RBM4通过稳定HOXB13 mRNA促进鼻咽癌生长和转移

文献信息

中文摘要

鼻咽癌（NPC）仍然是一个重大的临床挑战，尤其是在晚期阶段。RNA结合蛋白（RBPs）是肿瘤发生的重要转录后调控因子，但其在NPC中的作用仍知之甚少。本研究探讨了RNA结合基序蛋白4（RBM4）是否通过稳定同源盒B13（HOXB13）mRNA，从而激活致癌信号以促进NPC进展。生物信息学分析鉴定了NPC中的差异表达基因。使用ENCORI预测靶向候选基因的潜在RNA结合蛋白（RBPs），并通过RNA免疫沉淀验证了预测的相互作用。通过集落形成和Transwell实验，以及调节RBM4、HOXB13、核因子κB（NF-κB）p65和β-catenin的表达，检测了HOXB13和RBM4在NPC细胞中的功能效应。在体内，使用小鼠异种移植和肺转移模型评估了RBM4/HOXB13轴对NPC肿瘤生长和转移的影响。HOXB13是NPC中上调最强的基因之一，RBM4被预测为靶向HOXB13 mRNA的候选RBP。RBM4在NPC模型中 also 上调，并增加了HOXB13 mRNA的稳定性。沉默RBM4抑制了NPC细胞增殖、迁移、侵袭和上皮-间质转化（EMT），同时增加凋亡并降低HOXB13表达以及NF-κB和Wnt/β-catenin信号传导。过表达HOXB13、NF-κB p65或β-catenin部分逆转了这些效应。在体内，沉默RBM4抑制了异种移植生长和实验性肺转移，而这些效应被HOXB13过表达部分逆转。RBM4通过稳定HOXB13 mRNA并激活NF-κB和Wnt/β-catenin通路，在NPC中充当促肿瘤RBP。因此，RBM4/HOXB13轴作为NPC的潜在分子靶点值得进一步研究。

英文摘要

Nasopharyngeal carcinoma (NPC) remains a major clinical challenge, particularly at advanced stages. RNA-binding proteins (RBPs) are important post-transcriptional regulators of tumorigenesis, but their roles in NPC remain poorly understood. This study investigated whether RNA-binding motif protein 4 (RBM4) stabilizes homeobox B13 (HOXB13) mRNA and thereby activates oncogenic signaling to promote NPC progression. Bioinformatics analysis identified differentially expressed genes in NPC. ENCORI was used to predict potential RNA-binding proteins (RBPs) targeting the candidate gene, and the predicted interaction was validated by RNA immunoprecipitation. Functional effects of HOXB13 and RBM4 in NPC cells were examined using colony formation and Transwell assays, along with modulating RBM4, HOXB13, nuclear factor kappa B (NF-κB) p65, and β-catenin expression. In vivo, effects of the RBM4/HOXB13 axis on NPC tumor growth and metastasis were evaluated using murine xenograft and lung metastasis models. HOXB13 was among the most strongly upregulated genes in NPC, and RBM4 was predicted to be a candidate RBP targeting HOXB13 mRNA. RBM4 was also upregulated in NPC models and increased HOXB13 mRNA stability. RBM4 silencing suppressed NPC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while increasing apoptosis and reducing HOXB13 expression and NF-κB and Wnt/β-catenin signaling. Overexpression of HOXB13, NF-κB p65, or β-catenin partially reversed these effects. In vivo, RBM4 silencing inhibited xenograft growth and experimental lung metastasis, and these effects were partially reversed by HOXB13 overexpression. RBM4 acts as a pro-tumorigenic RBP in NPC by stabilizing HOXB13 mRNA and activating the NF-κB and Wnt/β-catenin pathways. The RBM4/HOXB13 axis therefore warrants further investigation as a potential molecular target in NPC.