Promyelocytic leukaemia protein links DNA damage response and repair to hepatitis B virus‐related hepatocarcinogenesis

Abstract

DNA damage response and repair pathways are important barriers to carcinogenesis. Here, we show that promyelocytic leukaemia (PML, also known as TRIM19), involved in sensing DNA damage and executing homologous recombination repair, is down-regulated in non-tumour liver cells surrounding hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). No PML mutation or deletion was found in HBV-infected liver or HCC cells. Immunohistochemical analysis of liver biopsies from patients with breast or liver cancer and HBV reactivation after chemotherapy revealed PML up-regulation and HBV exacerbation in normal liver tissue in response to DNA damage (functional PML), PML down-regulation in HCC peritumour cells associated with high HBsAg accumulation and low HBV replication activity (suppressive PML), and heterogeneous nuclear PML expression in HCC cells that lost HBV DNA and HBsAg and were non-reactive to DNA damage (dysregulated PML). Loss of PML in HBsAg-transgenic mice promoted chromosome breaks in liver cells and accelerated the accumulation of body and liver fat and the development of a liver steatosis-dysplasia-adenoma-carcinoma sequence in an inflammation-independent and male-predominant manner, compared to PML knock-out or HBsAg-transgenic mice during the same time period. These results indicate that PML deficiency facilitates genomic instability and promotes HBsAg-related hepatocarcinogenesis, which also involves androgen and lipid metabolism. These findings uncover a novel PML link between HBV-related tumourigenesis, DNA repair, and metabolism.

Dual oncogenic and tumor suppressor roles of the promyelocytic leukemia gene in hepatocarcinogenesis associated with hepatitis B virus surface antigen

“…The ubiquitin E3-ligases, SIAH-1 and -2 (SIAH-1/2), are implicated in tumorigenesis through physical interaction with PML triggering its degradation [ 17 ][ 18 ][ 19 ][ 20 ]. In addition, our earlier study in 155 HBV-infected patients demonstrated that suppression of PML persisted until HBsAg expression was gradually down-regulated [ 21 ]; and our analysis of each HBV component effect by transfection assays revealed that HBsAg induced proteasome-mediated PML degradation [ 22 ]. These findings led us to ask whether the tumorigenesis of HBsAg was associated with SIAH-1/2-mediated PML loss [ 23 ].…”

Host transcription factor Speckled 110 kDa (Sp110), a nuclear body protein, is hijacked by hepatitis B virus protein X for viral persistence

“…Hepatitis B virus, a Hepadnaviridae family virus, is the cause of many chronic hepatic diseases leading to cirrhosis and hepatocellular carcinoma, but the association of HBV and the PML-NBs are not much explored. PML body resident protein p11, an S100 family member, has been reported to associate with HBV polymerase inside the PML body favoring viral replication (36), whereas knockdown of the PML gene leads to increased viral replication thereby causing HBV-induced HCC (37,38). A recent study showed that smc5/6 restricts viral transcription when localized in the PML body (23).We found that transcription factor Sp110, a nuclear body resident protein, shows a selective exit from the PML body upon infection and is hijacked by HBx to promote viral proliferation.…”

Interaction of Herpes Simplex Virus ICP0 with ND10 Bodies: a Sequential Process of Adhesion, Fusion, and Retention

“…ND10 and its organizer PML have been a hot spot for viral oncogenic studies (57)(58)(59)(60)(61). As a tumor suppressor gene, PML deficiency and subsequent ND10 loss have been observed in many cancer types, including viral-infection-related cancers.…”