Deficiency of Queuine, a Highly Modified Furine Base, in Transfer Rnas from Primary and Metastatic Ovarian Malignant Tumors in Women1

[CANCER RESEARCH 54, 446X-4471. August 15, 19

Wlodzimierz Baranowski,2 Guy Dirheimer, Jerzy Andrzej Jakowicki, and GÃ©rardKeith

Second Clinic of Gynecological Surgery, Academy of Medicine, 8 Jaczewski Street, Lublin 20849. Poland fW. B., J. A. J.J, and UnitÃ©"Structure des MacromolÃ©cules Biologiques et MÃ©canismesde Reconnaissance, " Institut de Biologie MolÃ©culaireet Cellulaire du CNRS, 15 rue RenÃ©Descartes, Strasbourg 67084, France [G. D., G. K.]

ABSTRACT queuine on their own despite its presence in their queuine family tRNAs. In mammals, queuine is provided by the intestinal flora or as The IUN As from rapidly growing tissues, particularly from neoplasia, a diet factor. Furthermore, in embryonic tissues and regenerating rat often exhibit queuine deficiency. In order to check whether different kinds liver (i.e., in rapidly growing tissues), the queuine family tRNAs are of ovarian tumors display queuine deficiencies we have analyzed tRNA partially queuine deficient (6, 9). Similar observations of queuine samples from 16 ovarian malignancies. The tRNAs from histologically normal myometrium (4 samples) and myoma (6 samples) were taken as deficiency have been made in queuine family tRNAs from placenta healthy tissue and benign tumor references. Queuine deficiency was de tissue despite the presence of a large amount of free queuine in the termined by an exchange assay using (8-'H]guanine and tRNA:guanine amniotic fluid (8, 10). It has in addition been observed that neoplastic transglycosylase from EscherÃ¬chiacoli. tissues very often exhibit significant deficiencies in the queuine con The mean values of queuine deficiencies in tRNAs were: 10.95 Â±2.21 tent of queuine family tRNAs (9). In induced animal tumors the (SD) pmol \ ,,,â€žingonadal and germ cell tumors (5 cases); 23.75 Â±7.89 queuine deficiency could be correlated with the histological signs of pmol/A260 in primary epithelial tumors (9 cases); and 34.58 Â±7.18 pinol malignancy (9), whereas similar observations could also be done in a A26V in metastatic tumors (2 cases). These values displayed statistically significant differences I/' = 0.0003, Kruskal-Wallis test). The queuine few cases of human malignancies, such as leukemias, lymphomas, and deficiencies in tRNAs significantly increased when moving from well- lung cancers (11, 12). differentiated through moderately differentiated to poorly differentiated Many different kinds of tumors, from benign to malignant through tumors, with the highest values found in poorly differentiated metastatic borderline malignant tumors can affect the ovary. The ovarian malig tumors i/' = 0.0002, Kruskal-Wallis test). Queuine deficiency determina nancies are generally of very poor prognosis due to silent growth and tion in tRNAs is proposed as a factor for clinical outcome prognosis of relative inaccessibility in the early stages of the diseases. Postopera- ovarian malignancies. tively, the basic factors for clinical outcome prognosis are the histo logical determination of the type of the tumor, the differentiation grade, and the tumor burden (13, 14). INTRODUCTION Our initial working hypothesis was that it might be possible that The high content of modified nucleosides is one of the character even in the early stages of the diseases the queuine content in tRNAs istic features of tRNAs. These modified nucleosides are posttranscrip- could already have been affected and could be determined in order to tionally synthesized either by direct modification of a major nucleo- consider it as a prognostic factor. We therefore undertook investiga side or by replacement of a major base by a modified one (editing) tions to estimate directly the extent of the queuine deficiency in (for a review see Refs. 1 and 2). The modified nucleosides at the first tRNAs from various human ovarian tumors in order to check for the position of the anticodon, the so-called "wobble position" in tRNA differences, if any, in relation to histopathological type of malignancy molecules, play an important role in fine tuning of codon-anticodon and grading of differentiation. interactions in tRNA-mediated message translation from mRNA into protein chain and as determinants or antideterminants of specificity of MATERIALS AND METHODS aminoacylation (for reviews see Refs. 1 and 3). The modifications at this position can be very simple, e.g., a single methylation, or very The tissues were collected from 1983 to 1992 during the operations in the complicated, as it is in the case of queuine, a highly modified purine Second Clinic of Gynecological Surgery of the Medical Academy, Lublin, (deazaguanine derivative), which is found in isoacceptor tRNAs for Poland. After surgery the samples were immediately immersed and kept in asparagine, aspartic acid, histidine, and tyrosine (queuine family liquid nitrogen until further processing. For routine histopathological charac tRNAs) (4, 5). Queuine is incorporated into tRNA posttranscription- terizations several probes from each tumor were fixed in formalin and embed ded in paraffin according to standard institutional procedure (Department of ally by a specific enzyme, the tRNA:guanine transglycosylase (EC Pathomorphology, Medical Academy, Lublin, Poland). 2.4.2.29), which mediates the exchange of the guanine by queuine As a healthy reference, the tRNAs from histologically normal myometrium without phosphodiester bond breakage (6). Investigations of the role were taken because no reference sample from normal ovary could be prepared of queuine in codon-anticodon interactions showed that queuine has due to the tissue heterogeneity of that organ. Myoma tRNA samples were used an essential function in the enhancement of correct translation of the as benign tumor controls. The reference tissues (myometrial and myoma codons (2). In addition it has been shown that queuine-lacking tRNA- specimens) were taken from the patients who were operated for reasons other Tyr in mammalian tissues could have amber suppressor activity (7). than ovarian cancer. No therapy other than surgery was applied to these Queuine, as a free base, is widely distributed in nature (8). How patients before specimens were taken. Consent statements for further analysis ever, mammals, as well as other animals, are not able to synthesize of collected tumors were obtained from each patient prior to surgery. The detailed clinical data concerning these patients are presented in Table 1. tRNA Preparation and Purification. tRNA was prepared by initial phe Received 2/17/94; accepted 6/16/94. nol extractions followed by selective isopropyl alcohol separation of the 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 nucleic acids according to the procedure of Sein el at. (15). Crude tRNA 18 U.S.C. Section 1734 solely lo indicale this fact. samples were further purified on DEAE-52 cellulose. Due to DNA contami 1This paper was presented at the European Society for Gynecologic and Obstetric nation, which was still present after Chromatographie purification, bulk tRNA Investigation "Growth and Differentiation in Reproductive Organs" Workshop, February was additionally treated by RNase-free DNase I (Promega, Madison, WI) for 6-12, 1994, Madonna di Campiglio, Italy. This work was supported by a grant from the 2 h at 37Â°Cin 40 mM Tris-HCI buffer, pH 7.9, containing 10 HIMNaCl and 6 French Ministry of Sciences and Technology and fellowships from the French Ministry of mM MgCU. After additional phenol extraction (0.5 h shaking at 4Â°C)and Sciences and Technology and Federation of European Biological Societies (W. B.). 2 To whom requests for reprints should be addressed. centrifugation, the water layer was collected and chromatographed on a Seph- 4468

