SET deregulation is an alteration that determines poor outcome in metastatic colorectal cancer (CRC) patients promoting cell growth and decreasing sensitivity to standard chemotherapeutic agents such as oxaliplatin and 5-fluorouracil. Moreover, this alteration represents a key event to inhibit the tumor suppressor PP2A in metastatic CRC. However, the role of SET in CRC progression and its potential clinical impact in early-stage CRC patients still remain to be investigated.
In this work, we studied the biological effects of SET on migration using wound-healing and transwell migration assays, and cell invasion ability was determined by colony-forming assays after SET silencing or overexpression. Moreover, we analyzed SET expression by immunostaining in a cohort of 231 CRC patients without metastatic disease at diagnosis. We also quantified the expression of the negative SET regulator miR-199b in a set of CRC patient samples.
We observed that SET deregulation promotes cell migration and markedly affects invasion ability of CRC cells. At the clinical level, SET overexpression was detected in 14.7% of cases. We found this alteration associated with worse ECOG performance status, and with relapse in the subgroup of stage II CRC patients. Moreover, SET overexpression determined significantly shorter overall survival and time to metastasis. Interestingly, its prognostic value was particularly evident in patients older than 70 years. We also identified miR-199b downregulation as a molecular mechanism to deregulate SET in CRC patients with localized disease.
Of importance, our results indicate that SET could serve to anticipate undesirable relapses in stage II CRC patients and define a subgroup of early stage CRC patients that could benefit by the use of SET antagonists or PP2A-activating drugs such as FTY720 in anticancer protocols.
Clinical trial identification
Legal entity responsible for the study
Fundación Jiménez Díaz.
This work was supported by PI15/00934 and PI16/01468 grants from “Instituto de Salud Carlos III FEDER”. BT is supported by Fundación Conchita Rábago de Jiménez Díaz.
All authors have declared no conflicts of interest.