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Molecular Biology and Genetics |
International Agency for Research on Cancer (IARC), 69008 Lyon, France [W-M. T., U. C., H. O., Z-Q. W.]; Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032 [M. P. H.]; Institute for Molecular and Human Genetics, Georgetown University Medical Center, Washington DC 20007 [L. R. C., B. R. H.]; and Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada [P. M. L.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-irradiation (Refs. 7
, 9
, 10
; see also Ref. 11
). PARP-1 null cells exhibit an increased degree of chromosomal instability characterized by an increased frequency of spontaneous SCE and DNA damage-induced micronuclei formation (7
, 9)
. Moreover, PARP-1 mutant mice and cells show shortened telomeres and chromosome aberrations, including chromosome fusions and fragmentation as well as chromosome loss and gain (12, 13, 14)
. These data suggest that PARP-1 plays an important role in stabilizing the genome, most likely via shuttling on and off DNA strand breaks. Previous studies have shown that, although PARP-1-/- mice rarely develop spontaneous tumors (summarized in Ref. 11
), in a p53-deficient background, these mice show increased tumor incidence and develop a wide spectrum of tumors including a high frequency of epithelial malignancy and brain tumors, in addition to sarcomas and lymphomas. This is most likely attributable to a combined effect of p53-mediated checkpoint failure, together with a high degree of chromosomal aberrations and impaired telomere function (14)
.
PARP-1 is proposed to be an anti-recombinogenic factor because it temporarily occupies DNA breaks to prevent accidental recombination between homologous DNA available in a local environment (4)
. Its inactivation, thus, results in a hyper-recombination activity as judged by spontaneously high levels of SCE (7
, 9)
. Genetic studies, using PARP-1-deficient SCID mice in which DNA-PKcs is mutated, have further tested this elevated recombination activity. Although a large proportion (
75%) of PARP-1/SCID double mutant mice die soon after birth, PARP-1 deficiency partially rescues T-cell development in the survivors because of improved V(D)J recombination in these cells (15)
. However, these mice succumbed to T-cell lymphoma, most likely because of increased anomalous V(D)J recombination (15)
.
Ku80 is a DNA-binding subunit of the DNA-PK complex that is a major component of NHEJ machinery and is involved in DNA double-strand break repair and antigen receptor V(D)J recombination (16)
. Mice lacking Ku80 are growth retarded and show deficiency in V(D)J recombination (17
, 18)
and hypersensitivity to -irradiation. Ku80-/- cells exhibit significant DNA repair defects (19
, 20)
, telomere shortening, and chromosome instability (21, 22, 23)
. Although Ku80-/- mice rarely develop spontaneous tumors (16)
, these mice in a p53-deficient background exhibit a high penetrance of pro-B-cell lymphoma caused by the specific translocation of c-myc and IgH locus (22
, 24)
. Although the increased cytogenetic aberrations have been detected in Ku80 heterozygous mutant cells (23)
, its relevance to cancer has not been reported.
Given the high affinity of PARP-1 and Ku80 for DNA strand breaks and their colocalization at telomeres (4 , 12 , 16 , 23) , it is speculated that an interaction of these two molecules at DNA ends may be important for genomic stability and for other chromatin functions. Biochemical studies have shown that on DNA damage, PARP-1 and Ku80 are rapidly activated and compete in DNA end binding (25) , and that a complex of PARP-1 and Ku proteins can be coimmunoprecipitated (26) , suggesting that these two DNA-break-sensing molecules interact in response to DNA strand breaks in vitro. However, the role of this interaction in vivo is largely unknown.
In the present study, we investigated the biological significance of the interaction between PARP-1 and Ku80, and questioned whether the hyper-recombination induced by PARP-1 deficiency would facilitate aberrant joining of chromosome ends stalled by NHEJ deficiency, which would lead to cancer by characterizing PARP-1 and Ku80 double mutant mice. We demonstrate that Ku80 heterozygosity potentiates liver tumor formation in PARP-1-deficient mice; these tumors are associated with chromosome translocations, fusions, and fragmentations. These data indicate that PARP-1 interacts with NHEJ machinery to minimize aberrant rejoining of chromosome ends and, thereby, prevent tumor development.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Histopathological Analyses.
