Inhibition of endoplasmic reticulum stress alleviates triple-negative breast cancer cell viability, migration, and invasion by Syntenin/SOX4/Wnt/β-catenin pathway via regulation of heat shock protein A4.
Inhibition of endoplasmic reticulum stress alleviates triple-negative breast cancer cell viability, migration, and invasion by Syntenin/SOX4/Wnt/β-catenin pathway via regulation of heat shock protein A4.
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DOI：
10.1080/21655979.2022.2062990
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发表时间：
2022-04
期刊：
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
--
作者：
内质网应激在恶性肿瘤的发生发展中是一把双刃剑。本研究旨在探讨内质网应激在三阴性乳腺癌（TNBC）转移和上皮-间质转化中的作用及其可能的机制。本研究通过给药4-PBA抑制内质网应激。使用细胞计数试剂盒-8测定细胞活力。通过伤口愈合和transwell实验分别鉴定细胞迁移和侵袭。采用酶联免疫吸附法和免疫组织化学染色法检测MMP2和MMP9的水平。Western blot检测内质网应激相关蛋白、Syndecan-1 (SDC-1)/Syntenin-1 (SDCBP-1)/ sry相关HMG-box 4 （SOX4）信号和Wnt/β-catenin信号水平。此外，通过异种移植小鼠模型来证实内质网应激在TNBC中的作用。这些数据表明，乳腺癌细胞的生存能力和转移能力比正常乳腺上皮细胞强。TNBC细胞比非TNBC细胞表现出更强的侵袭性。4-PBA显著抑制BC细胞的活力、迁移和侵袭，抑制SDC/SDCBP/SOX4轴和Wnt/β-catenin信号传导。此外，热休克蛋白A4 （HSPA4）过表达刺激内质网应激，激活SDC-1/SDCBP-1/SOX4通路和Wnt/β-catenin信号通路。动物实验结果相似，4-PBA抑制肿瘤生长并使这两条通路失活，而HSPA4过表达逆转了4-PBA的作用。综上所述，在体内和体外，抑制内质网应激可通过调控HSPA4抑制Syntenin/SOX4/Wnt/β-catenin通路对TNBC的存活、迁移和侵袭。
Endoplasmic reticulum stress (ER stress) is a double-edged sword in the occurrence and development of malignant cancer. The aim of this study was to explore the roles of ER stress in metastasis and epithelial-mesenchymal transitionin triple-negative breast cancer (TNBC) and potential mechanisms. In this study, 4-PBA was administrated to inhibit the ER stress. Cell viability was evaluated using a cell counting kit-8 assay. Cell migration and invasion were identified by wound healing and transwell assay, respectively. Levels of MMP2 and MMP9 were measured by enzyme-linked immunosorbent assay and immunohistochemical staining. Western blot assay was used to assess the levels of ER stress-related proteins, Syndecan-1 (SDC-1)/Syntenin-1 (SDCBP-1)/SRY-related HMG-box 4 (SOX4) signaling and Wnt/β-catenin signaling. Moreover, a xenograft mice model was conducted to confirm the role of ER stress in TNBC. The data indicate that the ability of viability and metastasis of breast cancer cells were stronger than normal mammary epithelial cells. More aggressiveness was manifested in TNBC cells than that in non-TNBC cells. 4-PBA significantly suppressed the viability, migration, and invasion in BC cells and inhibited the SDC/SDCBP/SOX4 axis and Wnt/β-catenin signaling. Furthermore, heat shock protein A4 (HSPA4) overexpression stimulated ER stress and activated the SDC-1/SDCBP-1/SOX4 pathway and Wnt/β-catenin signaling. Animal experiments showed similar results that 4-PBA repressed tumor growth and inactivated the two pathways, while HSPA4 overexpression reversed the effects of 4-PBA. In summary, inhibition of ER stress inhibited TNBC viability, migration, and invasion by Syntenin/SOX4/Wnt/β-catenin pathway via regulation of HSPA4 in vivo and in vitro.
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