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PubMed1994

Deficiency of queuine, a highly modified purine base, in transfer RNAs from primary and metastatic ovarian malignant tumors in women.

The tRNAs from rapidly growing tissues, particularly from neoplasia, often exhibit queuine deficiency. In order to check whether different kinds of ovarian tumors display queuine deficiencies we have analyzed tRNA samples from 16 ovarian malignancies. The tRNAs from histologically normal myometrium (4 samples) and myoma (6 samples) were taken as healthy tissue and benign tumor references. Queuine deficiency was determined by an exchange assay using [8-3H]guanine and tRNA:guanine transglycosylase from Escherichia coli. The mean values of queuine deficiencies in tRNAs were: 10.95 +/- 2.21 (SD) pmol/A260 in gonadal and germ cell tumors (5 cases); 23.75 +/- 7.89 pmol/A260 in primary epithelial tumors (9 cases); and 34.58 +/- 7.18 pmol/A260 in metastatic tumors (2 cases). These values displayed statistically significant differences (P = 0.0003, Kruskal-Wallis test). The queuine deficiencies in tRNAs significantly increased when moving from well-differentiated through moderately differentiated to poorly differentiated tumors, with the highest values found in poorly differentiated metastatic tumors (P = 0.0002, Kruskal-Wallis test). Queuine deficiency determination in tRNAs is proposed as a factor for clinical outcome prognosis of ovarian malignancies.

Adolescent↗
PubMed2000

An intronic splicing silencer causes skipping of the IIIb exon of fibroblast growth factor receptor 2 through involvement of polypyrimidine tract binding protein.

Alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) transcripts involves the mutually exclusive usage of exons IIIb and IIIc to produce two different receptor isoforms. Appropriate splicing of exon IIIb in rat prostate cancer DT3 cells requires a previously described cis element (ISAR, for "intronic splicing activator and repressor") which represses the splicing of exon IIIc and activates the splicing of exon IIIb. This element is nonfunctional in rat prostate AT3 cells, which repress exon IIIb inclusion and splice to exon IIIc. We have now identified an intronic element upstream of exon IIIb that causes repression of exon IIIb splicing. Deletion of this element abrogates the requirement for ISAR in order for exon IIIb to be spliced in DT3 cells and causes inappropriate inclusion of exon IIIb in AT3 cells. This element consists of two intronic splicing silencer (ISS) sequences, ISS1 and ISS2. The ISS1 sequence is pyrimidine rich, and in vitro cross-linking studies demonstrate binding of polypyrimidine tract binding protein (PTB) to this element. Competition studies demonstrate that mutations within ISS1 that abolish PTB binding in vitro alleviate splicing repression in vivo. Cotransfection of a PTB-1 expression vector with a minigene containing exon IIIb and the intronic splicing silencer element demonstrate PTB-mediated repression of exon IIIb splicing. Furthermore, all described PTB isoforms were equally capable of mediating this effect. Our results support a model of splicing regulation in which exon IIIc splicing does not represent a default splicing pathway but rather one in which active repression of exon IIIb splicing occurs in both cells and in which DT3 cells are able to overcome this repression in order to splice exon IIIb.

Adenocarcinoma↗
PubMed1997

Improved reverse transcriptase-polymerase chain reaction protocol with exogenous internal competitive control for prostate-specific antigen mRNA in blood and bone marrow.

The possibility of improving diagnosis of micrometastases from prostate cancer by further enhancing the detection of prostate-specific antigen-producing cells in circulation is being evaluated. We have developed a reverse transcriptase-PCR protocol with the desirable characteristics of low limit of detection, high specificity, reproducibility of response, and ease of performance. Among the procedural alterations that have contributed to these improvements are longer PCR primers, a two-step amplification cycle, and hot-start PCR. We have lowered the limit of detection to one LNCaP prostate-cancer cell in 10(8) peripheral blood mononuclear cells, and samples of blood and bone marrow from healthy donors have yielded no false positives. Because PCR procedures frequently exhibit tube-to-tube variability, we have incorporated a set of internal and external controls into the protocol-a significant advance in assuring assay reliability.

Bone Marrow↗
PubMed1987

Human papillomavirus type 17 transcripts expressed in skin carcinoma tissue of a patient with epidermodysplasia verruciformis.

