27-Hydroxycholesterol-induced EndMT acts via STAT3 signaling to promote breast cancer cell migration by altering the tumor microenvironment

Kailin Jiao, Jing Zhen, Maoxuan Wu, et al.

Abstract


Objective: The endothelial to mesenchymal transition (EndMT) plays a major role in cancer metastasis by regulating the complexityof the tumor microenvironment (TME). Here, we investigated whether 27-hydroxycholesterol (27HC) induces EndMT in endothelialcells (ECs).

Methods: EndMT markers in the human microvascular endothelial cell-1 (HMEC-1) cell line and human umbilical vein endothelialcells (HUVECs) stimulated with 27HC were evaluated with Western blot. Epithelial to mesenchymal transition (EMT) markers inbreast cancer (BC) cells cultured in conditioned medium were investigated with quantitative real time polymerase chain reaction(qRT-PCR). The MMP-2 and MMP-9 mRNA expression and activity were detected with qRT-PCR and gelatin zymography assays,respectively. The effect of activated STAT3 on 27HC-induced EndMT was validated by Western blot, immunofluorescence staining,and cell transfection assays. The migration ability of BC cells was evaluated with Transwell assays.

Results: We found that 27HC induced EndMT in HMEC-1 and HUVECs, and 27HC-induced EndMT facilitated EMT and BC cellmigration. The 27HC-induced EMT of BC cells also promoted EndMT and HUVEC migration. Investigation of the underlyingmolecular mechanisms revealed that STAT3 knockdown repressed EndMT in HUVECs as well as migration in BC cells inducedwith 27HC. In addition, C646 and resveratrol, inhibitors of STAT3 acetylation, repressed the expression of Ac-STAT3, p-STAT3, andEndMT markers in HUVECs exposed to 27HC; these HUVECs in turn attenuated the migration ability of BC cells in 27HC-inducedEndMT.

Conclusions: Cross-talk between 27HC-induced EndMT and EMT was observed in the TME. Moreover, activation of STAT3signaling was found to be involved in 27HC-induced EndMT.

Cite this article as: Jiao K, Zhen J, Wu M, Teng M, Yang K, Zhou Q, et al.27-Hydroxycholesterol-induced EndMT acts via STAT3 signaling to promotebreast cancer cell migration by altering the tumor microenvironment. CancerBiol Med. 2020; 17: 88-100. doi: 10.20892/j.issn.2095-3941.2019.0262


Keywords


27-Hydroxycholesterol; endothelial to mesenchymal transition; STAT3 acetylation; tumor microenvironment; breast cancer, migration

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