Jiménez-Martínez Marta, Ostalé Cristina M, van der Burg Lennart R, Galán-Martínez Javier, Hardwick James C H, López-Pérez Ricardo, Hawinkels Lukas J A C, Stamatakis Konstantinos, Fresno Manuel
Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 28049 Madrid, Spain.
Department of Molecular Biology, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain.
Cancers (Basel). 2019 Nov 9;11(11):1767. doi: 10.3390/cancers11111767.
Cell contact inhibition (CCI) is deregulated in cancer. Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. We found that dual-specificity phosphatase 10 (DUSP10) is involved in CRC. DUSP10 overexpression increased the growth of CRC cell lines and mouse xenografts, while the opposite phenotype was observed by DUSP10 silencing. High cell density (HD) induced DUSP10 expression in CRC cell lines, particularly within the nucleus. Yes-associated protein 1 (YAP1) is activated by dephosphorylation, controlling organ growth and CCI, both processes being deregulated in CRC. Expression levels and localization of DUSP10 matched with YAP1 levels in CRC cell lines. DUSP10 and YAP1 co-immunoprecipitated and their interaction was dependent on YAP1 Ser397. The existence of DUSP10 and YAP1 pathway in vivo was confirmed by using a transgenic model. Finally, in CRC patients' samples, high levels of nuclear DUSP10 correlated with nuclear YAP1 in epithelial tumor tissue. Strong nuclear DUSP10 staining also correlated with high tumor stage and poor survival. Overall, these findings describe a DUSP10-YAP1 molecular link in CRC cell lines promoting cell growth in HD. We present evidence suggesting a pro-tumorigenic role of nuclear DUSP10 expression in CRC patients.
细胞接触抑制（CCI）在癌症中失调。结直肠癌（CRC）是全球第三大常见诊断癌症。我们发现双特异性磷酸酶10（DUSP10）与CRC有关。DUSP10过表达增加了CRC细胞系和小鼠异种移植瘤的生长，而DUSP10沉默则观察到相反的表型。高细胞密度（HD）诱导CRC细胞系中DUSP10表达，特别是在细胞核内。Yes相关蛋白1（YAP1）通过去磷酸化被激活，控制器官生长和CCI，这两个过程在CRC中均失调。DUSP10的表达水平和定位与CRC细胞系中的YAP1水平相匹配。DUSP10和YAP1共免疫沉淀，它们的相互作用依赖于YAP1 Ser397。通过使用转基因模型证实了体内DUSP10和YAP1途径的存在。最后，在CRC患者样本中，上皮肿瘤组织中高水平的核DUSP10与核YAP1相关。强烈的核DUSP10染色也与高肿瘤分期和低生存率相关。总体而言，这些发现描述了CRC细胞系中DUSP10 - YAP1分子联系在HD中促进细胞生长。我们提供的证据表明核DUSP10表达在CRC患者中具有促肿瘤作用。
