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[Cancer Research 61, 5366-5369, July 15, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

DNA Polymerase {kappa}, Implicated in Spontaneous and DNA Damage-induced Mutagenesis, Is Overexpressed in Lung Cancer1

Jiyang O-Wang2, Kiyoko Kawamura, Yuji Tada, Haruo Ohmori, Hideki Kimura, Shigeru Sakiyama and Masatoshi Tagawa2

Divisions of Pathology [J. O-W., K. K., Y. T., S. S., M. T.] and Thoracic Diseases [H. K.], Chiba Cancer Center Research Institute, Chiba 260-8717, Japan, and Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan [H. O.]


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
DNA polymerase {kappa} (Pol {kappa}) is a newly identified low-fidelity polymerase implicated in spontaneous and DNA damage-induced mutagenesis. As an initial study to investigate its possible involvement in tumorigenesis, we compared the expression level of Pol {kappa} in tumors and adjacent nontumorous tissues by Northern blot, semiquantitative RT-PCR, and Western blot analyses. In this study, paired tumor and normal specimens from 29 patients with stages I to IIIb non-small cell lung cancer (NSCLC), including 13 adenocarcinomas, 15 squamous cell cancers, and 1 adenosquamous carcinoma, were analyzed, among which different levels of tumor-associated Pol {kappa} overexpression were observed in 21 of 29 matched specimens. In addition, five matched specimens exhibited elevated Pol {kappa} expression in both tumor and control tissues, whereas only one nontumorous tissue expressed a higher level of Pol {kappa} than its tumor counterpart. The preferential up-regulation of Pol {kappa} expression in tumors was highly significant (P < 0.001). There was no apparent correlation of Pol {kappa} expression levels with tumor histology, grade, and stage or with smoking history. Southern blot analysis did not show amplification of the Pol {kappa} gene, indicating that the elevated Pol {kappa} expression is likely attributable to dysregulated transcription. Our data suggest that Pol {kappa} may contribute to lung tumor development by accelerating the accumulation of mutations.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Accumulation of somatic mutations has been causally related to cancer development. Recent studies indicate that mutations can arise during the bypass of DNA damage (1, 2, 3) . Specialized low fidelity polymerases are required to bypass unrepaired lesions that otherwise block replication by normal polymerases. Recently, a number of such lesion-bypassing polymerases have been identified in mammalian cells, including Pol {zeta}, Pol {eta}, Pol {iota}, Pol {kappa}, and Rev1 (1, 2, 3) . Either error-free or error-prone bypass can be accomplished depending on the polymerases used, the type of lesions encountered, and the sequence context of the lesions. Errors, however, seem to occur in most cases and result in mutagenesis. Interestingly, deficiency in Pol {eta}, which is able to correctly bypass UV-induced cyclobutane thymine dimers, causes xeroderma pigmentosum variant, a genetically inherited disorder highly susceptible to sunlight-induced skin cancers (4 , 5) . Although this finding illustrates the significance of this class of polymerases in human disease, the biological functions of the other lesion-bypassing polymerases are still poorly understood.

Pol {kappa} is a low-fidelity polymerase with moderate processivity and is highly inaccurate when replicating undamaged DNA (6, 7, 8) . Pol {kappa} is the mammalian homologue of the Escherichia coli DinB (9 , 10) , which is required for {lambda}-phage untargeted mutagenesis (11) . Overexpression of DinB in E. coli greatly increases mutagenesis in the absence of exogenous DNA-damaging agent (12) . Likewise, transient expression of the Pol {kappa} gene in cultured mouse cells caused a 10-fold increase in the incidence of mutations in the endogenous Hprt locus (10) . In addition, Pol {kappa} can carry out error-prone bypass of certain DNA lesions (6 , 13) , including an abasic site, N-2-acetylaminofluorene guanine adduct and 8-oxoguanine. Collectively, these results have implicated Pol {kappa} in mutagenesis.

Despite the highly mutagenic properties of Pol {kappa}, no evidence has been provided that indicates its possible involvement in human cancer. In the present study, we have examined Pol {kappa} expression in paired tumor and normal specimens from NSCLC.3 The analysis revealed elevated Pol {kappa} expression in a high percentage of lung tumors in comparison with their nontumorous tissue counterparts. Our data suggest a link between Pol {kappa} expression and lung cancer and implicate a role for Pol {kappa} in tumorigenesis.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Tissue Specimen.
Surgically resected tumors and their adjacent normal tissue (>3 cm away from the tumor) were obtained from the Chiba Cancer Center Tissue Bank (Chiba, Japan) as fresh-frozen tissues. These included tissues from 29 patients with stages I to IIIb NSCLC, of which 13 patients had adenocarcinomas, 15 had squamous cell cancers, and 1 had adenosquamous carcinoma. These tissues were resected before the patients received chemotherapy and/or radiation therapy.

