ABSTRACT

Background

Breast cancer is the most common cancer in women, and triple-negative breast cancer (TNBC) accounts for about 15–20% of all breast cancer. High mobility group AT-hook 2 (HMGA2) is overexpressed in some tumors and closely associated with patients’ prognosis. However, the mechanisms involved in the regulation of HMGA2 in TNBC still remain unclear.

Methods

In this study, HMGA2 level in TNBC cell lines was analyzed by western blot. After knockdown of HMGA2 expression by RNA interference in TNBC cell lines MDA-MB-231 and SUM149, wound healing and transwell assays were conducted to examine the effects of HMGA2 on migration and invasion. Tumor metastasis was assessed in amouse xenograft model invivo. Furthermore, expression levels of epithelial–mesenchymal transition (EMT) biomarkers and involvement of the Hippo-YAP pathway were detected by western blot.

Results

Compared to normal breast epithelial cells, the expression levels of HMGA2 were significantly increased in TNBC cell lines (all P< .05). Downregulation of HMGA2 dramatically inhibited the migration and invasion of MDA-MB-231 and SUM149 cells (all P< .01) invitro, and suppressed the tumor metastasis of nude mice xenograft model invivo. Western blot analysis revealed alterations in EMT biomarkers: the expression of mesenchymal markers N-cadherin, Vimentin and Snail were decreased, while the expression of epithelial marker E-cadherin was increased. Downregulated expression of HMGA2 attenuated Hippo-YAP related protein expression and the stability of YAP.

Conclusions

HMGA2 is highly expressed in TNBC cells. Downregulation of HMGA2 inhibits the migration and invasion of TNBC and invivo tumor metastasis mediated through inhibition of EMT and Hippo-YAP pathway.

中文翻译：

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HMGA2通过调节Hippo-YAP信号通路促进乳腺癌转移

摘要

背景

乳腺癌是女性最常见的癌症，三阴性乳腺癌 (TNBC) 约占所有乳腺癌的 15-20%。高迁移率群 AT-hook 2 (HMGA2) 在一些肿瘤中过度表达，与患者的预后密切相关。然而，TNBC 中 HMGA2 的调控机制仍不清楚。

方法

在这项研究中，通过蛋白质印迹分析了 TNBC 细胞系中的 HMGA2 水平。在 TNBC 细胞系 MDA-MB-231 和 SUM149 中通过 RNA 干扰敲低 HMGA2 表达后，进行伤口愈合和 Transwell 测定以检查 HMGA2 对迁移和侵袭的影响。在体内异种移植模型中评估肿瘤转移。此外，通过蛋白质印迹检测上皮 - 间质转化（EMT）生物标志物的表达水平和 Hippo-YAP 途径的参与。

结果

与正常乳腺上皮细胞相比，HMGA2 的表达水平在 TNBC 细胞系中显着增加（所有P < .05）。HMGA2 的下调在体外显着抑制 MDA-MB-231 和 SUM149 细胞的迁移和侵袭（所有P < .01），并在体内抑制裸鼠异种移植模型的肿瘤转移。蛋白质印迹分析揭示了 EMT 生物标志物的改变：间充质标志物 N-钙粘蛋白、波形蛋白和蜗牛的表达降低，而上皮标志物 E-钙粘蛋白的表达增加。HMGA2 的下调表达减弱了 Hippo-YAP 相关蛋白的表达和 YAP 的稳定性。

结论

HMGA2 在 TNBC 细胞中高度表达。HMGA2 的下调抑制 TNBC 的迁移和侵袭以及通过抑制 EMT 和 Hippo-YAP 通路介导的体内肿瘤转移。