MiR-99a antitumor activity in human breast cancer cells through targeting of mTOR expression.
MiR-99a antitumor activity in human breast cancer cells through targeting of mTOR expression.
复制标题
DOI：
10.1371/journal.pone.0092099
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Tang L
中科院分区：
文献类型：
--
作者：
Hu Y;Zhu Q;Tang L
microRNAs（miRNAs）作为癌基因或肿瘤抑制因子在人类肿瘤发生中发挥重要作用。据报道，miR-99 a是人类多种癌症中的肿瘤抑制基因。然而，关于miR-99 a在人类乳腺癌中的功能的信息有限。在此，我们研究了miR-99 a在乳腺癌组织标本中的表达及其在乳腺癌细胞中的抗肿瘤活性。我们初步鉴定了miR-99 a在四种乳腺癌细胞系中的表达显著降低。更重要的是，我们在10名不同患者的乳腺癌标本中发现了miR-99 a的下调。我们进一步分析了miR-99 a抑制肿瘤发生的机制。基于细胞的检测显示miR-99 a的过表达不仅通过诱导细胞在亚G1期积聚和细胞凋亡降低乳腺癌细胞的活力，而且还抑制体内致瘤性。作为一个关键的miR-99 a靶点，我们已经发现，基于miR-99 a的荧光素酶报告分析极大地抑制了哺乳动物雷帕霉素靶蛋白（mTOR）的功能; miR-99 a的过表达降低了mTOR及其下游磷酸化蛋白（p-4 E-BP 1和p-S6 K1）的表达。与恢复miR-99 a表达相似，mTOR下调抑制细胞活力并增加细胞凋亡，而mTOR表达的恢复显著逆转了miR-99 a对mTOR/p-4 E-BP 1/p-S6 K1信号通路和miR-99 a抗肿瘤活性的抑制作用。在临床标本和细胞系中，mTOR通常过表达，其蛋白水平与miR-99 a表达呈统计学负相关。综上所述，这些结果表明，miR-99 a的抗肿瘤活性是通过靶向人乳腺癌细胞中的mTOR/p-4 E-BP 1/p-S6 K1通路实现的。这项研究提出了一种有效控制乳腺癌发展的潜在治疗策略。
MicroRNAs (miRNAs) play an important role in human tumorigenesis as oncogenes or tumor suppressors. miR-99a has been reported as a tumor suppressor gene in various cancers in humans. However, only limited information about the function of miR-99a in human breast cancers is available. Here we investigated the expression of miR-99a in breast cancer tissue specimens and its antitumor activity in breast cancer cells. We initially identified that the expression of miR-99a was significantly reduced in four breast cancer cell lines. More importantly, we found downregulation of miR-99a in breast cancer specimens from ten different patients. We then analyzed the mechanism of miR-99a in inhibiting tumorigenesis. Cell-based assays that showed overexpression of miR-99a not only reduced breast cancer cell viability by inducing accumulation of cells at sub-G1 phase and cell apoptosis, but also inhibited tumorigenicity in vivo. As a critical miR-99a target, we have shown that the function of mammalian target of rapamycin (mTOR) was greatly inhibited by miR-99a-based Luciferase report assay; overexpression of miR-99a reduced the expression of mTOR and its downstream phosphorylated proteins (p-4E-BP1 and p-S6K1). Similar to restoring miR-99a expression, mTOR downregulation suppressed cell viability and increased cell apoptosis, whereas restoration of mTOR expression significantly reversed the inhibitory effects of miR-99a on the mTOR/p-4E-BP1/p-S6K1 signal pathway and the miR-99a antitumor activity. In clinical specimens and cell lines, mTOR was commonly overexpressed and its protein levels were statistically inversely correlated with miR-99a expression. Taken together, these results have demonstrated that miR-99a antitumor activity is achieved by targeting the mTOR/p-4E-BP1/p-S6K1 pathway in human breast cancer cells. This study suggests a potential therapeutic strategy to effectively control breast cancer development.
登录
查看更多内容
影响因子：
3.8
作者：
Cui L;Zhou H;Zhao H;Zhou Y;Xu R;Xu X;Zheng L;Xue Z;Xia W;Zhang B;Ding T;Cao Y;Tian Z;Shi Q;He X
通讯作者：
He X
影响因子：
4.8
作者：
Li, Dong;Liu, Xingguang;Cao, Xuetao
通讯作者：
Cao, Xuetao
影响因子：
4.8
作者：
Gera, JF;Mellinghoff, IK;Lichtenstein, AK
通讯作者：
Lichtenstein, AK
影响因子：
11.5
作者：
Nam, Eun Ji;Yoon, Heejei;Kim, Sunghoon
通讯作者：
Kim, Sunghoon
影响因子：
5.3
作者：
Fingar, DC;Richardson, CJ;Blenis, J
通讯作者：
Blenis, J