The role of the Alzheimer's disease amyloid precursor protein and related peptides in colorectal cancer progression

The Faculty of Health and Medicine is pleased to offer a number of competitive scholarships to include fees plus a stipend to the equivalent of RCUK rates for outstanding UK/EU and overseas students wishing to undertake full time doctoral research in any Department within the Faculty of Health and Medicine.

Research question: What are the molecular mechanisms by which the amyloid precursor protein (APP) and related peptides regulate colorectal cancer (CRC) disease progression?

Background: APP has achieved notoriety for its role in the neurodegenerative condition, Alzheimer's disease. However, more recently, increased expression of the protein has been implicated as a negative prognostic factor in the progression of a range of cancers including CRC [1-5]. Conversely, the amyloid beta peptide (formed through cleavage of APP) is thought to impair CRC cell growth.

Aims: The student will over-express a range of APP molecular constructs in CRC cell lines and investigate their effects on cell proliferation and invasion. This will identify the parts of the molecule involved in the progression of CRC. The project will also seek to determine the molecular mechanisms through which amyloid beta and related peptides impair CRC cell growth and determine the specificity of this effect in relation to normal colorectal cells.

Outcomes: It is envisaged that the project will identify specific molecular targets or peptides that might be utilised in the treatment of CRC. The research should progress rapidly given the fact that all of the APP molecular constructs have been generated and characterised previously in Dr. Parkin's lab [6, 7]. Similarly, the necessary colorectal cell lines are already used routinely in Dr. Rigby's lab.

1. Hansel DE, Rahman A, Wehner S, Herzog V, Yeo CJ, Maitra A. Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res 2003; 63(21): 7032-7.
2. Ko SY, Lin SC, Chang KW, Wong YK, Liu CJ, Chi CW, et al. Increased expression of amyloid precursor protein in oral squamous cell carcinoma. Int J Cancer 2004; 111(5): 727-32.
3. Krause K, Karger S, Sheu SY, Aigner T, Kursawe R, Gimm O, et al. Evidence for a role of the amyloid precursor protein in thyroid carcinogenesis. J Endocrinol 2008; 198(2): 291-9.
4. Meng JY, Kataoka H, Itoh H, Koono M. Amyloid beta protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo. Int J Cancer 2001; 92(1): 31-9.
5. Takayama K, Tsutsumi S, Suzuki T, Horie-Inoue K, Ikeda K, Kaneshiro K, et al. Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res 2009; 69(1): 137-42.
6. Gough M, Blanthorn-Hazell S, Delury C, Parkin E. The E1 copper binding domain of full-length amyloid precursor protein mitigates copper-induced growth inhibition in brain metastatic prostate cancer DU145 cells. Biochem Biophys Res Commun 2014.
7. Gough M, Blanthorn-Hazell S, Parkin ET. The Histidine Composition of the Amyloid-beta Domain, but not the E1 Copper Binding Domain, Modulates beta-Secretase Processing of Amyloid-beta Protein Precursor in Alzheimer's Disease. J Alzheimers Dis 2014.

Students wishing to apply for this project should complete the Expression of Interest Form (this can be downloaded from http://www.lancaster.ac.uk/shm/study/doctoral_study/studentships/) and send this directly to the first named supervisor. The closing date for Expressions of Interest is 6 March 2015.