PO.BCS01.05 · 生物信息与计算
BRCA1、RNA结合蛋白与miR-18a：乳腺癌中的分子三重奏（胜利）
BRCA1, RNA-binding proteins, and miR-18a, a molecular tri(umph) in breast carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
乳腺癌常涉及miRNA的广泛失调，而其加工过程的变化可影响肿瘤行为。RNA结合蛋白（RBP）是关键的转录后调控因子，主要通过RNA代谢控制基因表达。RBP的失调与乳腺癌的治疗耐药有关，靶向关键RBP可能是逆转这种耐药的有前景的治疗方法。此前我们鉴定了一组RBP作为BRCA1和RBP核仁蛋白（NCL）的共同互作因子，即异质性核糖核蛋白A1（HNRNPA1）、异质性核糖核蛋白D（HNRNPD）、多聚腺苷酸结合蛋白胞质1（PABPC1）和TAR DNA结合蛋白43（TDP-43）。我们基于预测的对接情景，发表了这些RBP（包括NCL）关于其与miR-21竞争性对协同性结合的计算模型。NCL及其所调控的六种miR的生物合成在乳腺癌中频繁过表达，并直接参与肿瘤生长和进展。类似地，包含miR-18a的miR-17-92簇在包括乳腺肿瘤在内的恶性肿瘤中常常上调。在雌激素受体阳性乳腺癌中，已表明miR-18a直接靶向ER-alpha的3'UTR，增加对激素治疗的耐药性。尽管已知HNRNPA1结合pri-miR-18a的末端环并增强其被微加工复合体的加工，但NCL如何与miR-18a相互作用则完全未知。有趣的是，通过沉默或使用NCL特异性适配体靶向NCL会直接影响其对各种miR的控制，从而抑制肿瘤生长。在本研究中，我们聚焦于两种RBP，即NCL和HNRNPA1，及其在乳腺癌背景下与miR-18a的相互作用。我们对完整的初级miR-18a进行了建模，并展示了其与NCL和HNRNPA1的RNA结合结构域（RBD）的预测相互作用。我们比较和对比了这些分子相互作用，并突出了RBP与miR-18a相互作用界面所涉及的关键残基，最终目标是提出用于治疗的潜在可靶向位点。
查看英文原文 English abstract
Breast cancer frequently involves widespread dysregulation of miRNAs, and changes in their processing can influence tumor behavior. RNA binding proteins (RBPs) are key post-transcriptional regulators that predominantly control gene expression through RNA metabolism. Dysregulation of RBPs is implicated in therapy resistance of breast cancer and targeting key RBPs can be a promising therapeutic approach to reverse this resistance. Earlier we identified a group of RBPs as common interactors of BRCA1 and RBP-nucleolin (NCL), namely heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), heterogeneous nuclear ribonucleoprotein D (HNRNPD), polyadenylate binding protein cytoplasmic 1(PABPC1), and TAR DNA-binding protein 43 (TDP-43). We published computational models of these RBPs, including NCL for their competitive versus synergistic binding with miR-21, based on predicted docking scenarios. NCL and the biogenesis of the six-miRs that it regulates are frequently overexpressed in breast cancer and are directly implicated in tumor growth and progression. Similarly, the miR-17-92 cluster which includes miR-18a is often upregulated in malignancies, including breast tumors. In estrogen receptor-positive breast cancer, it has been shown that miR-18a directly targets the 3'UTR of ER-alpha, increasing resistance to hormonal therapy. Although it is known that HNRNPA1 binds the terminal loop of pri-miR-18a and enhances its processing by the microprocessor complex, how NCL interacts with miR-18a is completely unknown. Interestingly, targeting NCL either by silencing or using NCL-specific aptamers directly impacts its control of various miRs, and hence inhibition of tumor growth. In this study, we have focused on the two RBPs, NCL and HNRNPA1 and their interaction with miR-18a in the context of breast cancer. We have modeled the full primary miR-18a and show its predicted interaction with the RNA-binding domains (RBDs) of NCL and HNRNPA1. We compare and contrast the molecular interactions and highlight the key residues involved in the interaction interface for the RBPs and miR-18a with an end goal to suggest potential targetable sites for therapeutics.
利益披露 Disclosure
R. Satti, None..
A. Saxena, None..
S. M. Singh, None.