RNA Extraction and RT-PCR Analysis.
Surgically resected tissue (~100 mg) was homogenized mechanically in 1 ml of TRIzol reagent (Life Technologies, Inc., Rockville, MD), and the total RNA was extracted according to the manufacturer’s protocol. First-strand cDNA was synthesized from 5 µg of total RNA using SuperScript II reverse transcriptase (Life Technologies, Inc.) and random primers following the company’s protocol. PCR reaction was performed in 20 µl of buffer containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, 200 µM each dNTP, 5 pmol each primer, and 1 unit of Taq DNA polymerase (Toyobo, Osaka, Japan). For glyceraldehyde 3-phosphate dehydrogenase gene expression, forward (5'-ACCACAGTCCATGCCATCAC-3') and reverse (5'-TCCACCACCCTGTTGCTGTA-3') primers were used, and the amplification was performed at 94°C for 15 s, 60°C for 15 s, and 72°C for 40 s for 25 cycles. For human Pol {kappa} expression, forward (5'-GCCATGCCAGGATTTATTGCTA-3') and reverse (5'-CTCCTTTGTTGGTGTTTCCT-3') primers were used, and the reaction was performed at 95°C for 5 s, 61°C for 10 s, and 72°C for 2 min for 30 cycles. For Pol {eta} expression, forward (5'-ACCCAGGCAACTACCCAAAAC-3') and reverse (5'-GGGCTCAGTTCCTGTACTTTG-3') primers were used, and the amplification was carried out at 95°C for 5 s, 61°C for 10 s, and 72°C for 1 min for 30 cycles.

Northern and Southern Blot Analyses.
For Northern blot analysis, 10 µg of total RNA was resolved in 1% formaldehyde agarose gel and transferred to a nylon membrane (Hybond-N, Amersham Pharmacia Biotech). The membrane was baked at 80°C for 1 h under vacuum and hybridized with a 32P-labeled 1133-bp human Pol {kappa} cDNA fragment (corresponding to nucleotides +451 to +1583 relative to the translational start codon +1). The membrane was stripped and rehybridized with an 18S rRNA probe to ensure the equal loading of the RNA. For Southern blot analysis, 10 µg of high-molecular weight DNA was digested with HindIII, size-fractionated in 0.7% agarose gel, transferred to a nylon membrane, and hybridized with the same human Pol {kappa} probe. The membrane was similarly rehybridized with a human Rev3 probe corresponding to nucleotides 1772 to 2979 of the published sequence (14) .

Western Blot Analysis.
The tissue (100 mg) was homogenized in 1 ml of lysis buffer [50 mM Tris-HCl (pH 6.8), 2% SDS, 1 M 2-mercaptoethanol, and 10% glycerol] containing a cocktail of protease inhibitors (Sigma Chemical Co.), 1 mM phenylmethylsulfonyl fluoride, and 1 mM EDTA and then sonicated for 2 min. The lysate proteins were centrifuged at 5000 rpm for 3 min, and the supernatant was heated at 100°C for 5 min before loading to an 8% SDS polyacrylamide gel. The resolved proteins were transferred to a polyvinylidene difluoride membrane with a semidry blotter, blocked with I-block (Tropix, Bedford, MA) at 4°C overnight, reacted with 0.3 µg/ml of the rabbit antibodies to Pol {kappa} and then by horseradish peroxidase-labeled goat antibodies to rabbit IgG (Life Technologies, Inc.). The membrane was developed with enhanced chemiluminescence (Amersham Pharmacia Biotech), following the company’s protocol.


