PO.MCB07.03 · 分子与细胞生物学
利用特异性小分子抑制剂对三阴性乳腺癌中的HuR进行治疗性靶向
Therapeutic targeting of HuR using a specific small-molecule inhibitor in triple negative breast cancer
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
人类抗原R（HuR/ELAVL1）是一种RNA结合蛋白，与靶mRNA中富含U/AU的元件相互作用，其异常的胞质积累已在多种癌症中被观察到。HuR调控关键致癌及生存相关转录本的表达，从而驱动肿瘤进展、转移和治疗抵抗。鉴于这一核心作用，HuR是一个极具吸引力的癌症治疗分子靶点。本研究专门评估了CMLD2（一种高度选择性的HuR小分子抑制剂）在三阴性乳腺癌（TNBC）中的潜力。我们在计算机模拟（in silico）和体外模型中，使用CMLD2和DHTS进行了对比评估。对71例TNBC样本的免疫组化分析显示，66%的病例存在HuR过表达，同时HuR下游靶点MMP9的表达也升高（56%）。此外，计算机模拟分析确立了HuR过表达与患者生存不良之间的显著关联（p = 0.028）。在TNBC细胞系MDA-MB-231和MDA-MB-468中的功能实验表明，两种抑制剂均抑制增殖、侵袭和克隆形成能力；然而，CMLD2在抑制HuR功能方面表现出明显更高的特异性和一致性。机制上，CMLD2处理下调了HuR及其下游效应因子MMP9和beta-catenin，同时逆转了上皮-间质转化（EMT）标志物的表达（E-cadherin、N-cadherin和Vimentin）。免疫荧光和细胞分级分离证实了对胞质HuR的有效抑制。此外，CMLD2明显抑制了有氧糖酵解，表现为细胞外酸化降低及关键糖酵解介导因子——PFKP、LDHA和MCT4——的下调，这在转录本和蛋白水平均得到验证。通过siRNA沉默HuR的实验支持了HuR在糖酵解调控和TNBC进展中的作用。在体内，CMLD2显著削弱了雌性BALB/c小鼠的肿瘤形成能力。总之，这些发现强调了CMLD2作为一种特异性、强效HuR抑制剂的治疗前景，为其作为三阴性乳腺癌靶向干预手段的进一步开发提供了强有力的实验依据。
查看英文原文 English abstract
Human Antigen R (HuR/ELAVL1) is an RNA-binding protein that interacts with U/AU-rich elements in target mRNAs, and its aberrant cytoplasmic accumulation have been observed in multiple cancers. HuR modulates the expression of key oncogenic and survival-related transcripts, thereby driving tumor progression, metastasis, and therapeutic resistance. Given this central role, HuR represents a compelling molecular target for cancer therapy. The present study specifically evaluates the potential of CMLD2, a highly selective small-molecule inhibitor of HuR, in the context of Triple-Negative Breast Cancer (TNBC). Comparative assessments were conducted using CMLD2 and DHTS across in silico and in vitro models. Immunohistochemical analysis of 71 TNBC samples revealed HuR overexpression in 66% of cases, along with elevated expression of HuR downstream target MMP9 (56%). Furthermore, in silico analysis established significant association between HuR overexpression and poor patient survival (p = 0.028). Functional assays in TNBC cell lines MDA-MB-231 and MDA-MB-468 demonstrated that both inhibitors suppressed proliferation, invasion, and clonogenicity; however, CMLD2 exhibited markedly higher specificity and consistency in inhibiting HuR function. Mechanistically, CMLD2 treatment downregulated HuR and its downstream effectors MMP9 and beta-catenin, while reversing epithelial-mesenchymal transition (EMT) marker expression (E-cadherin, N-cadherin and Vimentin). Immunofluorescence and cell fractionation confirmed effective cytoplasmic HuR inhibition. Moreover, CMLD2 distinctly suppressed aerobic glycolysis, evidenced by reduced extracellular acidification and downregulation of key glycolytic mediators-PFKP, LDHA, and MCT4-validated at both transcript and protein levels. HuR silencing by siRNA supported the role of HuR in glycolytic regulation and TNBC progression. In vivo , CMLD2 significantly impaired tumor-forming ability in female BALB/c mice. Together, these findings underscore the therapeutic promise of CMLD2 as a specific and potent HuR inhibitor, providing strong experimental rationale for its further development as a targeted intervention in Triple-Negative Breast Cancer.
利益披露 Disclosure
A. Dev J R, None..
A. Gogia, None..
S. R. Mathur, None..
A. Mishra, None..
C. P. Prasad, None.