Certain types of human papillomavirus (HPV) are involved in skin carcinogenesis in epidermodysplasia verruciformis. However, no gene or gene product of HPV associated with skin carcinogenesis has yet been identified. Here, we report HPV-17 transcripts expressed in skin carcinoma tissue of an epidermodysplasia verruciformis patient infected with HPV-17. Further, we show that one of these transcripts was localized to a portion of the genome which contains the 3' open reading frames of the early region (E2, E3, E4 and E5). The analogous region in bovine papillomavirus type I has been shown to contain a transforming gene (Nakabayashi et al., 1983; Sarver et al., 1984; Yang et al., 1985a).

Bovine papillomavirus 1↗
PubMed2001

Interrelationship between Epstein-Barr virus infection in gastric carcinomas and the expression of apoptosis-associated proteins.

AIMS: Epstein-Barr virus (EBV) and its associated proteins may be protective against the occurrence of apoptosis that would normally inhibit cancer development and progression. Alternatively, the viral infection may cause altered or mutated expression of oncogenes or tumour suppressor genes that are necessary for tumour development, an action that may also involve apoptosis. In this study, a relationship was sought between occurrence of EBV infection, expression of apoptosis-associated proteins (tumour suppressor gene p53 and oncogenes c-myc and bcl-2) and levels of cell death (apoptosis or necrosis) in 119 cases of gastric carcinoma. METHODS AND RESULTS: The EBV status of the gastric carcinomas (using the EBV-encoded small RNA I (EBER-1) and in-situ hybridization), stage and grade of tumour and sex of patients were compared for bcl-2, p53 and c-myc expression patterns. EBER-1 was detected in approximately 20% of cases studied. There was no significant correlation between levels of cell death in the tumour tissue and EBV status. In the protein analyses, development and progression of gastric carcinoma, with or without EBV infection, was independent of bcl-2 expression. However, in gastric cancers with EBV infection, p53 overexpression was inhibited and c-myc expression was increased in early stage cancers, in comparison with decreased c-myc expression in late stage cancers. CONCLUSIONS: The p53 and c-myc expression patterns indicate that EBV-infected gastric carcinomas are less likely to have a natural regression via apoptosis at an early stage and explain, in part, the resistance to treatment of late stage of gastric cancers.

Adenocarcinoma↗
PubMed2003

Expression of telomerase activity, human telomerase RNA, and telomerase reverse transcriptase in gastric adenocarcinomas.

Telomerase is an RNA-dependent DNA polymerase that synthesizes TTAGGG telomeric DNA onto chromosome ends to compensate for sequence loss during DNA replication. It has been detected in 85-90% of all primary human cancers, implicating that the telomerase seems to be reactivated in tumors and that such activity may play a role in the tumorigenic process. The purpose of this study was to evaluate telomerase activity, human telomerase RNA (hTR), and telomerase reverse transcriptase (TERT) in stomach cancer and to determine their potential relationships to clinicopathologic parameters. Frozen and corresponding methacarn-fixed paraffin-embedded tissue samples were obtained from 51 patients with gastric adenocarcinoma and analyzed for telomerase activity by using a TRAPeze ELISA kit. Tissue sections of all the samples were further investigated for hTR and TERT by in situ hybridization and a sensitive immunohistochemical technique, respectively. Telomerase activity was detected in 37 (73%) tumors. Telomerase positivity from methacarn-fixed paraffin blocks was found to be 35% of that from frozen tissues. hTR was overexpressed in 46 (90%) samples: 33/37 (89%) with and 13/14 (93%) without telomerase activation. Expression of TERT was demonstrated in 40 (78%) cases: 30/37 (81%) with and 10/14 (71%) without telomerase. Telomerase activity correlated well with depth of invasion (P =.037) and tumor differentiation (P =.022), whereas hTR significantly correlated with nodal metastasis (P=.047) and tumor size (P=.023). These data suggest that reactivated telomerase may play a significant role in the tumorigenesis of gastric cancer and may reflect, along with enhanced hTR, the malignant potential of the tumor. It is noteworthy that methacarn-fixed tissue cannot as yet substitute for the frozen section in the TRAP assay.

Adenocarcinoma↗
PubMed1976

Changes in transfer RNA's in human malignant trophoblastic cells (BeWo line).