Animals were killed by ether anesthesia on decline in health (i.e., weight loss, paralysis, ruffling of fur, or inactivity). A full necropsy was performed and organs were fixed in 4% neutral-buffered formaldehyde, followed by dehydration and paraffin embedding. Histopathological analysis was carried out on a 3-µm-thick section stained with H&E. Immunostaining was essentially as described previously (14)
. Antibodies were monoclonal antimouse E-cadherin (ECCD-2; Zymed Laboratories, San Francisco, CA) and monoclonal antimouse ß-catenin (Clone 14; Transduction Laboratories, Lexington, KY).
Southern Blotting, SSCP Analysis, and Direct DNA Sequencing.
For SSCP analysis, HCC samples from four PARP-1+/-Ku80+/- and seven PARP-1-/-Ku80+/- male mice at age 15–24 months were screened for mutations in exon 3 of the ß-catenin gene (28)
. DNA was extracted from tumor cells microdissected from paraffin sections, and samples that showed mobility shift in SSCP analysis were further analyzed by direct DNA sequencing.
Cytogenetic Analyses and SKY.
Primary MEFs were isolated from embryos derived from intercrosses of PARP-1+/-Ku80+/-, or of PARP-1-/-Ku80+/-, according to protocols described previously (7)
. For the fluorescence in situ hybridization (FISH), metaphase spreads were prepared following standard procedures and were stained with DAPI. Telomere staining was performed using Cy-3-labeled (CCCTAA)3 peptide nucleic acid (14)
. SKY of the primary HCC cells was performed as described previously (29)
. For the SKY hybridization, whole-chromosome mouse probes were used (Applied Spectral Imaging, Inc.). At least 10 metaphases were analyzed for each of the HCC cases. Structural aberrations were determined to be clonal if found in two or more metaphases.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. However, 8 PARP-1-/-Ku80-/- embryos were readily identified at E9.5 after 44 embryos were analyzed (Fig. 1A)
. These fetuses were distinguishable from their littermates by being smaller in size, having 15–18 somites (versus 28–32 in normal embryos), and not having turned completely (Fig. 1B)
, indicative of growth retardation. To further define the stage when the growth retardation starts, we genotyped 74 embryos at E8.5 and 63 at E7.5. Whereas no obvious morphology alterations were found with E7.5 embryos, the smaller size of PARP-1-/-Ku80-/- embryos could be detected at E8.5 (Fig. 1A)
. Together, PARP-1-/-Ku80-/- embryos became growth retarded as early as E8.5 and died shortly after E9.5.
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. Strikingly, 52% of metaphases that were derived from PARP-1-/-Ku80+/- MEFs displayed numerous chromosomal aberrations, including Robertsonian translocation, dicentrics, and chromosomal fragments/breaks compared with those in PARP-1-/-Ku80+/+ or PARP-1+/+Ku80+/- cells (Table 1)
, indicating that Ku80 heterozygosity enhanced chromosomal abnormalities of PARP-1-/- cells. Furthermore, PARP-1+/-Ku80+/- MEFs exhibited intermediate increase of end-to-end fusions (27%) and fragmentations (21%; Table 1
). These data suggest that that PARP-1 and Ku80 play a synergistic role in minimizing the aberrant joining of chromosome ends as well as chromosomal fragmentations.
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. Specifically, 40 (63%) of 64 PARP-1+/-Ku80+/- and 72 (79%) of 91 PARP-1-/-Ku80+/- mice developed tumors after 24 months of age with mainly epithelial tumors, whereas 6 (10%) of 58 control mice (wild-type, PARP-1+/+Ku80+/- and PARP-1+/-Ku80+/+) developed tumors in 24 months (Table 2)
. Notably, frequent hepatocellular adenomas and carcinomas (HCC) were observed in aged (1224 months) PARP-1+/-Ku80+/- (28%) and PARP-1-/-Ku80+/- mice (60%; Table 2
; Fig. 2, A and B
). These liver tumors were predominantly associated with male PARP-1-deficient Ku80+/- mice (75% of liver tumor-bearing mice). Histological analysis revealed that numerous foci of adenoma were presented in various lobes of liver (Fig. 2C)
; and in those, HCC tumor cells were arranged often as trabecular or pseudoglandular structures (Fig. 2D)
, characteristic of the multistage progression. It was also noted that 10 (28%) of 36 PARP-1-/-Ku80+/+ mice developed liver tumor, i.e., 7 with hepatocellular adenomas and 3 with HCC (Table 2)
.
