Promotion of astrocytoma cell invasion by micro RNA–22 targeting of tissue inhibitor of matrix metalloproteinase–2

Yu-ichiro Ohnishi Departments of Neurosurgery and

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 MD, PhD
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Koichi Iwatsuki Departments of Neurosurgery and

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Masahiro Ishihara Departments of Neurosurgery and

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Toshika Ohkawa Department of Neurosurgery, Yao Municipal Hospital; and

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Manabu Kinoshita Department of Neurosurgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

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Koei Shinzawa Molecular Genetics, Osaka University Medical School;

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Yasunori Fujimoto Departments of Neurosurgery and

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Toshiki Yoshimine Departments of Neurosurgery and

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OBJECTIVE

Diffuse astrocytomas (DAs) have a high recurrence rate due to diffuse infiltration into the brain and spinal cord. Micro RNAs (miRNAs) are small noncoding RNAs that regulate gene expression by binding to complementary sequences of target messenger RNA (mRNA). It has been reported that miRNA-22 (miR-22) is involved in the invasion of some cancer cell lines. The aim of this study was to identify the biological effects of miR-22 in regard to the invasion of human DAs.

METHODS

The authors evaluated whether the level of miR-22 is elevated in human spinal DAs by using miRNA chips. Next, the role of miR-22 in 1321N1 human astrocytoma cells was investigated. Finally, to elucidate whether miR-22 promotes invasion by astrocytoma cells in vivo, the authors transplanted miR-22 overexpressed astrocytoma cells into mouse thoracic spinal cord.

RESULTS

The miR-22 significantly upregulated the invasion capacity of 1321N1 cells. Computational in silico analysis predicted that tissue inhibitor of matrix metalloproteinase–2 (TIMP2) is a target gene of miR-22. This was confirmed by quantitative reverse transcription polymerase chain reaction and Western blotting, which showed that miR-22 inhibited TIMP2 mRNA and protein expression, respectively. Luciferase reporter assays demonstrated that miR-22 directly bound the 3′-untranslated regions of TIMP2. The authors further showed that miR-22 promoted invasiveness in 1321N1 astrocytoma cells when transplanted into mouse spinal cord.

CONCLUSIONS

These data suggest that miR-22 acts to regulate invasion of 1321N1 astrocytoma cells by targeting TIMP2 expression. Additional studies with more cases and cell lines are required to elucidate the findings of this study for a novel treatment target for spinal DAs.

ABBREVIATIONS

DA = diffuse astrocytoma; ECM = extracellular matrix; miRNA, miR-22, mRNA = micro RNA, micro RNA–22, messenger RNA; MMP = matrix metalloproteinase; PFA = paraformaldehyde; RT-PCR = reverse transcription polymerase chain reaction; TBST = Tris-buffered saline with Triton X-100; TIMP2 = tissue inhibitor of matrix metalloproteinase–2; 3′-UTR = 3′-untranslated region.
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