Neuropilin‐1 regulated by miR‐320 contributes to the growth and metastasis of cholangiocarcinoma cells

Liver International - Tập 38 Số 1 - Trang 125-135 - 2018
Huaqiang Zhu1, Xian Jiang2, Xu Zhou1, Xuesong Dong2, Kai Xie1, Chuncheng Yang1, Hongchi Jiang2, Xueying Sun2, Jun Lu1
1Department of Hepatobiliary Surgery, ShanDong Provincial Hospital affiliated to ShanDong University, Jinan, China
2Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China

Tóm tắt

AbstractBackground & AimsNeuropilin‐1 (NRP‐1) activates signalling pathways as multifunctional co‐receptors in cancer cells. However, its role and how it is regulated by miRNAs in cholangiocarcinoma (CCA) have not yet been investigated.MethodsThe expression of NRP‐1, miR‐320 and key molecules involved in cell proliferation, migration and related signalling pathways were detected by immunohistochemistry, immunoblotting and qRT‐PCR. Stable transfectants depleted of NRP‐1 were generated. The regulatory effect of miR‐320 on NRP‐1 was evaluated by luciferase reporter assays. Cell proliferation, cell cycle distribution and migration were examined. Xenograft tumour models were established to assess tumourigenesis, tumour growth and lung metastasis.ResultsCholangiocarcinoma tissues expressed higher levels of NRP‐1 than adjacent normal biliary tissues, and its expression negatively correlated with miR‐320. NRP‐1 depletion inhibited cell proliferation and induced cell cycle arrest in the G1/S phase by upregulating p27, and downregulating cyclin E and cyclin‐dependent kinase 2; and reduced cell migration by inhibiting the phosphorylation of focal adhesion kinase. NRP‐1 depletion suppressed tumourigenesis, tumour growth and lung metastasis by inhibiting cell proliferation and tumour angiogenesis in experimental animals. Depletion of NRP‐1 inhibited the activation of VEGF/VEGFR2, EGF/EGFR and HGF/c‐Met pathways stimulated by respective ligands. MiR‐320 negatively regulated the expression of NRP‐1 by binding to the 3′‐UTR of NRP‐1 promoter, and miR‐320 mimics inhibited cell proliferation and migration, and the growth of established tumours in animals by downregulating NRP‐1.ConclusionsThe present results indicate that NRP‐1 is negatively regulated by miR‐320, and both of them may be potentially therapeutic targets for CCA.

Từ khóa


Tài liệu tham khảo

10.1016/j.jhep.2014.01.021

10.1056/NEJMoa0908721

10.18632/oncotarget.11060

10.18632/oncotarget.626

10.1091/mbc.E09-12-1061

10.1084/jem.20111424

10.1136/gutjnl-2011-300007

10.1016/j.jhep.2011.01.033

10.1111/his.12098

10.1097/MPA.0000000000000117

10.1016/j.ajpath.2015.11.021

Li L, 2016, Neuropilin‐1 is associated with clinicopathology of gastric cancer and contributes to cell proliferation and migration as multifunctional co‐receptors, J Exp Clin Cancer Res, 35, 16, 10.1186/s13046-016-0291-5

10.1016/j.jhep.2008.09.015

10.1007/s10456-013-9394-1

10.1038/ncb2396

10.1093/carcin/bgs371

10.18632/oncotarget.8937

10.1038/nrgastro.2011.131

10.1007/s00432-016-2121-8

10.1016/j.cellsig.2013.01.011

10.18632/oncotarget.4814

10.1158/1078-0432.CCR-10-0752

10.1016/j.jhep.2014.03.033

10.1002/mc.22449

10.1158/0008-5472.CAN-12-0995

10.1186/s12943-015-0310-8

10.1158/0008-5472.CAN-07-3256

10.1517/14728222.2011.641951

Iyer RV, 2016, A multicenter phase II study of gemcitabine, capecitabine, and bevacizumab for locally advanced or metastatic biliary tract cancer, Am J Clin Oncol

10.1007/s11912-012-0242-z

10.1016/j.drudis.2012.11.013

10.1083/jcb.201307067

10.1038/ncb3250

10.1074/jbc.275.28.21486

10.1242/bio.010918

10.1038/ncomms6811

10.1002/path.1779

10.1038/sj.bjc.6604129

10.1002/hep.27402

Thông tin
Thông tin xuất bản

Liver International

Tập 38 Số 1

125-135

Thông tin tác giả