Deregulation of the PP2A inhibitor SET shows promising therapeutic implications and determines poor clinical outcome in patients with metastatic colorectal cancer.
OBJECTIVE
SET is an endogenous PP2A inhibitor that might represent a novel molecular target for antitumor therapy. The aim of this study was to evaluate the molecular effects of SET deregulation and its potential clinical significance in metastatic colorectal cancer (mCRC).


METHODS
We studied the biologic effects of SET on cell growth, colonosphere formation, caspase activity, PP2A activation status, and sensitivity to oxaliplatin and FTY720 treatments. Moreover, we analyzed SET expression by immunostaining in 242 patients with mCRC.


RESULTS
SET deregulation promotes cell growth and colonosphere formation and inhibits PP2A, thereby impairing its antitumor effects. Moreover, SET reduces sensitivity to oxaliplatin in colorectal cancer cell lines, which is restored after FTY720 treatment. SET overexpression was detected in 24.8% (60 of 242) of patients with mCRC and determined significantly shorter overall (8.6 vs. 27 months; P < 0.001) and progression-free survival (7.1 vs. 13.7 months; P < 0.001), and poor response to oxaliplatin-based chemotherapy (P = 0.004). Interestingly, its prognostic value was particularly evident in patients younger than 70 years and in those harboring KRAS mutations.


CONCLUSIONS
SET overexpression is a frequent event in mCRC that plays a potential oncogenic role associated with worse outcome and resistance to oxaliplatin. Moreover, this alteration defines a subgroup of patients who could benefit from therapies containing PP2A activators such as FTY720.
Translational Oncology Division, Oncohealth institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz," Madrid, Spain.
Ion
I
Cristóbal
Translational Oncology Division, Oncohealth institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz," Madrid, Spain.
Raúl
R
Rincón
Pathology Department, IIS "Fundación Jiménez Diaz," UAM, Madrid, Spain.
Rebeca
R
Manso
Translational Oncology Division, Oncohealth institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz," Madrid, Spain.
Cristina
C
Caramés
Pathology Department, IIS "Fundación Jiménez Diaz," UAM, Madrid, Spain.
Sandra
S
Zazo
Pathology Department, IIS "Fundación Jiménez Diaz," UAM, Madrid, Spain.
Juan
J
Madoz-Gúrpide
Pathology Department, IIS "Fundación Jiménez Diaz," UAM, Madrid, Spain. jgfoncillas@gmail.com frojo@fjd.es.
Federico
F
Rojo
Translational Oncology Division, Oncohealth institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz," Madrid, Spain. jgfoncillas@gmail.com frojo@fjd.es.
Jesús
J
García-Foncillas
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D056488:Histone Chaperones / Q000502:physiology*; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000077150:Oxaliplatin; D016016:Proportional Hazards Models; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D012189:Retrospective Studies; D014157:Transcription Factors / Q000502:physiology*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D009944:Organoplatinum Compounds; C513473:SET protein, human; D014157:Transcription Factors; D000077150:Oxaliplatin; D054648:Protein Phosphatase 2