Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

MiR-134, Mediated by IRF1, Suppresses Tumorigenesis and Progression by Targeting VEGFA and MYCN in Osteosarcoma

Author(s): Zhuo Ma, Kai Li, Peng Chen, Qizheng Pan, Xuyang Li and Guoqing Zhao*

Volume 20 , Issue 10 , 2020

Page: [1197 - 1208] Pages: 12

DOI: 10.2174/1871520620666200402074752

Price: $65


Background: Osteosarcoma (OS) is a prevalent primary bone malignancy and its distal metastasis remains the main cause of mortality in OS patients. MicroRNAs (miRNAs) play critical roles during cancer metastasis.

Objective: Thus, elucidating the role of miRNA dysregulation in OS metastasis may provide novel therapeutic targets.

Methods: The previous study found a low miR-134 expression level in the OS specimens compared with paracancer tissues. Overexpression of miR-134 stable cell lines was established. Cell viability assay, cell invasion and migration assay and apoptosis assay were performed to evaluate the role of miR-134 in OS in vitro.

Results: We found that miR-134 overexpression inhibits cell proliferation, migration and invasion, and induces cell apoptosis in both MG63 and Saos-2 cell lines. Mechanistically, miR-134 targets the 3'-UTR of VEGFA and MYCN mRNA to silence its translation, which was confirmed by luciferase-reporter assay. The real-time PCR analysis illustrated that miR-134 overexpression decreases VEGFA and MYCN mRNA levels. Additionally, the overexpression of VEGFA or MYCN can partly attenuate the effects of miR-134 on OS cell migration and viability. Furthermore, the overexpression of miR-134 dramatically inhibits tumor growth in the human OS cell line xenograft mouse model in vivo. Moreover, bioinformatic and luciferase assays indicate that the expression of miR-134 is regulated by Interferon Regulatory Factor (IRF1), which binds to its promoter and activates miR-134 expression.

Conclusion: Our study demonstrates that IRF1 is a key player in the transcriptional control of miR-134, and it inhibits cell proliferation, invasion and migration in vitro and in vivo via targeting VEGFA and MYCN.

Keywords: IRF1, miR-134, VEGFA, MYCN, osteosarcoma, tumorigenesis.

