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As the most prevalent bone tumor in children and adolescents, the pathogenesis and metastasis of osteosarcoma (OS) remain largely unclear. Here, we investigated the expression and function of a novel circular RNA (circRNA), circROCK1-E3/E4, which is back-spliced from exons 3 and 4 of Rho-associated coiled-coil containing protein kinase 1 (ROCK1) in OS. We found that circROCK1-E3/E4, regulated by the well-known RNA-binding protein quaking (QKI), was downregulated in OS and correlated with unfavorable clinical features of patients with OS. Functional proliferation and cell motility assays indicated that circROCK1-E3/E4 serves as a tumor suppressor in OS cells. Mechanistically, circROCK1-E3/E4 suppressed proliferation and migration by upregulating phosphatase and tensin homolog (PTEN) through microRNA-532-5p (miR-532-5p) sponging. In the constructed nude mouse model, circROCK1-E3/E4 inhibited tumor growth and lung metastasis in vivo. This study demonstrates the functions and molecular mechanisms of circROCK1-E3/E4 in the progression of OS. These findings may identify novel targets for the molecular therapy of OS.

Shanshan Li1 *,* Yize Liu2 *,* Guanzhen Qiu,2 Yinzhou Luo,2 Lan Luan,3 Tiance Xu,4 Yong Wang,2,5 Shuyue Xia1,6 1Respiratory Department, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning, 110024, People’s Republic of China; 2 4th Department of Orthopedics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning, 110024, People’s Republic of China; 3Department of Pathology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning, 110024, People’s Republic of China; 4 2nd Department of Neurology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning, 110024, People’s Republic of China; 5Central Laboratory, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning, 110024, People’s Republic of China; 6Dean’s Office, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning, 110024, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong WangCentral Laboratory and 4th Department of Orthopedics, Central Hospital Affiliated to Shenyang Medical College, 5 South Seven West Road, Shenyang, Liaoning, 110024, People’s Republic of ChinaEmail wy_smc@163.comShuyue XiaRespiratory Department, Central Hospital Affiliated to Shenyang Medical College, 5 South Seven West Road, Shenyang, Liaoning, 110024, People’s Republic of ChinaEmail syx262@126.comIntroduction: Non-coding RNAs, including long non-coding (lnc)RNAs and microRNAs (miRs), play crucial roles in numerous malignant tumors, including non-small cell lung cancer (NSCLC).Methods: The expression levels of chromatin-associated RNA Intergenic 10 (CAR10), gap junction protein beta 2 (GJB2) and miR-892a in NSCLC were evaluated by reanalyzing three Gene Expression Omnibus (GEO) datasets, and performing reverse transcription-quantitative PCR, immunohistochemistry staining and Western blot analysis, accordingly. Functionally, Transwell and Matrigel assays were performed to measure changes in the migration and invasion abilities of the A549 and H1299 cell lines. The targeted binding effects between CAR10 and miR-892a, as well as between miR-892a and GJB2 were confirmed by conducting dual-luciferase reporter and RNA pull-down assays, respectively.Results: The present study demonstrated that CAR10 was upregulated in patients with NSCLC, which was also associated with a poor prognosis. Functionally, CAR10 was confirmed to be oncogenic and promoted NSCLC cell migration and invasion, using overexpression and knockdown Transwell assays. Furthermore, GJB2 expression was revealed to be upregulated and was positively correlated with CAR10 expression in NSCLC. A further mechanistic study revealed that GJB2 was a downstream target of CAR10, which induced the migration and invasive potential of the A549 and H1299 cell lines. More specifically, miR-892a was found to serve as a bridge between CAR10 and GJB2, via similar miRNA response elements. The RNA pull-down and luciferase assays indicated that miR-892a directly binds both CAR10 and GJB2.Conclusion: CAR10 promoted NSCLC cell migration and invasion by upregulating GJB2 and sponging miR-892a. These findings illustrated that the CAR10/miR-892a/GJB2 axis may be a novel molecular target for the treatment of NSCLC.Keywords: chromatin-associated RNA 10, gap junction protein beta 2, microRNA-892a, metastasis, non-small cell lung cancer

Osteoporosis, which is caused by an imbalance in osteoblasts and osteoclasts, is a global age-related metabolic disease. Osteoblasts induce osteocyte and bone matrix formation, while osteoclasts play an important role in bone resorption. Maintaining a balance between osteoblast formation and osteoclastic absorption is crucial for bone remodeling. Circular RNAs (circRNAs), which are characterized by closed-loop structures, are a class of novel endogenous transcripts with limited protein-coding abilities. Accumulating evidence indicates that circRNAs play important roles in various bone diseases, such as osteosarcoma, osteoarthritis, osteonecrosis, and osteoporosis. Recent studies have shown that circRNAs regulate osteoblast and osteoclast differentiation and may be potential biomarkers for osteoporosis. In the current review, we summarize the expression, function, and working mechanisms of circRNAs involved in osteoblasts, osteoclast differentiation, and osteoporosis.

Circular RNAs (circRNAs) are a class of novel endogenous transcripts with limited protein-coding abilities. CircRNAs have been demonstrated to function as critical regulators of tumor development and distant metastasis through binding to microRNAs (miRNAs) and interacting with RNA-binding proteins, thereby regulating transcription and translation. Emerging evidence has illustrated that certain circRNAs can serve as biomarkers for diagnosis and prognosis of cancer, and/or serve as potential therapeutic targets. Expression of functional circRNAs is commonly dysregulated in cancer and this is correlated with advanced Tumor-Node-Metastasis stage, lymph node status, distant metastasis, poor differentiation and shorter overall survival of cancer patients. Recently, an increasing number of studies have shown that circRNAs are closely associated with NSCLC. Functional experiments have revealed that circRNAs are intricately associated with the pathological progression of NSCLC. The present review provides an overview of the regulatory effect of circRNAs in the development and progression of NSCLC, taking into consideration various physiological and pathological processes, such as proliferation, apoptosis, invasion and migration, and their potential value as biomarkers and therapeutic targets.