Cristóbal Ion, Torrejón Blanca, Rubio Jaime, Santos Andrea, Pedregal Manuel, Caramés Cristina, Zazo Sandra, Luque Melani, Sanz-Alvarez Marta, Madoz-Gúrpide Juan, Rojo Federico, García-Foncillas Jesús
Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, IIS-Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain.
Translational Oncology Division, Oncohealth Institute, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain.
J Clin Med. 2019 Mar 12;8(3):346. doi: 10.3390/jcm8030346.
SET nuclear proto-oncogene (SET) deregulation is a novel molecular target in metastatic colorectal cancer (CRC). However, its role in CRC progression and its potential clinical impact in early-stage CRC patients remain unknown. Here, we studied the biological effects of SET on migration using wound-healing and transwell assays, and anchorage-independent cell growth using soft agar colony formation assays after ectopic SET modulation. SET was analyzed by immuno-staining in 231 early-stage CRC patients, and miR-199b expression was quantified by real-time PCR in a set of CRC patients. Interestingly, SET enhances cell migration, markedly affects the colony-forming ability, promotes epithelial to mesenchymal transition, and induces the expression of the MYC proto-oncogene (c-MYC) in CRC cells. SET overexpression was detected in 15.4% of cases and was associated with worse Eastern Cooperative Oncology Group (ECOG) status ( = 0.021) and relapse in stage-II CRC patients ( = 0.008). Moreover, SET overexpression predicted shorter overall survival ( < 0.001) and time to metastasis ( < 0.001), and its prognostic value was particularly evident in elderly patients. MiR-199b downregulation was identified as a molecular mechanism to deregulate SET in patients with localized disease. In conclusion, SET overexpression is a common alteration in early-stage CRC, playing an oncogenic role associated with progression and aggressiveness, and portends a poor outcome. Thus, SET emerges as a novel potential molecular target with clinical impact in early-stage in CRC.
SET核原癌基因（SET）失调是转移性结直肠癌（CRC）中的一个新分子靶点。然而，其在CRC进展中的作用以及对早期CRC患者的潜在临床影响仍不清楚。在此，我们通过伤口愈合和Transwell实验研究了SET对迁移的生物学效应，并在异位调节SET后，使用软琼脂集落形成实验研究了其对非锚定依赖性细胞生长的影响。通过免疫染色分析了231例早期CRC患者的SET，并通过实时PCR对一组CRC患者的miR-199b表达进行了定量。有趣的是，SET增强细胞迁移，显著影响集落形成能力，促进上皮-间质转化，并诱导CRC细胞中MYC原癌基因（c-MYC）的表达。在15.4%的病例中检测到SET过表达，且与较差的东部肿瘤协作组（ECOG）状态（P = 0.021）和II期CRC患者的复发相关（P = 0.008）。此外，SET过表达预示着较短的总生存期（P < 0.001）和转移时间（P < 0.001），其预后价值在老年患者中尤为明显。miR-199b下调被确定为局部疾病患者中SET失调的分子机制。总之，SET过表达是早期CRC中的常见改变，发挥着与进展和侵袭性相关的致癌作用，并预示着不良预后。因此，SET成为早期CRC中具有临床影响的新潜在分子靶点。
