MicroRNA-155 Functions as an OncomiR in Breast Cancer by Targeting the Suppressor of Cytokine Signaling 1 Gene
MicroRNA-155 Functions as an OncomiR in Breast Cancer by Targeting the Suppressor of Cytokine Signaling 1 Gene
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MicroRNA-155 通过靶向细胞因子信号传导 1 基因的抑制子在乳腺癌中发挥 OncomiR 的作用
DOI：
10.1158/0008-5472.can-09-4250
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Wang, En-Duo
中科院分区：
文献类型：
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作者：
Jiang, Shuai;Zhang, Hong-Wei;Wang, En-Duo
微小RNA - 155（miR - 155）在许多人类癌症中过度表达；然而，miR - 155作为一种假定的致癌微小RNA（oncomiR）其作用机制在很大程度上是未知的。在此，我们报道细胞因子信号传导抑制因子1（suppressor of cytokine signaling 1，socs1）这一肿瘤抑制基因是乳腺癌细胞中miR - 155在进化上保守的靶标。我们发现miR - 155的表达与乳腺癌细胞系以及一部分原发性乳腺癌中的socs1表达呈负相关。我们还在一个乳腺癌肿瘤中发现SOCS1 3'非翻译区的miR - 155结合位点存在24A→G突变，该突变降低了miR - 155的抑制作用，这暗示了一种微小RNA靶标逃避抑制的机制。miR - 155的异位表达显著促进乳腺癌细胞的增殖、体外软琼脂集落的形成以及裸鼠体内肿瘤的发展。在乳腺癌细胞中，socs1的RNA干扰沉默重现了miR - 155的致癌效应，而socs1表达的恢复减弱了miR - 155的促肿瘤发生功能，这表明miR - 155通过负调控socs1发挥其致癌作用。乳腺癌细胞中miR - 155的过度表达通过Janus激酶（Janus - activated kinase，JAK）途径导致信号转导和转录激活因子3（signal transducer and activator of transcription 3，STAT3）的组成性激活，并且炎症细胞因子干扰素 - γ（IFN - γ）和白细胞介素 - 6（interleukin - 6，IL - 6）、脂多糖（lipopolysaccharide，LPS）以及多聚肌苷酸：多聚胞苷酸[poly（I:C）]对乳腺癌细胞的刺激显著上调miR - 155的表达，这表明miR - 155可能作为炎症和癌症之间的桥梁。总之，我们的研究揭示miR - 155是乳腺癌中的一种致癌微小RNA，并且miR - 155可能是乳腺癌治疗的一个潜在靶点。《癌症研究》；70(8)；3119 - 27。（C）2010美国癌症研究协会。
MicroRNA-155 (miR-155) is overexpressed in many human cancers; however, the mechanisms by which miR-155 functions as a putative oncomiR are largely unknown. Here, we report that the tumor suppressor gene suppressor of cytokine signaling 1 (socs1) is an evolutionarily conserved target of miR-155 in breast cancer cells. We found that mir-155 expression is inversely correlated with socs1 expression in breast cancer cell lines as well as in a subset of primary breast tumors. We also identified a 24A-->G mutation in the miR-155 binding site of the SOCS1 3' untranslated region in a breast tumor that reduced miR-155 repression, implicating a mechanism for miRNA targets to avoid repression. Ectopic expression of miR-155 significantly promoted the proliferation of breast cancer cells, the formation of soft agar foci in vitro, and the development of tumors in nude mice. In breast cancer cells, RNA interference silencing of socs1 recapitulates the oncogenic effects of miR-155, whereas restoration of socs1 expression attenuates the protumorigenesis function of miR-155, suggesting that miR-155 exerts its oncogenic role by negatively regulating socs1. Overexpression of miR-155 in breast cancer cells leads to constitutive activation of signal transducer and activator of transcription 3 (STAT3) through the Janus-activated kinase (JAK) pathway, and stimulation of breast cancer cells by the inflammatory cytokines IFN-gamma and interleukin-6 (IL-6), lipopolysaccharide (LPS), and polyriboinosinic: polyribocytidylic acid [poly(I:C)] significantly upregulates mir-155 expression, suggesting that miR-155 may serve as a bridge between inflammation and cancer. Taken together, our study reveals that miR-155 is an oncomiR in breast cancer and that miR-155 may be a potential target in breast cancer therapy. Cancer Res; 70(8); 3119-27. (C) 2010 AACR.