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.
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