The AP-1 repressor protein, JDP2, potentiates hepatocellular carcinoma in mice
© Bitton-Worms et al; licensee BioMed Central Ltd. 2010
Received: 20 December 2009
Accepted: 9 March 2010
Published: 9 March 2010
The AP-1 transcription factor plays a major role in cell proliferation, apoptosis, differentiation and developmental processes. AP-1 proteins are primarily considered to be oncogenic. Gene disruption studies placed c-Jun as an oncogene at the early stage of a mouse model of hepatocellular carcinoma. Mice lacking c-Jun display reduced number and size of hepatic tumors attributed to elevated p53 expression and increased apoptosis. This suggests that c-Jun inhibition may serve as a therapeutic target for liver cancer. The c-Jun dimerization protein 2, JDP2 is an AP-1 repressor protein that potently inhibits AP-1 transcription. On the other hand, the JDP2 locus was found at a recurring viral integration site in T-cell lymphoma. We sought to examine the potential of JDP2 to inhibit c-Jun/AP-1 oncogenic activity in mice. Towards this end, we generated a tetracycline inducible transgenic mouse expressing JDP2 specifically in the liver. We used diethylnitrosamine (DEN) injection to initiate liver cancer in mice and assessed the extent of liver cancer in JDP2-transgenic and wild type control mice by biochemical and molecular biology techniques.
JDP2-transgenic mice display normal liver function. JDP2-transgenic mice displayed potentiation of liver cancer, higher mortality and increased number and size of tumors. The expression of JDP2 at the promotion stage was found to be the most critical for enhancing liver cancer severity.
This study suggests that JDP2 expression may play a critical role in liver cancer development by potentiating the compensatory proliferative response and increased inflammation in the DEN liver cancer model.
Hepatocellular carcinoma (HCC) is the fifth most frequent cancer. Approximately 500,000 cases of HCC are diagnosed each year and it is the third leading cause of cancer-related deaths . The majority of cases of HCC are due to hepatitis B virus, hepatitis C infections and alcohol consumption . During the course of chronic infection, continuous intra-hepatic inflammation maintains a cycle of liver cell destruction and regeneration that often terminates in HCC [3, 4]. Various mouse models for HCC were developed to study the molecular mechanisms involved in various stages of liver cancer . These mouse models mimic the etiology of liver cancer in man. Certain chemical carcinogens which induce hepatocyte DNA damage can result in HCC. Mice injected with a single injection of tumor initiator diethylnitrosamine (DEN) results in liver cancer [6–8]. Inflammation is a known factor that plays a casual role in cancer in general and liver cancer in particular [8–10].
AP-1 is one of the transcription factors found at the receiving end of multiple signaling pathways. AP-1 is composed of either homo or hetero dimers of basic leucine zipper (bZIP) family members . Dimerization is required for specific binding to a DNA sequence known as the TPA response element (TRE) found in the promoter region of many genes. Although the role of AP-1 in cell proliferation is well established , activating mutations of this complex have never been found in human cancer. Most of the important insights regarding the specific function of AP-1 proteins have been established through the use of mice with either loss- or gain-of-function manipulations of various members of the bZIP protein family .
The most-studied member of the AP-1 family is c-Jun. Despite its ability to transform chicken embryo fibroblasts, c-Jun over-expression alone does not result in transformation of rodent fibroblasts. On the other hand, c-Jun cooperates with Ha-Ras in cell transformation . In mice, c-Jun disruption causes embryonic lethality at midgestation. The affected embryos exhibit heart defects and arrested liver development . Conditional c-Jun knockout in the liver of adult mice prevents the appearance of HCC in the DEN liver cancer model, implicating c-Jun as a crucial player in the initiation steps of liver carcinogenesis .
