Breakthrough in etiology and targeted therapy for liver cancer
A research team from the West China Second University Hospital is making significant breakthrough in resolving the mystery of how liver cancer arises.
An on-line published article in the journal of Hepatology (February 21, 2019) reported a progress from Dr Cong Liu's team on the unexpected role of Hepatitis B virus (HBV) in triggering liver cancer. The virus, responsible for 350-million infected people worldwide, is considered one of the most aggressive risk factors for the onset of hepatocellular carcinoma (HCC) in east Asian population. At the molecular level, the viral oncoprotein (HBx) has been found to be the trigger for oncogenesis over the decades, though the precise mechanism remains elusive.
In this work, Dr Liu’s team found that in hepatocytes with HBV infection or integration, an enzymatic process called DNA end resection is impaired at DNA double-strand breaks. This results in a severe defect of homologous recombination (HR) that protects the genomic DNA of host cells. The cause of this genomic threat is HBx, which effectively inhibits the extension of histone H2B mono-ubiquitination and directly perturbs the structural integrity of a ubiquitin ligase complex (CRL4WDR70), both of which are required for HR and repair of DNA breaks. This report also vigorously demonstrated that the anti-resection activity of HBx contributes to genomic instability and tumorigenesis.
Supported by these data, the team claims that HBV-related HCC is a new type of tumor exhibiting HR-defective (HRD) phenotype, providing a novel angle for the understanding of pathogenesis of HBV replication and liver cancer. It also strongly suggests that PARP inhibitors, which was originally designed for HRD types of breast cancer carrying BRCA1/BRCA2 mutations, have great potential in treating HCC with robust HBV activities. Dr Liu is leading a pre-clinical trial to test this novel targeted therapy.
The article, entitled ‘The anti-resection activity of the X protein encoded by hepatitis Virus B’, (https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.30571), is corresponded to Dr Cong Liu in the West China Second University Hospital. Drs Laifeng Ren, MingZeng, Zizhi Tang and Mingyuan Li made equal contribution to this work. The work was greatly aided by collaborators from domestic and overseas institutes, notably Prof Ning Zheng in the University of Seattle and Profs Antony Carr and Penelope Jeggo in the Genome Damage and Stability Centre, United Kingdom.
This work has been financially supported by the intramural research funding of the hospital and the National Natural Science Foundation of People’s Republic of China (31471276, 31771580).