Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1
Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1
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Cullin5 缺陷通过稳定整合素β1 促进小细胞肺癌转移
DOI：
10.1172/jci122779
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发表时间：
2019-03-01
影响因子：
15.9
通讯作者：
Ji, Hongbin
中科院分区：
文献类型：
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作者：
Zhao, Gaoxiang;Gong, Liyan;Ji, Hongbin
转移是小细胞肺癌 (SCLC) 患者死亡的主要原因，更好地了解 SCLC 转移的分子机制可能会改善临床治疗。通过使用 CRISPR/Cas9 库对小鼠 Rb1(-/-) Trp53(-/-) SCLC 转移的关键调节因子进行基因组规模筛选，我们确定了 Cullin5 (CUL5) 和细胞因子信号传导抑制因子 3 (SOCS3)（Cullin-RING E3 泛素连接酶复合物的两个成分）为最佳候选因子。从机制上讲，CUL5或SOCS3的缺乏破坏了E3连接酶复合物的功能形成，并阻止了整合素β1的降解，从而稳定了整合素β1并激活了下游粘着斑激酶/SRC（FAK/SRC）信号传导，最终驱动了SCLC转移。在 128 名 SCLC 临床患者的大型队列中，CUL5 和 SOCS3 的低表达水平与高整合素 β1 水平和不良预后显着相关。此外，CUL5 缺陷的 SCLC 很容易受到 FDA 批准的 SRC 抑制剂达沙替尼的治疗。总的来说，这项工作确定了 CUL5 和 SOCS3 介导的整合素 β 1 周转在控制 SCLC 转移中的重要作用，这可能具有治疗意义。
Metastasis is the dominant cause of patient death in small-cell lung cancer (SCLC), and a better understanding of the molecular mechanisms underlying SCLC metastasis may potentially improve clinical treatment. Through genome-scale screening for key regulators of mouse Rb1(-/-) Trp53(-/-) SCLC metastasis using the pooled CRISPR/Cas9 library, we identified Cullin5 (CUL5) and suppressor of cytokine signaling 3 (SOCS3), two components of the Cullin-RING E3 ubiquitin ligase complex, as top candidates. Mechanistically, the deficiency of CUL5 or SOCS3 disrupted the functional formation of the E3 ligase complex and prevented the degradation of integrin beta 1, which stabilized integrin beta 1 and activated downstream focal adhesion kinase/SRC (FAK/SRC) signaling and eventually drove SCLC metastasis. Low expression levels of CUL5 and SOCS3 were significantly associated with high integrin beta 1 levels and poor prognosis in a large cohort of 128 clinical patients with SCLC. Moreover, the CUL5-deficient SCLCs were vulnerable to the treatment of the FDA-approved SRC inhibitor dasatinib. Collectively, this work identifies the essential role of CUL5- and SOCS3-mediated integrin beta 1 turnover in controlling SCLC metastasis, which might have therapeutic implications.