miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway.
miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway.
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miR-29c 通过靶向 TIMP3/STAT1/FOXO1 通路在乳腺癌中发挥抑制作用。
DOI：
10.1186/s13148-018-0495-y
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发表时间：
2018
影响因子：
5.7
通讯作者：
Du G
中科院分区：
文献类型：
--
作者：
Li W;Yi J;Zheng X;Liu S;Fu W;Ren L;Li L;Hoon DSB;Wang J;Du G
背景miR-29c 与许多癌症的进展有关。然而，miR-29c在乳腺癌中的功能和机制尚未得到很好的研究。方法采用实时定量PCR检测miR-29c和DNMT3B mRNA的表达。使用蛋白质印迹和免疫化学检测乳腺癌细胞和组织中 DNA 甲基转移酶 3B (DNMT3B) 蛋白的表达。分别使用MTT、transwell小室、软琼脂和3D Matrigel培养物评估miR-29c在乳腺癌细胞中的功能作用，例如增殖、迁移、侵袭、集落形成和3D生长。此外，使用荧光素酶报告基因测定来检查miR-29c是否结合DNMT3B的3'UTR。还使用蛋白质印迹和甲基特异性 qPCR 检查了 miR-29c 对 DNMT3B/TIMP3/STAT1/FOXO1 通路的影响。利用STAT1的特异性抑制剂氟达拉滨进一步检查乳腺癌细胞中miR-29c的功能机制。在DNMT3B siRNA细胞系中进行细胞功能研究。结果miR-29c的表达随着乳腺癌的进展而降低，并且与患者的总生存率密切相关。 miR-29c 的过表达抑制 3D Matrigel 中的增殖、迁移、侵袭、集落形成和生长，而 miR-29c 的敲低则促进乳腺癌细胞中的这些过程。此外，miR-29c被发现与DNMT3B的3'UTR结合并抑制DNMT3B的表达，DNMT3B的表达在乳腺癌中升高。此外，与对照相比，miR-29c 敲低细胞中 TIMP3 的蛋白水平降低，而 TIMP3 甲基化增加。相反，与对照相比，在 miR-29c 过表达细胞中 TIMP3 的蛋白水平增加，而 TIMP3 的甲基化减少。 DNMT3B 的敲除减少了乳腺癌细胞系的增殖、迁移和侵袭。最后，我们的结果表明，miR-29c通过调节TIMP3/STAT1/FOXO1通路在乳腺癌中发挥其功能。结论结果表明，miR-29c在抑制乳腺癌进展中发挥着重要作用，miR-29c可能作为乳腺癌的生物标志物。
BackgroundmiR-29c has been associated with the progression of many cancers. However, the function and mechanism of miR-29c have not been well investigated in breast cancers.MethodsReal-time quantitative PCR was used to assess expression of miR-29c and DNMT3B mRNA. Western blot and immunochemistry were used to examine the expression of DNA methyltransferase 3B (DNMT3B) protein in breast cancer cells and tissues. The functional roles of miR-29c in breast cancer cells such as proliferation, migration, invasion, colony formation, and 3D growth were evaluated using MTT, transwell chambers, soft agar, and 3D Matrigel culture, respectively. In addition, the luciferase reporter assay was used to check if miR-29c binds the 3′UTR of DNMT3B. The effects of miR-29c on the DNMT3B/TIMP3/STAT1/FOXO1 pathway were also examined using Western blot and methyl-specific qPCR. The specific inhibitor of STAT1, fludarabine, was used to further check the mechanism of miR-29c function in breast cancer cells. Studies on cell functions were carried out in DNMT3B siRNA cell lines.ResultsThe expression of miR-29c was decreased with the progression of breast cancers and was closely associated with an overall survival rate of patients. Overexpression of miR-29c inhibited the proliferation, migration, invasion, colony formation, and growth in 3D Matrigel while knockdown of miR-29c promoted these processes in breast cancer cells. In addition, miR-29c was found to bind 3′UTR of DNMT3B and inhibits the expression of DNMT3B, which was elevated in breast cancers. Moreover, the protein level of TIMP3 was reduced whereas methylation of TIMP3 was increased in miR-29c knockdown cells compared to control. On the contrary, the protein level of TIMP3 was increased whereas methylation of TIMP3 was reduced in miR-29c-overexpressing cells compared to control. Knockdown of DNMT3B reduced the proliferation, migration, and invasion of breast cancer cell lines. Finally, our results showed that miR-29c exerted its function in breast cancers by regulating the TIMP3/STAT1/FOXO1 pathway.ConclusionThe results suggest that miR-29c plays a significant role in suppressing the progression of breast cancers and that miR-29c may be used as a biomarker of breast cancers.
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