Tissue microarray cytometry reveals positive impact of homeodomain interacting protein kinase 2 in colon cancer survival irrespective of p53 function
The American Journal of Pathology. 2011-05-01; 178(5): 1986-1998
DOI: 10.1016/j.ajpath.2011.01.021
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The human p53 gene is a tumor suppressor mutated in half of colon cancers.
Although p53 function appears important for proliferation arrest and apoptosis
induced by cancer therapeutics, the prognostic significance of p53 mutations
remains elusive. This suggests that p53 function is modulated at a
posttranslational level and that dysfunctions affecting its modulators can have a
prognostic impact. Among p53 modulators, homeodomain interacting protein kinase
(HIPK) 2 emerges as a candidate « switch » governing p53 transition from a
cytostatic to a proapoptotic function. Thus, we investigated the possible
prognostic role of HIPK2 on a retrospective series of 80 colon cancer cases by
setting up a multiplexed cytometric approach capable of exploring correlative
protein expression at the single tumor cell level on TMA. Crossing the data with
quantitative PCR and p53 gene sequencing and p53 functional assays, we observed
the following: despite a strong impact on p21 transcription, the presence of
disabling p53 mutations has no prognostic value, and the increased expression of
the HIPK2 protein in tumor cells compared with paired normal tissue cells has a
strong impact on survival. Unexpectedly, HIPK2 effect does not appear to be
mediated by p53 function because it is also observed in p53-disabling mutated
backgrounds. Thus, our results point to a prominent and p53-independent role of
HIPK2 in colon cancer survival.