   Results
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Pol {kappa} Expression in Tumors and Their Matched Nontumorous Tissue.
Matched specimens from 29 NSCLC patients were analyzed for Pol {kappa} expression. The clinicopathological features of these cancers are summarized in Table 1Citation . Northern blot analysis was performed with 21 matched specimens from which sufficient amounts of RNA were obtained. In 16 of 21 matched specimens (cases 1 through 10 and cases 12, 13, 15, 17, 18, and 20), Pol {kappa} was overexpressed in tumors but not in their nontumorous tissue counterparts (Fig. 1A)Citation . Pol {kappa} expression was elevated both in tumor and nontumorous tissues in four matched specimens (cases 11, 16, 19, and 21) and was undetectable in one matched specimen (case 14; Fig. 1ACitation ). RT-PCR analysis was performed for the remaining matched specimens, which revealed elevated Pol {kappa} expression in five of eight tumors (cases 23, 24, and 26–28) and decreased Pol {kappa} expression in one tumor (case 29) relative to their control tissues (Fig. 1B)Citation . Pol {kappa} expression could be detected both in tumor and nontumorous tissues in case 22, whereas only faint bands were detectable in case 25. The preferential up-regulation of Pol {kappa} expression in tumor relative to nontumor is statistically significant (P < 0.001; Fisher’s exact test), and the overall expression pattern of the Pol {kappa} gene is summarized in Table 1Citation . We also examined the expression of Pol {eta}, a related translesional DNA polymerase belonging to the same Dinb/UmuC superfamily (9 , 10) . In contrast to Pol {kappa}, Pol {eta} was expressed at similar levels in both tumor and normal specimens (Fig. 1C)Citation , indicating that the up-regulation of Pol {kappa} expression is specific for lung cancer.


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  		Table 1 Clinicopathological features of NSCLC patients

 


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  		Fig. 1. A, Northern blot analysis of Pol {kappa} expression in 21 tumors and their matched nontumorous tissue. Arrow, the expected 4.9 kb Pol {kappa} mRNA. B, RT-PCR analysis of Pol {kappa} expression in eight matched specimens. C, RT-PCR analysis of Pol {eta} expression in 29 matched specimens. T, tumor; N, adjacent nontumorous tissue.

 
Representative matched specimens were analyzed further by Western blot analysis to evaluate the levels of Pol {kappa} protein. Consistent with the results of Northern blot and RT-PCR analysis, the Mr 96,000 Pol {kappa} protein was observed in tumors but not in their control tissues in cases 3–5 and was undetectable in case 25 (Fig. 2)Citation . We noted that in case 2, the size of the Pol {kappa} protein was reduced to Mr ~85,000. This smaller product is likely derived from alternatively spliced transcripts (9) . Although in general the elevated Pol {kappa} RNA expression was accompanied by an increase in Pol {kappa} protein, the nontumorous tissue of case 11 expressed a higher level of Pol {kappa} mRNA (Fig. 1A)Citation but a lower level of Pol {kappa} protein (Fig. 2)Citation relative to its tumor counterpart. This suggests that Pol {kappa} expression may be regulated by both transcriptional and posttranscriptional mechanisms. The Mr 96,000 band could also be detected in COS-7 cells transfected with a human Pol {kappa} cDNA but not an empty vector (Fig. 2)Citation , confirming that it is the Pol {kappa} gene product. There was no apparent correlation between Pol {kappa} expression levels and specific clinicopathological features of the NSCLC. A greater number of lung cancer specimens are now under investigation to determine whether elevated Pol {kappa} expression might be related to smoking history, metastasis, and clinical outcome.



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  		Fig. 2. Western blot analysis of representative matched specimens and COS-7 cells transfected with a human Pol {kappa} cDNA or an empty pcDNA3.1 vector. T, tumor; N, nontumorous tissue. Arrow, the Mr 96,000 Pol {kappa} protein.

 
Pol {kappa} Gene Is Not Amplified.
Southern blot analysis was performed to reveal the copy number of the Pol {kappa} gene. On the basis of the relative band intensities between the Pol {kappa} gene and Rev3, a ubiquitously expressed gene (15) , we concluded that the Pol {kappa} gene was not amplified in the tumors (Fig. 3)Citation . The Pol {kappa} probe detected four bands (5, 3.8, 3.3, and 2.1 kb) in all tumor and nontumorous tissues, as well as in the control placental DNA. There were no aberrant bands in any of the tumor tissues examined. Therefore, no chromosomal translocations were evident with the Pol {kappa} probe we used.



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  		Fig. 3. Southern blot analysis of DNA from tumor and normal specimens. Genomic DNA was extracted from paired tumor and nontumorous tissues (cases 5–11) or from tumor tissues only (cases 1–4, 13, 15, 12, and 17). Human placental DNA was used as a normal control. Arrowheads, multiple bands detected by the Pol {kappa} probe. A human Rev3 cDNA fragment was used as a control probe and gave rise to the predicted 1.4 kb band. T, tumor; N, matched nontumorous tissue.

