MicroRNA-503 Acts as a Tumor Suppressor in Osteosarcoma by Targeting L1CAM

Deregulated microRNAs and their roles in tumorigenesis have attracted much attention in recent years. Although miR-503 was shown to be important in tumorigenesis, its role in osteosarcoma remains unknown. In this study, we focused on the expression and mechanisms of miR-503 in osteosarcoma development. We found that miR-503 was down-regulated in osteosarcoma cell lines and primary tumor samples, and the restoration of miR-503 reduced cell proliferation, migration and invasion. Low level of miR-503 in patients with osteosarcoma was associated with considerably shortened disease-free survival. Furthermore, bioinformatic prediction and experimental validation revealed that the anti-tumor effect of miR-503 was probably exerted through targeting and repressing of L1CAM expression. L1CAM was up-regulated in osteosarcoma cell lines and primary tumor samples and the expression level of L1CAM were negatively correlated with miR-503 levels in osteosarcoma tissues. Collectively, our data identify the important roles of miR-503 in osteosarcoma pathogenesis, indicating its potential application in cancer therapy.

[1]  H. Mehdorn,et al.  The neural adhesion molecule L1CAM confers chemoresistance in human glioblastomas , 2012, Neurochemistry International.

[2]  Jing Zhou,et al.  Analysis of microRNA expression profiling identifies microRNA‐503 regulates metastatic function in hepatocellular cancer cell , 2011, Journal of surgical oncology.

[3]  S. Yamada,et al.  Overexpression of L1CAM is Associated with Tumor Progression and Prognosis via ERK Signaling in Gastric Cancer , 2014, Annals of Surgical Oncology.

[4]  R. Xu,et al.  L1cam promotes tumor progression and metastasis and is an independent unfavorable prognostic factor in gastric cancer , 2013, Journal of Hematology & Oncology.

[5]  Kevin B. Jones,et al.  miRNA signatures associate with pathogenesis and progression of osteosarcoma. , 2012, Cancer research.

[6]  Haiyang Xie,et al.  MicroRNA-503 inhibits the G1/S transition by downregulating cyclin D3 and E2F3 in hepatocellular carcinoma , 2013, Journal of Translational Medicine.

[7]  M. Gazouli,et al.  Expression of microRNAs, miR‐21, miR‐31, miR‐122, miR‐145, miR‐146a, miR‐200c, miR‐221, miR‐222, and miR‐223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance , 2013, Molecular carcinogenesis.

[8]  J. Yustein,et al.  The Adolescent and Young Adult with Cancer: State of the Art - Bone Tumors , 2013, Current Oncology Reports.

[9]  J. Bergquist,et al.  L1CAM from human melanoma carries a novel type of N-glycan with Galβ1-4Galβ1- motif. Involvement of N-linked glycans in migratory and invasive behaviour of melanoma cells , 2012, Glycoconjugate Journal.

[10]  Y. Mo,et al.  Systematic validation of predicted microRNAs for cyclin D1 , 2009, BMC Cancer.

[11]  R. Burbano,et al.  Epigenetic mechanisms in gastric cancer. , 2012, Epigenomics.

[12]  Jing Zhou,et al.  miR-503 regulates metastatic function through Rho guanine nucleotide exchanger factor 19 in hepatocellular carcinoma. , 2014, The Journal of surgical research.

[13]  P. Altevogt,et al.  L1CAM promotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression , 2014, Molecular oncology.

[14]  D. Hughes How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize. , 2009, Cancer treatment and research.

[15]  Anne-Marie Cleton-Jansen,et al.  Modulation of the Osteosarcoma Expression Phenotype by MicroRNAs , 2012, PloS one.

[16]  M. Frotscher,et al.  Role of L1CAM for axon sprouting and branching , 2012, Cell and Tissue Research.

[17]  Shuogui Xu,et al.  The miRNAs in the pathgenesis of osteosarcoma. , 2013, Frontiers in bioscience.

[18]  P. Altevogt,et al.  Role of miR-34a as a suppressor of L1CAM in endometrial carcinoma , 2014, Oncotarget.

[19]  Y. Huo,et al.  MicroRNA‐503 suppresses proliferation and cell‐cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1 , 2013, The FEBS journal.

[20]  Wei Zhang,et al.  New molecular insights into osteosarcoma targeted therapy , 2013, Current opinion in oncology.

[21]  X. Liu,et al.  Expression of miR-29c, miR-93, and miR-429 as Potential Biomarkers for Detection of Early Stage Non-Small Lung Cancer , 2014, PloS one.

[22]  Shanhu Huang,et al.  Tumor suppressive microRNA-424 inhibits osteosarcoma cell migration and invasion via targeting fatty acid synthase , 2013, Experimental and therapeutic medicine.

[23]  F. X. Donadeu,et al.  Differential miRNA expression between equine ovulatory and anovulatory follicles. , 2013, Domestic animal endocrinology.

[24]  Tongshan Wang,et al.  MiR‐503 regulates cisplatin resistance of human gastric cancer cell lines by targeting IGF1R and BCL2 , 2014, Chinese medical journal.

[25]  P. Altevogt,et al.  L1CAM , 2012, Cell adhesion & migration.

[26]  Z. Duan,et al.  MicroRNA Involvement in Osteosarcoma , 2012, Sarcoma.

[27]  P. Altevogt,et al.  L1CAM malfunction in the nervous system and human carcinomas , 2010, Cellular and Molecular Life Sciences.

[28]  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.