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. Strikingly, E-cadherin expression was largely undetectable in HCC (Fig. 2F)
, reminiscent of human HCC. Moreover, the progression changes of E-cadherin expression were evident in a subset of liver tumors containing mixed areas of adenoma and carcinoma, in which expression of E-cadherin was focally lost only in the HCC areas (data not shown). These data are consistent with the notion that down-regulation or loss of E-cadherin is involved in the transition from adenoma to carcinoma (30)
.
We next analyzed expression of ß-catenin in these mice and found no difference in ß-catenin expression pattern between normal hepatocytes and adenoma cells, namely localization on the hepatocyte membrane (Fig. 2G)
. During the progression of adenoma to HCC, ß-catenin expression accumulated in the cytoplasm, and then in the nucleus (Fig. 2H)
. This transition of expression pattern was evident in 55% of the tumors analyzed. The nuclear accumulation of ß-catenin correlated well with the proliferation of tumor cells as evidenced by positive staining for proliferating cell nuclear antigen (PCNA) (data not shown). The alteration of E-cadherin and ß-catenin expression has also been seen in the tumor sections derived from PARP-1-/-Ku80+/+ and PARP-1+/-Ku80+/- mice (data not shown).
Because the relocation of ß-catenin to cell nuclei in tumors is often caused by mutations in this molecule (31
, 32) , mutation of the ß-catenin gene was analyzed by SSCP and subsequent sequencing. Microdissection of tumor areas from histological sections was performed and tumor DNA was subject to PCR amplification. SSCP analysis revealed band shifts of ß-catenin in 4 of the 11 HCC tumors analyzed (data not shown). Subsequent sequencing of PCR products from these tumor cells showed four GAC
GCC mutations in codon 17 and one ACCGCC mutation in codon 40 of the ß-catenin gene (Fig. 2I)
, indicating frequent ß-catenin mutations associated with HCC development in PARP-1-deficient Ku80+/- mice.
High Rate of Chromosomal Abnormalities in HCCs Derived from PARP-1-/-Ku80+/- Mice.
To understand the genetic basis of enhanced tumor development, we performed cytogenetic analysis on chromosomal structures from primary HCC cells derived from PARP-1-/-Ku80+/- mice. SKY analysis of metaphases prepared from primary HCC cells revealed both structural and numerical changes of chromosomes in tumor cells (Fig. 3)
. In tumor N1104, 42% of the cells analyzed were near-tetraploid, whereas the rest of the cells were near-diploid (40–42 chromosomes); all of the cells analyzed in tumor N1029 had a near-diploid karyotype (40–43 chromosomes). In N1029 tumor cells, we detected a consistent NRT between chromosomes 11 and 19 in every cell, t(11;19) (Fig. 3, A and B)
, suggesting clonal chromosomal aberrations. We confirmed the t(11;19) finding using standard FISH analysis with chromosomes 11- and 19-specific painting probes (Fig. 3C)
. On the basis of the appearance of this chromosome in an inverted DAPI image and the FISH and SKY results, this derivative chromosome [t(11;19)] is consistent with a pseudodicentric chromosome composed of the proximal regions of chromosomes 11 and 19 (Fig. 3B)
. In addition, all of the metaphases had a Robertsonian translocation either involving the two chromosome 1 homologues, rob(1;1) (Fig. 3, A and B)
or between chromosomes 1 and 2, rob(1;2), (Fig. 3, D and E)
. Small acentromeric markers (fragmentations) originating from different chromosomes including 9 and 14 were detected in 33% of the metaphases (Fig. 3, D and E)
. In tumor N1104, we detected a Robertsonian translocation involving chromosomes 2 and 18, rob(2;18), in over 90% of the cells with near-diploid complement and in about 10% of the near-tetraploid cells (Fig. 3, D and E)
. These cytogenetic data indicated both clonal and nonclonal NRTs in these HCCs.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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40% of the bodyweight of their wild-type, and 65% the bodyweight of their PARP-1+/+Ku80-/- littermates, throughout their life, reminiscent of small body sizes of PARP-1-/- SCID mice (15)
