Nicotine-Induced ILF2 Facilitates Nuclear mRNA Export of Pluripotency Factors to Promote Stemness and Chemoresistance in Human Esophageal Cancer
Nicotine-Induced ILF2 Facilitates Nuclear mRNA Export of Pluripotency Factors to Promote Stemness and Chemoresistance in Human Esophageal Cancer
复制标题
尼古丁诱导的 ILF2 促进多能因子的核 mRNA 输出，促进人类食管癌的干细胞性和化疗耐药性
DOI：
10.1158/0008-5472.can-20-4160
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发表时间：
2021-07-01
期刊：
影响因子：
11.2
通讯作者：
Song, Libing
中科院分区：
文献类型：
--
作者：
Li, Yue;Wang, Meng;Song, Libing
这项研究定义了尼古丁调节的ILF 2在促进核mRNA输出以促进癌症干性方面的先前未表征的作用，这表明了针对尼古丁诱导的食管癌化疗耐药性的潜在治疗策略。平衡mRNA核输出动力学与其核衰变对于mRNA稳态控制至关重要。这种平衡是如何在食管癌中被异常破坏以获得癌症干细胞特性的仍然不清楚。在这里，我们发现RNA结合蛋白白细胞介素增强子结合因子2（ILF 2）通过激活JAK 2/STAT 3信号被烟草烟雾的主要化学成分尼古丁强烈上调，并与重度吸烟食管癌患者的预后不良显著相关。ILF 2结合THO复合蛋白THOC 4作为调节辅因子，以诱导与多能性转录因子mRNA的选择性相互作用，从而促进其组装成具有输出能力的信使核糖核蛋白复合物。ILF 2促进核mRNA输出并抑制hMTR 4介导的外泌体降解，以促进SOX 2、NANOG和SALL 4的稳定和表达，从而增强食管癌细胞的干性和肿瘤起始能力。重要的是，诱导型ILF 2的耗竭显著增加了顺铂的治疗效率，并在体外和体内消除了尼古丁诱导的化疗耐药性。这些发现揭示了ILF 2在肿瘤干细胞核mRNA输出和维持中的新作用，并为克服吸烟介导的食管癌化疗耐药性开辟了新途径。重要性：这项研究定义了尼古丁调节的ILF 2在促进核mRNA输出以促进癌症干性方面的先前未表征的作用，这表明了针对尼古丁诱导的食管癌化疗耐药性的潜在治疗策略。
This study defines a previously uncharacterized role of nicotine-regulated ILF2 in facilitating nuclear mRNA export to promote cancer stemness, suggesting a potential therapeutic strategy against nicotine-induced chemoresistance in esophageal cancer. Balancing mRNA nuclear export kinetics with its nuclear decay is critical for mRNA homeostasis control. How this equilibrium is aberrantly disrupted in esophageal cancer to acquire cancer stem cell properties remains unclear. Here we find that the RNA-binding protein interleukin enhancer binding factor 2 (ILF2) is robustly upregulated by nicotine, a major chemical component of tobacco smoke, via activation of JAK2/STAT3 signaling and significantly correlates with poor prognosis in heavy-smoking patients with esophageal cancer. ILF2 bound the THO complex protein THOC4 as a regulatory cofactor to induce selective interactions with pluripotency transcription factor mRNAs to promote their assembly into export-competent messenger ribonucleoprotein complexes. ILF2 facilitated nuclear mRNA export and inhibited hMTR4-mediated exosomal degradation to promote stabilization and expression of SOX2, NANOG, and SALL4, resulting in enhanced stemness and tumor-initiating capacity of esophageal cancer cells. Importantly, inducible depletion of ILF2 significantly increased the therapeutic efficiency of cisplatin and abrogated nicotine-induced chemoresistance in vitro and in vivo. These findings reveal a novel role of ILF2 in nuclear mRNA export and maintenance of cancer stem cells and open new avenues to overcome smoking-mediated chemoresistance in esophageal cancer. Significance: This study defines a previously uncharacterized role of nicotine-regulated ILF2 in facilitating nuclear mRNA export to promote cancer stemness, suggesting a potential therapeutic strategy against nicotine-induced chemoresistance in esophageal cancer.