MCPIP1 Selectively Destabilizes Transcripts Associated with an Antiapoptotic Gene Expression Program in Breast Cancer Cells That Can Elicit Complete Tumor Regression.
MCPIP1 Selectively Destabilizes Transcripts Associated with an Antiapoptotic Gene Expression Program in Breast Cancer Cells That Can Elicit Complete Tumor Regression.
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DOI：
10.1158/0008-5472.can-15-1115
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发表时间：
2016-03-15
期刊：
影响因子：
11.2
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Lu W;Ning H;Gu L;Peng H;Wang Q;Hou R;Fu M;Hoft DF;Liu J
癌细胞逃避凋亡的能力是由促凋亡和抗凋亡基因表达程序之间的平衡变化决定的。单核细胞趋化蛋白诱导蛋白1(MCPIP1)是一种锌指RNA结合蛋白，在介导炎症反应中具有重要作用。MCPIP1在不同类型的癌细胞中过表达与诱导抗肿瘤反应有关，但MCPIP1在细胞凋亡中的直接作用尚未确定。在这项研究中，我们证明了MCPIP1作为一种有效的肿瘤抑制因子，通过选择性地促进抗凋亡基因转录产物Bcl2L1、Bcl2A1、RelB、Birc3和Bcl3的mRNA降解来诱导乳腺肿瘤细胞的凋亡。从机械上讲，MCPIP1通过其PIN结构域与这些转录本3‘UTR区的茎环结构相互作用，导致mRNA不稳定。此外，我们还发现MCPIP1在乳腺肿瘤细胞中的表达受到抑制，MCPIP1的过表达诱导了细胞的凋亡，而MCPIP1的缺失则促进了癌细胞的增殖。此外，在体内诱导MCPIP1导致已建立的肿瘤完全消退，并显著减少转移性疾病。值得注意的是，乳腺癌患者肿瘤样本中MCPIP1的低表达与13年随访的低存活率密切相关。总而言之，我们的结果强调了MCPIP1是一种新的乳腺癌肿瘤抑制因子，它通过改变平衡有利于促凋亡基因的表达来诱导细胞死亡。
The ability of cancer cells to evade apoptosis is dictated by a shift in the balance between pro- and anti-apoptotic gene expression programs. Monocyte chemotactic protein induced protein 1 (MCPIP1) is a zinc finger RNA binding protein with important roles in mediating inflammatory responses. Overexpression of MCPIP1 in different cancer cell types has been implicated in eliciting an antitumor response, but a direct role of MCPIP1 in apoptosis has not been established. In this study, we demonstrate that MCPIP1 functions as a potent tumor suppressor that induces apoptosis of breast tumor cells by selectively enhancing mRNA decay of anti-apoptotic gene transcripts including Bcl2L1, Bcl2A1, RelB, Birc3, and Bcl3. Mechanistically, MCPIP1 physically interacted with a stem-loop structure in the 3'UTR of these transcripts through its PIN domain, causing mRNA destabilization. Furthermore, we found that MCPIP1 expression was repressed in breast tumor cells, and overexpression of MCPIP1 induced apoptosis, whereas its depletion enhanced cancer cell proliferation. Moreover, MCPIP1 induction in vivo resulted in complete regression of established tumors and a significant reduction in metastatic disease. Notably, low MCPIP1 expression in tumor samples from breast cancer patients was strongly associated with poor survival over 13 years of follow up. Collectively, our results highlight MCPIP1 is a new tumor suppressor in breast cancer that induces cell death by tipping the balance in favor of pro-apoptotic gene expression.