The role of the non-canonical NF-κB pathway in colorectal cancer

RB Pathology;RD Surgery;RM Therapeutics. Pharmacology

Patel, Meera ; Edwards, Joanne

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: Colorectal cancer, NF-kB, IKK-alpha, biomarker.;   

Others  :  http://theses.gla.ac.uk/81319/13/2019PatelMeeraPhDc.pdf

来源: University of Glasgow

【 摘 要 】

Colorectal cancer (CRC) is the fourth most common cancer in the UK and despite earlier detection and improved treatments, it remains the second most common cause of cancer death. Currently, TNM staging is widely used to determine patient prognosis and the need for adjuvant therapies however, it is well recognised that CRC is a heterogeneous disease and patients with the same stage of disease can have very different survival outcomes. The molecular mechanisms underpinning these differences, and difficulties associated with treatment resistance have yet to be fully elucidated. This requires attention. Understanding molecular signalling pathways allows the discovery of new therapeutic targets and identification of biomarkers to enable treatments to be directed towards those patients who will benefit the most. Nuclear Factor kappa B (NF-κB) has key roles in tumourigenic processes described as the hallmarks of cancer. However, the majority of this evidence is based on investigation of the canonical NF-κB pathway. The aims of the present study were to understand the role of the non-canonical NF-κB pathway in the development and progression of CRC, establish if expression of non-canonical pathway members could be employed as prognostic biomarkers and assess the viability of inhibiting key non-canonical kinase IKKα as a potential therapeutic strategy in CRC.Using a tissue microarray (TMA), immunohistochemistry was used to assess expression of key members of the non-canonical NF-κB pathway in patients who had undergone surgery for stage I-III CRC. High cytoplasmic expression of IKKα was associated with adverse pathological tumour features including increasing T stage, poor tumour differentiation, tumour necrosis and low proliferation status. Key pathway members were also investigated in a cohort of patients who underwent treatment for screen-detected T1/2 CRC. Even in this cohort of early-stage disease, IKKα was associated with a more invasive phenotype. An unfamiliar ‘punctate’ pattern of IKKα expression was observed and this was associated with significantly inferior survival outcome in patients who had undergone surgery for stage I-III CRC, this was potentiated in patients with BRAF wild-type status. Using immunochemistry the present study was able to demonstrate the pattern of punctate IKKα expression was not associated with two IKKα phosphorylation sites. To investigate the distribution and localisation of IKKα further, markers of cellular transport were investigated using immunofluorescence. IKKα was co-located with a marker of the Golgi apparatus. This observation raises a number of possible hypotheses that require further investigation. Expression of the non-canonical NF-κB pathway was investigated in two colon cancer cell lines with contrasting mutational landscapes. Using western blot the present study was able to demonstrate the non-canonical NF-κB pathway can be inhibited with first-in-class IKKα inhibitors. This data, together with results from tissue studies suggest investigation of IKKα in CRC should be pursued further. Additional studies are required to investigate the predictive capacity of IKKα in the context of existing therapies used in the treatment of CRC.