Abstract
Hypoxia and its induced vasculogenic mimicry (VM) formation, which both closely related with stem-like side population (SP) cells, are the main culprits leading to tumor invasion and metastasis. Sinomenine exhibits excellent anticancer activity in breast cancer, but whether and how it affects hypoxia-triggered VM formation in breast cancer SP cells remains unclear. In this study, breast cancer SP cells were sorted from MDA-MB-231 cells and cultured with sinomenine under hypoxic conditions. Sinomenine obviously repressed the migration and VM formation of breast cancer SP cells. Through downregulating SIAH2 and HIF-1α, sinomenine can inhibit epithelial-mesenchymal transition process of breast cancer SP cells. SIAH2 was identified as a target of miR-340-5p and was downregulated by it, and sinomenine can upregulate miR-340-5p. Hypoxia-induced downregulation of miR-340-5p and activation of SIAH2/HIF-1α pathway can be both counteracted by the sinomenine. Moreover, miR-340-5p inhibition and SIAH2 overexpression can partly counteract the anticancer effects of sinomenine. Taken together, sinomenine inhibits hypoxia-caused VM formation and metastasis of breast cancer SP cells by regulating the miR-340-5p/SIAH2 axis.
Highlights
As the third most prevalent malignant tumor worldwide, breast cancer caused millions of illnesses and hundreds of thousands of deaths every year globally [1]
Vasculogenic mimicry (VM), which is considered a microvascular channel-like structure formed by nonendothelial cells [2], has been generally recognized as a new pattern of neovascularization which closely associated with the tumor tumorigenesis, aggressiveness, metastasis, drug resistance, and poor prognosis in multiple aggressive malignancies [3]
Since hypoxia is the main culprit causing tumor invasion and metastasis [15], and the breast cancer Cancer stem cells (CSCs) populations has a higher proportion in MDA-MB-231 cells than other breast cancer cell lines [16], this study explored the effects of sinomenine on hypoxia-triggered VM formation and metastasis of breast cancer side population (SP) cells sorted from MDA-MB231 cells
Summary
As the third most prevalent malignant tumor worldwide, breast cancer caused millions of illnesses and hundreds of thousands of deaths every year globally [1]. Vasculogenic mimicry (VM), which is considered a microvascular channel-like structure formed by nonendothelial cells [2], has been generally recognized as a new pattern of neovascularization which closely associated with the tumor tumorigenesis, aggressiveness, metastasis, drug resistance, and poor prognosis in multiple aggressive malignancies [3]. Multiple factors, such as hypoxia inducible factor (HIF)-1α, vascular endothelial (VE)-cadherin, epithelial-mesenchymal transition (EMT), matrix metalloproteinases (MMPs), and several microRNAs (miRs) [2], have been reported to be involved in the formation of VM and regulate the malignant behavior of breast
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