Posttranscriptional upregulation of HER3 by HER2 mRNA induces trastuzumab resistance in breast cancer.
Posttranscriptional upregulation of HER3 by HER2 mRNA induces trastuzumab resistance in breast cancer.
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HER2 mRNA 转录后上调 HER3 诱导乳腺癌曲妥珠单抗耐药
DOI：
10.1186/s12943-018-0862-5
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发表时间：
2018-08-02
期刊：
影响因子：
37.3
通讯作者：
Meng S
中科院分区：
文献类型：
--
作者：
Li X;Xu Y;Ding Y;Li C;Zhao H;Wang J;Meng S
HER2基因扩增产生了大量的HER2转录本，但在乳腺癌中对包括HER家族成员在内的内源性miRNA靶点的整体影响尚不清楚。我们制作了一个HER2 - 3 ' utr表达载体来测试HER2低表达的T47D和MCF7细胞的促瘤特性。通过微阵列分析和实时PCR分析，我们确定了受HER2-3'UTR调控的基因。通过miRNA表达的阳性和阴性操作、应答元件突变研究和转录报告基因检测来探索HER2 3'UTR竞争性封存miR125a/miRNA125b的机制。为了研究曲妥珠单抗诱导的HER3上调是否也通过miRNA去抑制介导，我们使用CRISPR/cas9在HER2过表达的Au565细胞中突变内源性HER2 mRNA。最后，我们观察了我们自己和TCGA的乳腺癌样本队列，以显示HER2和HER3 mrna是否相互关联。HER2 3'UTR明显促进细胞增殖、集落形成和乳腺肿瘤生长。高通量测序显示HER2 3 ‘非翻译区（3’UTR）的HER3 mRNA和蛋白水平显著升高。携带共享miR-125a/b应答元件的HER2 3'UTR诱导miR-125a/b隔离，从而导致HER3 mRNA下调。曲妥珠单抗治疗通过升高HER2 mRNA表达上调HER3，导致曲妥珠单抗耐药。miR-125a/b的缺失增强了曲妥珠单抗的抗肿瘤活性。来自her2过表达原发性乳腺癌的微阵列数据显示，与非靶标相比，预测miR-125a/b靶标的mrna显著升高。这些结果表明，HER2 3 ' utr介导的HER3上调参与了乳腺细胞转化、肿瘤生长增加和抗HER2治疗的抵抗。联合靶向HER3 mRNA或miR-125a/b可能为乳腺癌治疗提供一种有效的工具。本文的在线版本（10.1186/s12943-018- 0865 -5）包含补充材料，仅供授权用户使用。
HER2 gene amplification generates an enormous number of HER2 transcripts, but the global effects on endogenous miRNA targets including HER family members in breast cancer are unexplored. We generated a HER2–3’UTR expressing vector to test the tumor-promoting properties in HER2 low expressing T47D and MCF7 cells. Through microarray analysis and real-time PCR analysis we identified genes that were regulated by HER2–3’UTR. Positive and negative manipulation of miRNA expression, response element mutational studies and transcript reporter assays were performed to explore the mechanism of competitive sequestration of miR125a/miRNA125b by HER2 3’UTR. To investigate if trastuzumab-induced upregulation of HER3 is also mediated through miRNA de-repression, we used the CRISPR/cas9 to mutate the endogenous HER2 mRNA in HER2 over-expressing Au565 cells. Finally, we looked at cohorts of breast cancer samples of our own and the TCGA to show if HER2 and HER3 mRNAs correlate with each other. The HER2 3’UTR pronouncedly promoted cell proliferation, colony formation, and breast tumor growth. High-throughput sequencing revealed a significant increase in HER3 mRNA and protein levels by the HER2 3’untranslated region (3’UTR). The HER2 3’UTR harboring a shared miR-125a/b response element induced miR-125a/b sequestration and thus resulted in HER3 mRNA derepression. Trastuzumab treatment upregulated HER3 via elevated HER2 mRNA expression, leading to trastuzumab resistance. Depletion of miR-125a/b enhanced the antitumor activity of trastuzumab. Microarray data from HER2-overexpressing primary breast cancer showed significant elevation of mRNAs for predicted miR-125a/b targets compared to non-targets. These results suggest that HER2 3’UTR-mediated HER3 upregulation is involved in breast cell transformation, increased tumor growth, and resistance to anti-HER2 therapy. The combinatorial targeting of HER3 mRNA or miR-125a/b may offer an effective tool for breast cancer therapy. The online version of this article (10.1186/s12943-018-0862-5) contains supplementary material, which is available to authorized users.
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影响因子：
37.3
作者：
Ferracin M;Bassi C;Pedriali M;Pagotto S;D'Abundo L;Zagatti B;Corrà F;Musa G;Callegari E;Lupini L;Volpato S;Querzoli P;Negrini M
通讯作者：
Negrini M
影响因子：
50.3
作者：
Agus, DB;Akita, RW;Sliwkowski, MX
通讯作者：
Sliwkowski, MX
DOI：
10.1186/s12964-015-0084-z
发表时间：
2015-01-29
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Bischoff A;Bayerlová M;Strotbek M;Schmid S;Beissbarth T;Olayioye MA
通讯作者：
Olayioye MA
影响因子：
3.9
作者：
Berghoff, Anna S.;Bartsch, Rupert;Birner, Peter
通讯作者：
Birner, Peter
DOI：
10.1073/pnas.1018001108
发表时间：
2012-02-21
影响因子：
11.1
作者：
Chakrabarty, Anindita;Sanchez, Violeta;Arteaga, Carlos L.
通讯作者：
Arteaga, Carlos L.