Overexpression of Promyelocytic Leukemia Protein and Alteration of PML Nuclear Bodies in Early Stage of Hepatocarcinogenesis

Yoon, Ghil Suk; Yu, Eunsil

doi:10.3346/jkms.2001.16.4.433

Cited by 13 publications

(13 citation statements)

References 21 publications

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“…Interestingly, Gurrieri et al demonstrated that loss of PML correlates with higher tumor grading in breast adenocarcinomas, prostate carcinomas, and CNS tumors, which confirmed previous data from gastric cancers [73,74]. However, other immunohistochemistry studies have reported variable expression of PML in different human tumors and, in some cases, even overexpression of PML [44,77]. Additional tissue microarray studies, employing a combination of PML antibodies, alongside gene expression analysis may prove insightful in investigating this apparent discrepancy.…”

Section: Pml Role In Cancermentioning

confidence: 53%

The Role of PML in the Nervous System

Salomoni¹,

Betts-Henderson

2010

Mol Neurobiol

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The promyeloctic leukemia protein PML is a tumor suppressor that was originally identified due to its involvement in the (15;17) translocation of acute promyelocytic leukemia. While the majority of early research has focused upon the role of PML in the pathogenesis of leukemia, more recent evidence has identified important roles for PML in tissues outside the hemopoietic system, including the central nervous system (CNS). Here, we review recent literature on the role of PML in the CNS, with particular focus on the processes of neurodevelopment and neurodegeneration, and propose new lines of investigation.

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Section: Pml Role In Cancermentioning

confidence: 53%

The Role of PML in the Nervous System

Salomoni¹,

Betts-Henderson

2010

Mol Neurobiol

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“…Delocalization of PML from the PML-NB is related to leukemogenesis, and nuclear PML protein expression is frequently lost in human solid cancers of multiple histological origins, including prostate, colon, breast, lung, lymphoma, brain, and germ cells (14). However, for liver cancers, previous studies contradictorily have reported heterogeneous nuclear expression of the PML protein in normal and neoplastic liver tissues and no change or a gradual increase of PML levels as the liver transformation progressed from benign dysplasia to carcinoma (50,51). The present study found that when liver cells were treated with radiation, up-regulation of PML, representing active DNA damage sensing, was noted only in the liver cells without HBsAg expression and was positively correlated with HBV replication activity before HBsAg accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…If HBsAg is persistently expressed, as in HBV carriers, long‐term suppression of PML may cause genomic instability, which in turn could lead to loss of partial HBV DNA and HBsAg expression with time; after that process, PML is then reexpressed, which might indicate loss of HBsAg inhibition on PML expression and explain the heterogeneous nuclear PML expression noted in patients with HBV‐related HCC. However, the heterogeneous nuclear PML expression in HCC cells seems to represent dysregulated PML signaling in response to DNA damage (50, 51).…”

Section: Discussionmentioning

confidence: 99%

Defective DNA damage response and repair in liver cells expressing hepatitis B virus surface antigen

Chung

2013

FASEB j.

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Hepatitis B virus (HBV) is implicated in liver cancer. The aim of this study was to find out whether HBV or its components [HBV surface antigen (HBsAg), HBV core protein (HBc), and HBV X protein (HBx)] could interfere with the host DNA damage response and repair pathway. The full HBV genome or individual HBV open-reading frame (ORF) was introduced into HepG2 cells to examine the effect on host genomic stability, DNA repair efficacy in response to double-strand DNA damage, and DNA damage-induced cell death. Responses to apoptosis induction in the HBV ORF-transfected HepG2 cells were also compared with those in HBV-positive and HBV-negative human hepatocellular carcinoma (HCC) cells. In the absence of HBV replication, accumulation of HBsAg in liver cells without other HBV proteins enhanced DNA repair protein and tumor suppressor promyelocytic leukemia (PML) degradation, which resulted in resistance to apoptosis induction and deficient double-strand DNA repair. However, HBsAg-positive cells exhibited increased cell death with exposure to the poly(ADP-ribose) polymerase inhibitor that blocks single-strand DNA repair. These results indicate that suppression of PML by HBsAg disrupts cellular mechanisms that respond to double-strand DNA damage for DNA repair or apoptosis induction, which may facilitate hepatocarcinogenesis and open up a synthetic lethality strategy for HBsAg-positive HCC treatment.

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“…Delocalization of PML from the PML-NB is related to leukaemogenesis, and nuclear PML protein expression is frequently lost in human solid cancers of multiple histological origins, including prostate, colon, breast, lung, lymphoma, brain, and germ cells [12]. However, for liver cancers, several studies have demonstrated overexpression of nuclear PML in neoplastic liver tissue and have reported a gradual increase in PML levels as transformation progresses from normal cells to carcinoma [22,23]. Our analysis of human HBV-related HCC specimens also showed that many HBV-related HCC cells expressed nuclear PML rather than loss of PML expression.…”

Section: Discussionmentioning

confidence: 99%

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

Chung

2013

The Journal of Pathology

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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.

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Overexpression of Promyelocytic Leukemia Protein and Alteration of PML Nuclear Bodies in Early Stage of Hepatocarcinogenesis

Cited by 13 publications

References 21 publications

The Role of PML in the Nervous System

The Role of PML in the Nervous System

Defective DNA damage response and repair in liver cells expressing hepatitis B virus surface antigen

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

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