The c-Jun dimerization protein 2, JDP2, encodes an 18 kDa bZIP protein that interacts with c-Jun . JDP2 can bind TRE DNA elements as well as the cyclic AMP response element (CRE) as a homo- or hetero dimer [17, 18]. Upon dimerization with c-Jun, DNA binding is potentiated, but the transcription is inhibited . JDP2 inhibits transcription by multiple mechanisms [17, 19]. JDP2 is involved in cell differentiation processes, such as differentiation of skeletal muscle cells , osteoclasts  and in stress response to ultraviolet irradiation . Various studies suggest that JDP2 has a dual role in malignant transformation. On the one hand, it is well established that JDP2 counteracts AP-1 transcription , and thus may interfere with the oncogenic properties of c-Jun. JDP2 has been found to inhibit cell transformation induced by Ras in vitro and in xenografts injected into SCID mice . On the other hand, JDP2 has been identified as a candidate oncogene in a high-throughput screen based on viral insertional mutagenesis in mice [24–26]. Serial analysis of gene expression identified increased levels of JDP2 in a number of cancers including prostate, kidney, liver and skeletal muscle http://www.genecards.org/cgi-bin/carddisp.pl?gene=JDP2&search=JDP2. In order to examine whether JDP2 increased expression may be a coincidence or may play a role in liver cancer development, we have generated transgenic mice with liver specific JDP2 expression and examined the consequence in a chemically induced liver cancer model. We found that JDP2 increases liver cancer severity and that JDP2 expression at the promotion stage is most important for this activity.
The role of JDP2 in carcinogenesis is a matter of debate. On the one hand, JDP2 over-expression results in cell cycle arrest  and reduced foci formation in Ras dependent cell transformation . In addition, prostate cancer cell lines with JDP2 over-expression form smaller tumors in mice . On the other hand, JDP2 over-expression in chicken embryo fibroblasts imparts a partial oncogenic phenotype . Moreover, JDP2 locus was identified at viral integration sites resulting in T cell lymphoma [24–26, 31]. Most of JDP2 proteins that are expressed as a result of the viral integration lack the N-terminal JDP2 domain, yet some integrations enhance the expression of full length JDP2 [25, 31]. The mechanisms through which JDP2 acts as an oncogene remain to be determined. In addition, whether or not JDP2 plays a role in carcinogenesis in humans is yet to be demonstrated.
Here we described the generation of JDP2-transgenic mice that express JDP2 specifically in the liver. Although JDP2-expressing mice highly express JDP2, JDP2-transgenic mice display no liver dysfunction phenotype unless faced with specific perturbations such as DEN administration. Thus, c-Jun inhibition by JDP2 during pregnancy is effective only from day 10-12 and therefore may bypass the critical timing resulting in the adverse effect of inhibition of fetal liver development. Similar results were obtained with dominant negative IkB transgenic mice that were able to complete full term and still efficiently inhibit NFkB activity in adult mice . It appears that the LAP promoter that is driving the expression of the tTA is expressed at extremely low levels in utero. Therefore, the transgene expression is insufficient to completely inactivate either NFkB or c-Jun both of which are required for liver development.
c-Jun was found to promote liver cancer. Mice with c-Jun conditional knockout in the liver display reduced liver cancer development following the well established DEN model. c-Jun-KO mice displayed increased apoptosis in the liver. c-Jun was suggested to act through a p53 dependent mechanism and activation of the pro-apoptotic gene Noxa . Previous studies directed towards inhibition of c-Jun transcription activity used c-Jun lacking its transcription activation domain, TAM67. Indeed, expression of TAM67 in the skin resulted in inhibition of tumor promotion in two stage skin carcinogenesis model . JDP2 was previously shown to inhibit cell proliferation in vitro and directly inhibit the transcription of cell cycle proteins such as cyclin D1 . In view of these results, we expected that JDP2 over-expression in the liver will mimic c-Jun disruption and thus may result in inhibition of liver cancer development in this model. In contrast, JDP2 potentiated the severity of liver cancer in the two DEN induced hepatocellular cancer models. JDP2-transgenic mice displayed numerous enlarged visible tumors and higher liver/body ratio as well as increased level of liver damage. Gene expression analysis revealed an increase in the inflammatory response at four months old JDP2-transgenic mice. Interestingly, CHOP10 is expressed at high levels in JDP2-transgenic mice. We have demonstrated that JDP2 can act as a strong transcription activator depending on the leucine zipper protein member it is associated with. CHOP10 protein can form stable heterodimer with JDP2 and is found to activate transcription from TRE dependent genes . Indeed, CHOP10 expression level is highly induced in mice injected with DEN during the promotion stage as well. The mechanism by which CHOP10 expression is augmented is yet to be determined. The potentiation of TRE dependent genes such as those elevated during the promotion stage in JDP2-trangenic mice could be the result of JDP2-CHOP10 transcription activity. In addition to CHOP10, ATF3 expression level is highly elevated in the liver of four months old JDP2-transgenic mice. Interestingly, both CHOP10 and ATF3 were identified as JDP2 target genes [35, 36]. ATF3 was found to act as an oncogene in breast tumors . Therefore, ATF3 high expression levels observed in the liver of JDP2-transgenic mice may a play a positive role at the tumor promotion stage of liver cancer.
