HKUMed researchers unveil a novel molecular mechanism underlying liver cancer drug resistance and tumour recurrence

Researchers at the LKS Faculty of Medicine, The University of Hong Kong (HKUMed) have uncovered a novel signalling pathway triggered by a protein called FUT1 to promote cancer stemness, contributing to drug resistance and tumour recurrence of liver cancer cells. The findings are now published in The Journal of Clinical Investigation (J Clin Invest) [link to publication].

FUT1 was found to be frequently overexpressed in hepatocellular carcinoma (HCC) patients and that its overexpression to be correlated with worse patient prognosis. The study shed light onto the promise of targeting FUT1 to eradicate HCC tumours and utilising FUT1 as a prognostic marker for HCC patients.

HCC is the most common form of liver cancer, with particularly high prevalence in Hong Kong. HCC is characterised by rapid tumour growth resulting in large tumour masses that are deficient of oxygen and nutrients in their innermost tumour regions because of poor vascular supply. However, cancer cells are smart and HCC tumours can respond to these restrictions by inducing molecular adaptations that promote survival, resulting in selection of a more malignant stemness phenotype. Understanding the mechanisms that drive cancer stemness, which we now know represents the root of therapy failure and tumour recurrence, is fundamental to the design of improved therapeutic strategies.

About the study
The research team identified a novel regulatory mechanism involving a post-translation modification called fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumour recurrence. Specifically, the team demonstrated clinical significance of FUT1, where HCC patients with high levels of FUT1 showed worse survival outcomes. FUT1 inhibition could mitigate tumour initiation, self-renewal and drug resistance.

The team also unravelled the underlying molecular mechanism by which FUT1 drives HCC. Through integrating fucosylated peptide screening and proteomic profiling, fucosylation of membrane-bound proteins, including CD147, EGFR, ICAM-1 and EPHA2, by FUT1 was identified. Fucosylation of these proteins will then consequently converge on a deregulated AKT-mTOR-4EBP1 signalling, frequently altered in HCC. Treatment with an α-(1,2)-fucosylation inhibitor sensitised HCC tumours to sorafenib, a first-line molecular targeted drug used for advanced HCC patients, and reduced the tumour-initiating subset.

‘Our findings identified FUT1 as a key component in a novel molecular mechanism underlying liver cancer drug resistance and tumour recurrence. By targeting FUT1 to inhibit HCC tumour growth at its roots, this research has laid the foundation for the future development of new treatments,’ said Dr Stephanie Ma, Associate Professor of the School of Biomedical Sciences, HKUMed, who initiated the study. ‘Further, FUT1 overexpression and/or CD147, ICAM-1, EGFR and EPHA2 fucosylation may also be good prognostic markers for HCC patients.’

About the research team
The study was conducted by Dr Stephanie Ma’s research group including PhD student Ms Jane Loong Ho-chun, with assistance from Dr Wong Tin-lok, Dr Tong Man, Dr Zhou Lei, Dr Ng Kai-yu, Ms Yu Huajian and Dr Li Chi-han. Collaborators included Professor Lo Chung-mau and Professor Nancy Man Kwan from the Department of Surgery, Professor Guan Xinyuan from the Department of Clinical Oncology and Dr Rakesh Sharma from the Centre for PanorOmic Sciences at HKUMed, Professor Yun Jingping from the Department of Pathology, Sun Yat-Sen University Cancer Center as well as Dr Terence Lee Kin-wah from the Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University.

The study was supported in part by Research Grants Council – Theme Based Research Scheme (T12-704/16-R and T12-710/16-R), Collaborative Research Fund (C7026-18G); Health and Medical Research Fund from Food and Health Bureau of the Government of the Hong Kong Special Administrative Region (07183206), as well as the Laboratory for Synthetic Chemistry and Chemical Biology Limited under the Health@InnoHK Programme launched by Innovation and Technology Commission.

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