links between defective osteogenic differentiation and bone tumorigenesis. Existing data indicate osteosarcoma tumors display a broad range of genetic and molecular alterations, including the gains, losses, or arrangements of chromosomal regions, inactivation of tumor suppressor genes, and the deregulation of major signaling pathways. However, except for p53 and/or RB mutations, most alterations are not constantly detected in the majority of osteosarcoma tumors. With a rapid expansion of our knowledge about stem cell biology, emerging evidence suggests osteosarcoma should be regarded as a differentiation disease caused by genetic and epigenetic changes that interrupt osteoblast differentiation from mesenchymal stem cells. Understanding the molecular pathogenesis of human osteosarcoma could ultimately lead to the development of diagnostic and prognostic markers, as well as targeted therapeutics for osteosarcoma patients.