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Mol Cancer. 2018 Jan 18;17(1):10. doi: 10.1186/s12943-018-0760-x.

The microRNA-15a-PAI-2 axis in cholangiocarcinoma-associated fibroblasts promotes migration of cancer cells.

Author information

1
Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
2
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
3
Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
4
Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
5
Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
6
Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
7
Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
8
Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
9
Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
10
Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. chanitra.thu@mahidol.ac.th.
11
Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan. yasusei@tokushima-u.ac.jp.

Abstract

BACKGROUND:

Cholangiocarcinoma (CCA) has an abundance of tumor stroma which plays an important role in cancer progression via tumor-promoting signals. This study aims to explore the microRNA (miRNA) profile of CCA-associated fibroblasts (CCFs) and the roles of any identified miRNAs in CCA progression.

METHODS:

miRNA expression profiles of CCFs and normal skin fibroblasts were compared by microarray. Identified downregulated miRNAs and their target genes were confirmed by real-time PCR. Their binding was confirmed by a luciferase reporter assay. The effects of conditioned-media (CM) of miRNA mimic- and antagonist-transfected CCFs were tested in CCA migration in wound healing assays. Finally, the levels of miRNA and their target genes were examined by real-time PCR and immunohistochemistry in clinical CCA samples.

RESULTS:

miR-15a was identified as a downregulated miRNA in CCFs. Moreover, PAI-2 was identified as a novel target gene of miR-15a. Recombinant PAI-2 promoted migration of CCA cells. Moreover, CM from miR-15a mimic-transfected CCFs suppressed migration of CCA cells. Lower expression of miR-15a and higher expression of PAI-2 were observed in human CCA samples compared with normal liver tissues. Importantly, PAI-2 expression correlated with poor prognosis in CCA patients.

CONCLUSIONS:

These findings highlight the miR-15a/PAI-2 axis as a potential therapeutic target in CCA patients.

KEYWORDS:

Cancer-associated fibroblasts; Cholangiocarcinoma; Migration; PAI-2; Tumor microenvironment; microRNA (miRNA)

PMID:
29347950
PMCID:
PMC5773154
DOI:
10.1186/s12943-018-0760-x
[Indexed for MEDLINE]
Free PMC Article

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