RBMS2 通过稳定乳腺癌中的 P21 mRNA 来抑制增殖。
RBMS2 inhibits the proliferation by stabilizing P21 mRNA in breast cancer.
机构信息
Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
Research Division of Clinical Pharmacology, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
出版信息
J Exp Clin Cancer Res. 2018 Dec 4;37(1):298. doi: 10.1186/s13046-018-0968-z.
BACKGROUND
RNA binding proteins (RBPs) play an important role in regulating the metabolism of target RNAs. Aberrant expression of RBPs plays a vital role in the initiation and development of many cancers. The RBM family, which has the conserved RNA binding motif RNP1 and RNP2, shares the similar function in RNA processing and RBMS2 is a member of them. P21, also named CDKN1A, promotes cell cycle arrest and plays an important role in halting cell proliferation. In our study, we identified RBMS2 as a tumor suppressor in breast cancer. It inhibited the proliferation of breast cancer by positively regulating the stability of P21 mRNA in posttranscriptional way.
METHODS
TCGA was used to identify differentially expressed RBPs in breast cancer. The effect of RBMS2 on breast cancer proliferation was evaluated in vitro using CCK-8 assays, colony formation assays and cell-cycle assays and the in vivo effect was investigated using a mouse tumorigenicity model. The main pathway and genes regulated by RBMS2 was detected by RNA sequencing. The RNA immunoprecipitation combined with dual-luciferase reporter assay were conducted to testify the direct binding between RBMS2 and P21. Rescue assay was used to detect P21 as the main target of RBMS2.
RESULTS
The expression of RBMS2 was lower in breast cancer compared with normal tissues and was a favorable biomarker in breast cancer. RBMS2 inhibited the proliferation of breast cancer and P21 was the main target of RBMS2. RBMS2 stabilized the mRNA of P21 by directly binding to the AU-rich element of 3'-UTR region. Anti-proliferation activity induced by overexpression of RBMS2 was rescued by interfering with the expression of P21.
CONCLUSION
In conclusion, RBMS2 acted as a tumor suppressor in breast cancer and positively regulated the expression of P21 by stabilizing its mRNA.
背景
RNA 结合蛋白（RBPs）在调节靶 RNA 代谢中发挥重要作用。RBPs 的异常表达在许多癌症的发生和发展中起着至关重要的作用。RBM 家族具有保守的 RNA 结合基序 RNP1 和 RNP2，在 RNA 加工中具有相似的功能，RBMS2 是它们的成员之一。P21，也称为 CDKN1A，可促进细胞周期停滞，在阻止细胞增殖中发挥重要作用。在我们的研究中，我们将 RBMS2 鉴定为乳腺癌中的肿瘤抑制因子。它通过正调控 P21 mRNA 的转录后稳定性来抑制乳腺癌的增殖。
方法
使用 TCGA 鉴定乳腺癌中差异表达的 RBPs。通过 CCK-8 测定、集落形成测定和细胞周期测定评估 RBMS2 对乳腺癌增殖的影响，通过小鼠肿瘤发生模型研究其体内作用。通过 RNA 测序检测 RBMS2 调控的主要通路和基因。通过 RNA 免疫沉淀结合双荧光素酶报告基因测定检测 RBMS2 与 P21 之间的直接结合。通过挽救实验检测 P21 作为 RBMS2 的主要靶标。
结果
与正常组织相比，RBMS2 在乳腺癌中的表达较低，是乳腺癌的有利生物标志物。RBMS2 抑制乳腺癌的增殖，P21 是 RBMS2 的主要靶标。RBMS2 通过直接结合 3'-UTR 区的富含 AU 元件稳定 P21 的 mRNA。过表达 RBMS2 诱导的抗增殖活性可通过干扰 P21 的表达来挽救。
结论
总之，RBMS2 在乳腺癌中作为肿瘤抑制因子发挥作用，通过稳定其 mRNA 来正向调节 P21 的表达。
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