Abstract
BackgroundLincRNAs have been revealed to be tightly associated with various tumorigeneses and cancer development, but the roles of specific lincRNA on tumor-related angiogenesis was hardly studied. Here, we aimed to investigate whether linc-OIP5 in breast cancer cells affects the angiogenesis of HUVECs and whether the linc-OIP5 regulations are involved in angiogenesis-related Notch and Hippo signaling pathways.MethodsA trans-well system co-cultured HUVECs with linc-OIP5 knockdown breast cancer cell MDA-MB-231 was utilized to study the proliferation, migration and tube formation abilities of HUVECs and alterations of related signaling indicators in breast cancer cells and their conditioned medium through a series of cell and molecular experiments.ResultsOverexpressed linc-OIP5, YAP1, and JAG1 were found in breast cancer cell lines MCF7 and MDA-MB-231 and the expression levels of YAP1 and JAG1 were proportional to the breast cancer tissue grades. MDA-MB-231 cells with linc-OIP5 knockdown led to weakened proliferation, migration, and tube formation capacity of co-cultured HUVECs. Besides, linc-OIP5 knockdown in co-cultured MDA-MB-231 cells showed downregulated YAP1 and JAG1 expression, combined with a reduced JAG1 level in conditioned medium. Furthermore, a disrupted DLL4/Notch/NRP1 signaling in co-cultured HUVECs were also discovered under this condition.ConclusionHence, linc-OIP5 in MDA-MB-231 breast cancer cells may act on the upstream of the YAP1/Notch/NRP1 signaling circuit to affect proliferation, migration, and tube formation of co-cultured HUVECs in a non-cellular direct contact way through JAG1 in conditioned medium. These findings at least partially provide a new angiogenic signaling circuit in breast cancers and suggest linc-OIP5 could be considered as a therapeutic target in angiogenesis of breast cancers.
Highlights
LincRNAs have been revealed to be tightly associated with various tumorigeneses and cancer development, but the roles of specific lincRNA on tumor-related angiogenesis was hardly studied
Compared with normal breast MCF-10 cells, expression levels of them were obviously higher in MDA-MB-231 and MCF-7 cells (Fig. 1a), indicating that these molecules were all positively correlated with the development of breast cancer
Immunohistochemistry analysis of breast cancer tissues showed that YAP1 and Jagged 1 (JAG1) were differentially expressed in breast cancers with different grades
Summary
LincRNAs have been revealed to be tightly associated with various tumorigeneses and cancer development, but the roles of specific lincRNA on tumor-related angiogenesis was hardly studied. DLL4 activates Notch signaling in the stalk ECs to inhibit sprouting angiogenesis and results in fewer but larger vessels, whereas JAG1 mainly increases sprouting angiogenesis and enhances the amount rather than the size of vessels by signaling to tumor cells and ECs [1,2,3, 8,9,10,11,12,13,14,15,16] Both of them promote the growth of tumors, but different downstream signaling pathways activated by DLL4 and JAG1 lead to distinct vasculature phenotypes [1, 8, 17,18,19]
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