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miRNA-15a-PAI-2 轴在胆管癌相关成纤维细胞中促进癌细胞迁移。

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

机构信息

Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.

出版信息

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

DOI:10.1186/s12943-018-0760-x
PMID:29347950
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5773154/
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.

摘要

背景

胆管癌（CCA）有丰富的肿瘤基质，通过促进肿瘤的信号在癌症进展中发挥重要作用。本研究旨在探索与 CCA 相关的成纤维细胞（CCF）中的 microRNA（miRNA）谱，以及任何鉴定出的 miRNA 在 CCA 进展中的作用。

方法

通过微阵列比较 CCF 和正常皮肤成纤维细胞的 miRNA 表达谱。通过实时 PCR 确认鉴定出的下调 miRNA 及其靶基因。通过荧光素酶报告基因检测证实其结合。通过划痕愈合试验测试 miRNA 模拟物和拮抗剂转染的 CCF 条件培养基（CM）对 CCA 迁移的影响。最后，通过实时 PCR 和免疫组织化学检查临床 CCA 样本中的 miRNA 及其靶基因的水平。

结果

miR-15a 被鉴定为 CCF 中下调的 miRNA。此外，PAI-2 被鉴定为 miR-15a 的新靶基因。重组 PAI-2 促进了 CCA 细胞的迁移。此外，miR-15a 模拟物转染的 CCF 的 CM 抑制了 CCA 细胞的迁移。与正常肝组织相比，人 CCA 样本中 miR-15a 的表达较低，PAI-2 的表达较高。重要的是，PAI-2 的表达与 CCA 患者的预后不良相关。

结论

这些发现强调了 miR-15a/PAI-2 轴作为 CCA 患者潜在治疗靶点的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a241/5773154/5c6ed9af0e6b/12943_2018_760_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a241/5773154/8d671fa2a6c0/12943_2018_760_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a241/5773154/660752c39985/12943_2018_760_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a241/5773154/dcb692d21f32/12943_2018_760_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a241/5773154/222558166ad3/12943_2018_760_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a241/5773154/5c6ed9af0e6b/12943_2018_760_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a241/5773154/8d671fa2a6c0/12943_2018_760_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a241/5773154/660752c39985/12943_2018_760_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a241/5773154/dcb692d21f32/12943_2018_760_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a241/5773154/222558166ad3/12943_2018_760_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a241/5773154/5c6ed9af0e6b/12943_2018_760_Fig5_HTML.jpg

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