Endoplasmic reticulum stress inhibits 3D Matrigel-induced vasculogenic mimicry of breast cancer cells via TGF-β1/Smad2/3 and β-catenin signaling.
Endoplasmic reticulum stress inhibits 3D Matrigel-induced vasculogenic mimicry of breast cancer cells via TGF-β1/Smad2/3 and β-catenin signaling.
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内质网应激通过 TGF-β1/Smad2/3 和 β-连环蛋白信号抑制 3D 基质胶诱导的乳腺癌细胞血管生成拟态。
DOI：
10.1002/2211-5463.13259
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发表时间：
2021-09
期刊：
影响因子：
2.6
通讯作者：
Mi K
中科院分区：
文献类型：
--
作者：
Liu H;Wang H;Chen D;Gu C;Huang J;Mi K
内质网应激是一种由内源性和外源性因素引起的内质网折叠能力紊乱的细胞应激状态。内质网应激信号通路影响肿瘤的恶性生长、血管生成和进展，并促进某些药物的抗肿瘤作用。然而，内质网应激对癌细胞血管生成拟态(VM)表型的影响还没有得到很好的解决。Vm是一种通过形成图案化的管状网络来模拟血管生成的表型，这与癌细胞的干性和侵袭行为有关。在这项研究中，我们使用未折叠蛋白反应(UPR)激活剂衣霉素(TM)在侵袭性三阴性MDA-MB-231乳腺癌细胞中诱导ER应激，该细胞在3D Matrigel培养中呈现VM表型。TM诱导的内质网应激可抑制Vm表型。除抑制Vm表型的肿瘤球体表型外，我们还观察到整合素β1的糖基化改变，VE-钙粘素丢失和干细胞标志物Bmi-1的减少。进一步研究发现激活的转化生长因子β1，Smad2/3，磷酸化Smad2和β-连环蛋白降低。β-catenin基因敲除可显著抑制Vm表型，并导致VE-钙粘附素丢失。结果提示，内质网应激的激活通过转化生长因子β1/SMAD2/3和β-连环蛋白信号通路抑制乳腺癌细胞Vm表型的形成。乳腺癌中涉及内质网应激和VM的预期调控机制的发现可能导致更精确的靶向治疗，从而抑制血管形成和影响肿瘤进展。衣霉素诱导的内质网应激抑制3DMatrigel培养的乳腺癌细胞的Vm表型。细胞表现为肿瘤球状表型，整合素β1糖基化改变，VE-钙粘附素丢失，细胞干性降低。进一步研究发现，活化的转化生长因子β1、SMAD2/3、磷酸化SMAD2和β-连环蛋白水平降低，提示内质网应激激活通过转化生长因子β1/SMAD2/3和β-连环蛋白信号通路抑制VM表型。
Endoplasmic reticulum (ER) stress is a cellular stress condition involving disturbance in the folding capacity of the ER caused by endogenous and exogenous factors. ER stress signaling pathways affect tumor malignant growth, angiogenesis and progression, and promote the antitumor effects of certain drugs. However, the impact of ER stress on the vasculogenic mimicry (VM) phenotype of cancer cells has not been well addressed. VM is a phenotype that mimics vasculogenesis by forming patterned tubular networks, which are related to stemness and aggressive behaviors of cancer cells. In this study, we used tunicamycin (TM), the unfolded protein response (UPR)‐activating agent, to induce ER stress in aggressive triple‐negative MDA‐MB‐231 breast cancer cells, which exhibit a VM phenotype in 3D Matrigel cultures. TM‐induced ER stress was able to inhibit the VM phenotype. In addition to the tumor spheroid phenotype observed upon inhibiting the VM phenotype, we observed alterations in glycosylation of integrin β1, loss of VE‐cadherin and a decrease in stem cell marker Bmi‐1. Further study revealed decreased activated transforming growth factor β1, Smad2/3, Phospho‐Smad2 and β‐catenin. β‐Catenin knockdown markedly inhibited the VM phenotype and resulted in the loss of VE‐cadherin. The data suggest that the activation of ER stress inhibited VM phenotype formation of breast cancer cells via both the transforming growth factor β1/Smad2/3 and β‐catenin signaling pathways. The discovery of prospective regulatory mechanisms involved in ER stress and VM in breast cancer could lead to more precisely targeted therapies that inhibit vessel formation and affect tumor progression. Tunicamycin‐induced endoplasmic reticulum stress inhibited the VM phenotype of breast cancer cells in 3D Matrigel cultures. Cells exhibited tumor spheroid phenotype, alterations in glycosylation of integrin β1, loss of VE‐cadherin and a decrease in stemness. Further study revealed decreased levels of activated transforming growth factor β1, Smad2/3, Phospho‐Smad2 and β‐catenin, suggesting that activation of endoplasmic reticulum stress inhibited the VM phenotype via both the transforming growth factor β1/Smad2/3 and β‐catenin signaling pathways.
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影响因子：
11.2
作者：
Samanta S;Yang S;Debnath B;Xue D;Kuang Y;Ramkumar K;Lee AS;Ljungman M;Neamati N
通讯作者：
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影响因子：
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影响因子：
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影响因子：
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作者：
Maiti, Aparna;Qi, Qianya;Hait, Nitai C.
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影响因子：
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作者：
Qi L;Song W;Liu Z;Zhao X;Cao W;Sun B
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