microRNA-454 shows anti-angiogenic and anti-metastatic activity in pancreatic ductal adenocarcinoma by targeting LRP6.

Our previous work has shown that microRNA-454 (miR-454) can inhibit the growth of pancreatic ductal adenocarcinoma (PDAC) by blocking the recruitment of bone marrow-derived macrophages. In the present study, we aimed to explore its role in the proliferation, invasion, and pro-angiogenic activity of PDAC cells in vitro and lung metastasis in vivo. PANC-1 and MiaPaCa-2 cells were transfected with a miR-454-expressing plasmid and tested for cell proliferation, colony formation, cell cycle distribution, invasion, and pro-angiogenic activity. The target gene(s) that mediated the action of miR-454 was identified. The effect of miR-454 overexpression on lung metastasis of PDAC was evaluated in nude mice. Of note, overexpression of miR-454 significantly inhibited PDAC cell proliferation and colony formation and arrests PDAC cells at the G2/M phase. Decreased invasiveness was observed in miR-454-overexpressing PDAC cells. Conditioned media from miR-454-overexpressing PANC-1 cells contained lower levels of vascular endothelial growth factor and had reduced capacity to induce endothelial cell tube-like structure formation. Mechanistically, miR-454 was found to target the mRNA of LRP6 and inhibit the activation of Wnt/β-catenin signaling in PDAC cells. Ectopic expression of LRP6 significantly reversed the suppressive effects of miR-454 on PDAC cells. In vivo studies confirmed that miR-454-overexpressing PANC-1 cells formed significantly less lung metastases than control cells. Altogether, miR-454 functions as a suppressor in tumor growth, angiogenesis, and metastasis in PDAC, likely through downregulation of LRP6.

[1]  R. Moffitt,et al.  Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer , 2016, Oncotarget.

[2]  G. Tsongalis,et al.  Role of microRNAs in regulation of the TNF/TNFR gene superfamily in chronic lymphocytic leukemia. , 2016, Clinical biochemistry.

[3]  Y. Shang,et al.  DOT1L promotes angiogenesis through cooperative regulation of VEGFR2 with ETS-1 , 2016, Oncotarget.

[4]  Xiangnan Li,et al.  MiR-454 promotes the progression of human non-small cell lung cancer and directly targets PTEN. , 2016, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[5]  Yonghui Wang,et al.  Diabetes mellitus stimulates pancreatic cancer growth and epithelial-mesenchymal transition-mediated metastasis via a p38 MAPK pathway , 2016, Oncotarget.

[6]  D. Tuveson,et al.  Title : Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis , 2016 .

[7]  I. Herr,et al.  MicroRNA-101-3p reverses gemcitabine resistance by inhibition of ribonucleotide reductase M1 in pancreatic cancer. , 2016, Cancer letters.

[8]  Wei Wei,et al.  MicroRNA-454 regulates stromal cell derived factor-1 in the control of the growth of pancreatic ductal adenocarcinoma , 2016, Scientific Reports.

[9]  Yao Liu,et al.  MicroRNA-323-3p inhibits cell invasion and metastasis in pancreatic ductal adenocarcinoma via direct suppression of SMAD2 and SMAD3 , 2016, Oncotarget.

[10]  Ș. Purcaru,et al.  New perspectives in glioblastoma antiangiogenic therapy , 2015, Contemporary oncology.

[11]  Shan Wang,et al.  Tumor cell-secreted angiogenin induces angiogenic activity of endothelial cells by suppressing miR-542-3p. , 2015, Cancer letters.

[12]  Jie Zhao,et al.  miR-126 inhibits papillary thyroid carcinoma growth by targeting LRP6. , 2015, Oncology reports.

[13]  Lei Sun,et al.  MicroRNA‐454 functions as an oncogene by regulating PTEN in uveal melanoma , 2015, FEBS letters.

[14]  R. Evans,et al.  Calcipotriol Targets LRP6 to Inhibit Wnt Signaling in Pancreatic Cancer , 2015, Molecular Cancer Research.

[15]  Guangfeng Niu,et al.  miR‐454 is down‐regulated in osteosarcomas and suppresses cell proliferation and invasion by directly targeting c‐Met , 2015, Cell proliferation.

[16]  Shangfeng Liu,et al.  LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis , 2015, Nature Communications.

[17]  G. Davidson,et al.  CD44 functions in Wnt signaling by regulating LRP6 localization and activation , 2014, Cell Death and Differentiation.

[18]  T. Psaltopoulou,et al.  VEGF and Id-1 in pancreatic adenocarcinoma: prognostic significance and impact on angiogenesis. , 2014, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[19]  Michael Simons,et al.  Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance. , 2014, Cancer cell.

[20]  T. Gress,et al.  Current concepts and novel targets in advanced pancreatic cancer , 2012, Gut.

[21]  Xin Zhou,et al.  Dauricine inhibits insulin-like growth factor-I-induced hypoxia inducible factor 1α protein accumulation and vascular endothelial growth factor expression in human breast cancer cells , 2009, Acta Pharmacologica Sinica.

[22]  M. Korc,et al.  Vascular Endothelial Growth Factor-Trap Suppresses Tumorigenicity of Multiple Pancreatic Cancer Cell Lines , 2004, Clinical Cancer Research.

[23]  L. Ellis,et al.  Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. , 2001, Cancer biotherapy & radiopharmaceuticals.