title: Tissue microarray cytometry reveals positive impact of homeodomain interacting protein kinase 2 in colon cancer survival irrespective of p53 function.
abstract: 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.
authors.affiliation: INSERM U916, Institut Bergonié, Université Victor Segalen Bordeaux 2, Bordeaux, France. francesca.degiorgi-ichas@inserm.fr
authors.forename: Isabelle
authors.initials: I
authors.lastname: Soubeyran
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mahouche
authors.forename: Aude
authors.initials: A
authors.lastname: Grigoletto
authors.forename: Thierry
authors.initials: T
authors.lastname: Leste-Lasserre
authors.forename: Guillaume
authors.initials: G
authors.lastname: Drutel
authors.forename: Christophe
authors.initials: C
authors.lastname: Rey
authors.forename: Stephane
authors.initials: S
authors.lastname: Pedeboscq
authors.forename: France
authors.initials: F
authors.lastname: Blanchard
authors.forename: Veronique
authors.initials: V
authors.lastname: Brouste
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sabourin
authors.forename: Yves
authors.initials: Y
authors.lastname: Bécouarn
authors.forename: Josy
authors.initials: J
authors.lastname: Reiffers
authors.forename: François
authors.initials: F
authors.lastname: Ichas
authors.forename: Francesca
authors.initials: F
authors.lastname: De Giorgi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases