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Coordinated targeting of MMP-2/MMP-9 by miR-296-3p/FOXCUT exerts tumor-suppressing effects in choroidal malignant melanoma

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Abstract

Choroidal melanoma is the most common intraocular tumor in adults, and overexpression of matrix metalloproteinase-2 or matrix metalloproteinase-9 (MMP-2/MMP-9) is associated with angiogenesis and tumor metastasis of the choroidal malignant melanoma (CMM). This study aims to investigate the functions and mechanisms of microRNA or long non-coding RNA-targeted MMP-2/MMP-9 in CMM. We demonstrated that expressions of MMP-2/MMP-9 were increased in CMM tissues and C918 cells in comparison with normal choroidal melanocytes. Bio-informatics prediction and our experiments validated that MMP-2 and MMP-9 were simultaneously targeted by miR-296-3p and FOXC1 promoter upstream transcript (FOXCUT); the latter two exerted tumor-suppressing effects on CMM cells by inhibiting cell proliferation, cell cycle progression, migration, invasion, and induction of cell apoptosis. Furthermore, significant downregulations of miR-296-3p and FOXCUT were found in C918 cells compared with choroidal melanocytes from the unaffected eyes, and a positive correlation was observed between their levels in three cases of eye malignant melanomas. Our data indicated that MMP-2/MMP-9 was coordinately targeted by two non-coding RNAs, miR-296-3p and FOXCUT, which were decreased, and tumor-suppressing factors in CMM. Further study will show the possibility of developing them as therapeutic candidates for CMM.

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Abbreviations

MMP-2/MMP-9:

Matrix metalloproteinase-2/matrix metalloproteinase-9

CMM:

Choroid malignant melanoma

miRNA:

MicroRNA

lncRNA:

Long non-coding RNA

FOXCUT:

FOXC1 promoter upstream transcript

ECM:

Extracellular matrix

ncRNAs:

Non-coding RNAs

ISH:

In situ hybridization

IHC:

Immunohistochemistry

FCS:

Fetal calf serum

FBS:

Fetal bovine serum

NC mimic:

A negative control sequence

RT:

Reverse transcription

qPCR:

Quantitative PCR

RAP:

RNA antisense purification

CCK-8:

Cell Counting Kit-8

FCM:

Flow cytometry assay

SD:

Standard deviation

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The authors declare that there are no sources of funding to be acknowledged.

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Authors and Affiliations

  1. Department of Ophthalmology, The First Hospital of China Medical University, No. 155, Nanjing Bei Street, Heping District, Shenyang, 110001, Liaoning Province, China

    Xinhe Wang, Yuedong Hu, Yun Zhou & Lei Chen

  2. The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning Province, China

    Jianyi Cui

Authors
  1. Xinhe Wang
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  2. Yuedong Hu
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  3. Jianyi Cui
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  4. Yun Zhou
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  5. Lei Chen
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Contributions

X.W., Y.H., and J.C. wrote the paper and conceived and designed the experiments. Y.Z. analyzed the data. X.W. and Y.H. prepared the manuscript and revised it. L.C. is responsible for the guarantee of integrity of the entire study. All authors read and approved the final manuscript.

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Correspondence to Lei Chen.

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Wang, X., Hu, Y., Cui, J. et al. Coordinated targeting of MMP-2/MMP-9 by miR-296-3p/FOXCUT exerts tumor-suppressing effects in choroidal malignant melanoma. Mol Cell Biochem 445, 25–33 (2018). https://doi.org/10.1007/s11010-017-3248-x

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  • DOI: https://doi.org/10.1007/s11010-017-3248-x

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