. These observations indicate that functional synergy between DNA damage-signaling molecules is essential for embryonic development. Although PARP-1 mutant mice did not show development of spontaneous tumors in previous studies (6, 7, 8) , PARP-1 null mice showed an enhanced tumor susceptibility in the SCID background (15) . In addition, it has recently been shown that there is an increase in the formation of sarcomas and adenomas when PARP-1 mutant mice are treated with nitrosamine (34) . PARP-1-/-Ku80+/+ mice in the present study exhibited a relatively high frequency (28%) of liver lesions, suggesting that after sequential intercrossing of PARP-1-/- mice, presumably having eliminated the potential interference by genetic background, the colony becomes predisposed to liver malignancy. Although we cannot formally rule out the possibility that a modifier locus linked to the PARP-1 knockout allele contributes to HCC development, several lines of evidence support the hypothesis that PARP-1 may be a limiting factor for hepatocyte transformation. For example, the susceptibility of PARP-1 null mice to liver lesions has also been observed in a 129/Sv background after multiple intercrosses of the PARP-1-/- genotype.4 In addition, the inhibition of PARP-1 activity by 3-aminobenzamide (3-AB) enhances liver carcinogenesis in rats induced by diethylnitrosamine (35) or phenobarbital (36) . This notion is also supported by the observation that male rats fed with a niacin-deficient diet, resulting in low PARP-1 activity, are susceptible to HCC (37) . Our preliminary data have also shown that PARP-1-/- mice are susceptible to diethylnitrosamine-induced liver tumors.4 Finally, because the liver is the major detoxification organ that is constantly exposed to genotoxic agents and metabolites, it is plausible that a proficient DNA repair machinery would be critical to prevent accumulation of genetic mutations in tumor suppressors and oncogenes.
Strikingly, PARP-1-/- mice, carrying a heterozygous mutation of Ku80, exhibit enhanced HCC formation as reflected by the 60% incidence in PARP-1-/-Ku80+/- mice compared with 28% in PARP-1-/-Ku80+/+ genotype. This is apparently consistent with the observation that haplo-insufficiency of another NHEJ molecule Lig4 induces soft tissue sarcomas in Ink4a/arf-/- mice (38) . These findings are in agreement with the notion that the compromised NHEJ activity induces tumor development in murine models as well as in humans (reviewed in 39 , 40 ). Although mutations of components of the NHEJ pathway cause lymphoid malignancy (Ku80 in Ref. 22 , 24 ; DNA-PKcs in Ref. 15 , 41 , 42 ; Lig4, in Ref. 43 ; and XRCC4 in Ref. 44 ) and soft tissue sarcomas (Lig4 in Ref. 38 ), Ku80 heterozygosity promotes the malignant transformation of hepatocytes. All of these data point to NHEJ activity as possibly playing an important role in suppressing the malignancy of various cell origins.
One of the hallmarks of malignant transformation is genomic instability caused by mutations in genome caretaker genes, which promotes a wide range of genetic mutations, chromosome deletion and translocations, gene amplification, and aneuploidy (1, 2, 3)
. Because PARP-1 and Ku80 function in DNA repair and recombination and telomere regulation as well as in chromosome stabilization (9
, 12
, 13
, 21, 22, 23)
, both molecules can synergistically maintain telomere function (see Ref. 14
) and minimize aberrant chromosome end-joining, and, thereby, suppress tumorigenesis. This hypothesis is supported by the observation that an increased frequency of chromosome end-to-end fusions and fragmentations/breaks was found in PARP-1-/-Ku80+/- MEFs, when compared with that observed in PARP-1-/-Ku80+/+, PARP-1+/+Ku80+/- and PARP-1+/-Ku80+/- cells (see Table 1
). Moreover, our SKY analysis has shown that primary HCC cells derived from PARP-1/Ku80 double mutant mice exhibit frequent end-to-end fusions, NRTs, and Robertsonian-like configurations, as well as a high degree of fragmentation. A plausible explanation for these cytogenetic alterations is that the persistence and aberrant repair of double-strand breaks caused by reduced Ku80 activity and PARP-1 mutation provide substrates for the end-joining of chromosomes, the quality of which is otherwise monitored by the NHEJ machinery (2)
. On the other hand, because PARP-1 is proposed to be an anti-recombinogenic factor (4)
and PARP-1-/- cells exhibit a high degree of SCE (7
, 9)
, this elevated recombinogenic activity induced by PARP-1 deficiency may facilitate aberrant joining of chromosome ends stalled by Ku80 deficiency leading to chromosomal translocations and fusions.