Table 1 Queuine deficiencies in total tRNAs from human ovarian tumors and uterus tissues

stage courseResultsWell (FIGO diameter examination (grade [3H]guanine PatientOvarian classification)1AIAIAnc1CIIIIIIIIIIIIIVIIIIIIIIIIIIMetastatic(cm)5126610101087881079512Histopalhologicaldifferentiation)Dysgerminomaof (pmol/A260)12.2113.488.0911.709.2523.7431.9612.2425.6335.2823.7523.h911.0324.0429.5039.663.493.675.527.157.425.326.166.293.447.614.4750.96Years5.011.06.02.5Data1.01.04.50.51.54.03.03.52.02.01.5Survival malignancy1. T.A.2. (W-D)Dysgerminoma (NSDfWell M.A.3. (W-D)Granulosa (NSD)Well K.T.4. (W-D)Granulosacell tumor (NSD)Well B.E.5. (W-D)Teratomacell lumor (NSD)not K.B.6. (W-D)Serousmalignisatum availableDiedDiedRDDiedDiedDiedDiedRDDiedDiedDied W.W.7. (M-D)Carcinomaadenocarcinoma W.J.8. (P-D)Serous anaplasticum M.H.9. (M-D)Serousadenocarcinoma M.A.10. (P-D)Serousadenocarcinoma M-R.Z.ll.G. (M-D)Serousadenocarcinoma W.12. (M-D)Serousadenocarcinoma P.H.13. (M-D)Serousadenocarcinoma J.J.14. (M-D)Serousadenocarcinoma M.I.15. (M-D)Carcinomaadenocarcinoma K.M.16. tumorMetastatic (MP-D)Neoplasmaendometriale S.K.Reference tumorTumor (P-D)MyometriumMyometriumMyometriumMyometriumMyomamesenchymale prob, angiogenes tissues'"17. L.R.18. K.H.19. J.M.20. K.B.'21.