Ten aminoacyl transfer RNA's prepared from human malignant trophoblastic cells (BeWo line) were compared with the corresponding aminoacyl transfer RNA's from normal human chorionic tissue by cochromatography on a RPC-5 column. Phenylalanyl transfer RNA (Phe-tRNA) of BeWo cells had, in addition to the single species of Phe-tRNA found in normal chorionic tissues, an early eluting component. When Phe-tRNA from the chorion was exposed to mild acid, which selectively excises the Y base, it eluted in the same position as the early eluting Phe-tRNA of BeWo cells. Therefore, the BeWo Phe-tRNA is partially undermodified. Tyrosyl transfer RNA of BeWo cells exhibited a broad-based peak which eluted later than the normal and probably consists of two or more tyrosyl transfer RNA's. Seryl transfer RNA of BeWo cells showed two peaks of acceptor activity, while seryl transfer RNA of normal chorion had a third peak that eluted at a higher salt concentration. In addition, in an early eluting methionyl and lysyl transfer RNA and in a late eluting arginyl transfer RNA from BeWo cells and normal charion, quantitative alterations were detected. The remaining four transfer RNA's, leucyl, aspartyl, valyl, and histidyl, from the two sources did not show any significant differences in elution profiles. These alterations of the chromatographic profile appeared to be due to new or altered species of transfer RNA. They were not due to differences in the aminoacyl transfer RNA synthetase. The transfer RNA methyltransferase capacity of the enzymes from BeWo cells was 2-fold higher than that of the enzymes extracted from the chorion.

Amino Acids↗
PubMed1994

[Hypomodified phenylalanine transfer RNAs (tRNA(Phe)) in uterine myoma tissue of women].

Phenol extracted crude tRNA samples obtained from uterine myoma tissue were additionally purified on DEAE-cellulose column and were finally fractionated on BD-cellulose column. Fractions eluted by ethanol gradient (concentration from 0% to 20%) were hybridized by dot blot technique with DNA probe which consisted of 15 nucleotides fragment complementary to 3' end of the tRNA(Phe). Five separate distinct peaks were found. According to genetic code rules restricted to two the number of tRNA(Phe) isoacceptors, it is assumed that three major peaks representing roughly 70% of total tRNA(Phe) pool, probably are hypomodified.

Chromatography, DEAE-Cellulose↗
PubMed2001

Selective Differential Display of RNAs containing interspersed repeats: analysis of changes in the transcription of HERV-K LTRs in germ cell tumors.

A technique for the Selective Differential Display of RNAs containing Interspersed Repeats (SDDIR) has been elaborated. SDDIR involves two main steps: (1) selective amplification by RT-PCR of a subset of the total cellular RNA containing a certain type of repetitive element, and (2) side-by-side display of the amplicons derived from the tissues under comparison by means of gel electrophoresis in parallel lanes. The technique was used to compare the expression of transcripts containing LTR (Long Terminal Repeat) sequences derived from human endogenous retrovirus K (HERV-K) in testicular germ cell tumors and in corresponding normal tissue. SDDIR enabled us to obtain an overview of LTRs represented in the total transcribed fraction and to reveal differences in transcription patterns of the LTRs in normal and tumor tissues. An unexpectedly large number of LTRs was found to be transcribed, and the levels of many of the transcripts differed between normal and tumor tissues.

Base Sequence↗
PubMed2004

Reversal of multidrug resistance of gastric cancer cells by down-regulation of ZNRD1 with ZNRD1 siRNA.

The over-expression of a new zinc ribbon (ZNRD1) gene has been shown previously to promote a multidrug-resistant phenotype in gastric cancer cells through the up-regulation of permeability-glycoprotein (P-gp). In the present study, siRNA eukaryotic expression vectors of ZNRD1 are constructed and transfected into SGC7901/VCR cells to examine whether or not down-regulation of ZNRD1 increases cell sensitivity towards chemotherapeutic drugs. After transfection, ZNRD1 expression decreased dramatically in ZNRD1 siRNA transfectants compared with that in parental cells and empty vector control cells. Down-regulation of ZNRD1 significantly enhanced the sensitivity of SGC7901/VCR cells to vincristine, adriamycin and etoposide, but not to 5-fluorouracil and cisplatin. Cell capacity to efflux adriamycin decreased markedly in ZNRD1 siRNA transfectants, and correlation between ZNRD1 down-regulation and increased multidrug resistance 1 (MDR1) gene transcriptional activity was observed. These results suggest that the ZNRD1 siRNA constructs down-regulate the expression of ZNRD1 effectively and reverse the resistant phenotype of gastric cancer cells. Furthermore, ZNRD1 might influence transcription of the MDR1 gene and thus play an important role in multidrug resistance in gastric carcinoma.

