MYC-dependent regulation and prognostic role of CIP2A in gastric cancer.
BACKGROUND
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified human oncoprotein that stabilizes the c-Myc (MYC) protein. However, the clinical relevance of CIP2A to human cancers had not been demonstrated, but the mechanism of its regulation and its clinical role in cancer were completely unknown.


METHODS
Tissue microarrays consisting of 223 gastric adenocarcinoma specimens were evaluated for the presence of CIP2A using immunohistochemistry, and the association of CIP2A expression with survival was assessed using Kaplan-Meier analysis. The effects of MYC and CIP2A on each other's expression and on cell proliferation were investigated in several gastric cancer cell lines using small interfering RNAs to CIP2A and MYC and immunoblotting. To further evaluate the role of MYC in CIP2A regulation, an inhibitor of MYC dimerization, 10058-F4, and an inducible MycER model were used.


RESULTS
Expression of CIP2A protein was associated with reduced overall survival for gastric cancer patients with tumors 5 cm or smaller, with a 10-year overall survival in the CIP2A-immunopositive group of 8.1% as compared with 37.6% in the CIP2A-negative group (difference = 29.5%, 95% confidence interval = 12.5% to 46.5%, P = .001). In gastric cancer cell lines, CIP2A depletion led to decreased proliferation and anchorage-independent growth of the cells, as well as to reduced stability and expression of MYC protein. Interestingly, MYC depletion led to reduced expression of CIP2A mRNA and protein. Moreover, experiments with an MYC inhibitor and activator suggested that MYC directly promotes CIP2A gene expression. Finally, CIP2A and MYC immunopositivities were associated in gastric cancer specimens (P = .021).


CONCLUSIONS
CIP2A immunopositivity is a predictor of survival for some subgroups of gastric cancer patients. CIP2A and MYC appear to be regulated in a positive feedback loop, wherein they promote each other's expression and gastric cancer cell proliferation.
Khanna
Anchit
A
Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.
Böckelman
Camilla
C
Hemmes
Annabrita
A
Junttila
Melissa R
MR
Wiksten
Jan-Patrik
JP
Lundin
Mikael
M
Junnila
Siina
S
Murphy
Daniel J
DJ
Evan
Gerard I
GI
Haglund
Caj
C
Westermarck
Jukka
J
Ristimäki
Ari
A
D000230:Adenocarcinoma / Q000737:chemistry* / Q000401:mortality; D001324:Autoantigens / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D025461:Feedback, Physiological; D005387:Finland; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D053208:Kaplan-Meier Estimate; D008565:Membrane Proteins / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D011237:Predictive Value of Tests; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000032:analysis; D012042:Registries; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000401:mortality; D046888:Tissue Array Analysis
D001324:Autoantigens; D014408:Biomarkers, Tumor; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering