Identification and functional characterization of circRNA-0008717 as an oncogene in osteosarcoma through sponging miR-203

Circular RNA (circRNA) is a key regulator in the development and progression of human cancers, however its role in osteosarcoma tumorigenesis is not well understood. The present study aims to investigate the expression profiles and potential modulation of circRNA on osteosarcoma carcinogenesis. Human circRNA microarray was performed to screen for abnormally expressed circRNA in osteosarcoma tissue and circRNA-0008717 was identified as one circRNA significantly upregulated in osteosarcoma tissue. Osteosarcoma patients with high circRNA-0008717 expression had shortened survival. Gain and loss functional assays suggested that knockdown of circRNA-0008717 suppressed cell proliferation, migration and invasion, but promoted cell apoptosis. By using biotin-labeled circRNA-0008717 probe to perform RNA precipitation in osteosarcoma cells, we identified miR-203 as the circ0008717-associated microRNA. Subsequently, Bmi-1 was identified as the functional target of miR-203. In addition, overexpression of circRNA-0008717 in osteosarcoma could elevate Bmi-1 expression, resulting in the promotion of osteosarcoma cell proliferation and invasion. Furthermore, the tumor promoting effect of circRNA-0008717 was abolished by miR-203 mimics or Bmi-1 silencing vector. In conclusion, circRNA-0008717 plays an oncogenic role in osteosarcoma and may serve as a promising prognostic biomarker for osteosarcoma patients. Therefore, silence of circRNA-0008717 could be a future direction to develop a novel treatment strategy.

[1]  Hai-Feng Liang,et al.  Circular RNA circ-ABCB10 promotes breast cancer proliferation and progression through sponging miR-1271. , 2017, American journal of cancer research.

[2]  Bing Zhou,et al.  A novel identified circular RNA, circRNA_010567, promotes myocardial fibrosis via suppressing miR-141 by targeting TGF-β1. , 2017, Biochemical and biophysical research communications.

[3]  Y. Shao,et al.  Global circular RNA expression profile of human gastric cancer and its clinical significance , 2017, Cancer medicine.

[4]  Jun Shen,et al.  Circular RNA participates in the carcinogenesis and the malignant behavior of cancer , 2017, RNA biology.

[5]  B. Xiao,et al.  Using circular RNA hsa_circ_0000190 as a new biomarker in the diagnosis of gastric cancer. , 2017, Clinica chimica acta; international journal of clinical chemistry.

[6]  Deye Song,et al.  MALAT1 promotes osteosarcoma development by regulation of HMGB1 via miR-142–3p and miR-129–5p , 2017, Cell cycle.

[7]  Juanjuan Wen,et al.  Analysis of circulating long non-coding RNA UCA1 as potential biomarkers for diagnosis and prognosis of osteosarcoma. , 2017, European review for medical and pharmacological sciences.

[8]  Walter J. Lukiw,et al.  Deficiency in the Ubiquitin Conjugating Enzyme UBE2A in Alzheimer’s Disease (AD) is Linked to Deficits in a Natural Circular miRNA-7 Sponge (circRNA; ciRS-7) , 2016, Genes.

[9]  Rogerio Margis,et al.  Circular RNAs are miRNA sponges and can be used as a new class of biomarker. , 2016, Journal of biotechnology.

[10]  R. Chen,et al.  Circular RNA has_circ_0067934 is upregulated in esophageal squamous cell carcinoma and promoted proliferation , 2016, Scientific Reports.

[11]  Xi Jin,et al.  CircRNA expression pattern and circRNA-miRNA-mRNA network in the pathogenesis of nonalcoholic steatohepatitis , 2016, Oncotarget.

[12]  M. Mann,et al.  Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans , 2016, Nature Communications.

[13]  Yan Li,et al.  Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs , 2016, Nature Communications.

[14]  H. Xie,et al.  Emerging roles of circRNA_001569 targeting miR-145 in the proliferation and invasion of colorectal cancer , 2016, Oncotarget.

[15]  Weining Yang,et al.  Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2 , 2016, Nucleic acids research.

[16]  L. Du,et al.  MicroRNA-218 is a prognostic indicator in colorectal cancer and enhances 5-fluorouracil-induced apoptosis by targeting BIRC5. , 2015, Carcinogenesis.

