MiR-148a and miR-152 reduce tamoxifen resistance in ER plus breast cancer via downregulating ALCAM
MiR-148a and miR-152 reduce tamoxifen resistance in ER plus breast cancer via downregulating ALCAM
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DOI：
10.1016/j.bbrc.2017.01.012
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发表时间：
2017-02-05
影响因子：
3.1
通讯作者：
Shen, Ching-Ju
中科院分区：
文献类型：
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作者：
Chen, Ming-Jenn;Cheng, Ya-Min;Shen, Ching-Ju
活化白细胞粘附分子（ALCAM），也称为CD 166，是免疫球蛋白超家族的一种105 kDa跨膜糖蛋白。在这项研究中，我们研究了ER +乳腺癌中ALCAM表达与他莫昔芬耐药之间的关系，并进一步研究了ALCAM在癌细胞中的调节方式。IHC染色数据显示，来自无应答者（N = 20）的肿瘤组织通常具有比来自他莫昔芬应答者（N = 16）显著更强的ALCAM染色。体外细胞试验还证实，ALCAM在他莫昔芬耐药（TamR）MCF-7细胞中的表达上调高于他莫昔芬敏感（TamS）MCF-7细胞。ALCAM过表达可显著减轻4-OHT诱导的TamS MCF-7细胞活力抑制和细胞凋亡，而ALCAM敲低可显著增强4-OHT诱导的TamR MCF-7细胞活力抑制和细胞凋亡。去甲基化试剂处理显著恢复了TamR MCF-7细胞中miR-148 a和miR-152的表达。miR-148 a和miR-152可直接靶向ALCAM 3 'UTR并降低ALCAM表达。miR-148 a过表达在增强4-OUT诱导的TamR MCF-7细胞中的细胞活力抑制和细胞凋亡方面具有与ALCAM siRNA相似的效果。MiR-152单独过表达会导致TamR MCF-7细胞的生长抑制和细胞凋亡增加。它还增强了4-OHT的作用。同时抑制miR-148 a和miR-152可显著保护TamS MCF 7细胞免受4-OHT诱导的细胞活力抑制和细胞凋亡。基于这些发现，我们推断miR-148 a和miR-152至少通过下调ALCAM可以使TamR MCF-7细胞对他莫昔芬敏感。(C)2017爱思唯尔公司All rights reserved.
Activated leukocyte cell adhesion molecule (ALCAM), also called CD166 is a 105-kDa transmembrane glycoprotein of the immunoglobin superfamily. In this study, we studied the association between ALCAM expression and tamoxifen resistance in ER + breast cancer and further investigated how ALCAM is regulated in the cancer cells. IHC staining data showed that the tumor tissues from non-responders (N = 20) generally had significantly stronger ALCAM staining than that from tamoxifen responders (N = 16). In vitro cell assay also confirmed ALCAM upregulation in tamoxifen resistant (TamR) MCF-7 cells than in tamoxifen sensitive (TamS) MCF-7 cells. ALCAM overexpression significantly alleviated 4Hydroxytestosterone (4-0HT) induced cell viability inhibition and cell apoptosis in TamS MCF-7 cells, while ALCAM knockdown remarkably enhanced 4-OHT induced cell viability inhibition and cell apoptosis in TamR MCF-7 cells. Demethylation reagent treatment significantly restored miR-148a and miR-152 expression in TamR MCF-7 cells. MiR-148a and miR-152 can directly target ALCAM 3'UTR and decrease ALCAM expression. MiR-148a overexpression had similar effect as ALCAM siRNA on enhancing 4-OUT induced cell viability inhibition and cell apoptosis in TamR MCF-7 cells. MiR-152 overexpression alone caused growth inhibition and increased cell apoptosis in TamR MCF-7 cells. It also enhanced the effect of 4-OHT. Simultaneous inhibition of miR-148a and miR-152 significantly protected TamS MCF7 cells from 4-OHT induced cell viability inhibition and cell apoptosis. Based on these findings, we infer that MiR-148a and miR-152 can sensitize TamR MCF-7 cells to tamoxifen at least via downregulating ALCAM. (C) 2017 Elsevier Inc. All rights reserved.