雌激素受体 α 上调长链非编码 RNA LINC00472 的表达，后者抑制乳腺癌中 NF-κB 的磷酸化。
ERα upregulates the expression of long non-coding RNA LINC00472 which suppresses the phosphorylation of NF-κB in breast cancer.
机构信息
University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
Department of Surgical Sciences, Gynecology, AOU Città della Salute, University of Torino, Turin, Italy.
出版信息
Breast Cancer Res Treat. 2019 Jun;175(2):353-368. doi: 10.1007/s10549-018-05108-5. Epub 2019 Mar 4.
PURPOSE
Low expression of long intergenic non-coding RNA LINC00472 in breast cancer is associated with aggressive tumors and unfavorable disease outcomes in multiple clinical datasets, but the reasons for these associations were unknown.
METHODS
To study the mechanisms underlying the lncRNA's connection to breast cancer, we investigated the molecular targets and regulation of LINC00472 in breast cancer cells, and analyzed relevant molecular features in relation to patient survival. Gene expression profiles of breast cancer cells overexpressing LINC00472 were analyzed for its regulatory pathways and downstream targets. Effects of LINC00472 overexpression on cell behaviors were evaluated in vitro and in vivo. Meta-analysis was performed using online datasets and our own study.
RESULTS
Analysis of LINC00472 transcriptome revealed ERα upregulation of LINC00472 expression, and an ERα-binding site in the LINC00472 promoter was identified. Evaluation of LINC00472 overexpression also indicated a possible link between LINC00472 and NF-κB. Cell experiments confirmed that LINC00472 suppressed the phosphorylation of p65 and IκBα through binding to IKKβ, inhibiting its phosphorylation. High LINC00472 expression inhibited tumor growth both in vitro and in vivo and suppressed aggressive tumor cell behaviors in vitro. Suppressing LINC00472 expression in ER-positive tumor cells increased cell aggressive behaviors. Tamoxifen treatment of ER-positive cells inhibited ERα and LINC00472 expression and increased p65 and IκBα phosphorylation. Meta-analysis showed that LINC00472 expression were higher in ER-positive than ER-negative tumors and that high expression was associated with better disease outcomes in ER-positive patients.
CONCLUSIONS
The study demonstrates that ERα upregulates LINC00472 which suppresses the phosphorylation of NF-κB, and suggests that endocrine treatment may lower LINC00472 and increase NF-κB activities, leading to tumor progression and disease recurrence.
目的
在多个临床数据集，低表达长链非编码 RNA LINC00472 与乳腺癌侵袭性肿瘤和不良预后相关，但这些关联的原因尚不清楚。
方法
为了研究 lncRNA 与乳腺癌之间联系的机制，我们研究了 LINC00472 在乳腺癌细胞中的分子靶标和调控，分析了与患者生存相关的相关分子特征。分析了过表达 LINC00472 的乳腺癌细胞的基因表达谱，以研究其调控途径和下游靶标。在体外和体内评估了 LINC00472 过表达对细胞行为的影响。使用在线数据集和我们自己的研究进行了荟萃分析。
结果
LINC00472 转录组分析显示 ERα 上调 LINC00472 的表达，并且在 LINC00472 启动子中鉴定出 ERα 结合位点。对 LINC00472 过表达的评估也表明 LINC00472 与 NF-κB 之间可能存在联系。细胞实验证实，LINC00472 通过与 IKKβ 结合抑制其磷酸化，从而抑制 p65 和 IκBα 的磷酸化。LINC00472 高表达在体外和体内均抑制肿瘤生长，并抑制体外侵袭性肿瘤细胞行为。抑制 ER 阳性肿瘤细胞中的 LINC00472 表达增加了细胞侵袭行为。他莫昔芬治疗 ER 阳性细胞抑制 ERα 和 LINC00472 的表达并增加 p65 和 IκBα 的磷酸化。荟萃分析表明，LINC00472 在 ER 阳性肿瘤中的表达高于 ER 阴性肿瘤，高表达与 ER 阳性患者的较好预后相关。
结论
该研究表明 ERα 上调 LINC00472，抑制 NF-κB 的磷酸化，提示内分泌治疗可能降低 LINC00472 并增加 NF-κB 的活性，导致肿瘤进展和疾病复发。
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