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德研究发现癌变“刹车”小RNA分子:miR- 520

2011/12/23 来源:科学网
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近日来自德国癌症研究中心的科学家们证实一种称为miR- 520的小RNA分子在防止细胞癌变的过程中发挥了重要的“刹车”功能。相关研究论文于12月12日发表在《自然》旗下的期刊《癌基因》(Oncogene)上。

近日来自德国癌症研究中心的科学家们证实一种称为miR- 520的小RNA分子在防止细胞癌变的过程中发挥了重要的“刹车”功能。此外,研究发现在雌激素受体阴性的乳腺癌中,miR- 520表达受到显著抑制,并与肿瘤的恶化程度密切相关。低水平表达miR-520的癌细胞有着显著的转移倾向。相关研究论文于12月12日发表在《自然》旗下的期刊《癌基因》(Oncogene)上。

近年随着肿瘤研究的深入,miRNA已经成为肿瘤生物治疗领域的一个新亮点,越来越引起研究人员的关注。miRNA是一类长度在19-24 个核苷酸(nt)左右的内源性非编码小分子单链RNA, 在进化过程中高度保守, 能通过与靶基因mRNA特异性的碱基互补配对, 引起靶基因mRNA的降解或者抑制其翻译, 广泛地负调控靶基因的表达。目前,人类已经发现400余种miRNA,可以调控人体中1/3基因的表达水平。过去的研究表明如果相关的miRNA发生突变,激活相关癌基因的表达或引发抑癌基因的缺失,就会导致肿瘤的发生。

转录因子NfkappaB是癌症形成中的一个关键因子,它作为一个重要的分子开关调控着大量与促炎性效应相关的基因。在这篇文章中,德国癌症研究中心Stefan Wiemann教授及同事与德国蒂宾根大学医院Heidelberg领导的研究小组展开合作,探究了乳腺癌中对NFkappaB生成起重要调控作用的microRNAs。研究人员在对800种miRNAs进行筛查后,发现了一类称之为miR-520的小分子RNA家族。“miR-520通过显著抑制NfkappaB生成,对促炎性分子信号发挥重要的负调控功能。由于这些分子信号具有增强细胞侵袭力,促进新血管形成和转移的作用,因此miR-520在肿瘤生成中充当了重要的‘分子刹车’,”文章的首作者Ioanna Keklikoglou说道。

在随后的试验中,Wiemann发现miR-520不仅可通过抑制NfkappaB发挥癌症“刹车”作用,它同时还阻断了另一条由生长因子TGF-β触发的致癌信号通路。过去的研究表明TGF-β信号与癌症的侵袭转移密切相关。

接下来,研究人员又在临床采集的患者癌组织样本中对体外实验结果进行了再次验证。研究人员发现在来自76名患者的样本中, miR-520表达水平与癌转移程度密切相关。但这种相关性仅存在于雌激素受体阴性的乳腺癌样本中。

“我们的实验结果表明miR-520通过两条不同的途径参与遏制了癌变,起到了关键性的刹车作用,”Stefan Wiemann说:“这种癌细胞分子刹车似乎在大量的雌激素受体阴性乳腺癌以及一些其他类型的癌症中受到了抑制。”

雌激素受体阴性乳腺癌是当前临床众所周知的生存率极低的疑难疾病。miR-520具有的靶向多种促癌信号通路的特性,为癌症治疗提供了一个有潜力的理想靶标。

 

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

I Keklikoglou, C Koerner, C Schmidt, J D Zhang, D Heckmann, A Shavinskaya, H Allgayer, B Gückel, T Fehm, A Schneeweiss, Ö Sahin, S Wiemann and U Tschulena

MicroRNAs (miRNAs) as modulators of gene expression have been described to display both tumor-promoting and tumor-suppressive functions. Although their role has been studied in different tumor types, little is known about how they regulate nuclear factor κB (NF-κB) signaling in breast cancer. Here, we performed an unbiased whole genome miRNA (miRome) screen to identify novel modulators of NF-κB pathway in breast cancer. The screen identified 13 miRNA families whose members induced consistent effects on NF-κB activity. Among those, the miR-520/373 family inhibited NF-κB signaling through direct targeting of RELA and thus strongly reduced expression and secretion of the pro-inflammatory cytokines interleukin (IL)-6 and IL-8. With a combination of in vitro and in vivo approaches, we propose a metastasis-suppressive role of miR-520/373 family. miR-520c and miR-373 abrogated both in vitro cell invasion and in vivo intravasation of highly invasive MDA-MB-231 cells. However, knockdown of RELA did not affect their metastatic ability. mRNA profiling of MDA-MB-231 cells on overexpression of miR-520/373 members revealed a strong downregulation of transforming growth factor-β (TGF-β) signaling. Mechanistically, the metastasis-suppressive role of miR-520/373 can be attributed to direct suppression of TGFBR2, as the silencing of TGFBR2 phenocopied the effects of miR-520/373 overexpression on suppression of Smad-dependent expression of the metastasis-promoting genes parathyroid hormone-related protein, plasminogen activator inhibitor-1 and angiopoietin-like 4 as well as tumor cell invasion, in vitro and in vivo. A negative correlation between miR-520c and TGFBR2 expression was observed in estrogen receptor negative (ER−) breast cancer patients but not in the ER positive (ER+) subtype. Remarkably, decreased expression of miR-520c correlated with lymph node metastasis specifically in ER− tumors. Taken together, our findings reveal that miR-520/373 family has a tumor-suppressive role in ER− breast cancer by acting as a link between the NF-κB and TGF-β pathways and may thus contribute to the interplay of tumor progression, metastasis and inflammation.

文献链接:http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2011571a.html

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