The mechanism by which the impaired HCC development following c-Jun disruption was proposed to be due increased hepatocyte apoptosis in a cell autonomous manner . In contrast, using the DEN model in mice with liver disruption of IKKβ, it appears that hepatocyte death is the main driving force that promotes cell proliferation leading to liver cancer development in a non cell autonomous manner . Retroviral activation of JDP2 in T-cell lymphomas of mice is the only evidence for a gain-of-function potential of JDP2 in cancer development. Although the fact that most of the resulted JDP2 transcripts lacks the N-terminal histone acetylation inhibitory (INHAT) domain , some tumors represent elevation of canonical full length JDP2 transcript . Expression of low levels of JDP2 together with mutant NRas (G12D) resulted in anchorage independent growth . In contrast, JDP2 over-expression resulted in inhibition of Ha-Ras dependent foci formation in NIH3T3 . It was postulated that high JDP2 expression level results in a cellular toxicity and therefore, inhibited cellular transformation by Ras. However, in the liver such cellular toxicity may serve as the driving force in potentiating liver cancer through compensatory proliferation mechanism . Collectively, it seems that JDP2 plays a protective role in a cell autonomous manner in vitro but the same process can have a positive outcome in a non cell autonomous way resulting in potentiation of liver cancer.
To examine whether or not JDP2 has an effect at the tumor initiation stage, we tested the expression of genes 24 h following DEN injection. The expression of numerous genes revealed no significant alteration of expression between wild type and JDP2 transgenic mice. This suggested that liver damage and tumor initiation is alike in mice independent of JDP2 expression. Consistently, JDP2-transgenic mice in which transgene expression was suppressed during the first three weeks of life displayed very similar liver cancer severity as compared with a mice cohort in which JDP2 was expressed at all stages. In contrast, mice in which JDP2 expression was suppressed during the initiation and promotion stages showed similar liver cancer levels as compared with wild type mice. Collectively, JDP2 expression during the promotion stage is found to be important for potentiation of liver cancer by acting as a tumor promoter in the DEN model.
JDP2 over-expression potentiaes DEN induced liver cancer development. JDP2 role at the promotion stage is demonstrated. The increase of CHOP10 expression may provide a possible explanation for JDP2 potentiation of gene transcription at the promotion phase of liver cancer development. Collectively, JDP2 plays a dual role in carcinogenesis depending on the cellular and tissue context.
All studies involving mice were performed according to the protocol approved by the Technion Animal Inspection Committee. The Technion holds an NIH animal approval license, number A5026-01.
Mouse strain with tetracycline activator (tTA) liver expression under the control of a tissue-specific C/EBPβ (LAP) promoter . The system represents the Tet-off system. Doxycycline hydrochloride (D-9891, Sigma-Aldrich) 0.2 mg/ml is dissolved in 5% sucrose and supplied in the drinking water to counteract the bitter taste of the antibiotic.
JDP2 transgenic mice
The tet-promoter is designed to drive bi-directionally the expression of β-galactosidase gene and HA-JDP2 . Crossing the homozygous LAP-driver with the heterozygous JDP2-responder, single copies of the tTA and JDP2 are present in the double transgenic mice (JDP2-transgenic, tg), and a single copy of the tTA transgene (control, wt).
