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Twist promotes angiogenesis in pancreatic cancer by targeting miR-497/VEGFA axis.

ABSTRACT: Angiogenesis is a critical step in the growth and dissemination of malignant diseases, including pancreatic cancer. Twist has been shown to stimulate angiogenesis in the tumor site. However, whether Twist contributes to angiogenesis in pancreatic cancer remains unknown. In this paper, we found that the expression of Twist was significantly increased in human pancreatic cancer cell lines and pancreatic cancer specimens. It is also closely engaged to adverse clinical feature, diminished survival and angiogenesis in pancreatic cancer patients. The up-regulation of Twist was found to be promoting cell growth, invasion and tubule formation of human umbilical vein endothelial cells (HUVECs) in vitro. By contrast, the silencing of Twist inhibited orthotopic xenograft tumor growth, metastasis and angiogenesis. Subsequent investigations disclosed that Twist was regulated by miR-497 directly, leading to the increased level of Vascular Endothelial Growth Factor-A (VEGFA). Moreover, gain-of-function and loss-of-function studies demonstrated that miR-497 could suppress the pro-proliferative, angiogenic and metastatic ability of pancreatic cancer cells. The ectopic expression of VEGFA obviously abrogated the anti-angiogenic effect induced by Twist knockdown, whereas the silencing of VEGFA markedly rescued the pro-angiogenic effect of Twist. By analyzing the expression levels of miR-497, Twist was found inversely correlated with miR-497 in pancreatic cancer tissues, and a positive correlation was found between Twist and VEGFA levels in pancreatic cancer specimens. In conclusion, our results suggested that the Twist/miR-497/VEGFA axis is significantly correlated with metastasis and angiogenesis in pancreatic cancer.

SUBMITTER: Liu A

PROVIDER: S-EPMC5041945 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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Twist promotes angiogenesis in pancreatic cancer by targeting miR-497/VEGFA axis.

Liu An A Huang Chenggang C Cai Xuehong X Xu Jia J Yang Dinghua D

Oncotarget 20160501 18

Angiogenesis is a critical step in the growth and dissemination of malignant diseases, including pancreatic cancer. Twist has been shown to stimulate angiogenesis in the tumor site. However, whether Twist contributes to angiogenesis in pancreatic cancer remains unknown. In this paper, we found that the expression of Twist was significantly increased in human pancreatic cancer cell lines and pancreatic cancer specimens. It is also closely engaged to adverse clinical feature, diminished survival a ...[more]

PMID: 27015364

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Project description:BackgroundBreast cancer (BC) is a common malignant tumor with poor prognosis. Angiogenesis is related to the growth and progression of solid tumors and associated with prognosis. ZLM-7, SP1, VEGFA and miR-212-3p were associated with BC angiogenesis and proliferation, however the detailed mechanism was not clear. This study aimed to reveal the regulatory mechanism of angiogenesis of BC.MethodsBC cell lines were treated with 10 nM ZLM-7 for 8 h. We detected protein expression level by western blot and RNA expression level by qRT-PCR. Overexpression or inhibition of miR-212-3p is performed using miR-212-3p mimics or miR-212-3p inhibitor, Sp1 overexpression using pcDNA3.1 vector. Angiogenesis was analyzed by co-culturing BC cell lines and HUVEC cells. To evaluate regulatory relationship between miR-212-3p and Sp1, dual luciferase assay was performed. Besides, the direct interaction between Sp1 and VEGFA was analyzed by ChIP. Migration and invasion were analyzed by transwell assay and proliferation was detected by clone formation assay. In mice xenograft model developed using BC cells, we also detected angiogenesis marker CD31 through immunohistochemistry.ResultsZLM-7 up-regulated miR-212-3p and inhibited invasion, migration, proliferation and angiogenesis of BC, while miR-212-3p inhibitor antagonized such effects. Binding sequence was revealed between miR-212-3p and Sp1, and expression of Sp1 was inhibited by miR-212-3p on both protein and mRNA level. Sp1 could interact with VEGFA and promoted its expression. Overexpression of miR-212-3p inhibited migration, invasion, proliferation and angiogenesis of BC cell lines, while Sp1 overexpression showed the opposite effect and could antagonize these effects of miR-212-3p overexpression. ZLM-7 decreased VEGFA expression, which was rescued by co-transfection with miR-212-3p inhibitor. Similar, ZLM-7 could inhibit tumor growth and angiogenesis through the miR-212-3p/Sp1/VEGFA axis in vivo.ConclusionsZLM-7 could directly up-regulate miR-212-3p in BC. MiR-212-3p could inhibit VEGFA expression through Sp1, thereby inhibiting angiogenesis and progression of BC.

Dataset Information

Twist promotes angiogenesis in pancreatic cancer by targeting miR-497/VEGFA axis.

Publications

Twist promotes angiogenesis in pancreatic cancer by targeting miR-497/VEGFA axis.

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