Overexpression of miR-26a-2 in human liposarcoma is correlated with poor patient survival
Overexpression of miR-26a-2 in human liposarcoma is correlated with poor patient survival
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DOI：
10.1038/oncsis.2013.10
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发表时间：
2013-05-01
期刊：
影响因子：
6.2
通讯作者：
Koeffler, H. P.
中科院分区：
文献类型：
--
作者：
Lee, D. H.;Amanat, S.;Koeffler, H. P.
大约90%的高分化/去分化脂肪肉瘤（WDLPS/DDLPS），最常见的LPS亚型，在12 q13-q22有染色体扩增。该区域的许多蛋白质编码基因，如MDM 2和，已被研究为LPS治疗的潜在治疗靶点，但成功率很低。在MDM 2基因附近的扩增区域，我们对75个LPS样本的单核苷酸多态性（SNP）阵列分析鉴定了miR-26 a-2的频繁扩增。miR-26 a-2在WDLPS/DDLPS组和粘液样/圆细胞LPS组中均呈高表达（P < 0.001），但在扩增子中无表达（P> 0.05）。此外，Kaplan-Meier生存分析显示，miR-26 a-2的过表达与两种类型LPS中的患者生存率差显著相关（WDLPS/DDLPS P < 0.05; MRC P < 0.001）。基于这些发现，我们假设miR-26 a-2在LPS肿瘤发生中具有重要作用，而与LPS亚型无关。miR-26 a-2在三种LPS细胞系（SW 872、LPS 141和LP 6）中的过表达增强了这些细胞的生长和存活，包括更快的细胞增殖和迁移、增强的克隆形成、抑制脂肪细胞分化和/或抗凋亡。使用抗miR-26 a-2抑制LPS细胞中的miR-26 a-2导致相反的反应。为了进一步解释miR-26 a-2过表达在LPS细胞中的作用，我们进行了计算机模拟分析并鉴定了93个miR-26 a-2的候选靶点。在这些基因中，RCBTB 1（regulator of chromosome condensation and BTB domain-containing protein 1）位于13 q12.3-q14.3，即LPS中的复发性杂合性丢失（洛）区域。事实上，RCBTB 1的过表达或抑制分别使LPS细胞对凋亡更敏感或更耐受。总之，我们的研究首次揭示了miR-26 a-2对LPS肿瘤发生的贡献，部分通过抑制RCBTB 1，表明miR-26 a-2是人类LPS的新治疗靶点。
Approximately 90% of well-differentiated/de-differentiated liposarcomas (WDLPS/DDLPS), the most common LPS subtype, have chromosomal amplification at 12q13-q22. Many protein-coding genes in the region, such as MDM2 and, have been studied as potential therapeutic targets for LPS treatment, with minimal success. In the amplified region near the MDM2 gene, our single nucleotide polymorphism (SNP) array analysis of 75 LPS samples identified frequent amplification of miR-26a-2. Besides being in the amplicon, miR-26a-2 was overexpressed significantly in WDLPS/DDLPS (P < 0.001), as well as in myxoid/round cell LPS (MRC) (P < 0.05). Furthermore, Kaplan-Meier survival analysis showed that overexpression of miR-26a-2 significantly correlated with poor patient survival in both types of LPS (P < 0.05 for WDLPS/DDLPS; P < 0.001 for MRC). Based on these findings, we hypothesized that miR-26a-2 has an important role in LPS tumorigenesis, regardless of LPS subtypes. Overexpression of miR-26a-2 in three LPS cell lines (SW872, LPS141 and LP6) enhanced the growth and survival of these cells, including faster cell proliferation and migration, enhanced clonogenicity, suppressed adipocyte differentiation and/or resistance to apoptosis. Inhibition of miR-26a-2 in LPS cells using anti-miR-26a-2 resulted in the opposite responses. To explain further the effect of miR-26a-2 overexpression in LPS cells, we performed in silico analysis and identified 93 candidate targets of miR-26a-2. Among these genes, RCBTB1 (regulator of chromosome condensation and BTB domain-containing protein 1) is located at 13q12.3-q14.3, a region of recurrent loss of heterozygosity (LOH) in LPS. Indeed, either overexpression or inhibition of RCBTB1 made LPS cells more susceptible or resistant to apoptosis, respectively. In conclusion, our study for the first time reveals the contribution of miR-26a-2 to LPS tumorigenesis, partly through inhibiting RCBTB1, suggesting that miR-26a-2 is a novel therapeutic target for human LPS.