The Role of Heat Shock Proteins, Amyloid Precursor Protein and B-cell CLL/lymphoma 3 and their Co-chaperones in Colorectal Cancer

Abstract

The elevated expression of Heat shock proteins (HSPs) has been implicated in CRC prognosis and tumour cells may require the expression of HSPs and BCL2-associated athanogene (BAG1), the HSP co-chaperone, to survive. BAG1 is a regulator of amyloid precursor protein (APP); both are important in cellular proliferation and cancer. B-cell CLL/lymphoma 3 (BCL3) is an agonist in the tumour-associated NF-κB pathway. This study aims to establish the mutational status of TP53, KRAS and PIK3CA, and the activation status of AKT, in primary CRCs and then investigate the role of HSPs, BAG1, APP, and BCL3. Oncogene induced senescence (OIS) is a potential roadblock to CRC. Recent cell culture studies suggest that OIS mediated by PI3K/AKT activation can be circumvented by high expression of HSPs in the absence of TP53 mutation. 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. KRAS mutations, PI3K/AKT activation and TP53 mutations are all common features of CRCs. For HSP to inhibit OIS in CRC may be dependent on the tumour’s mutation spectrum. CRCs with oncogenic activation of the AKT pathway were associated with increased HSP27 expression, which may represent an important mechanism in suppressing p53 dependent senescence. No association was found between HSP27 or HSP72 expression with TP53 mutation status, but HSP27 expression was strongly associated with the co-presence of wildtype KRAS and activated PI3K/AKT, indicating a possible 4 role of HSP27 in overcoming PI3K/AKT induced OIS in tumours. There was no correlation between BAG1 and APP co-expression in CRCs. BCL3 expression was heterogeneous, and elevated at the invasive edge. The expression of HSPs, APP, BCL3 was not correlated with any CRC clinicopathological features. Our studies suggest a role for using archival tissues in validating hypotheses generated from cell culture based investigations