科学家揭示非小细胞肺癌对疗法的耐药性如何被克服

  一种潜在的癌症疗法制剂截至目前为止对于常见肺部肿瘤或许效果甚微；近日，发表于国际杂志PNAS上的一篇研究报道中，来自曼彻斯特大学的研究人员通过研究或许就可以克服肺癌对这种新型疗法的耐受性。
  文章中研究者检测了常见类型的肺癌对特殊因子的作用，而这种常见类型的肺癌对名为TRAIL细胞因子耐受，TRAIL会促进多种类型的肿瘤细胞死亡。非小细胞肺癌在所有肺癌中占85%的比例，而在这种类型的癌症中，名为miR-148a的小RNA分子在TRAIL耐受的癌症细胞中处于被抑制的状态，而miR-148a可以促进肿瘤细胞对细胞因子TRAIL敏感，从而使得肿瘤萎缩。
  研究者Michela Garofalo说道，阐明肺癌对细胞因子TRAIL耐受的机制对于开发新型疗法来治疗非小细胞肺癌提供了一定的研究基础和希望。miR-148a分子似乎在癌细胞耐药性上扮演着重要角色。文章中研究者还发现了另外一种特殊机制可以使肿瘤对TRAIL耐受，NF-κB是一种特殊蛋白，在耐药性的肺部肿瘤中TRAIL自身就可以增加NF-κB的供给，通过抑制细胞中NF-κB的水就可以使得TRAIL更加有效地促进癌细胞死亡。
  当前在临床试验中TRAIL用于其它类型癌症的治疗，但很少有人知道为何非小细胞肺癌对TRAIL如此耐受，本文研究就阐明了肺癌细胞对TRAIL产生耐药性的分子机制，对于后期开发新型疗法来抑制促进癌细胞耐药的因子提供了新的思路，当然TRAIL或许也会被开发成为一种有用的疗法。（转化医学网360zhyx.com）
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A set of NF-κB–regulated microRNAs induces acquired TRAIL resistance in Lung cancer
PNAS    doi: 10.1073/pnas.1504630112
Young-Jun Jeona, Justin Middletona, Taewan Kima,b, Alessandro Laganàa, Claudia Piovana,c, Paola Secchierod, Gerard J. Nuovoa, Ri Cuia, Pooja Joshia, Giulia Romanoa, Gianpiero Di Levaa, Bum-Kyu Leee, Hui-Lung Suna, Yonghwan Kimf, Paolo Faddaa, Hansjuerg Aldera, Michela Garofalog,1, and Carlo M. Crocea,1
TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-κB, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-κB, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-κB inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.