MYC-dependent regulation and prognostic role of MYC stabilizing protein, CIP2A, in  human gastric cancer


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Anchit Khanna1,Camilla Böckelman2,Annabrita Hemmes2,Melissa R Junttila3,Jan-Patrik Wiksten2,Mikael Lundin2,Siina Junnila2,Daniel J. Murphy3,Gerard I. Evan3,Caj Haglund2,Jukka Westermarck1,Ari Ristimäki2
1Institute of Medical Technology,University of Tampere and Tampere University Hospital,, Tampere, Finland,2University of Helsinki, Helsinki, Finland,3University of California, San Francisco, United States

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.

Method

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 a MYC inhibitor and an activator suggested that MYC directly promotes CIP2A gene expression. Finally, CIP2A and MYC immunopositivities were associated in gastric cancer specimens ( P = .021).

Conclusion

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