K.B.c22. cellulareLeiomyoma B.T.23. uteriLeiomyoma O.Z.24. uteriLeiomyoma N.M.25. uteriLeiomyoma N.M.26. uteriLeiomyoma W.A.E. uteripartim cellulareInserted coliYeast (S. cerevisiae)Age142042472257hi565952405453hi495338424339ÃŽ94344hi4544Clinical " NSD, no signs of disease; RD. recurrence of disease; W-D. well differentiated; M-D, moderately differentiated; MP-D. moderately to poorly differentiated; P-D, poorly differentiated. Due to heterogeneity of normal ovary no reference sample from that organ could be prepared. ( The same patient. adex G-25 column to remove the salts and the traces of phenol. With the use ing to a mean Â±SD of 20.95 Â±9.99 pmol/A260) as compared to of that method, the amount of total tRNA obtained varied from 60 to 400 /xg/g normal tissue tRNAs (myometrium, 4.96 Â± 1.73 pmol//4260, depending on the kind of tumor. To check the purity of the tRNA samples, P = 0.0004) and benign tumors (myomas, 6.04 Â±1.53 pmoU426(), 10% polyacrylamide gel electrophoresis in semidenaturating conditions (4 M P = 0.00003). The P values were calculated using the Wilcoxon W urea, pH 8.3) was performed. Detection of RNA fractions was done by test. There is no statistically significant difference in queuine defi mÃ©thylÃ¨nebluestaining or UV shadowing (16). ciency between normal myometrium and myoma tissue tRNAs Queuine Deficiency Determination in Unfractionated tRNAs. Queuine deficiency was determined by an exchange assay using tRNA:guanine trans- (P = 0.5). In order to find the correlation, if any, between histopatho- glycosylase (6) obtained from an overproducing MRE-600 Escherichia coli logical type of tumor and queuine deficiency, the set of 16 patients strain (generous gift from Dr. K. Reuter, University of Erlangen, Nuremberg, with malignant ovarian tumors was divided into 3 groups. The first Germany). [S-'HjGuanine (specific activity, 10.4 Ci/mmol) was from Sigma group consisted of 5 patients with gonadal and germ cell tumors Chemical Co. (St. Louis, MO). The reaction mixture in a total volume of [dysgerminoma (2 cases), granulosa cell tumor (2 cases), and teratoma 100 pii contained 4 pig (0.1 A2ha) of tRNA, 2 fig (approximately 4 units) of malignisatum (1 case)]. The mean of queuine-deficient tRNAs in this tRNA:guanine transglycosylase, and 50 pmol (0.5 /^Ci) of [S-^HJguanine group was 10.95 Â±2.21 pmol/A260. This value was significantly dissolved in buffer (70 mM Tris-HCl, pH 7.0-20 mM MgCl2-0.1 M NaCl-6 mM ÃŸ-mercaptoethanol). Incubation time was for l h at 37Â°C.The reaction was lower than the mean value of the second group, which consisted of 9 patients with epithelial tumors (23.48 Â±7.89 pmolM26(), P = 0.012), stopped with 15% trichloroacetic acid. The precipitate was collected on Whatman No. 3MM discs and washed three times with 5% trichloroacetic acid and the third group, which consisted of 2 patients with metastatic and twice with 95% ethanol. The sample was dried and counted by liquid tumors (34.58 Â±7.18 pmol/A26(l, P = 0.022) (Fig. 1). scintillation (Beckman Model 6000SLC). Each tRNA sample was estimated in We also examined the queuine deficiency in tRNAs as a function of triplicate. E. coli and Saccharomyces cerevisiae tRNAs, both from Boehringer grading of differentiation by dividing the cancer patients into 4 tumor Mannheim (Mannheim, Germany) were used as references for either com groups: group 1. well differentiated; group 2, moderately differenti pletely queuine-modified or queuine-lacking tRNAs, respectively. The results were expressed as pmol of [8-3H]guanine incorporated/,4 260of tRNA. ated; group 3, moderately to poorly differentiated; and group 4, poorly differentiated. Because we found only one case of the moderately to Statistical analyses were performed using the Wilcoxon rank sum and Kruskal-Wallis tests. poorly differentiated tumor, we decided to include the corresponding value for the purpose of statistical analysis to the group of poorly differentiated tumors. This kind of classification led to the following RESULTS results for queuine deficiency: group 1, 10.95 Â±2.21 pmol/A2f)0; The values of queuine deficiency in 16 malignant ovarian tumor group 2, 21.97 Â±5.97 pmol/A26(); and groups 3 and 4, 31.69 Â±8.22 tRNAs were significantly higher (range, 8.09-39.66 pmol//4260, lead pmol/A2M>. When analyzed by the Kruskal-Wallis test, these results 4469

solid tumors. Among these tumors, in contrast to our results, 2 O vO metastatic ovarian neoplasm tRNAsAsp were not queuine deficient. N Â±7.1823.48Â±789T Furthermore, Singhal and Vakharia (18) did not observe any queuine deficiency in tRNAAsp from neoplasma tissue but their investigations

