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HER2 介导的 GLI2 稳定促进乳腺癌细胞的抗失巢凋亡和转移。

HER2-mediated GLI2 stabilization promotes anoikis resistance and metastasis of breast cancer cells.

机构信息

Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA.

Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA; Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX, 79601, USA.

出版信息

Cancer Lett. 2019 Feb 1;442:68-81. doi: 10.1016/j.canlet.2018.10.021. Epub 2018 Oct 26.

DOI:10.1016/j.canlet.2018.10.021
PMID:30409762
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6311434/
Abstract

Breast cancer metastasis is a multi-step process and requires cells to overcome anoikis. Anoikis is defined as cell-death that occurs due to loss of cell adhesion. During the course of cancer progression, tumor cells acquire resistance to anoikis. However, mechanisms of anoikis resistance are not clear. Human epidermal growth receptor 2 (HER2) overexpressing breast tumors are known to be highly aggressive and metastatic. The mechanisms correlating HER2 with metastasis are poorly understood. We observed increased anoikis resistance in HER2 overexpressing breast cancer cells. In addition, we identified that HER2 overexpression was also associated with increased sonic hedgehog (SHH) signaling especially GLI2, and that inhibition of SHH pathway suppressed anoikis resistance. GSK3β is known to facilitate proteasome-mediated degradation of GLI2. Moreover, we observed that silencing of GLI2 resulted in reduced migration and invasion of HER2 overexpressing cells. Anoikis resistant HER2 overexpressing cells also showed increased rate and extent of metastasis in vivo, as compared to wild type anoikis resistant cells. Taken together, this study indicates a novel role of HER2/GSK3β/GLI2 axis in anoikis resistance and metastasis, and that GLI2 could be a potential target for anti-cancer therapies.

摘要

乳腺癌转移是一个多步骤的过程，需要细胞克服失巢凋亡。失巢凋亡是指由于细胞黏附丧失而导致的细胞死亡。在癌症进展过程中，肿瘤细胞获得对失巢凋亡的抗性。然而，失巢凋亡抗性的机制尚不清楚。人表皮生长因子受体 2（HER2）过表达的乳腺癌肿瘤已知具有高度侵袭性和转移性。与 HER2 相关的转移机制尚未完全了解。我们观察到 HER2 过表达的乳腺癌细胞的失巢凋亡抗性增加。此外，我们发现 HER2 过表达也与 sonic hedgehog（SHH）信号通路的增加特别是 GLI2 相关，并且抑制 SHH 通路可抑制失巢凋亡抗性。GSK3β 已知可促进蛋白酶体介导的 GLI2 降解。此外，我们观察到沉默 GLI2 可导致 HER2 过表达细胞的迁移和侵袭减少。与野生型失巢凋亡抗性细胞相比，失巢凋亡抗性 HER2 过表达细胞在体内的转移速度和程度也增加。综上所述，这项研究表明 HER2/GSK3β/GLI2 轴在失巢凋亡抗性和转移中的新作用，并且 GLI2 可能是癌症治疗的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c111/6311434/d1da8fd67b1b/nihms-1511749-f0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c111/6311434/d1da8fd67b1b/nihms-1511749-f0007.jpg

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