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KEAP1突变激活NRF2通路以驱动细胞生长和迁移,并减弱甲状腺癌中药物反应
Nicholas E Bambach1, Julio C Ricarte-Filho1, Erin R Reichenberger2
1Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
最近发现KEAP1突变是甲状腺癌的重要驱动因素,激活NRF2通路,影响细胞行为和药物反应.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 遗传学是一种遗传学.
背景情况:
- KEAP1/NRF2通路调节氧化应激,并且在癌症中经常失调.
- KEAP1突变在各种癌症中很常见,但在甲状腺癌中没有研究过.
研究的目的:
- 调查儿童甲状腺瘤中KEAP1突变的患病率和功能意义.
- 探索KEAP1损失对NRF2通路和甲状腺癌中细胞功能的影响.
主要方法:
- 儿科甲状腺瘤的测序和公共数据集的分析.
- 确定KEAP1突变和19p13.2异性丧失 (LOH).
- 在体外细胞系模型评估KEAP1淘汰的功能后果.
主要成果:
- 在甲状腺瘤中通过19p13.2 LOH识别了81个KEAP1突变和频繁的双基KEAP1损失.
- KEAP1突变导致NRF2通路激活,增加增殖,迁移和药物敏感性的改变.
- 在KEAP1突变病例中,MAPK变化是相互排斥的,其中19p13.2 LOH是KEAP1突变病例.
结论:
- KEAP1突变是甲状腺癌的流行和致癌驱动因素.
- KEAP1/NRF2通路失调会影响瘤的行为,并可能影响治疗反应.
- 在甲状腺癌研究和临床实践中,应该考虑KEAP1突变概况.
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