Don't miss our weekly PhD newsletter | Sign up now Don't miss our weekly PhD newsletter | Sign up now

  Understanding L1 ORF1p and Pin1 interaction to exploit it as a therapeutic strategy for liver cancer (ref: SF22/HLS/APP/SHUKLA)


   Faculty of Health and Life Sciences

   Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Primary liver cancer, predominantly hepatocellular carcinoma (HCC), is the 4th commonest cause of cancer death globally. HCC is amongst the cancers with the most rapid rate of growth in both incidence and mortality in recent decades and is projected to be the cancer with the highest average annual increase over the next 15 years consequent to an obesity epidemic causing fatty liver and cancer. Thus, there is an urgent need of developing novel treatment strategies for this cancer to improve patient outcome. Alteration of signalling pathways due to inactivation of tumour suppressor genes and activation of oncogenes are key players of carcinogenesis. This could be due to accumulation of genetic and epigenetic changes in cells. Around half of the human genome is made up of ‘transposable elements’ (TEs) – stretches of DNA that can move from one place in the genome to another, potentially causing changes in DNA function. LINE-1 (L1) retrotransposon (a type of TE) constitutes ~17% of the human genome and moves around via a ‘copy and paste’ mechanism called retrotransposition. This is mediated by two proteins produced by L1 – ORF1 and ORF2. Increased L1 activity (ORF1/2 protein expression and movement) has been implicated in several forms of cancer including HCC. We have demonstrated L1 activation in liver cancer and have recently shown that L1 ORF1p regulates key pathways linked to carcinogenesis via interaction with host proteins especially Pin1. However, other interacting partners of the ORF1p-Pin1 complex are unknown. This project will focus on characterising L1 ORF1p-Pin1 complex in liver cancer cells and develop strategies to target this complex. This is because, Pin1 is central to various signalling pathways and is a cancer therapeutic target. Thus, such research could have benefits in terms of cancer prevention and treatment.

This is an interdisciplinary project in collaboration with Dr Agnieszka Bronowska, Senior Lecturer in Computational Medicinal Chemistry, Newcastle University. The project will provide an opportunity to learn cutting-edge cancer biology techniques including but not limited to cell and molecular biology techniques related to transgenic cell lines generation, cellular assays, cell imaging. In addition, transcripts and protein analysis will be used to characterise interaction of L1 ORF1p-Pin1 and model interfering peptides/small molecules to target the interaction. Besides wet lab work, computational modelling, data analysis and presentation skills will be developed to lay a solid foundation for the student to purse carrier in biomedical sciences research.

Eligibility and How to Apply:

Please note eligibility requirement:

•      Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non- UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above)

•      Appropriate IELTS score, if required

For further details of how to apply, entry requirements and the application form, see https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/

 

Please note: All applications must include a covering letter (up to 1000 words maximum) including why you are interested in this PhD, a summary of the relevant experience you can bring to this project and of your understanding of this subject area with relevant references (beyond the information already provided in the advert). Applications that do not include the advert reference (e.g. SF22/…) will not be considered.

 

Deadline for applications: Ongoing

Start Date: 1st October and 1st March are the standard cohort start dates each year.

Northumbria University takes pride in, and values, the quality and diversity of our staff and students. We welcome applications from all members of the community.

Informal enquiries to Dr Ruchi Shukla ()

Biological Sciences (4)

Funding Notes

This project is fully self-funded and available to applicants worldwide. Tuition fees will depend on the running cost of the individual project, in line with University fee bands found at View Website. The fee band will be discussed and agreed at interview stage.
Most laboratory based PhDs are band 3 or 4.
Please note: to be classed as a Home student, candidates must meet the following criteria:
• Be a UK National (meeting residency requirements), or
• have settled status, or
• have pre-settled status (meeting residency requirements), or
• have indefinite leave to remain or enter.

References

1. Zadran, B., Sudhindar, P.D., Wainwright, D., Bury, Y., Luli, S., Howarth, R., McCain, M., Watson, R., Huet, H., Berlinguer, R.P., Casement, J., Mann, D.A., Oakley, F., Lunec, J., Reeves, H., Faulkner, G.J., and Shukla, R. ‘Impact of retrotransposon protein L1 ORF1p expression on oncogenic pathways in hepatocellular carcinoma: the role of cytoplasmic PIN1 upregulation’ (2023) British Journal of Cancer, doi: 10.1038/s41416-023-02154-9. Online ahead of print.
2. Marco Y W, Sari F Alhasan, Ruchi Shukla, Misti McCain, Maja Laszczewska, Daniel Geh, Gillian L Patman, Despina Televantou, Anna Whitehead, João P Maurício, Ben Barksby, Lucy M Gee, Hannah L Paish, Jack Leslie, Ramy Younes, Alastair D Burt, Lee A Borthwick, Huw Thomas, Gary S Beale, Olivier Govaere, Daniela Sia, Quentin M Anstee, Dina Tiniakos, Fiona Oakley, Helen L Reeves. ‘Sulfatase-2 from Cancer Associated Fibroblasts: An Environmental Target for Hepatocellular Carcinoma?’ (2022) Liver Cancer, 11(6), 540.
3. Sudhindar, P.D., Wainwright, D., Saha, S., Howarth, R., McCain, M., Bury, Y., Saha, S.S., McPherson, S., Reeves, H., Patel, A.H., Faulkner, G.J., Lunec, J., and Shukla, R. ‘HCV activates somatic L1 retrotransposition influencing hepatocarcinogenesis beyond viral clearance’ (2021) Cancers, 13(20), 5079.
4. Nardeen Eldafashi, Rebecca Darlay, Ruchi Shukla, Misti Vanette McCain, Robyn Watson, Yang Lin Liu, Nikki McStraw, Moustafa Fathy, Michael Atef Fawzy, Marco Y W Zaki, Ann K Daly, João P Maurício, Alastair D Burt, Beate Haugk, Heather J Cordell, Cristiana Bianco, Jean-François Dufour, Luca Valenti, Quentin M Anstee, Helen L Reeves. ‘A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC?’ (2021) Cancers, 13(6):1412.
5. Schauer, S.N., Carreira, P.E., Shukla, R., Gerhardt, D.J., Gerdes, P., Sanchez-Luque, F.J., Ghisletti, S., Faivre, J., Ewing, A.D., Richardson, S.R., and Faulkner, G.J. L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis. (2018) Genome Research, 28(5):639.
6. Shukla, R., Upton, K.R., Muñoz-Lopez, M., Gerhardt, D.J., Fisher, M.E., Nguyen, T., Brennan, P.M., Baillie, J.K., Collino, A., Ghisletti, S., Sinha, S., Iannelli, F., Radaelli, E., Dos Santos, A., Rapoud, D., Guettier, C., Samuel, D., Natoli, G., Carninci, P., Ciccarelli, F.D., Garcia-Perez, J.L., Faivre, J., and Faulkner, G.J. Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma (2013) Cell, 153 (1):101.

Register your interest for this project



Where will I study?

Search Suggestions
Search suggestions

Based on your current searches we recommend the following search filters.