Although the functional alterations and phenotypical consequences of genes at break/fusion points remain to be investigated, we were able to show a high frequency of E-cadherin and ß-catenin alterations in HCCs of these double mutant mice. The activation of oncogenes or loss of inhibitory effect mediated by adhesion molecules has been proposed in neoplastic transformation and tumor progression (30)
. In this regard, we found frequent down-regulation or loss of E-cadherin expression in these HCCs (see Fig. 2
). These data are consistent with the notion that down-regulation or loss of E-cadherin is involved in tumor progression in animal models and human samples (30)
. Moreover, specific gene mutations, such as those in ß-catenin, render hepatocytes susceptible to a selective growth advantage leading to cancer (32)
.
These HCCs, prevalent in males and exhibiting a typical multistage progression characterized by the gradual loss of E-cadherin and the nuclear accumulation of ß-catenin, as well as chromosome translocations and fragmentations, are reminiscent of human HCC (31 , 32 , 45, 46, 47, 48, 49, 50) . Cytogenetic studies of human HCC have revealed frequent abnormalities in chromosome 1q, such as translocation, trisomy, or amplification (45 , 47 , 51) and, also, loss of heterozygosity of chromosome 1q42–43 and 2q35–37 in human HCC (52 , 53) . These studies imply that HCC-susceptible genes may localize at chromosome 1q and/or 2q. It is interesting to note that PARP-1 and Ku80 are located at human chromosome 1q41–42 (54) and 2q33–34 (55) , respectively. However, further investigation is required on whether the imbalance or loss of chromosome 1q may alter human PARP-1 gene expression or its ADP-ribosylation activity, and whether loss of heterozygosity of 2q35–37 in humans may lead to Ku80 deficiency, together with PARP-1 dysfunction, contributing to HCC formation.
HCC is one of the most common human malignant tumors in the world. Although infections by hepatitis B and C viruses, excessive alcohol intake, and exposure to aflatoxin B1 are major etiological factors for liver cancer, the molecular changes leading to hepatocyte transformation and cancer development remain largely unknown, partly because of the limited animal models available. The present study has demonstrated the interaction of PARP-1 and Ku80 as genome caretakers in suppressing liver tumorigenesis and the role that the NHEJ pathway plays in suppressing tumorigenesis. The high incidence of liver tumors (60%) in PARP-1-deficient Ku80+/- mice is associated with the molecular and genetic alterations that often occur in human HCC; therefore, these mice represent a potential model for human HCC, which would allow the exploration of the molecular and genetic mechanism of HCC and of the possible applications in developing therapeutic strategies.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This research and Z-Q. W.’s laboratory are supported by the Association for International Cancer Research, United Kingdom, and by the Association pour la Recherche contre le Cancer, France. The work by M. P. H. and P. M. L. for this study was supported by a grant from the National Cancer Institute of Canada with funds from the Terry Fox Run. 
2 To whom requests for reprints should be addressed, at International Agency for Research on Cancer, 150 cours Albert-Thomas, 69008 Lyon, France. Phone: 33-4-72-73-8510; Fax: 33-4-72-73-8329; E-mail: zqwang{at}iarc.fr
3 The abbreviations used are: PARP, poly(ADP-ribose) polymerase; SCE, sister chromatid exchange; SCID, severe combined immunodeficient; NHEJ, nonhomologous end joining; DNA-PK, DNA-dependent protein kinase; DNA-PKcs, catalytic subunit of DNA-PK; SSCP, single-strand conformational polymorphism; HCC, hepatocellular carcinoma; MEF, mouse embryonic fibroblast; DAPI, 4',6-diamidino-2-phenylindole; SKY, spectral karyotyping; NRT, nonreciprocal translocation; FISH, fluorescence in situ hybridization.
4 W-M. Tong and Z-Q. Wang, unpublished observations.
Received 5/29/02. Accepted 10/ 4/02.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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