Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin Induction of the tumor suppressor miRNA let-7a and suppression of the TGFβ-induced oncomiR miRNA-181a
Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin Induction of the tumor suppressor miRNA let-7a and suppression of the TGFβ-induced oncomiR miRNA-181a
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DOI：
10.4161/cc.10.7.15210
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发表时间：
2011-04-01
期刊：
影响因子：
4.3
通讯作者：
Menendez, Javier A.
中科院分区：
文献类型：
--
作者：
Oliveras-Ferraros, Cristina;Cufi, Slvia;Menendez, Javier A.
一种未知的分子情景可能解释抗糖尿病药物二甲双胍对乳腺癌发生的抑制影响，这与二甲双胍调节微小(Mi)RNA表达状态的能力有关。在此，我们首次报道了在二甲双胍存在下培养的人乳腺癌细胞的miRNA表达谱。我们进行了实时转录聚合酶链式反应(qRT-PCR)阵列定量比较了88个癌症相关miRNA序列在MCF-7细胞处理前后的表达谱，这些细胞被用作高分化上皮样细胞对照，使用不同浓度的二甲双胍。二甲双胍处理的MCF-7细胞与未处理的对照细胞相比，miRNA致死-7a(let-7a)的表达显著增加18倍。我们证实，MCF-7细胞在细胞因子TGFβ作用下发生上皮向间充质(EMT)转变，显著上调(类似于五倍)miRNA-181a的表达，并显示出更好的乳房形成能力。然后，我们探索了二甲双胍以miRNA-181a相关的方式阻止转化生长因子β增强的乳腺癌干细胞形成乳房的倾向的能力。值得注意的是，在二甲双胍存在的情况下，转化生长因子β处理不能上调miRNA-181a的表达，这能够完全取消转化生长因子β促进的乳房形成能力。此外，二甲双胍联合治疗完全阻止了转化生长因子β诱导的肿瘤抑制基因miRNA-96的下调(类似于十倍)。二甲双胍预防浸润性乳腺癌的分子功能可以解释为它能够有效上调抑癌miRNAs let-7a和miRNA-96，抑制致癌miRNA-181a，从而在表观遗传上保留乳腺上皮的分化表型，同时阻止EMT相关癌症启动细胞的自我更新。
An unexplored molecular scenario that might explain the inhibitory impact of the anti-diabetic drug metformin on the genesis of breast cancer relates to metformin's ability to modulate the expression status of micro (mi)RNAs. We here report the first miRNA expression profiling of human epithelial breast cancer cells cultured in the presence of metformin. We conducted real-time transcription polymerase chain reaction (qRT-PCR) Arrays to quantitatively compare the expression profile of 88 cancer-related miRNA sequences before and after treatment of MCF-7 cells, which were used as well-differentiated, epithelioid cell controls, with graded concentrations of metformin. Metformin-treated MCF-7 cells notably exhibited up to 18-fold increases in miRNA lethal-7a (let-7a) expression compared with untreated control cells. We confirmed that MCF-7 cells undergoing epithelial-to-mesenchymal (EMT) transition in response to the cytokine TGF beta notably upregulated (similar to five-fold) miRNA-181a expression and exhibited better mammosphere-forming capabilities. We then explored the ability of metformin to impede TGF beta-enhanced propensity of breast cancer stem cells to form mammospheres in a miRNA-181a-related manner. Remarkably, TGF beta treatment failed to upregulate miRNA-181a expression in the presence of metformin, which was able to fully abrogate TGF beta-enhanced mammosphere-forming ability. In addition, metformin co-treatment fully prevented TGF beta-induced downregulation of the tumor suppressor miRNA-96 (similar to ten-fold). Metformin's molecular functioning to prevent invasive breast cancer can be explained in terms of its previously unrecognized ability to efficiently upregulate the tumor-suppressive miRNAs let-7a & miRNA-96 and inhibit the oncogenic miRNA-181a, thus epigenetically preserving the differentiated phenotype of mammary epithelium while preventing EMT-related cancer-initiating cell self-renewal.