Mouse genotyping is routinely performed by PCR on genomic DNA extracted from mouse tail (XNAT, Sigma-Aldrich). PCR Primers used for genotyping: JDP2F atgatgcctgggcagatccca, JDP2R tcacttcttgtccagctgctcc, tTAF gctgcttaatgaggtcgcaatcg, tTAR gccccacagcgctgagtgcat. PCR was performed using RedyMix™ reaction mix (R2648, Sigma-Aldrich)
Mice were injected intraperitoneally with DEN either with 25 mg/Kg at two weeks of age or 100 mg/Kg at four weeks of age followed by addition of 0.07% phenobarbital in the drinking water containing 5% sucrose at eight weeks of age.
Blood samples were rapidly taken from the heart of anesthetized mice. Serum was separated and alanine aminotransferase (ALT) level was determined at the Biochemistry Department Rambam Medical Center.
Harvesting mouse liver
Livers were excised from anesthetized animals. Externally visible nodules and tumors were counted and measured. Part of the liver was fixed in 4% buffered formaldehyde and paraffin embedded for histological analysis, and the remaining liver tissue was quickly frozen in liquid nitrogen and stored at -80°c until use.
Tissue sections (6 μm) were stained with Hematoxylin and Eosin (H&E) for general morphology or with antibodies against JDP2  and PCNA (Santa-Cruz, SC-7907). Immunostaining was performed using the EnVision™ G\2 System alkaline phosphatase kit (DakoCytomation K5355, Dako). Staining was performed according to the manufacturers' instructions. Sections were visualized using an Olympus light microscope.
Apoptosis was determined by the TUNEL staining kit. Sections were stained by the in situ death detection POD kit (Roche Diagnostics). Proliferation was determined by anti-PCNA staining (Santa-Cruz, SC-7907).
Data are expressed as means ± SEM in n number of experiments. Differences were analyzed by Student's t test. P values < 0.05 were considered significant. Overall survival analysis was studied by Kaplan-Meier curves.
Nuclear Extract and Western blotting
Western blotting with liver nuclear protein extract was performed as previously described .
JDP2  and anti-HA antibodies were used at 1:500 dilution, anti-α-tubulin (Sigma-Aldrich) was used at 1:5000 dilution.
Sequence - Primer Name
TNF-a- F-ccagaccctcacactcagatca R-cacttggtggtttgctacgac
18s - F-tagagggacaagtggcgttca R-cccggacatctaagggcat
Jun-D - F-ggcgggattgaaaccaggg R-agcccgttggactggatga
IL-1 - F-gcaccttacacctaccagagt R-aaacttctgcctgacgagctt
Myd88 - F-aggacaaacgccggaactttt R-gccgatagtctgtctgttctagt
p21 - F-cgagaacggtggaactttgac R-cagggctcaggtagaccttg
Mdm2 - F-aggagatgtgtttggagtccc R-ctcagcgatgtgccagagtc
Noxa - F-gcagagctaccacctgagttc R-cttttgcgacttcccaggca
p53 - F-ctctcccccgcaaaagaaaa R-ctcctctgtagcatgggcatc
CHOP10 - F-gggccaacagaggtcacac R-cttcatgcgttgcttccca
IL-6 - F-tagtccttcctaccccaatttcc R-ttggtccttagccactccttc
c-Jun - F-ccttctacgacgatgccctc R-ggttcaaggtcatgctctgttt
JUNB - F-tcacgacgactcttacgcag Rccttgagaccccgataggga
JDP2 - F-ctcactcttcacgggttgg R-gctgaaatacgctgacatc
fos - F-ccagcagaagttccgggtag R-gtagggatgtgagcgtggata
CycD1 - F-gcgtaccctgacaccaatctc R-ctcctcttcgcacttctgctc
ATF3 - F-gaggattttgctaacctgacc R-ttgacggtaactgactccc
ß2-microglubulin - F-ttctggtgcttgtctcactga R-cagtatgttcggcttcccattc
List of abbreviation
Activating protein 1
Activating transcription factor 3
basic leucine zipper
C/EBP homologous protein 10
Inhibitor of kB
IkB kinase β
c-Jun dimerization protein 2
liver activating protein
Nuclear factor kB
The authors wish to thank Ms. Aviva Cohen, Ms. Shoshana Ben-Eliezer and Mr. Ran Levi for their excellent technical assistance. This work was supported by C. Rosenblatt Cancer Research Fund, by the Israeli Ministry of Health (Grant # 3-3955) and the Israel Cancer Association to A.A.
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