TP53INP1 inhibits hypoxia‐induced vasculogenic mimicry formation via the ROS/snail signalling axis in breast cancer

Abstract

Tumour protein p53‐inducible nuclear protein 1 (TP53INP1) is a tumour suppressor associated with malignant tumour metastasis. Vasculogenic mimicry (VM) is a new tumour vascular supply pattern that significantly influences tumour metastasis and contributes to a poor prognosis. However, the molecular mechanism of the relationship between TP53INP1 and breast cancer VM formation is unknown. Here, we explored the underlying mechanism by which TP53INP1 regulates VM formation in vitro and in vivo. High TP53INP1 expression was not only negatively correlated with a poor prognosis but also had a negative relationship with VE‐cadherin, HIF‐1α and Snail expression. TP53INP1 overexpression inhibited breast cancer invasion, migration, epithelial‐mesenchymal transition (EMT) and VM formation; conversely, TP53INP1 down‐regulation promoted these processes in vitro by functional experiments and Western blot analysis. We established a hypoxia model induced by CoCl2 and assessed the effects of TP53INP1 on hypoxia‐induced EMT and VM formation. In addition, we confirmed that a reactive oxygen species (ROS)‐mediated signalling pathway participated in TP53INP1‐mediated VM formation. Together, our results show that TP53INP1 inhibits hypoxia‐induced EMT and VM formation via the ROS/GSK‐3β/Snail pathway in breast cancer, which offers new insights into breast cancer clinical therapy.

Toll-Iike Receptor-3 Activation Enhances Malignant Traits in Human Breast Cancer Cells Through Hypoxia-inducible Factor-1α

“…Moreover, to further verify HIF1α involvement in VM, we mimicked hypoxia using cobalt chloride and observed a strong increase in vessel-like structure formation which was totally blocked by HIF1α siRNA as well as in the presence of the pharmacological HIF1 inhibitor acriflavine. Altogether our data on TNBC agree with other studies in different tumor types (57,59) and interestingly provide the first evidence that TLR3 stimulation induces HIF1αmediated VM in a very aggressive breast cancer cell line.…”

“…Many studies reported that VM is related to hypoxia-activated signaling pathways and metastatic phenotype (50,55). It has been demonstrated that the overexpression of HIF1α protein is associated with VM in human gallbladder cell lines (56) as well as in breast cancer (57). TNBC is a subtype which is aggressive, metastasizes and has a poor prognosis.…”

The EMT transcription factor, Twist1, as a novel therapeutic target for pulmonary sarcomatoid carcinomas

“…In previous studies, the EMT regulators Twist1, Slug and Snail were found to play a role in EMT and VM in hepatocellular carcinoma and breast cancer (19,24,27). Therefore, this study examined Twist1, Slug and Snail expression in PSCs and PSCCs (Fig.…”

Vasculogenic mimicry in carcinogenesis and clinical applications

“…These transcription factors can bind to the E-cadherin promoter to regulate transcriptional activity, and the decreased levels of E-cadherin result in decreased cell adhesion and increased cell invasion and metastasis [22,30]. EMT involves a large number of signaling pathways, such as the transforming growth factor-beta (TGF-β) signaling pathway [13,47], Wnt signaling pathway [48,49] and Notch signaling pathway [31,32,50,51]. Furthermore, there are two miRNA regulatory networks that are considered prominent regulators of EMT: the miR34-SNAIL1 and miR200-ZEB1 axes that regulate EMT epigenetically [47].…”

“…Research has shown that snai1 and slug regulate the process of EMT by repressing E-cadherin transcription to disrupt cell-tocell adhesion. Furthermore, reactive oxygen species; (ROS) can activate Snai1 to promote cancer progression [48]. It has been demonstrated that slug expression was significantly associated with the CSCs phenotype and VM formation in HCC [49].…”