30 - were carried out several days after transplantation of human adenocarcinoma ovaries into athymic mice. Results obtained in our group of patients were very close to those published by Emmerich et al. (Il) n and Huang et al. (12). The differences between our estimations and s m 20 - the results of GÃ¼ndÃ¼zetal (17) and Singhal and Vakharia (18) could be a result of the different methodologies used. The clinical outcome of ovarian malignancies depends on several Â±2.21â€” factors, such as histopathological type of tumor, grade of differenti ation, clinical stage recognized during laparotomy, and size of resid 10 - Fâ€”i34.58 Â±1.53 ual tumor (13, 14). The recently developed amplification of the Â±1.73TÃ¯Ã¯fe6.04 . .T. . .10.95 HER-2/neu proto-oncogene (19, 20) and cancer-associated galactosyltransferase (21) could be prognostic markers in epithelial tumors [serous and clear cell (mesonephroid), respectively] but they are not n -4.96 suitable for prognosis of the other kinds of ovarian tumors (gonadal, B D germinal, and other kinds of epithelial originating tumors). Fig. 1. Queuine deficiency in tRNAs from normal myometrium (A), myomas (ÃŸ), Particularly in granulosa cell tumor-diseased patients, the postop germ cells and gonadal tumors (C), epithelial tumors (Â£>),andmetastatic tumors (Â£).The differences among normal myometrium and different tumor groups are statistically erative outcome prognosis based primarily on histopathological ex significant (P = 0.0003, Kruskal-Wallis test). Columns, mean bars, SD. amination is extremely difficult. The course of granulosa cell tumor can be either slow or very rapid and progressive, even when recog nized at the early stages (22). Supporting the previous observation, e vo Scully (23) described the occurrence of two kinds of granulosa cell M 31.69 tumors, one being highly malignant and the other being low malig Â±8.22 nant, but prognosis of the clinical outcome could not be established I histologically. In the present paper we have shown in tRNAs obtained 30 - 21.97 from 2 cases of granulosa cell tumors that the queuine deficiency was low and close to queuine estimations in tRNAs from myoma tissue and almost identical to tRNAs from human placenta (10). After 2.5- iâ„¢ D and 6-year observation periods, these two granulosa cell tumor pa 20 tients presented no signs of disease recurrence. The extent of queuine deficiency in tRNAs correlated with cell proliferations, and could 10.95 Â±2.21 therefore be used as a complementary factor for clinical outcome prognosis in the case of granulosa cell tumors. The problem seems to 10 - 6.04 be very important for clinicians when they have to consider postop 4.96 Â±1.53 Â±1.73 erative treatment (radiotherapy and sometimes chemotherapy) in mkm young (i.e., reproductive age) women. However, other investigations and longer times of observation are needed to confirm these promising but only preliminary results. I III IV Additional support for the use of the queuine content in tRNAs for Fig. 2. Queuine deficiency in tRNAs from normal myometrium (/), myomas (//), well the prognosis of the postoperative outcome of disease could be con differentiated (///), moderately differentiated (Â¡V),and moderately to poorly and poorly firmed by further observations on several patients in epithelial and differentiated (V) ovarian tumors. The differences among particular groups are statisti cally significant (P = 0.0002. Kruskal-Wallis test). Columns, mean; bars, SD. metastatic groups. Indeed, patients with the highest values of queuine- deficient tRNAs died within 1-4 years after operation (patients 6, 7, 9-12, and 14-16) but it should be noted that these patients had indicated a strong correlation between the grades of differentiation advanced neoplastic process; therefore, the prognosis of clinical out and the queuine deficiencies (Fig. 2). come was already poor. Patients 8 (4.5 years after operation) and 13 (4 years after operation), who presented the lowest values of queuine DISCUSSION deficiency in epithelial tumor group, are alive but are under treatment due to recurrence of the disease. Germ cell tumor patients who To date, only a few papers have dealt with queuine deficiency in presented the low values of queuine deficiency in tRNAs (patients 1 tRNAs from human malignancies. Among them, Emmerich et al. (Il) and 2) did not show any signs of recurrence even 5 and 11 years after found a different extent of queuine-deficient tRNAs in human leuke- operation, respectively. At this stage of the study, the investigations mias and lymphomas, which they correlated with the grade of malig could not be completed for the entire group of the patients due to the nancy (histopathologically and clinically considered). Similar obser short time of observation after surgery. vations were done for human lung cancer tRNAs by Huang et al. (12). The queuine-lacking tRNAs were often found in induced animal The latter authors found a significant correlation between (a) queuine tumors and transformed cell cultures but the reason why tRNAs from deficiency in tRNAs extracted from lung carcinomatous tissues, (b) tumor are hypomodified with respect to queuine nucleoside is, to date, grading of differentiation (histologically recognized), and (c) survival unclear. One explanation could be the lack of tRNA:guanine trans- rate of the patients. Recently, GÃ¼ndÃ¼zetal. (17), using a Chromato glycosylase activity in cancer cells, as reported by GÃ¼ndÃ¼zetal. (17). graphie method, found queuine-deficient tRNAAsp in only 10 of 46 Another suggestion comes from Katze et al. (24), who proposed that 4470

