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Dipalmitoylphosphatidic acid inhibits breast cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway.

ABSTRACT: Tumour growth depends on a continual supply of the nutrients and oxygen, which are offered by tumour angiogenesis. Our previous study showed that dipalmitoylphosphatidic acid (DPPA), a bioactive phospholipid, inhibits the growth of triple-negative breast cancer cells. However, its direct effect on angiogenesis remains unknown. Our work showed that DPPA significantly suppressed vascular growth in the chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models. Meanwhile, tumour angiogenesis and tumour growth were inhibited by DPPA in the tumour tissues of an experimental breast cancer model, a subcutaneous xenograft mouse model and a genetically engineered spontaneous breast cancer mouse model (MMTV-PyMT). Furthermore, DPPA directly inhibited the proliferation, migration and tube formation of vascular endothelial cells. The anti-angiogenic effect of DPPA was regulated by the inhibition of Cut-like homeobox1 (CUX1), which transcriptionally inhibited fibroblast growth factor 1 (FGF1), leading to the downregulation of hepatocyte growth factor (HGF). This work first demonstrates that DPPA directly inhibits angiogenesis in cancer development. Our previous work along with this study suggest that DPPA functions as an anti-tumour therapeutic drug that inhibits angiogenesis.

SUBMITTER: Chen J

PROVIDER: S-EPMC6156235 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Dipalmitoylphosphatidic acid inhibits breast cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway.

Chen Jian J Zhou Zijun Z Yao Yuying Y Dai Jianwei J Zhou Dalei D Wang Lijing L Zhang Qian-Qian QQ

Journal of cellular and molecular medicine 20180716 10

Tumour growth depends on a continual supply of the nutrients and oxygen, which are offered by tumour angiogenesis. Our previous study showed that dipalmitoylphosphatidic acid (DPPA), a bioactive phospholipid, inhibits the growth of triple-negative breast cancer cells. However, its direct effect on angiogenesis remains unknown. Our work showed that DPPA significantly suppressed vascular growth in the chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models. Meanwhile, tumour ...[more]

PMID: 30010249

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Project description:BackgroundNontraumatic osteonecrosis of the femoral head (NONFH) is a common, progressive, and refractory orthopaedic disease. Decreased osteogenesis and angiogenesis are considered the main factors in the pathogenesis of NONFH. We aimed to figure out whether exosomes and exosomal miRNA from necrotic bone tissues of patients with NONFH are involved in the pathogenesis of NONFH and reveal the underlying mechanisms.MethodsRT-PCR and western blotting (WB) were used to detect the expression of osteogenic, adipogenic, and angiogenic markers. ALP staining and Alizarin Red S (ARS) staining were used to evaluate osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). Oil Red O staining was performed to assess the adipocyte deposition. A tube formation assay was used to study angiogenesis of human umbilical vascular endothelial cells (HUVECs). H&E staining and immunohistochemistry (IHC) staining were used to detect the effect of the NONFH exosomes in vivo. MicroRNA sequencing was conducted to identify potential regulators in the NONFH exosomes. The target relationship between miR-100-5p and BMPR2 was predicted and confirmed by a dual luciferase reporter assay and WB.ResultsThe NONFH exosomes reduced the osteogenic differentiation of hBMSCs and angiogenesis of HUVECs. In addition, the injection of the NONFH exosomes caused thinning and disruption of bone trabeculae in the femoral heads of rats. MiR-100-5p expression was upregulated in the NONFH exosomes and inhibited the osteogenesis of hBMSCs and angiogenesis of HUVECs by targeting BMPR2 and suppressing the BMPR2/SMAD1/5/9 signalling pathway. Silencing miR-100-5p expression rescued the reduction in osteogenesis and angiogenesis caused by the NONFH exosomes by activating the BMPR2/SMAD1/5/9 signalling pathway.ConclusionThe NONFH exosomal miR-100-5p can lead to NONFH-like damage by targeting BMPR2 and suppressing the BMPR2/SMAD1/5/9 signalling pathway, which may be involved in the pathophysiological mechanisms of nontraumatic osteonecrosis of the femoral head (NONFH).

Project description:BackgroundBreast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear.MethodsThe prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model.ResultsACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs.ConclusionsOur findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway.Trial registrationRetrospectively registered.

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Dipalmitoylphosphatidic acid inhibits breast cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway.

Publications

Dipalmitoylphosphatidic acid inhibits breast cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway.

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