CDK5RAP3 作为肿瘤抑制因子，负调控自我更新和侵袭，其在人胃癌中的表达受 ERK1/2 信号通路调控。
CDK5RAP3 as tumour suppressor negatively regulates self-renewal and invasion and is regulated by ERK1/2 signalling in human gastric cancer.
机构信息
Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China.
Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
出版信息
Br J Cancer. 2020 Sep;123(7):1131-1144. doi: 10.1038/s41416-020-0963-y. Epub 2020 Jul 1.
BACKGROUND
Toward identifying new strategies to target gastric cancer stem-like cells (CSCs), we evaluated the function of the tumour suppressor CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) in gastric CSC maintenance.
METHODS
We examined the expression of CDK5RAP3 and CD44 in gastric cancer patients. The function and mechanisms of CDK5RAP3 were checked in human and mouse gastric cancer cell lines and in mouse xenograft.
RESULTS
We show that CDK5RAP3 is weakly expressed in gastric CSCs and is negatively correlated with the gastric CSC marker CD44. CDK5RAP3 overexpression decreased expression of CSC markers, spheroid formation, invasion and migration, and reversed chemoresistance in gastric CSCs in vitro and vivo. CDK5RAP3 expression was found to be regulated by extracellular-related kinase (ERK) signalling. ERK inhibitors decreased spheroid formation, migration and invasion, and the expression of epithelial-to-mesenchymal transition (EMT)-related proteins in both GA cells and organoids derived from a genetically engineered mouse model of GA. Finally, CDK5RAP3 expression was associated with reduced lymph-node metastasis and better prognosis, even in the presence of high expression of the EMT transcription factor Snail, among patients with CD44-positive GA.
CONCLUSIONS
Our results demonstrate that CDK5RAP3 is suppressed by ERK signalling and negatively regulates the self-renewal and EMT of gastric CSCs.
背景
为了确定针对胃癌干细胞（CSC）的新策略，我们评估了肿瘤抑制因子 CDK5 调节亚单位相关蛋白 3（CDK5RAP3）在胃 CSC 维持中的作用。
方法
我们检测了 CDK5RAP3 和 CD44 在胃癌患者中的表达。在人源和鼠源胃癌细胞系以及鼠异种移植模型中，我们检测了 CDK5RAP3 的功能和机制。
结果
我们发现 CDK5RAP3 在胃 CSCs 中弱表达，与胃 CSC 标志物 CD44 呈负相关。CDK5RAP3 过表达降低了胃 CSCs 中 CSC 标志物的表达、球体形成、侵袭和迁移，并在体内和体外逆转了胃 CSCs 的化疗耐药性。ERK 信号通路调节 CDK5RAP3 的表达。ERK 抑制剂降低了 GA 细胞球体形成、迁移和侵袭以及上皮间质转化（EMT）相关蛋白的表达，在 GA 的基因工程小鼠模型衍生的类器官中也观察到了同样的结果。最后，即使在 EMT 转录因子 Snail 高表达的情况下，CDK5RAP3 的表达与淋巴结转移减少和预后改善相关，存在于 CD44 阳性的 GA 患者中。
结论
我们的研究结果表明，ERK 信号抑制 CDK5RAP3 的表达，负调控胃 CSCs 的自我更新和 EMT。
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