Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells.
Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells.
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DOI：
10.1186/1476-4598-13-52
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发表时间：
2014-03-08
期刊：
影响因子：
37.3
通讯作者：
Bourguignon LY
中科院分区：
文献类型：
--
作者：
Chen L;Bourguignon LY
MicroRNA-21（miR-21）与包括乳腺癌在内的实体瘤进展的发展相关。在这项研究中，我们研究了基质透明质酸（HA）-CD 44（一种主要HA受体）与MDA-MB-468乳腺癌细胞[一种三阴性（雌激素受体阴性/孕激素受体阴性/HER 2阴性）乳腺癌细胞系]中c-Jun N-末端激酶（JNK）/c-Jun信号转导的相互作用。我们的研究结果表明，HA结合CD 44促进c-Jun核转位和转录激活。进一步的分析表明，miR-21受到含有AP 1结合位点的上游启动子的调节，染色质免疫沉淀（CHIP）测定表明，HA/CD 44相互作用对miR-21表达的刺激在这些乳腺癌细胞中是c-Jun依赖性的。该过程导致抗凋亡蛋白Bcl-2的增加和凋亡蛋白家族（IAP）的抑制剂的上调以及MDA-MB-468细胞中的化学抗性。用c-Jun特异性小干扰RNA治疗有效地阻断HA介导的c-Jun信号传导并消除miR-21的产生，以及引起存活蛋白（Bcl-2和IAP）的下调和化学敏感性的增强。此外，我们的结果表明，抗miR-21抑制剂不仅下调Bcl-2/IAP表达，而且增加HA处理的乳腺癌细胞的化疗敏感性。总之，这些发现表明HA/CD 44诱导的c-Jun信号传导在miR-21产生中起关键作用，导致三阴性乳腺癌细胞如MDA-MB-468细胞系中的存活蛋白（Bcl-2/IAP）上调和化学抗性。这种新的HA/CD 44介导的c-Jun信号通路和miR-21的产生为未来治疗乳腺癌的干预策略提供了新的药物靶点。
MicroRNA-21 (miR-21) is associated with the development of solid tumors progression including breast cancer. In this study we investigated matrix hyaluronan (HA)-CD44 (a primary HA receptor) interaction with c-Jun N-Terminal Kinase (JNK)/c-Jun signaling in MDA-MB-468 breast cancer cells [a triple-negative (estrogen receptor-negative/progesterone receptor-negative/HER2-negative) breast cancer cell line]. Our results indicated that HA binding to CD44 promotes c-Jun nuclear translocation and transcriptional activation. Further analyses revealed that miR-21 is regulated by an upstream promoter containing AP1 binding site(s), and chromatin immunoprecipitation (CHIP) assays demonstrated that stimulation of miR-21 expression by HA/CD44 interaction is c-Jun-dependent in these breast cancer cells. This process results in an increase of the anti-apoptosis protein Bcl-2 and upregulation of inhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in MDA-MB-468 cells. Treatment with c-Jun specific small interfering RNAs effectively blocks HA-mediated c-Jun signaling and abrogates miR-21 production as well as causes downregulation of survival proteins (Bcl-2 and IAPs) and enhancement of chemosensitivity. In addition, our results demonstrated that anti-miR-21 inhibitor not only downregulates Bcl-2/IAP expression but also increases chemosensitivity in HA-treated breast cancer cells. Together, these findings suggest that the HA/CD44-induced c-Jun signaling plays a pivotal role in miR-21 production leading to survival protein (Bcl-2/IAP) upregulation and chemoresistance in triple negative breast cancer cells such as MDA-MB-468 cell line. This novel HA/CD44-mediated c-Jun signaling pathway and miR-21 production provide a new drug target for the future intervention strategies to treat breast cancer.
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影响因子：
8
作者：
Bourguignon, L. Y. W.;Earle, C.;Wong, G.;Spevak, C. C.;Krueger, K.
通讯作者：
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影响因子：
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