 

   Discussion
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Despite the error-prone properties of Pol {kappa} for both undamaged and damaged DNA, no evidence has been provided thus far to indicate its relevance in human cancer. The present study is the first documentation that Pol {kappa} is overexpressed in malignant human tissues compared with their matched normal tissue counterparts. Because Pol {kappa} is highly mutagenic when copying undamaged DNA, the elevated Pol {kappa} expression might cause an increased spontaneous mutation rate. In addition, the ability of Pol {kappa} to erroneously bypass an abasic site, N-2-acetylaminofluorene-adduct and 8-oxoguanine, implicates that mutagenesis induced by these DNA lesions may be greatly enhanced. Pol {kappa} may thus contribute to tumorigenesis by accelerating the accumulation of both spontaneous and DNA damage-triggered mutations. Moreover, elevated Pol {kappa} expression in the majority of NSCLCs, irrespective of their stages, suggests its possible involvement in both the initiation and progression of tumors.

Using the same matched specimens of NSCLC, we have recently shown that the human Rev3 gene, which encodes the catalytic subunit of Pol {zeta}, is not overexpressed in tumors (15) . Whereas human Rev3 appears to be involved in UV-induced mutagenesis (14) , its biochemical properties for undamaged and damaged DNA have not been defined. In addition, we have shown in the present study that the expression of Pol {eta} is not altered in these lung cancer cells, indicating that the elevated Pol {kappa} expression does not simply reflect some global alteration associated with tumorigenesis but is specific for lung cancer. The lack of Rev3 and Pol {eta} overexpression in the same NSCLC indicates that the expression of these polymerases is differentially regulated. Their potential roles in tumorigenesis may differ depending on the type, origin, and tissue specificity of cancers.

The most important risk factor for lung cancer is tobacco smoking. Among the many constituents found in tobacco smoke, BaP is the most potent carcinogen known (16 , 17) . In E. coli, the induction of -1 frameshift mutations by a BaP adduct in one particular template sequence of 5'-GGGBaP-3' was shown to require DinB (18) . In contrast, human Pol {kappa}, the homologue of E. coli DinB, was reported to bypass a different BaP adduct in a relatively error-free manner under in vitro conditions (13) . Although additional studies are required to reveal the biochemical properties of Pol {kappa}, it is possible that error-free or error-prone bypass of BaP adducts by Pol {kappa} may depend on the type of adducts and the sequence context. It remains an interesting issue as to whether elevated Pol {kappa} expression may be relevant to a smoking-associated increase of lung cancer incidence. In any case, the mutagenic properties of Pol {kappa} for several other types of DNA lesions, as well as its extreme inaccuracy when replicating undamaged DNA, strongly suggest that its elevated expression may result in enhanced mutagenesis, thereby contributing to tumorigenesis.

It is unclear what causes the up-regulation of Pol {kappa} expression in such a high percentage of lung tumors and in some nontumorous tissues. Pol {kappa} is normally expressed at low levels in most tissues except for the testis (9 , 10) . Our data indicate that the enhanced Pol {kappa} expression is not attributable to its gene amplification. One possibility for the elevated Pol {kappa} transcription is its translocation to the vicinity of an actively transcribed gene locus. With the Pol {kappa} probe used, however, we could not detect apparent gene rearrangements within the Pol {kappa} locus, although the possibility that translocations might occur in the 5' or 3' flanking region cannot be excluded. A more likely possibility is that Pol {kappa} gene expression may be under the control of certain transcription factors whose expressions are dysregulated during the course of neoplastic transformation. An intriguing possibility is that Pol {kappa} transcription might be directly or indirectly regulated by the tumor suppressor p53, which is mutated in ~60% of the lung cancers, or by the products of the Myc family of oncogenes, which are frequently amplified and overexpressed in tumors.

Deficiency in DNA repair genes is associated with high susceptibility to cancer. In this regard, DNA repair genes are tumor suppressors. The highly mutagenic properties of Pol {kappa} and its elevated expression in tumor tissues as revealed in the present study collectively suggest that Pol {kappa} could act as an oncogene. Future studies are required to determine the function of Pol {kappa} in vivo, in particular its role in tumorigenesis. It remains to be examined whether other members of the recently identified lesion-bypassing DNA polymerases (1, 2, 3) might also be overexpressed in human malignancies.


   ACKNOWLEDGMENTS
 
We thank Drs. Tomoo Ogi and Eiji Ohashi for preparing the rabbit antibodies to human Pol {kappa}.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Culture and Technology in Japan. Back

2 To whom requests for reprints should be addressed, at Chiba Cancer Center Research Institute, Division of Pathology, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan. Back

3 The abbreviations used are: NSCLC, non-small cell lung cancer; RT-PCR, reverse transcription-PCR; BaP, benzo(a)pyrene; Pol, DNA polymerase. Back

Received 3/28/01. Accepted 5/24/01.


   REFERENCES
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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