Antibiotics, Antineoplastic↗
PubMed1999

[Detection and characterization of gastric carcinoma associated with epstein-barr herpes virus].

The present investigation was carried out to estimate the incidence of Epstein-Barr virus (EBV)-associated cases among gastric carcinoma (GC) patients in Russia. Carcinoma specimens from 184 patients with GC treated at the Cancer Research Center were investigated by EBV encoded RNA-1 (EBER-1) in situ hybridization. Seventeen (9.24%) cases showed uniform EBER-1 expression restricted to the carcinoma cells. Hybridized signals were not detected in the non-neoplastic gastric epithelium. EBV involvement was significantly more frequent among males, especially in the tumors belonging to less differentiated types (moderately differentiated tubular adenocarcinomas and poorly differentiated solid adenocarcinomas) and located in the upper stomach (cardia and middle part). Most EBV-positive GCs were characterized by great lymphoid compartment involvement. The findings of the distribution of EBV-positive. GCs by sex, site, and histology are similar to those in Japan; however, the detection rate of EBV-positive cases in Russia is higher than that in Japan (6.7%) and lower than that in the USA (16%).

Adenocarcinoma↗
PubMed1979

Nucleolar morphology in estimation of urinary bladder cancer in man: study on surface contact preparations.

The special feature of nucleolar morphology which reflects the intensity of ribosomal RNA precursor molecule formation and thus also the intensity of proteosynthesis was studied in contact surface preparations from tissue samples of 28 patients with epithelial tumors of the bladder and in tissue samples of bladder mucosa from 16 patients with prostata hypertrophy (7 of them suffered also from cystolithiasis). In malignant lesions of the bladder mucosa, especially in tumors of medium and high grade malignancy, very low values of metabolically resting cells with ring shaped nucleoli and micronucleoli were found.

Carcinoma, Papillary↗
PubMed1987

A human papilloma virus type 11 transcript encoding an E1--E4 protein.

The human papilloma virus (HPV) associated with a genital wart (condyloma acuminatum) was determined to be type 11. The majority of the viral DNA molecules were monomeric circles present in the cells at high copy number, as demonstrated by one- and two-dimensional agarose gell electrophoretic separation followed by Southern blot analysis. A cDNA library in phage lambda gt11 was constructed from poly(A)-selected mRNA recovered from the tissue. Recombinant clones corresponding to the most abundant 1.2-kb viral mRNA species detected by Northern blot hybridization and by electron microscopic analysis of R loops were isolated and their nucleotide sequence was determined. Comparison to the prototype HPV-11 DNA sequence revealed that this message consisted of two exons. The promotor-proximal exon spanned nucleotides 716 through 847 and the distal exon included nucleotides 3325 through 4390 or 4392. The mRNAs were alternatively polyadenylated after either of these latter two sites, in both cases following a G and preceding a U residue. Fourteen or sixteen bases upstream from the poly(A) was the hexanucleotide AGUAAA, which apparently serves as the signal for cleavage and polyadenylation of the nascent message. The splice donor and acceptor sites conformed to the usual /GU. . .AG/pattern. The exons joined open reading frame (ORF) E1, which contributed the initiation codon and four additional triplets, to ORF E4, which specified 85 amino acids to encode a protein of 10,022 Da. The cDNA also contained the ORFs E5a and E5b toward the 3' end. The complete sequence of the cDNA revealed three single-base changes from the prototype HPV-11, two resulting in altered amino acids in E4. Neither affects the coding potential of the overlapping E2 ORF. The function of the E1--E4 protein is unknown.

Base Sequence↗
PubMed1991

Influence of chromosomal integration on glucocorticoid-regulated transcription of growth-stimulating papillomavirus genes E6 and E7 in cervical carcinoma cells.

