MicroRNA regulating stanniocalcin-1 is a metastasis and dissemination promoting factor in glioblastoma
MicroRNAs (miRs) regulate many biological processes, such as invasion, angiogenesis, and metastasis. Glioblastoma (GBM) patients with metastasis/metastatic dissemination have a very poor prognosis; therefore, inhibiting metastasis/metastatic dissemination has become an important therapeutic strategy for GBM treatment.
Using 76 GBM tissues, we examined the expression levels of 23 GBM-related miRs and compared the miRs’ expression levels between GBMs with metastasis/metastatic dissemination and GBMs without metastasis/metastatic dissemination. Using the bioinformatics web site, we searched the target genes of miRs. To analyze the function of target gene, several biological assays and survival analysis by the Kaplan–Meier method were performed.
We found that eight miRs were significantly decreased in GBM with metastasis/metastatic dissemination. By the bioinformatics analysis, we identified stanniocalcin-1 (STC1) as the most probable target gene against the combination of these miRs. Four miRs (miR-29B, miR-34a, miR-101, and miR-137) have predictive binding sites in STC1 mRNA, and mRNA expression of STC1 was downregulated by mimics of these miRs. Also, mimics of these miRs and knockdown of STC1 by siRNA suppressed invasion in GBM cells. GBM with metastasis/metastatic dissemination had significantly higher levels of STC1 than GBM without metastasis/metastatic dissemination. Finally, Kaplan–Meier analysis demonstrated that GBMs with high STC1 level had significantly shorter survival than GBMs with low STC1 level.
STC1 may be a novel metastasis/metastatic dissemination promoting factor regulated by several miRs in GBM. Because STC1 is a secreted glycoprotein and functions via the autocrine/paracrine signals, inhibiting STC1 signal may become a novel therapeutic strategy for GBM.
KeywordsSTC1 Metastases Dissemination Glioblastoma MicroRNA Biomarker
We thank Naoko Sato and Takiko Uno for performing the immunohistochemical experiments.
This study was supported in part by a Grant-in-Aid for Scientific Research to Eiji Kohmura (17K10898), Takashi Sasayama (17K10863), and Kazuhiro Tanaka (17K10864), Satoshi Nakamizo (17K16648), Hirotomo Tanaka (16K20010), and Masamitsu Nishihara (15K10332) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
Compliance with ethical standards
Conflict of interest
There are no potential conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the institutional ethics board (Nos. 1160 and 1518, and No. 1714 in Kobe University Hospital, No. 2016-383 (1521) in Kanazawa University Hospital, No. 14072 in Osaka University Hospital, No 1312245169 in Osaka International Cancer Institute).
Informed consent was obtained from all individual participants included in the study.
- 1.Piccirilli M, Brunetto GM, Rocchi G, Giangaspero F, Salvati M (2008) Extra central nervous system metastases from cerebral glioblastoma multiforme in elderly patients. Clinico-pathological remarks on our series of seven cases and critical review of the literature. Tumori J 94:40–51CrossRefGoogle Scholar
- 2.Sharma D, Gupta A, Dhillon GS, Chhabra SS (2016) Late onset leptomeningeal and whole spine metastasis from supratentorial glioblastoma multiforme: An uncommon manifestation of a common tumor. J Craniovertebr Junction Spine 7:118–120. https://doi.org/10.4103/0974-8237.181878 CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Tanaka H, Sasayama T, Tanaka K, Nakamizo S, Nishihara M, Mizukawa K, Kohta M, Koyama J, Miyake S, Taniguchi M, Hosoda K, Kohmura E (2013) MicroRNA-183 upregulates HIF-1alpha by targeting isocitrate dehydrogenase 2 (IDH2) in glioma cells. J Neurooncol 111:273–283. https://doi.org/10.1007/s11060-012-1027-9 CrossRefPubMedGoogle Scholar
- 17.Chen R, Liu H, Cheng Q, Jiang B, Peng R, Zou Q, Yang W, Yang X, Wu X, Chen Z (2016) MicroRNA-93 promotes the malignant phenotypes of human glioma cells and induces their chemoresistance to temozolomide. Biol Open 5:669–677. https://doi.org/10.1242/bio.015552 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Bier A, Giladi N, Kronfeld N, Lee HK, Cazacu S, Finniss S, Xiang C, Poisson L, deCarvalho AC, Slavin S, Jacoby E, Yalon M, Toren A, Mikkelsen T, Brodie C (2013) MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting RTVP-1. Oncotarget 4:665–676. https://doi.org/10.18632/oncotarget.928 CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Moller HG, Rasmussen AP, Andersen HH, Johnsen KB, Henriksen M, Duroux M (2013) A systematic review of microRNA in glioblastoma multiforme: micro-modulators in the mesenchymal mode of migration and invasion. Mol Neurobiol 47:131–144. https://doi.org/10.1007/s12035-012-8349-7 CrossRefPubMedGoogle Scholar
- 30.Ma X, Gu L, Li H, Gao Y, Li X, Shen D, Gong H, Li S, Niu S, Zhang Y, Fan Y, Huang Q, Lyu X, Zhang X (2015) Hypoxia-induced overexpression of stanniocalcin-1 is associated with the metastasis of early stage clear cell renal cell carcinoma. J Transl Med 13:56. https://doi.org/10.1186/s12967-015-0421-4 CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Pena C, Cespedes MV, Lindh MB, Kiflemariam S, Mezheyeuski A, Edqvist PH, Hagglof C, Birgisson H, Bojmar L, Jirstrom K, Sandstrom P, Olsson E, Veerla S, Gallardo A, Sjoblom T, Chang AC, Reddel RR, Mangues R, Augsten M, Ostman A (2013) STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer. Cancer Res 73:1287–1297. https://doi.org/10.1158/0008-5472.CAN-12-1875 CrossRefPubMedGoogle Scholar
- 38.Clavreul A, Etcheverry A, Chassevent A, Quillien V, Avril T, Jourdan ML, Michalak S, Francois P, Carre JL, Mosser J, Grand Ouest Glioma Project N, Menei P (2012) Isolation of a new cell population in the glioblastoma microenvironment. J Neurooncol 106:493–504. https://doi.org/10.1007/s11060-011-0701-7 CrossRefPubMedGoogle Scholar
- 42.Li Y, He ZC, Zhang XN, Liu Q, Chen C, Zhu Z, Chen Q, Shi Y, Yao XH, Cui YH, Zhang X, Wang Y, Kung HF, Ping YF, Bian XW (2018) Stanniocalcin-1 augments stem-like traits of glioblastoma cells through binding and activating NOTCH1. Cancer Lett 416:66–74. https://doi.org/10.1016/j.canlet.2017.11.033 CrossRefPubMedGoogle Scholar