MiR-122 inhibits cell proliferation and tumorigenesis of breast cancer by targeting IGF1R.
MiR-122 inhibits cell proliferation and tumorigenesis of breast cancer by targeting IGF1R.
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DOI：
10.1371/journal.pone.0047053
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Wang B;Wang H;Yang Z
MiRNAs正在成为癌症发生和肿瘤进展的关键调控因子。近年来，microRNA-122(miR-122)已被证实在肝细胞癌中发挥重要作用，但其在乳腺癌中的作用尚不清楚。在本研究中，我们报告miR-122在BC标本和BC细胞系中普遍下调，具有重要的功能后果。过表达miR-122不仅在体外通过诱导G1期细胞周期停滞而显著抑制细胞的增殖和集落形成，而且在体内也降低了致瘤性。然后我们筛选和鉴定了一个新的miR-122靶点--胰岛素样生长因子1受体(IGF1R)，并通过荧光素酶实验进一步证实了它的存在。MiR-122的过表达会特异性地显著降低其表达。与恢复miR-122表达类似，IGF1R下调抑制细胞生长和细胞周期进程，而IGF1R过表达挽救miR-122的抑制作用。为了确定其机制，我们研究了Akt/mTOR/p70S6K通路，发现Akt、mTOR和p70S6K的表达受到抑制，而不含3‘UTR的IGF1R的重新表达完全逆转了Akt/mTOR/p70S6K信号通路的抑制。我们还发现了一个新的、可能的miR-122靶基因PI3CG，它是PI3K家族的成员，这进一步表明miR-122可能是PI3K/Akt通路的关键调节因子。在临床标本中，IGF1R广泛过表达，其mRNA水平与miR-122的表达呈负相关。综上所述，我们的结果表明miR-122作为一种肿瘤抑制因子，通过靶向IGF1R和调节PI3K/Akt/mTor/p70S6K通路在抑制肿瘤发生中发挥重要作用。鉴于此，miR-122可能成为治疗BC的一种新的治疗或诊断/预后靶点。
miRNAs are emerging as critical regulators in carcinogenesis and tumor progression. Recently, microRNA-122 (miR-122) has been proved to play an important role in hepatocellular carcinoma, but its functions in the context of breast cancer (BC) remain unknown. In this study, we report that miR-122 is commonly downregulated in BC specimens and BC cell lines with important functional consequences. Overexpression of miR-122 not only dramatically suppressed cell proliferation, colony formation by inducing G1-phase cell-cycle arrest in vitro, but also reduced tumorigenicity in vivo. We then screened and identified a novel miR-122 target, insulin-like growth factor 1 receptor (IGF1R), and it was further confirmed by luciferase assay. Overexpression of miR-122 would specifically and markedly reduce its expression. Similar to the restoring miR-122 expression, IGF1R downregulation suppressed cell growth and cell-cycle progression, whereas IGF1R overexpression rescued the suppressive effect of miR-122. To identify the mechanisms, we investigated the Akt/mTOR/p70S6K pathway and found that the expression of Akt, mTOR and p70S6K were suppressed, whereas re-expression of IGF1R which did not contain the 3′UTR totally reversed the inhibition of Akt/mTOR/p70S6K signal pathway profile. We also identified a novel, putative miR-122 target gene, PI3CG, a member of PI3K family, which further suggests miR-122 may be a key regulator of the PI3K/Akt pathway. In clinical specimens, IGF1R was widely overexpressed and its mRNA levels were inversely correlated with miR-122 expression. Taken together, our results demonstrate that miR-122 functions as a tumor suppressor and plays an important role in inhibiting the tumorigenesis through targeting IGF1R and regulating PI3K/Akt/mTOR/p70S6K pathway. Given these, miR-122 may serve as a novel therapeutic or diagnostic/prognostic-target for treating BC.
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