In most cervical carcinoma cells the E6 and E7 genes of specific human papillomaviruses are transcribed from viral sequences integrated into host cell chromosomes. Glucocorticoids activate the promoter elements of various human papillomaviruses in transient-expression assays. We have analyzed the effect of dexamethasone on the transcription rate of human papillomavirus 18 E6 and E7 genes integrated at different chromosomal sites in four cervical cancer cell lines. Dexamethasone led to an increase in the transcription rate of the integrated E6-E7 sequences in C4-1 and C4-2 cells but led to a decrease in SW 756 cells and did not affect the transcription rate in HeLa cells. However, when the viral promoter elements derived from HeLa or SW 756 cells, in which dexamethasone does not activate transcription of the integrated E6-E7 sequences, were tested in transient-expression assays within the same cell lines, dexamethasone consistently activated the viral promoter. It thus appears that dominant regulatory mechanisms presumably depending on the chromosomal integration site are able to override the response of the viral promoter to steroid hormones. The growth rate of all dexamethasone-treated cell lines correlated consistently with the expression of the papillomavirus E6 and E7 genes, supporting their role in the maintenance of the proliferative phenotype of cervical carcinoma cells. Since human papillomaviruses are integrated into the host cell genome at variable, presumably randomly selected chromosomal loci, regulatory mechanisms that influence viral gene expression, and hence cell growth, may differ among cancers of independent clonal origin.

Cell Line↗
PubMed1993

Quantification of HPV-16 E6-E7 transcription in cervical intraepithelial neoplasia by reverse transcriptase polymerase chain reaction.

Human papillomavirus type 16 (HPV-16) is associated with neoplastic lesions of the uterine cervix. Viral transforming functions have been localized to the E6-E7 open reading frame (ORF) and this ORF is conserved consistently in cervical intraepithelial neoplasia (CIN). Two mRNAs, generated by alternative splicing, are expressed from the E6-E7 ORF. These are known as E6*I and E6*II, and potentially encode the viral E7 and E6 proteins, respectively. It is believed that the HPV-16 transforming ability is mediated by the E6 and E7 proteins. A quantitative RT-PCR assay, developed by us to characterize the relative expression of E6-E7 spliced transcripts, was applied to exfoliated cervical cells obtained from patients in varying stages of clinically defined CIN and who were infected with HPV-16. The relationship between viral expression, disease stage, oral contraceptive use and age was studied. No association was observed between age or oral contraceptive use and HPV-16 E6-E7 expression. However, when both E6*I and E6*II were detected, a direct correlation was observed between relative proportions of E6*I/E6*II mRNAs greater than 95%/5% and increased disease severity. This study underscores the importance of the relationship between quantities of viral transforming gene transcript and the course of cervical disease. It also suggests that quantification of HPV-16 E6-E7 transcription may be useful as a prognostic tool to identify women who are at increased risk of developing cervical cancer.

Adolescent↗
PubMed1998

Telomerase activity and expression of telomerase RNA component and telomerase catalytic subunit gene in cervical cancer.

Telomerase, a ribonucleoprotein complex that includes the telomerase RNA component (hTR) and the telomerase catalytic subunit gene (hTERT) product, has been shown to be activated in the majority of cancer tissues and immortalized cells. To study telomerase activation during the progression of cervical cancer, the expression of hTR and hTERT RNAs in tissues of various stages of cervical cancer was analyzed using the in situ hybridization method and compared with proliferative activity as estimated by Ki-67 immunostaining. To test whether expression of these components is reflected in enzyme activity, we determined the levels of the RNAs in cervical cancer and normal tissues and in primary and immortal keratinocytes by reverse transcription-polymerase chain reaction and RNase protection assays and compared the results to telomerase activities as detected by telomeric repeat amplification protocol assay. In situ hybridization signals of hTR and hTERT were present not only in carcinoma tissues but also in normal epidermal layers. In many adenocarcinoma and fewer squamous cell carcinoma tissues, both signals were focally increased where high proliferative activity was present at the stages of dysplasia/metaplasia, in situ carcinoma, and invasive carcinoma. The level of bTERT, as quantitated by RNase protection assay, was not different between cancer and control tissues or immortal and a subset of primary keratinocytes and did not correlate with telomerase activity. These results indicate that expression of hTR and bTERT is up-regulated in at least a subset of neoplastic cells at an early stage of carcinogenesis and that unidentified factors, such as the modulation or coordination of its protein level with other products, may contribute to the activation of telomerase in cervical cancer.

Cell Division↗