Lung cancer remains a leading cause of cancer death, with unclear mechanisms driving the transition to aggressive cancer with poor prognosis. The RAS→RAF→MEK→ERK pathway is hyper-activated in ~50% of human lung adenocarcinoma (LUAD). An initial activating mutation induces homeostatic feedback mechanisms that limit ERK activity. Additional, undefined genetic hits overcome the feedback, leading to high ERK activity that drives malignant progression. At detection, the majority of LUADs express the homeobox transcription factor NKX2-1, which also limits malignant progression. NKX2-1 constrains LUAD, in part, by maintaining a well-differentiated state with features of pulmonary identity. We asked if loss of NKX2-1 might also contribute to the release of ERK activity that drives tumor progression. Using human tissue samples and cell lines, xenografts, and genetic mouse models, we show that NKX2-1 induces the ERK phosphatase DUSP6. In tumor cells from late-stage LUAD with silenced NKX2-1, re-introduction of NKX2-1 induces DUSP6 and inhibits cell proliferation and migration and tumor growth and metastasis. CRISPR knockout studies show that DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo. Further, DUSP6 expression is sufficient to inhibit RAS-driven LUAD. We conclude that NKX2-1 silencing, and thereby DUSP6 downregulation, is a mechanism by which early LUAD can unleash ERK hyperactivation for tumor progression.

中文翻译：

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NKX2-1通过诱导DUSP6抑制ERK活性来控制肺癌的进展

肺癌仍然是导致癌症死亡的主要原因，目前尚不清楚的机制促使人们向预后不良的侵袭性癌症过渡。RAS→RAF→MEK→ERK途径在约50％的人肺腺癌（LUAD）中被过度激活。最初的激活突变诱导限制ERK活性的稳态反馈机制。额外的，不确定的遗传命中克服了反馈，导致了高ERK活性，推动了恶性进程。在检测时，大多数LUAD表达同源盒转录因子NKX2-1，这也限制了恶性进展。NKX2-1通过维持具有肺同一性特征的高分化状态来部分限制LUAD。我们询问NKX2-1的丢失是否也可能有助于释放ERK活性，从而驱动肿瘤进展。使用人体组织样本和细胞系，异种移植物，和遗传小鼠模型，我们显示NKX2-1诱导ERK磷酸酶DUSP6。在具有沉默的NKX2-1的晚期LUAD的肿瘤细胞中，重新引入NKX2-1会诱导DUSP6，并抑制细胞增殖和迁移以及肿瘤的生长和转移。CRISPR敲除研究表明，DUSP6对于NKX2-1介导的体内肿瘤进展抑制作用是必需的。此外，DUSP6表达足以抑制RAS驱动的LUAD。我们得出结论，NKX2-1沉默，进而DUSP6下调，是早期LUAD可以释放ERK过度激活以促进肿瘤进展的一种机制。CRISPR敲除研究表明，DUSP6对于NKX2-1介导的体内肿瘤进展抑制作用是必需的。此外，DUSP6表达足以抑制RAS驱动的LUAD。我们得出结论，NKX2-1沉默，进而DUSP6下调，是早期LUAD可以释放ERK过度激活以促进肿瘤进展的一种机制。CRISPR敲除研究表明，DUSP6对于NKX2-1介导的体内肿瘤进展抑制作用是必需的。此外，DUSP6表达足以抑制RAS驱动的LUAD。我们得出结论，NKX2-1沉默，进而DUSP6下调，是早期LUAD可以释放ERK过度激活以促进肿瘤进展的一种机制。