Stathmin 1 is a potential novel oncogene in melanoma
Stathmin 1 is a potential novel oncogene in melanoma
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DOI：
10.1038/onc.2012.141
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发表时间：
2013-03-07
期刊：
影响因子：
8
通讯作者：
Tron, V. A.
中科院分区：
文献类型：
--
作者：
Chen, J.;Abi-Daoud, M.;Tron, V. A.
在以前的研究中，我们证明了miR-193 b在黑色素瘤中的表达相对于良性痣减少，并且miR 193 b抑制细胞周期蛋白D1和Mcl-1的表达。我们认为stathmin 1（STMN 1）可能是miR-193 b的作用靶点。STMN 1通常通过隔离游离微管蛋白异二聚体或通过促进微管灾难来调节微管动力学。在多种人类恶性肿瘤中观察到STMN 1表达增加，但其与黑色素瘤的相关性尚不清楚。我们现在报道，STMN 1在黑色素瘤相对于良性痣的进展过程中上调，并且STMN 1直接受miR-193 b调节。使用实验性细胞培养方法，使用合成microRNA过表达miR-193 b抑制STMN 1表达，而使用抗miR寡核苷酸抑制miR-193 b增加黑素瘤细胞中STMN 1表达。使用荧光素酶报告基因测定证实miR-193 b通过靶向STMN 1 mRNA的3 '非翻译区直接调控STMN 1。我们进一步证明，在两个独立的黑色素瘤队列中，与痣相比，STMN 1在恶性黑色素瘤中过表达，并且其水平与miR-193 b表达呈负相关。然而，STMN 1表达与患者生存率、Breslow深度、有丝分裂计数或患者年龄无显著相关性。在黑色素瘤细胞中通过小干扰RNA敲低STMN 1显著抑制了细胞增殖和迁移潜力，而使用慢病毒异位表达STMN 1增加了细胞增殖和迁移率。随后的基因表达分析表明，相互连接的细胞骨架网络直接影响后STMN 1敲低。此外，我们确定了与增殖和迁移相关的失调基因，并揭示了p21（Cip 1/Waf 1）和p27（Kip）可能是STMN 1信号转导的下游效应子。总之，我们的研究表明，下调miR-193 b可能有助于增加STMN 1在黑色素瘤中的表达，从而促进肿瘤细胞的迁移和增殖。Oncogene（2013）32，1330-1337; doi：10.1038/onc.2012.141; 2012年6月4日在线发表
In previous studies, we demonstrated that miR-193b expression is reduced in melanoma relative to benign nevi, and also that miR193b represses cyclin D1 and Mcl-1 expression. We suggested that stathmin 1 (STMN1) might be a target of miR-193b. STMN1 normally regulates microtubule dynamics either by sequestering free tubulin heterodimers or by promoting microtubule catastrophe. Increased expression of STMN1 has been observed in a variety of human malignancies, but its association with melanoma is unknown. We now report that STMN1 is upregulated during the progression of melanoma relative to benign nevi, and that STMN1 is directly regulated by miR-193b. Using an experimental cell culture approach, overexpression of miR-193b using synthetic microRNAs repressed STMN1 expression, whereas inhibition of miR-193b with anti-miR oligos increased STMN1 expression in melanoma cells. The use of a luciferase reporter assay confirmed that miR-193b directly regulates STMN1 by targeting the 3'-untranslated region of STMN1 mRNA. We further demonstrated that STMN1 is overexpressed in malignant melanoma compared with nevi in two independent melanoma cohorts, and that its level is inversely correlated with miR-193b expression. However, STMN1 expression was not significantly associated with patient survival, Breslow depth, mitotic count or patient age. STMN1 knockdown by small-interfering RNA in melanoma cells drastically repressed cell proliferation and migration potential, whereas ectopic expression of STMN1 using lentivirus increased cell proliferation and migration rates. Subsequent gene expression analysis indicated that interconnected cytoskeletal networks are directly affected following STMN1 knockdown. In addition, we identified deregulated genes associated with proliferation and migration, and revealed that p21(Cip1/Waf1) and p27(Kip) could be downstream effectors of STMN1 signaling. Taken together, our study suggests that downregulation of miR-193b may contribute to increased STMN1 expression in melanoma, which consequently promotes migration and proliferation of tumor cells. Oncogene (2013) 32, 1330-1337; doi:10.1038/onc.2012.141; published online 4 June 2012