FBX8 promotes metastatic dormancy of colorectal cancer in liver
FBX8 promotes metastatic dormancy of colorectal cancer in liver
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DOI：
10.1038/s41419-020-02870-7
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发表时间：
2020-08
影响因子：
9
通讯作者：
Xiaohui Zhu;Feifei Wang;Xuehui Wu;Zhou Li;Zhizhi Wang;X. Ren;Yangshu Zhou;F. Song;Yunshi Liang-Y
中科院分区：
文献类型：
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作者：
Xiaohui Zhu;Feifei Wang;Xuehui Wu;Zhou Li;Zhizhi Wang;X. Ren;Yangshu Zhou;F. Song;Yunshi Liang-Y
结直肠癌（CRC）患者经常在原发性治疗后数年内发生肝脏转移性休眠肿瘤细胞的恶性再生。FBX8参与抑制肿瘤转移。通过短期化疗实验和原位注射入盲肠的肝转移小鼠模型来构建休眠模型。GST-pull-down法、Co-IP法和免疫荧光法证实FBX8与底物的结合。FBX8上调上皮和干性标志物的表达，下调与肿瘤细胞休眠相关的间充质和增生性标志物的表达。FBX8促进CRC细胞转移性休眠的维持。机制上，FBX8通过其Sec7结构域直接与HIF-1α、CDK4和C-myc结合，导致这些蛋白的泛素降解，从而抑制细胞周期进程、增殖、血管生成和转移。临床上，FBX8表达与结直肠癌组织中HIF-1α、CDK4、c-Myc呈负相关。我们的研究揭示了FBX8调控肝脏肿瘤转移休眠的新机制，为结直肠癌转移的治疗提供了新的策略。
Patients with colorectal cancer (CRC) often develop malignant regrowth of metastatic dormant tumor cells in liver years after primary treatment. FBX8 is involved in suppressing tumor metastasis. Short-term chemotherapy experiments and liver metastasis mice model of orthotopic injection into the cecum were performed to construct the dormant models. GST-pull-down assay, Co-IP and immunofluorescence were used to confirm the bindings among FBX8 and its substrates. FBX8 upregulated the expression of epithelial and stemness markers, while downregulated the expression of mesenchymal and proliferative markers associated with tumor cell dormancy. FBX8 promoted the maintenance of metastatic dormancy of CRC cells. Mechanistically, FBX8 directly bound to HIF-1α, CDK4 and C-myc through its Sec7 domain and led to the ubiquitin degradation of these proteins, thereby inhibiting cell cycle progression, proliferation, angiogenesis, and metastasis. Clinically, FBX8 expression was negatively correlated with the HIF-1α, CDK4, and c-Myc in CRC tissues. Our study reveals a novel mechanism of FBX8 in regulating tumor metastatic dormancy in liver and provides new strategies for the treatment of CRC metastasis.