Graphical Abstract
Mogilyansky, E.; Rigoutsos, I. The miR-17/92 cluster: A comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ., 2013, 20(12), 1603-1614.
[] [PMID: 24212931]
Aqeilan, R.I.; Calin, G.A.; Croce, C.M. miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. Cell Death Differ., 2010, 17(2), 215-220.
[] [PMID: 19498445]
Jones, M.; Lal, A. MicroRNAs, wild-type and mutant p53: More questions than answers. RNA Biol., 2012, 9(6), 781-791.
[] [PMID: 22664917]
Chen, J.; Zhou, J.; Chen, X.; Yang, B.; Wang, D.; Yang, P.; He, X.; Li, H. miRNA-449a is downregulated in osteosarcoma and promotes cell apoptosis by targeting BCL2. Tumour Biol., 2015, 36(10), 8221-8229.
[] [PMID: 26002578]
Osaki, M.; Takeshita, F.; Sugimoto, Y.; Kosaka, N.; Yamamoto, Y.; Yoshioka, Y.; Kobayashi, E.; Yamada, T.; Kawai, A.; Inoue, T.; Ito, H.; Oshimura, M.; Ochiya, T. MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression. Mol. Ther.: J. Am. Soc. Gene Ther., 2011, 19(6), 1123-1130.
He, C.; Xiong, J.; Xu, X.; Lu, W.; Liu, L.; Xiao, D.; Wang, D. Functional elucidation of MiR-34 in osteosarcoma cells and primary tumor samples. Biochem. Biophys. Res. Commun., 2009, 388(1), 35-40.
[] [PMID: 19632201]
Pan, J.Y.; Zhang, F.; Sun, C.C.; Li, S.J.; Li, G.; Gong, F.Y.; Bo, T.; He, J.; Hua, R.X.; Hu, W.D.; Yuan, Z.P.; Wang, X.; He, Q.Q.; Li, D.J. miR-134: A human cancer suppressor? Mol. Ther. Nucleic Acids, 2017, 6, 140-149.
[] [PMID: 28325280]
Mirzadeh Azad, F.; Naeli, P.; Malakootian, M.; Baradaran, A.; Tavallaei, M.; Ghanei, M.; Mowla, S.J. Two lung development related microRNAs, miR-134 and miR-187, are differentially expressed in lung tumors. Gene, 2016, 577(2), 221-226.
[] [PMID: 26642897]
O’Brien, K.; Lowry, M.C.; Corcoran, C.; Martinez, V.G.; Daly, M.; Rani, S.; Gallagher, W.M.; Radomski, M.W.; MacLeod, R.A.; O’Driscoll, L. miR-134 in extracellular vesicles reduces triple negative breast cancer aggression and increases drug sensitivity. Oncotarget, 2015, 6(32), 32774-32789.
[] [PMID: 26416415]
Liu, Y.; Zhang, M.; Qian, J.; Bao, M.; Meng, X.; Zhang, S.; Zhang, L.; Zhao, R.; Li, S.; Cao, Q.; Li, P.; Ju, X.; Lu, Q.; Li, J.; Shao, P.; Qin, C.; Yin, C. miR-134 functions as a tumor suppressor in cell proliferation and epithelial-to-mesenchymal Transition by targeting KRAS in renal cell carcinoma cells. DNA Cell Biol., 2015, 34(6), 429-436.
[] [PMID: 25811077]
Shuang, T.; Wang, M.; Shi, C.; Zhou, Y.; Wang, D. Down regulated expression of miR-134 contributes to paclitaxel resistance in human ovarian cancer cells. FEBS Lett., 2015, 589(20 Pt B), 3154-3164.
[] [PMID: 26363097]
Lu, L.; Ju, F.; Zhao, H.; Ma, X. MicroRNA-134 modulates resistance to doxorubicin in human breast cancer cells by downregulating ABCC1. Biotechnol. Lett., 2015, 37(12), 2387-2394.
[] [PMID: 26318721]
Zha, R.; Guo, W.; Zhang, Z.; Qiu, Z.; Wang, Q.; Ding, J.; Huang, S.; Chen, T.; Gu, J.; Yao, M.; He, X. Genome-wide screening identified that miR-134 acts as a metastasis suppressor by targeting integrin β1 in hepatocellular carcinoma. PLoS One, 2014, 9(2), e87665.
[] [PMID: 24498348]
Kitamura, K.; Seike, M.; Okano, T.; Matsuda, K.; Miyanaga, A.; Mizutani, H.; Noro, R.; Minegishi, Y.; Kubota, K.; Gemma, A. MiR-134/487b/655 cluster regulates TGF-β-induced epithelial mesenchymal transition and drug resistance to gefitinib by targeting MAGI2 in lung adenocarcinoma cells. Mol. Cancer Ther., 2014, 13(2), 444-453.
[] [PMID: 24258346]
Niu, C.S.; Yang, Y.; Cheng, C.D. MiR-134 regulates the proliferation and invasion of glioblastoma cells by reducing Nanog expression. Int. J. Oncol., 2013, 42(5), 1533-1540.
[] [PMID: 23467648]
Johnsen, J.I.; Segerström, L.; Orrego, A.; Elfman, L.; Henriksson, M.; Kågedal, B.; Eksborg, S.; Sveinbjörnsson, B.; Kogner, P. Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo. Oncogene, 2008, 27(20), 2910-2922.
[] [PMID: 18026138]
Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 2004, 116(2), 281-297.
[] [PMID: 14744438]
Kobayashi, E.; Hornicek, F.J.; Duan, Z. MicroRNA Involvement in Osteosarcoma. Sarcoma, 2012, 2012, 359739.
[] [PMID: 22550419]
Lulla, R.R.; Costa, F.F.; Bischof, J.M.; Chou, P.M. de F Bonaldo, M.; Vanin, E.F.; Soares, M.B. Identification of differentially expressed MicroRNAs in osteosarcoma. Sarcoma, 2011, 2011, 732690.
[] [PMID: 21789031]
Schaap-Oziemlak, A.M.; Raymakers, R.A.; Bergevoet, S.M.; Gilissen, C.; Jansen, B.J.; Adema, G.J.; Kögler, G.; le Sage, C.; Agami, R.; van der Reijden, B.A.; Jansen, J.H. MicroRNA hsa-miR-135b regulates mineralization in osteogenic differentiation of human unrestricted somatic stem cells. Stem Cells Dev., 2010, 19(6), 877-885.
[] [PMID: 19795981]
Zhang, T.; Niu, X.; Liao, L.; Cho, E.A.; Yang, H. The contributions of HIF-target genes to tumor growth in RCC. PLoS One, 2013, 8(11), e80544.
[] [PMID: 24260413]
Rankin, E.B.; Giaccia, A.J.; Schipani, E. A central role for hypoxic signaling in cartilage, bone, and hematopoiesis. Curr. Osteoporos. Rep., 2011, 9(2), 46-52.
[] [PMID: 21360287]
Yang, J.; Zhang, W. New molecular insights into osteosarcoma targeted therapy. Curr. Opin. Oncol., 2013, 25(4), 398-406.
[] [PMID: 23666471]
Versleijen-Jonkers, Y.M.; Vlenterie, M.; van de Luijtgaarden, A.C.; van der Graaf, W.T. Anti-angiogenic therapy, a new player in the field of sarcoma treatment. Crit. Rev. Oncol. Hematol., 2014, 91(2), 172-185.
[] [PMID: 24613529]
Bell, E.; Chen, L.; Liu, T.; Marshall, G.M.; Lunec, J.; Tweddle, D.A. MYCN oncoprotein targets and their therapeutic potential. Cancer Lett., 2010, 293(2), 144-157.
[] [PMID: 20153925]
Wu, X.; Cai, Z.D.; Lou, L.M.; Zhu, Y.B. Expressions of p53, c- MYC, BCL-2 and apoptotic index in human osteosarcoma and their correlations with prognosis of patients. Cancer Epidemiol., 2012, 36(2), 212-216.
[] [PMID: 21890444]
Gamberi, G.; Benassi, M.S.; Bohling, T.; Ragazzini, P.; Molendini, L.; Sollazzo, M.R.; Pompetti, F.; Merli, M.; Magagnoli, G.; Balladelli, A.; Picci, P. C-myc and c-fos in human osteosarcoma: Prognostic value of mRNA and protein expression. Oncology, 1998, 55(6), 556-563.
[] [PMID: 9778623]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy