miR-200c targets a NF-κB up-regulated TrkB/NTF3 autocrine signaling loop to enhance anoikis sensitivity in triple negative breast cancer.
miR-200c targets a NF-κB up-regulated TrkB/NTF3 autocrine signaling loop to enhance anoikis sensitivity in triple negative breast cancer.
复制标题
DOI：
10.1371/journal.pone.0049987
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Richer JK
中科院分区：
文献类型：
--
作者：
Howe EN;Cochrane DR;Cittelly DM;Richer JK
失巢凋亡是细胞从天然细胞外基质脱离后引发的细胞凋亡。由于转移需要脱离基底膜后的存活，因此抵抗失巢凋亡的能力有助于乳腺肿瘤的转移潜力。miR-200 c是上皮细胞向间充质转化的有效抑制因子，在腔型乳腺癌中表达，但在更具侵袭性的基底细胞样或三阴性乳腺癌（TNBC）中丢失。我们先前证明了miR-200 c通过直接靶向神经营养受体酪氨酸激酶TrkB来恢复对TNBC细胞的失巢凋亡敏感性。在这项研究中，我们确定了一种TrkB配体，神经营养因子3（NTF 3），能够激活TrkB诱导失巢凋亡抵抗，并表明NTF 3也是miR-200 c的直接靶点。我们提出了第一个证据，即失巢凋亡抗性TNBC细胞在悬浮时上调TrkB和NTF 3，并表明这种上调是悬浮生存所必需的。我们进一步证明，NF-κB活性在悬浮TNBC细胞中增加6倍，并鉴定RelA和NF-κB1为负责悬浮诱导的Trk B和NTF 3上调的转录因子。因此，抑制NF-κB活性可抑制失巢凋亡抗性。总之，我们的研究结果定义了一个关键的机制，转录和转录后控制悬浮诱导的TrkB和NTF 3的失巢凋亡抗性乳腺癌细胞的上调。
Anoikis is apoptosis initiated upon cell detachment from the native extracellular matrix. Since survival upon detachment from basement membrane is required for metastasis, the ability to resist anoikis contributes to the metastatic potential of breast tumors. miR-200c, a potent repressor of epithelial to mesenchymal transition, is expressed in luminal breast cancers, but is lost in more aggressive basal-like, or triple negative breast cancers (TNBC). We previously demonstrated that miR-200c restores anoikis sensitivity to TNBC cells by directly targeting the neurotrophic receptor tyrosine kinase, TrkB. In this study, we identify a TrkB ligand, neurotrophin 3 (NTF3), as capable of activating TrkB to induce anoikis resistance, and show that NTF3 is also a direct target of miR-200c. We present the first evidence that anoikis resistant TNBC cells up-regulate both TrkB and NTF3 when suspended, and show that this up-regulation is necessary for survival in suspension. We further demonstrate that NF-κB activity increases 6 fold in suspended TNBC cells, and identify RelA and NF-κB1 as the transcription factors responsible for suspension-induced up-regulation of TrkB and NTF3. Consequently, inhibition of NF-κB activity represses anoikis resistance. Taken together, our findings define a critical mechanism for transcriptional and post-transcriptional control of suspension-induced up-regulation of TrkB and NTF3 in anoikis resistant breast cancer cells.
登录
查看更多内容
影响因子：
5.6
作者：
Antonov, Alexander S.;Antonova, Galina N.;Munn, David H.;Mivechi, Nahid;Lucas, Rudolf;Catravas, John D.;Verin, Alexander D.
通讯作者：
Verin, Alexander D.
影响因子：
4.8
作者：
Eades, Gabriel;Yao, Yuan;Zhou, Qun
通讯作者：
Zhou, Qun
影响因子：
11.2
作者：
Geiger, Thomas R.;Peeper, Daniel S.
通讯作者：
Peeper, Daniel S.
影响因子：
11.2
作者：
Bracken, Cameron P.;Gregory, Philip A.;Goodall, Gregory J.
通讯作者：
Goodall, Gregory J.
影响因子：
7.7
作者：
Fusco, Amanda J.;Huang, De-Bin;Ghosh, Gourisankar
通讯作者：
Ghosh, Gourisankar