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1994 American Association for Cancer Research. OUEUINE DEFICIENCY IN HUMAN OVARIAN MALIGNANT TUMORS queuine deficiency in tRNAs from malignant tissues could be con tion for cancer diagnosis and therapy. Recent Results Cancer Res., 84: 401-412, nected with several different factors, such as: (a) low queuine uptake 1983. 10. Baranowski. W. Tomaszewski, J., and Keith, G. Unusual deficiency of the modified rate by cancer cells and higher tRNA synthesis as compared to normal purine base queuine in transfer ribonucleic acid from the human placenta as tested by cells; (b) the lack of inserting enzyme activity as already mentioned; enzymatic assay. Am. J. Obstet. Gynecol., 169: 581-582, 1993. 11. Emmerich. B.. Zubrod, E., Weber, H., Maubach, P. A., Kersten, H., and Kersten, W. (c) queuine competition with unknown factors (pteridines?); (d) Relationship of queuine-lacking transfer RNAs to the grade of malignancy in human higher catabolic rate of free queuine in cancer cells; or (e) queuine Icukcmias and lymphomas. Cancer Res., 45: 4308-4314, 1985. salvage deficiency in tumors, or, as Langgut and Kersten (25) found, 12. Huang, B-S.. Wu, R-T., and Chien, K-Y. Relationship of the queuine content of transfer ribonucleic acids to histopathological grading and survival in human lung the lack of free queuine availability for tRNA modifications in cancer. Cancer Res., 52: 4696-4700, 1992. cancer cells. 13. Barber, H. R. K. Ovarian Carcinoma. Etiology, Diagnosis, and Treatment, pp.121- 128, New York: Springer-Verlag, 1993. 14. Slotman. B. J., and Rao, B. R. Ovarian cancer (review): etiology, diagnosis, prog nosis, surgery, radiotherapy, chemotherapy, and endocrine therapy. Anticancer Res., ACKNOWLEDGMENTS S: 417-434, 1988. 15. Sein. K. T., Bacarevic, A., and Kanazir, D. A simple modified method for the We thank Dr. K. Reuter from the University of Erlangen (Nuremberg, extraction of liver sRNA. Anal. Biochem., 28: 65-73, 1969. Germany) for the gift oÃE. coli tRNA:guanine transglycosylase. 16. Keith, G. Nucleic acid Chromatographie isolation and sequence methods. In: C. W. Gehrke and K. C. T. Kuo (eds.). Chromatography and Modification of Nuclcosides, Part A, pp. A103-A141. Amsterdam: Elsevicr Science Publishers B. V., 1990. 17. Giindiiz, U., Elliott, M. S.. Seubert, P. H., Houghlon, J. A., Houghlon, P. J., Trewyn, REFERENCES R. W., and Katze, J. R. Absence of tRNA-guanine transglycosylase in a human colon adenocarcinoma cell line. Biochim. Biophys. Acta, 1139: 229-238, 1992. 1. Giege, R.. Puglisi. J., and Florentz, C. tRNA structure and aminoacylation efficiency. 18. Singhal. R. P., and Vakharia. V. N. The role of queuine in the aminoacylation of Prog. 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Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1994 American Association for Cancer Research. Deficiency of Queuine, a Highly Modified Purine Base, in Transfer RNAs from Primary and Metastatic Ovarian Malignant Tumors in Women

Wlodzimierz Baranowski, Guy Dirheimer, Jerzy Andrezj Jakowicki, et al.

Cancer Res 1994;54:4468-4471.

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