title: HSP27 expression in primary colorectal cancers is dependent on mutation of KRAS and PI3K/AKT activation status and is independent of TP53.
abstract: Colorectal adenomas display features of senescence, but these are often lost upon progression to carcinoma, indicating that oncogene induced senescence (OIS) could be a roadblock in colorectal cancer (CRC) development. Heat shock proteins (HSPs) have been implicated in the prognosis of CRC and HSP based therapy is a current interest for drug development. Recent cell culture studies have suggested that in the absence of a TP53 mutation, OIS mediated by PI3K/AKT activation can be circumvented by high expression of HSPs. Furthermore, while PI3K/AKT activation and KRAS mutations are independent inducers of OIS, PI3K/AKT activation can suppress KRAS-induced OIS when both are present in cultured cells. As KRAS mutations, PI3K/AKT activation and TP53 mutations are all common features of CRC, it is possible that the requirement for HSP to inhibit OIS in CRC is dependent on the mutation spectrum of a tumour. However, work on HSP that utilised mutation profiled human tumour tissues has been limited. Here, we characterised the expression of two major HSP proteins (HSP27 and 72) by immunohistochemistry (IHC), the mutation status of TP53, KRAS and PIK3CA genes by direct sequencing and the activation status of AKT by IHC in a cohort of unselected primary CRC (n=74). We compare our data with findings generated from cell-based studies. Expression of HSP27 and HSP72 was correlated to clinicopathological and survival data but no significant association was found. We also established the mutation status of TP53, KRAS and PIK3CA genes and the activation status of AKT in our CRC panel. We did not detect any associations between HSP27 or HSP72 expression with TP53 mutation status. However, HSP27 expression in CRCs was strongly associated with the co-presence of wildtype KRAS and activated PI3K/AKT (p=0.004), indicating a possible role of HSP27 in overcoming PI3K/AKT induced OIS in tumours. Our studies suggest a role for using archival tissues in validating hypotheses generated from cell culture based investigations.
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark St, Whitechapel, London, UK.
authors.forename: Anil
authors.initials: A
authors.lastname: Ghosh
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lai
authors.forename: Sarah
authors.initials: S
authors.lastname: McDonald
authors.forename: Nirosha
authors.initials: N
authors.lastname: Suraweera
authors.forename: Neel
authors.initials: N
authors.lastname: Sengupta
authors.forename: David
authors.initials: D
authors.lastname: Propper
authors.forename: Sina
authors.initials: S
authors.lastname: Dorudi
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016922:Cellular Senescence; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D011905:Genes, ras; D055551:HSP27 Heat-Shock Proteins / Q000096:biosynthesis*; D050884:HSP72 Heat-Shock Proteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
chemical_list: D055551:HSP27 Heat-Shock Proteins; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53; D018631:ras Proteins; C057725:HSPB1 protein, human; C117307:KRAS protein, human; C495901:TP53 protein, human