[17]  Wei Zhao,et al.  MicroRNA-210 is upregulated by hypoxia-inducible factor-1α in the stromal cells of giant cell tumors of bone. , 2015, Molecular medicine reports.

[18]  Jingnan Shen,et al.  Development and validation of a pretreatment prognostic index to predict death and lung metastases in extremity osteosarcoma , 2015, Oncotarget.

[19]  Guangpeng Liu,et al.  miR-203 Acts as a Tumor Suppressor Gene in Osteosarcoma by Regulating RAB22A , 2015, PloS one.

[20]  Haimin Li,et al.  Circular RNA: A new star of noncoding RNAs. , 2015, Cancer letters.

[21]  Mingjin Yang,et al.  An In Vivo Method to Identify microRNA Targets Not Predicted by Computation Algorithms: p21 Targeting by miR-92a in Cancer. , 2015, Cancer research.

[22]  Huajie Cai,et al.  cir-ITCH Plays an Inhibitory Role in Colorectal Cancer by Regulating the Wnt/β-Catenin Pathway , 2015, PloS one.

[23]  Cheng Wang,et al.  PI3K/Akt signaling in osteosarcoma. , 2015, Clinica chimica acta; international journal of clinical chemistry.

[24]  Xiaoyan Mo,et al.  Using circular RNA as a novel type of biomarker in the screening of gastric cancer. , 2015, Clinica chimica acta; international journal of clinical chemistry.

[25]  Baoan Ma,et al.  MicroRNA profiling identifies MiR-195 suppresses osteosarcoma cell metastasis by targeting CCND1 , 2015, Oncotarget.

[26]  Yifeng Zhou,et al.  Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/β-catenin pathway , 2015, Oncotarget.

[27]  G. Shan,et al.  Exon-intron circular RNAs regulate transcription in the nucleus , 2015, Nature Structural &Molecular Biology.

[28]  R. Parker,et al.  Circular RNAs: diversity of form and function , 2014, RNA.

[29]  N. Rajewsky,et al.  circRNA biogenesis competes with pre-mRNA splicing. , 2014, Molecular cell.

[30]  Jilong Yang,et al.  Advances in targeted therapy for osteosarcoma. , 2014, Discovery medicine.

[31]  Yifeng Zhou,et al.  A sequence polymorphism in miR-608 predicts recurrence after radiotherapy for nasopharyngeal carcinoma. , 2013, Cancer research.

[32]  Yong Huang,et al.  miR‐16 inhibits cell proliferation by targeting IGF1R and the Raf1–MEK1/2–ERK1/2 pathway in osteosarcoma , 2013, FEBS letters.

[33]  Phillip A. Sharp,et al.  A Circuitous Route to Noncoding RNA , 2013, Science.

[34]  Sebastian D. Mackowiak,et al.  Circular RNAs are a large class of animal RNAs with regulatory potency , 2013, Nature.

[35]  J. Kjems,et al.  Natural RNA circles function as efficient microRNA sponges , 2013, Nature.

[36]  J. Gu,et al.  MicroRNA in the pathogenesis and prognosis of esophageal cancer. , 2013, Current pharmaceutical design.

[37]  Jørgen Kjems,et al.  miRNA‐dependent gene silencing involving Ago2‐mediated cleavage of a circular antisense RNA , 2011, The EMBO journal.

[38]  H. Heneghan,et al.  MiRNAs as biomarkers and therapeutic targets in cancer. , 2010, Current opinion in pharmacology.

[39]  C. Haglund,et al.  Bmi-1 expression predicts prognosis in squamous cell carcinoma of the tongue , 2010, British Journal of Cancer.

[40]  L. Donehower,et al.  MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), amplified on chromosome 9, collaborate with p53 deficiency in mouse osteosarcoma progression. , 2009, Cancer research.

[41]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[42]  L. Liu,et al.  Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death , 2006, Oncogene.

[43]  Mark J Alkema,et al.  Characterization and chromosomal localization of the human proto-oncogene BMI-1. , 1993, Human molecular genetics.

[44]  D. Riesner,et al.  Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. , 1976, Proceedings of the National Academy of Sciences of the United States of America.